Cyberfriends: The help you're looking for is probably here.

Welcome to Ed's Pathology Notes, placed here originally for the convenience of medical students at my school. You need to check the accuracy of any information, from any source, against other credible sources. I cannot diagnose or treat over the web, I cannot comment on the health care you have already received, and these notes cannot substitute for your own doctor's care. I am good at helping people find resources and answers. If you need me, send me an E-mail at scalpel_blade@yahoo.com Your confidentiality is completely respected.

DoctorGeorge.com is a larger, full-time service. There is also a fee site at myphysicians.com, and another at www.afraidtoask.com.

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I'm still doing my best to answer everybody. Sometimes I get backlogged, sometimes my E-mail crashes, and sometimes my literature search software crashes. If you've not heard from me in a week, post me again. I send my most challenging questions to the medical student pathology interest group, minus the name, but with your E-mail where you can receive a reply.

Numbers in {curly braces} are from the magnificent Slice of Life videodisk. No medical student should be without access to this wonderful resource. Someday you may be able to access these pictures directly from this page.

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Especially if you're looking for information on a disease with a name that you know, here are a couple of great places for you to go right now and use Medline, which will allow you to find every relevant current scientific publication. You owe it to yourself to learn to use this invaluable internet resource. Not only will you find some information immediately, but you'll have references to journal articles which you can obtain by interlibrary loan, plus the names of the world's foremost experts and their institutions.

Clinical Queries -- PubMed from the National Institutes of Health. Take your questions here first.
HealthWorld
Yahoo! Medline lists other sites which may work well for you

Alternative (complementary) medicine has made real progress since my generally-unfavorable 1983 review linked below. If you are interested in complementary medicine, then I would urge you to visit my new Alternative Medicine page. If you are looking for something on complementary medicine, please go first to the American Association of Naturopathic Physicians. And for your enjoyment... here are some of my old pathology exams for medical school undergraduates.

I cannot examine every claim which my correspondents share with me. Sometimes the independent thinkers prove to be correct, and paradigms shift as a result. You also know that extraordinary claims require extraordinary evidence. When a discovery proves to square with the observable world, scientists make reputations by confirming it, and corporations are soon making profits from it. When a decades-old claim by a "persecuted genius" finds no acceptance from mainstream science, it probably failed some basic experimental tests designed to eliminate self-deception. If you ask me about something like this, I will simply invite you to do some tests yourself, perhaps as a high-school science project. Who knows? Perhaps it'll be you who makes the next great discovery!

Our world is full of people who have found peace, fulfillment, and friendship by suspending their own reasoning and simply accepting a single authority which seems wise and good. I've learned that they leave the movements when, and only when, they discover they have been maliciously deceived. In the meantime, nothing that I can say or do will convince such people that I am a decent human being. I no longer answer my crank mail.

This site is my hobby, and I presently have no sponsor.

This page was last updated February 6, 2006.

During the ten years my site has been online, it's proved to be one of the most popular of all internet sites for undergraduate physician and allied-health education. It is so well-known that I'm not worried about borrowers. I never refuse requests from colleagues for permission to adapt or duplicate it for their own courses... and many do. So, fellow-teachers, help yourselves. Don't sell it for a profit, don't use it for a bad purpose, and at some time in your course, mention me as author and KCUMB as my institution. Drop me a note about your successes. And special thanks to everyone who's helped and encouraged me, and especially the people at KCUMB for making it possible, and my teaching assistants over the years.

Whatever you're looking for on the web, I hope you find it, here or elsewhere. Health and friendship!

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Chest wall problems

structural... THE CHEST DEFORMITIES

neuromuscular...THE PARALYSIS & WEAKNESS SYNDROMES

Obstructed upper airway

structural... QUINSY ("PERITONSILLAR ABSCESS"); CROUP ("LTB"")

functional...THE SLEEP APNEAS

Obstructed large bronchi

all, subtotal... CHRONIC BRONCHITIS

one, total... OBSTRUCTIVE ATELECTASIS; ENDOGENOUS LIPID PNEUMONIA

Constricted small bronchi

mast-cell / inflammation mediated... THE ASTHMAS

platelet-mediated... PULMONARY EMBOLUS

apudoma products... CARCINOID SYNDROME

dense collagen... SOME CHRONIC BRONCHITIS VARIANTS

Fibrotic respiratory bronchioles... SILICOSIS

Collapsed respiratory bronchioles... EMPHYSEMA/"CHRONIC BRONCHITIS"

Fluid-filled alveolar spaces

transudate... ALVEOLAR PULMONARY EDEMA

exudate & pus... THE PNEUMONIAS

exudate, fibrin, debris... THE RESPIRATORY DISTRESS SYNDROMES

surfactant... ALVEOLAR LIPOPROTEINOSIS; ENDOGENOUS LIPID PNEUMONIAS

other lipid... EXOGENOUS LIPID PNEUMONIAS

blood... GOODPASTURE'S DISEASE; ANTI-NEUTROPHIL CYTOPLASMIC ANTIBODY DISEASES, ACUTE MOUNTAIN SICKNESS, OTHER PULMONARY BLEED SYNDROMES

organisms alone... PNEUMOCYSTOSIS, CRYPTOCOCCOSIS

Fluid-filled alveolar septa

transudate... INTERSTITIAL PULMONARY EDEMA

exudate...THE PNEUMONITIS FAMILY; VIRUSES; MYCOPLASMA

Fibrosis around ulcerated bronchi...BRONCHIECTASIS

Fibrosis of alveolar septa

slow... THE INTERSTITIAL RESTRICTIVE LUNG DISEASES; (Hamman-Rich, rheumatoid lung, sarcoid, asbestosis, many others)

fast... THE RESPIRATORY DISTRESS SYNDROMES

Collapsed alveoli

extrapulmonary disease... COMPRESSIVE ATELECTASIS

large-airway disease... OBSTRUCTIVE ATELECTASIS

alveolar disease... THE RESPIRATORY DISTRESS SYNDROMES

ischemia... PULMONARY EMBOLUS, SEVERE SHOCK

Necrotic lung ("cavities", etc.)

infarction... PULMONARY EMBOLUS (COMPLICATED)

suppurative... NECROTIZING PNEUMONIAS; LUNG ABSCESS

caseous... TUBERCULOSIS, HISTOPLASMOSIS, BLASTOMYCOSIS, COCCIDIOIDOMYCOSIS

weird immune... WEGENER'S GRANULOMATOSIS

malignant... LUNG CANCER

Pulmonary Hypertension

secondary to low alveolar oxygen... see above; also MOUNTAIN DWELLERS

secondary to alveolar fibrosis... see above

Left-to-right shunts / Eisenmenger's

primary... PULMONARY EMBOLUS; VASCULITIS; IDIOPATHIC

High P_aCO₂... all whole-lung ventilation problems

Low PO₂...

all whole-lung ventilation problems

perfusing non-ventilated lung

fluid/fibrosis in alveolar septa

MOUNTAIN DWELLERS

STUDY OBJECTIVES

Describe the essential gross and microscopic anatomy of the airways, from trachea to alveolar sacs. Distinguish the two principal types of pneumocytes (I and II). Describe the anatomic and functional barrier to gas exchange at the alveolar-capillary level.

Describe the factors that influence P_aCO₂ and P_aO₂. Describe how P_aO₂ correlates with the actual oxygen content of the blood. Give the conditions when cyanosis will appear.

List the principal causes of edema in the lung, and compare these to things that cause edema anywhere else in the body. Distinguish interstitial and alveolar edema. Explain why edema of the lung is bad for one's health.

Describe pulmonary congestion, and mention its pathologic sequelae.

Review the pathology and pathophysiology of pulmonary thromboemboli. Describe their frequency and clinical correlations.

List the common causes of increased resistance in the pulmonary arteries (the usual cause of "pulmonary hypertension"), and other causes of pulmonary hypertension. Explain why these things are so harmful. Explain the hypoxic vascular response, why it is useful in health, and why it is such a problem in disease.

Define adult respiratory distress syndrome and list a few of the many synonyms. Tell about the etiologies, gross and microscopic pathology, the pathophysiology, and the common clinical picture.

Explain the pathophysiology and clinical correlations of neonatal respiratory distress syndrome.

Define atelectasis. Tell how lung collapses due to obstruction, compression, and lack of surfactant, and give clinical examples of each situation.

Define "sudden infant death syndrome". Briefly describe what we think causes genuine "SIDS", and give a "differential diagnosis".

* Review how to order "arterial blood gases", what you get, and what they tell you. (Be able to do this at 3 AM as the only doctor on the ward.) This might be a good time to look at the Blood Gases" handout.

Describe the abnormal anatomy and functional problems that every cigaret smoker should expect.

Explain the importance of elastic recoil in keeping respiratory bronchioles patent during exhalation. Explain how this relates to the classic definition of emphysema as "an abnormal, permanent dilatation of part of all of the acinus, with destruction of alveolar walls."

Distinguish the two "classic" types of emphysema, and mention their alleged causes. Tell what we think causes emphysema in cigaret smokers and alpha-1 antitrypsin deficient patients. Tell what a "pink puffer" looks like clinically, and how emphysematous lungs look at autopsy. Describe the complication of "bullous emphysema".

Define "chronic bronchitis" and mention its common causes. Describe the gross and microscopic pathology and the pathophysiology. Be able to define the "Reid Index". Tell what a "blue bloater" looks like clinically, and mention the common organisms that superinfect these patients' lungs.

Define bronchial asthma. Describe its important causes, and distinguish "allergic" and "idiosyncratic" kinds. Describe the common pathophysiology. Tell what you will see at the autopsy of an asthmatic. Mention other causes of wheezing.

Define bronchiectasis. Describe the important causes, the abnormal anatomy, and the typical clinical picture.

Describe the various breathing problems that occur during sleep. Recognize sleep apnea as a common cause of several illnesses.

Describe the normal flora of the lungs in non-smokers and smokers, and recognize the range of micro-organisms that have caused lung infections. Recognize the tremendous clinical importance of lung infections.

Distinguish bronchopneumonia, lobar pneumonia, and pneumonitis. Describe the typical histopathology of lung infections caused by various agents.

List the etiologic agents of lobar pneumonia, the classic stages in its progression, the major complications, and those at risk for each form.

Describe the causes, underlying problems, pathophysiology, and morbid anatomy of bronchopneumonia, aspiration pneumonia, legionellosis, pneumocystosis, lung abscess, and viral and mycoplasmal pneumonias. Describe the distinctive features of hantavirus infection and SARS (the 2003 epidemic).

Describe the anatomic pathology, pathophysiology, and clinical picture of the "idiopathic pulmonary fibrosis" family of diseases. Identify "Hamman-Rich" syndrome, and mention its likely cause.

Define sarcoidosis, and describe a typical sarcoidosis patient. Explain the usual effects of sarcoidosis on the lungs, skin, and eyes. Mention the serious consequences of untreated sarcoidosis. Describe the histology, and give a differential diagnosis for a granuloma found on biopsy. Explain how sarcoidosis causes abnormalities of calcium metabolism. Recognize the Kveim test as of limited usefulness. Tell how to make the diagnosis of sarcoidosis, and how to treat sarcoid patients.

Explain the essential lesion of Goodpasture's disease involving the lung, and mention the clinical picture and diagnostic lab test, and essential treatment. Mention some "related" (?) causes of bleeding from the pulmonary alveoli.

Briefly describe the eosinophilic pneumonias, and the various lipid pneumonias and lipoproteinosis, focusing on their histopathology.

Give the numbers of new cases of lung cancer in U.S. men and women expected this year. Explain how rates are changing, and why. Describe the risk factors for lung cancer, mentioning the importance of cigaret smoking, industrial exposure, radon in the home, and indoor air pollution.

Explain how and why pathologists subclassify lung cancers. Recognize each of the nine members of the WHO-1999 classification:

• squamous cell carcinoma


• adenocarcinoma


• bronchioloalveolar carcinoma


• large-cell undifferentiated carcinoma


• small-cell ("oat cell") carcinoma


• carcinoid


• atypical carcinoid


• intermediate ("large cell") neuroendocrine carcinoma


• malignant lymphoma

Describe the important distinctions among the various types. Identify the common lung cancers under the microscope. Explain how pathologists use each of these to distinguish primary lung tumors:

• electron microscopy for neurosecretory granules (small-cell, carcinoids, atypical carcinoids, and intermediate neuroectodermal tumors positive)
• mucicarmine (most adenocarcinomas and bronchioloalveolars positive, others negative)
• immunoperoxidase for common leukocyte antigen (lymphomas positive, all others negative)
• immunoperoxidase for epithelial membrane antigen (lymphomas negative, all carcinomas positive)
• immunoperoxidase for chromogranin (typical carcinoid and atypical carcinoid positive, most large-cell neuroendocrines and oat-cells positive )
• immunoperoxidase for erbB product (adenocarcinomas, large-cell, squamous-cell positive; oat cell negative)
• immunoperoxidase for neuron-specific enolase (oat-cell, typical and atypical carcinoids, neuroendocrine CA positive)

Tell how bronchogenic carcinomas present. Describe the various paraneoplastic syndromes seen with lung cancer, especially the hypercalcemia syndromes and the small cell undifferentiated carcinoma syndromes.

Identify bronchial carcinoid, tell how it looks grossly and microscopically, how to recognize it, and describe its origin and its variants.

List the common problems that affect the larynx or trachea. List the different kinds of pleural effusions, and tell the significance of each. Describe the various kinds of pneumothorax and why they are important. Tell how pleural plaques look and what causes them.

Identify the cell of origin, risk factor, gross and microscopic appearance, and prognosis for malignant mesothelioma.

Mention the basic biology of ciliary dyskinesia syndromes, tell when you would suspect one, and how you would verify it.

As usual, given a gross lung or larynx, or a biopsy of any level of the respiratory tract, recognize any of the lesions exhibited in this section with at least 70% accuracy.

Respiratory Cornell Class notes with clickable photos

Healthy lungs Freshly-opened at autopsy WebPath

Healthy lung Formalin-inflated WebPath

Pulmonary surface lymphatics A bit accentuated due to pulmonary edema WebPath

Healthy lung Photomicrograph WebPath

Life is not measured by the number of breaths you take, but by the number of moments that take your breath away.

-- Attributed to George Carlin

* Click here for Dr. Karius's scheme for normal respiration. You must know this perfectly if you are going to be able to make sense out of lung pathology. Thanks Diane!

All about the uvula. A human's is much bigger than any other mammal's, and the uvula's job is probably to keep us from getting hoarse while talking (amazing, Yearbook of Path 1994, p. 97 describes its anatomy).

Review the gross anatomy of the respiratory system, and the general histology of a bronchus.

Bronchi are usually defined to be the airways with cartilage and/or complex glands (precise usage varies). The orders of bronchi end in membranous bronchioles.

* Future pathologists: Histopathology of the bronchioles. Am. J. Clin. Path. 101: 109, 1998.

The bronchioles divide further, leading to the terminal bronchioles, the last division with a continuous pseudostratified ciliated epithelium.

Remember the importance of the mucociliary elevator provided by this epithelium. The cilia are supposed to be extremely easy to damage and hard to recover, but they almost always are present in my autopsies, even on people who have been very sick for a very long time.

The portion of lung parenchyma supplied by one terminal bronchiole is called an acinus ("respiratory unit", diameter about 7 mm).

From the terminal bronchiole arise several orders of respiratory bronchioles, which have part of their walls alveolated and part with pseudostratified respiratory epithelium. These in turn give rise to alveolar ducts and then atria. The alveoli themselves are wide-mouthed sacs that open into all three of these divisions.

Remember that the elastic recoil of the surrounding lung tissue is what keeps the respiratory bronchioles from collapsing when a person starts to exhale.

Schematic diagram of the alveolar wall:



* Look closely. Did you know that the "thin" side has fused basement membranes, the "thick" side with more collagen has them separate?

Type I pneumocytes: simple squamous, stretchy, permeable to O₂ and CO₂, easily injured, do not divide

Type II pneumocytes: reserve cells; cuboidal, granular cytoplasm, produce and process surfactant ("lamellar bodies" in the cytoplasm), divide and flatten to become new type I pneumocytes.

* In health, look for them at the corners of alveoli (hence "corner cells").

The interstitium contains a few fibroblasts, smooth muscle cells, collagen, elastin.

There are probably no lymphatics in the respiratory membranes themselves, but there are many lymphatics in the fibrous septa between groups of alveoli.

Contrast the alveolar epithelium with that of the bronchi and bronchioles, which includes ciliated, goblet, reserve (basal), Kulchitsky ("K-"), Clara, and other types of cells.

Macrophages in the alveoli spaces ("alveolar macrophages") and in the septa ("interstitial macrophages") eat surfactant and most anything else that comes along, in addition to modulating the immune response locally.

Traditionally we've taught that these cells are monocyte-derived, but they undergo mitosis in various sorts of lung injury.

Remember that the lung receives a dual blood supply, from the pulmonary and bronchial arteries. The bronchial arterial supply is one of the first to stop in low-output states (left heart failure, shock; why?)

Bronchial lymphoid tissue (BALT) shouldn't be present until a baby is a few months old. Lymphocyte clusters in a newborn's large airways means infection. Smokers have much more "BALT" than do non-smokers.

Remember blood P_aCO₂ is almost entirely a function of overall alveolar ventilation.

Remember blood P_aO₂ is a function of the quality of ventilation-perfusion matching, alveolar septal thickening (if excessive), and overall ventilation. And remember that lung structures are generally much less permeable to O₂ than to CO₂ (a fact which becomes important only in disease.)

Don't forget either that blood with P_aO₂ of 65 torr is carrying almost as much oxygen as blood with P_aO₂ of 100 torr or higher, because most oxygen is bound to hemoglobin (recall the hemoglobin-oxygen dissociation curve....) It's when P_aO₂ drops to around 60 that you start getting into trouble, because the hemoglobin stops binding oxygen as well as it should.

Cyanosis appears when the arterial blood contains 5 gm % or more of unoxygenated hemoglobin.

All of the first group of diseases on the handout (except pulmonary thromboemboli) are patterns of lung injury, each of which has many different causes.

PULMONARY CONGESTION AND EDEMA

{37956} pulmonary edema gestalt

Pulmonary edema classically results from the same factors that cause edema in the rest of the body. These are:

1. Increased venous hydrostatic pressure (left-sided heart failure)

2. Fluid overload (renal failure, iatrogenic, etc.)

3. Decreased albumin in the blood (liver disease, nephrotic syndrome, poor nutrition, etc.)

4. Lymphatic obstruction (cancer, etc.)

5. Endothelial damage (i.e., the pneumonias; most striking is the hantavirus that first struck in the US southwest)

6. Getting strangled / physically asphyxiated (negative pressure)

You have to learn these causes of pulmonary edema for which the mechanisms are not well understood:

7. Acute CNS injury

8. Opiate overdose

9. Exposure to high altitudes (unacclimatized people)

The fluid is an exudate with some red cells. The conventional wisdom is that the veins as well as the arteries participate in the hypoxic vascular response, and that the much-increased blood pressure in the lung capillaries forces fluid out of them and causes some of them to burst. This is consistent with the results of lavage studies (JAMA 287: 2228, 2002).

However, this can't be the full story, because of the pharmacology (Br. Med. J. 321: 267, 2000). Dexamethasone (the familiar glucocorticoid) apparently prevents acute hypoxia from making endothelial cells more permeable, while how acetazolamide (a carbonic anhydrase inhibitor) works is anybody's guess. The finding that a beta-agonist helps is attributed to increased active transport of sodium from the alveolar fluid into the bloodstream (NEJM 346: 1631, 2002).

* The roles of various mediators are being worked out (endothelin 1: Circulation 99: 2665, 1999), and the whole business remains rather puzzling (see for example Lancet 357: 1342, 2001.)

* Populations that inhabit high mountains seem to survive only by making huge amounts of nitric oxide, which you can measure on their breath. See Nature 414: 411, 2001. Natural selection or physiologic adaptation? We don't yet know. It's finally documented that mountain dwellers have greatly expanded chest cavities: Resp. Phys. Neuro. 132: 223, 2002.

In each case, when the capacity of the lymphatics to drain the interstitial fluid is exceeded, interstitial edema develops, with loss of lung compliance and a barrier to oxygen exchange (alveolar-capillary block.)

As the interstitial pressure rises still further, the tight junctions between the alveolar epithelial cells open and fluid pours into the alveolar spaces, causing alveolar edema and stopping ventilation.

Alveolar edema fluid is a good culture medium for bacteria. Secondary pneumonia is common.

When you hear crackles (rales) through your stethoscope, you're hearing the little air bubbles in the alveoli. Your patient has alveolar pulmonary edema, and you must figure out why.

{10145} pulmonary edema (just enough protein content to stain...)
{11666} pulmonary edema

Pulmonary edema Cornell

Pulmonary edema Some stainable protein, hence an exudate WebPath

Pulmonary congestion of course results from increased pulmonary venous hydrostatic pressure, typically from left-sided heart failure especially mitral valve disease.

If marked or longstanding, microhemorrhages, fibrosis, and iron pigmentation ("brown induration") occur in the lungs. (Hemosiderin-laden macrophages are called "heart-failure cells.")

Congested lung Heart failure cells WebPath

Heart Failure Cells Hemosiderin-laden macrophages in the lung KU Collection

Congested lung Heart failure cells WebPath

Congested lung Heart failure cells WebPath

PULMONARY EMBOLIZATION ("embolism") AND INFARCTION (NEJM 339: 93, 1998; Lancet 363: 1295, 2004)

Pulmonary thromboemboli are very common (and still under-diagnosed -- see Arch. Int. Med. 148: 1345, 1988, also still good). Thrombi in unoperated pulmonary arteries are almost always emboli.

Most originate in the deep veins of the legs; they may also come from the pelvic veins.

Thrombosis in a leg vein can be uncomfortable ("thrombophlebitis"), but is most often asymptomatic. As a junior clerk, you will compare calf circumferences, check Homan's sign (be careful you don't break the thrombus off), etc.

The majority of pulmonary thromboemboli do no harm and eventually organize or lyse; many are fatal.

Pathologists report pulmonary emboli in 8-25% of autopsies on hospital patients. But in 3-5% of autopsies (figures vary), the embolus is the fatal event, and estimates of the number of U.S. deaths from pulmonary emboli are in the 50,000-150,000 range. (Without an autopsy, the clinicians will often tell the family, "heart attack".)

Virchow's triad. Typical settings for deep vein thrombosis and pulmonary thromboemboli include:

1. stasis
• immobilization of an extremity (bed rest, long plane flights -- see Lancet 2: 497, 1988; I first mentioned long plane flights years before Dan Quayle did, and now the New Zealand study has made it is clear that this is a major risk, about 1%: Lancet 362: 2039, 2003)


• right-sided congestive heart failure


• sickle cell anemia


• morbid obesity (Virchows Archiv 434: 529, 1999)

2. hypercoagulable states

• cancer (especially cancer of the pancreas)


• following burns, surgery, severe trauma


• pregnancy


• women on the old-fashioned high-estrogen oral contraceptive pill (suppressed antithrombin III levels)


• lupus anticoagulant, hereditary anti-coagulant deficiencies (protein S, protein C, antithrombin III, V-leiden, homocystine)


• smokers (not really super-strong relationship, but real)


• and don't forget the nephrotic syndrome, in which you lose proteins S and C (Am. J. Clin. Path. 101: 230, 1994)

3. damaged endothelium

• the one to remember is intravenous lines; CVP catheters occasionally serve as a nidus for a thrombus that embolizes.

For some reason, babies very seldom get or die of pulmonary thromboemboli: Arch. Path. Lab. Med. 114: 142, 1990.

Pulmonary thromboemboli cause several types of problems.

• Instant death ("saddle embolus" occluding the pulmonary trunk and/or both main pulmonary arteries)
• Acute "cor pulmonale" (maybe; this usually requires occlusion of 50% or more of the pulmonary arterial tree)
• Increase in non-perfused pulmonary "dead space" (of course); when enough of the lung becomes dead space and the remainder is receiving the entire right cardiac output, there won't be enough oxygen here and hypoxemia will result
• Ischemia with loss of surfactant and alveolar collapse (atelectasis; sometimes)
• Actual infarction of lung substance due to a pulmonary embolus may occur if the bronchial circulation is inadequate due to left-sided heart failure, shock, etc.

  Pulmonary infarcts are peripheral and hemorrhagic (and can even cause hemolytic jaundice if the patient survives. Rising bilirubin and rising LDH-3 -- think of a pulmonary infarct.) Listen for a friction rub; look for fibrin on the pleural surface at autopsy (why?). They can be distinguished best from regular intrapulmonary hemorrhages by the necrosis. Most will have the classic "wedge" shape.

  Infected thromboemboli can cause "septic infarcts" which may become lung abscesses.

• Bronchoconstriction and wheezing (sometimes, perhaps due to release of serotonin from platelets.)
• Chronic embolization leads to increased pulmonary vascular resistance ("pulmonary hypertension") and eventually cor pulmonale (* once considered rare, we now know this is fairly common, especially when the emboli turn into rather large scars: NEJM 350: 2257, 2004)

Any patient with sudden anxiety, chest pain, dyspnea, cough, hemoptysis or sudden death should make you think of pulmonary emboli. You'll learn how to make the diagnosis while on rotations -- but don't get over-confident; pulmonary embolization is the most-often-missed diagnosis in the hospital (Arch. Path. Lab. Med. 129: 201, 2005.

Angiography's the gold standard while the patient is alive.

Fibrin D-dimer is sensitive, but not specific: Arch. Path. Lab. Med. 123: 235, 1999. Some folks consider this the best screening test: Lancet 363: 1295, 2004.

As we have already mentioned, pulmonary emboli organize into fibrous bands which remain in the lung for the rest of the person's life (Arch. Path. Lab. Med. 123: 170, 1999).

{29052} pulmonary embolus, ancient, organized and turned into fibrous bands

Pulmonary infarct, healing Cornell

Pulmonary infarcts Cornell

Pulmonary Embolus Photo and mini-review Brown U.

Pulmonary Thromboembolus Australian Pathology Museum High-tech gross photos

Pulmonary thromboembolus Autopsy photo KU Collection

Saddle embolus Cornell

Pulmonary thromboembolus WebPath

Saddle embolus WebPath

Lung infarct WebPath

Lung infarct WebPath

Pulmonary embolus Actually, ALL antemortem thrombi are layered WebPath

Pulmonary embolus WebPath

Pulmonary embolus WebPath

Pulmonary embolus WebPath

Old recanalized pulmonary embolus WebPath

Old pulmonary embolus Organized WebPath

Pulmonary infarct Urbana Pathology

Other causes of lung infarction (immune or infection vasculitis, other things embolizing) are rare but not unheard-of (Chest 127: 1178, 2005).

Fat embolization remains mysterious. You're familiar with this dread complication of a bony fracture. Today's pathologists make the diagnosis during life by finding fat in the cells obtained by pulmonary lavage.

The deadly chest syndrome in sickle cell anemia may also result (at least sometimes) from fat embolization after a bony infarct (NEJM 342: 1904, 2000). The same picture can appear in sicklers with bacterial or viral infection or thromboembolization; often no cause is found. I suspect that cells sickling in the presence of reduced oxygen tension is part of the cause.

PULMONARY HYPERTENSION

Reviews JAMA 284: 3160, 2000; Am. Fam. Phys. 63: 1789, 2001 (by my fraternity brother Trent Nauser MD)

Pulmonary Arterial Sclerosis From Chile In Spanish

Pulmonary Vascular Disease Queen's U., Kingston Thanks Dr. Boag

A good working definition is pulmonary systolic pressure >25 mmHg (rest) and/or >30 mmHg (exercise), with wedge <15 mmHg.

Generally analogous to systemic arterial hypertension, pulmonary hypertension also results from a variety of causes.

1. Left-sided heart failure (especially mitral stenosis)

2. Increased blood flow into the pulmonary arteries (i.e., congenital cardiac malformations with left-to-right shunts, or after resection of a lung)

3. Increased pulmonary vascular resistance from any cause.

• Alveolar hypo-oxygenation from any cause (high altitude, ARDS, emphysema, sleep apnea, etc. etc.)

NOTE: This is important. The "hypoxic vascular response" causes constriction of arterioles supplying underoxygenated alveoli. If all the alveoli are underoxygenated, all the arterioles constrict, and the pulmonary arterial blood pressure has to rise. To this day, nobody knows which mediator produces the response.

• Fibrosing disease of the alveolar walls -- collagen around the vessels chokes them off
• Pulmonary emboli
• * Jamaican bush-tea drinking (getting high off the herb crotalaria specifically damages the pulmonary vessels)
• Immune disease with particular involvement of the pulmonary vessels, especially CREST syndrome, scleroderma, Wegener's

Persistent pulmonary hypertension of the newborn results from hyperplasia of the smooth muscle in the arteries, present at birth (usually term). It is likely to prevent closure of the foramen ovale and/or ductus, and produce a cyanotic baby. It is quite common, often causes serious brain damage, and has been overlooked for too long. One cause seems to be SSRI antidepressants taken late in pregnancy (NEJM 354: 579, 2006).

• "Idiopathic" ("Primary pulmonary vascular sclerosis / primary pulmonary hypertension"" -- an uncommon, deadly illness typically seen in young women -- probably caused by longstanding endothelin-mediated pulmonary vasoconstriction / hypertension which eventually damages the vessels irreversibly.)
Histopathology: Am. J. Path. 146: 389, 1995.

Treating it with calcium channel blockers (helps, no panacea): NEJM 327: 76, 1992; nitric oxide and continuous intravenous prostacyclin are new remedies (Chest 119: 970, 2001; Am. J. Card. 75: 51A, 1995; big review); also Lancet 352: 719, 1998; NEJM 338: 273, 1998; aerosolized iloprost (prostacyclin analogue: NEJM 342: 1866, 2000; reversal in a mouse model using a serine elastase inhibitor: Nat. Med. 6: 698, 2000.

* Bosentan, the endothelin receptor antagonist, seems to help "idiopathic" primary pulmonary hypertension: Lancet 358: 1119, 2001; NEJM 346: 896, 2002.

• Convicted: fenfluramine-family ("Pondimim", "Redux", "Fenphen", etc.) appetite suppressants, as a grisly, long-delayed after-effect. NEJM 335: 609, 1996. I predicted the fiasco two years before it happened, in these notes. Currently the explanation is that they produce a potassium channelopathy that causes excessive pulmonary vasoconstriction (Am. J. Med. Sci. 321: 292, 2001).
• * Other rare syndromes, including familial problems (one gene is bone morphogenetic protein receptor II (BMPR2): NEJM 345: 319, 2001; the finding is now robust) and Spanish toxic oil syndrome (Chest 95: 325, 1989).

NOTE: You'll frequently hear, "This patient is disabled because of pulmonary hypertension" or "This patient has right sided heart failure due to pulmonary hypertension". Of course, the real problem is increased pulmonary vascular resistance from thickened and narrowed arterioles.

Sustained pulmonary hypertension results in changes in the anatomy of the pulmonary arteries and arterioles, some of which are irreversible.

The current, principal molecular suspect is endothelin 1, derived from damaged endothelium. It is a potent vasoconstrictor, and makes smooth muscle proliferate. See Ann. Int. Med. 114: 213, 1991; NEJM 328: 1732, 1993.

* By contrast, the ability of the lung endothelium to produce nitric oxide ("endothelium derived relaxation factor", EDRF), a potent vasodilator, is much diminished in emphysema. There's also maybe a lack of prostacyclin. Nobody really understands this.

Unlike in "benign" systemic hypertension, some of these changes clearly contribute to the ongoing process.

Lesions include:

Main arteries: atherosclerosis (never severe)

Small arteries: hyalinization ("hyaline arteriolar sclerosis"), intimal onion-skinning ("hyperplastic arteriolar sclerosis"), extra elastic, extra muscle, fibrinoid.

Arterioles: muscle appears (should be none), plexiform lesions (bad sign)

The infamous "plexiform lesions" are little networks of blood vessels that look like renal glomeruli; they probably result from helter-skelter proliferation of endothelium (Am. J. Path. 144: 275, 1994.)

* A proposed standard histologic description of the vascular lesions: J. Am. Coll. Card. 42(12 S): 25-s, 2004.

Plexiform lesions
Lung pathology series
Dr. Warnock's Collection


Pulmonary hypertension (especially, pulmonary hypertension due to increased pulmonary vascular resistance) is common and under-appreciated.

A very common mechanism of sudden death in generalized lung disease is an arrhythmia arising in the strained right ventricle.

Of course, the right ventricle undergoes hypertrophy; *  morphologists see Am. J. Card. 78: 584, 1996.

And no matter what the underlying disease, the pulmonary vascular resistance is likely to determine the patient's exercise tolerance ("quality of life"). This commonly takes precedence over the "respiratory function tests" of spirometrists (Chest 92: 387, 1987).

Using nitric oxide to control pulmonary hypertension in ARDS seems natural and physiologic: NEJM 328: 399, 1993. More: Chest 115: 1407, 1999.

Talc in the lungs Pulmonary hypertension in druggies WebPath

Plexiform lesion WebPath

Pulmonary hypertension Narrowed artery WebPath

Crystals in the lungs of drug abusers Lung pathology series Dr. Warnock's Collection

ACUTE ADULT RESPIRATORY DISTRESS SYNDROME (ARDS -- review NEJM 332: 27, 1995).

Gassed WWI painting Mustard gas victims John Singer Sargent

This very common problem, deadly, and expensive problem results from anything that severely injures the Type I pneumocytes and capillary endothelial cells throughout the lungs.

There are at least 150,000 ARDS cases in the U.S. every year (as an autopsy pathologist, I'd say this about right).

ARDS first came to be recognized during the Vietnam War.

Soldiers who had survived extremely severe injuries and seemed to be recovering would suddenly develop intractable shortness of breath and die in a few days.

It was called "Da Nang lung". Originally there was concern about biological warfare. But it soon became clear that the pulmonary changes were remote effects of injuries which previous soldiers did not survive.

ARDS has many causes. These include...

• sepsis (the most common single cause)


• shock itself


• oxygen toxicity


• lung contusion


• viral infections of alveolar epithelium (influenza, herpesviruses, Navajo hantavirus Lancet 347: 739, 1996, others)


• burns


• radiation


• drugs (notably certain cancer chemotherapy agents, also remember amiodarone)


• poison gas


• silo-filler's disease (treacherous, since the inhaled nitrogen oxides hydrolyze into nitric / nitrous acid several hours after exposure)


• near-drowning


• the heart-lung machine


• aspiration of gastric contents


• severe multi-organ injury


• blood transfusion ("transfusion-associated acute lung injury"; antibodies against HLA and/or neutrophils in the donor plasma and/or lipids in banked blood that anger the patient's own neutrophils Am. J. Clin. Path. 121: 590, 2004. Quite common and usually mild, this can be deadly. Nowadays this is probably the most common cause of death from blood transfusion.


• pneumocystosis


• * gene therapy ("Jesse Gelsinger's disease" -- Science 288: 951, 2000, Sci. Am. 282(2): 36, Feb. 2000.)
• Even high-pressure mechanical ventilation itself wrecks this havoc on the lungs (Am. Rev. Resp. Dis. 143: 1115, 1991).

So ARDS also has many synonyms, including shock lung, traumatic wet lung, diffuse alveolar damage, "nonhydrostatic pulmonary edema", "high-permeability low-pressure pulmonary edema", white lung, etc. etc.

The "multiple organ injury syndrome" seen in survivors of severe trauma commonly produces ARDS in a week or so. Nobody knows why this is; probably widespread activation of complement throughout the body is part of the problem.

Mechanisms of injury are complex, with free radicals, complement, enzymes from marginated polys (can't be the whole story, since the neutropenic can and do get ARDS), microthrombi, aggregation of polys, "shock toxins", and many other ideas.

The major experimental model involves reperfusion of an animal's hindlimb rendered ischemic for a considerable time (J. Traum. 31: 760, 1991).

Interleukin-8, a great neutrophil attractant, abounds in fluid from ARDS lungs. We don't know why, but this probably has a lot to do with the problem.

Biopsy is often helpful to establish an underlying diagnosis even though these people are ver sick (Chest 125: 197, 2004. Here are some tips for guessing the cause of ARDS

• Oxygen toxicity: Collagen confined in the walls and/or as masses in the lumens


• Paraquat: Alveoli still well-defined but packed with dense scar


• Chemotherapy: Type II pneumocytes are very prominent and have big, bizarre nuclei


• Radiation, short interval: Fatty change of the myointimal cells of arteries


• Radiation, longer interval: Type II pneumocytes have hyperchromatic nuclei; small arteries are hyalinized


• Heroin: Edema is predominant


• Certain amphophilic drugs, notably clomipramine: Clusters of foamy macrophages / "alveolar proteinosis"


• Hantavirus: Very abundant T-immunoblasts



Hantavirus Pneumonia
Immunoperoxidase
Dr. Hjelle


Hantavirus
Electron micrograph showing
damaged basement membrane


Whatever causes the injury, the result pretty much the same:

When the alveolar cells are injured fluid leaks into the interstitial spaces and alveolar air spaces -- this is pulmonary edema.

Later, with cell necrosis, fibrin is released into the alveoli, producing hyaline membranes. Of course there is loss of surfactant, so many alveoli collapse.

During this early stage, the patient is very tachypneic and dyspneic, but the chest x-ray looks normal. (Why?)

NOTE: In "respiratory distress syndrome" or "hyaline membrane disease" of low-birth-weight infants, the lack of surfactant is one primary problem, though not the only one. In ARDS, surfactant is decreased secondary to diffuse alveolar damage.

* Surfactant aerosol-replacement flops for ARDS: NEJM 334: 1448, 1996.

As Type I pneumocytes are destroyed, Type II pneumocytes divide to replace them ("regenerative epithelial hyperplasia" or "cuboidalization" of alveolar epithelium.) Of course, they are not so permeable to oxygen as the healthy type I cells.

Fibrosis ensues as the intra-alveolar hyaline membranes and the interstitial exudate organize (Am. J. Path. 126: 171, 1987).

Of course, fibrotic lung (from any cause) is prone to develop bacterial infections (bronchopneumonia), since it is harder to mobilize the exudate and perhaps the neutrophils must travel farther in pursuit of the microbes.

Even where the alveoli remain ventilated, these factors combine to cause poor pulmonary compliance plus poor response to oxygen therapy ("alveolar-capillary block" in damaged alveolar walls.) Further, the pulmonary vascular bed is progressively obliterated.

ARDS WebPath

ARDS Hyaline membrane WebPath

ARDS UHS Case Photo by Ed

ARDS Urbana Pathology

ARDS Photomicrograph KU Collection

{06359} ARDS

The outcome depends on whether the patient can be supported and the underlying problem successfully treated before fibrosis becomes extensive.

High-dose steroids were tried in the '80's and failed to affect the outcome: NEJM 317: 1565, 1987.

Nobody knows exactly why (maybe relieving the weight pressing on the pulmonary veins), but putting the patient prone often helps oxygenation (thought not long-term survival: NEJM 345: 568, 2001).

About 50% of patients with ARDS die from it. Long, agonizing periods on the ventilator are fairly common.

* With more patients surviving ARDS nowadays, there is considerable interest in the quality of these survivals. There is often brain damage sufficient to impair the quality of life (AJRCCM 171: 340, 2005), post-traumatic stress disorder (Am. J. Psych. 161: 45, 2004), and of course impaired lung function (Chest 123: 845, 2003; NEJM 348: 683, 2003).

NEONATAL RESPIRATORY DISTRESS SYNDROME ("hyaline membrane disease", HMD, RDS, etc.)

This is the common cause of respiratory distress in premature infants (usually 1500 gm or under), beginning a few hours after birth.

In addition to prematurity, risk factors include maternal diabetes, caesarean sections, premature rupture of the membranes. Heroin addiction or glucocorticoid administration in the mother protects from RDS.

The pathophysiology is lack of surfactant plus high permeability of the immature pulmonary epithelium. A few air spaces are hyperinflated, the rest of the lung is collapsed.

The principal lesion is probably necrosis of the respiratory epithelial cells; why this happens to premature infants is unclear but probably has something to do with their being unable to tolerate even normal amounts of inspired oxygen.

Surfactant is also deficient in these patients and this accounts for part of the problem. Surfactant -- dipalmitoyl lecithin -- is the stuff that keeps the alveoli uniform in size. Recall the "two balloons on joining pipes" model in physiology.

In RDS, hyaline membranes line the open alveoli (mostly along the respiratory bronchioles). As in ARDS, they result from plasma proteins exuding through the alveolar walls. (*  These kids usually have patent ductus arteriosus with marked left-to-right shunting, which greatly exacerbates this problem.)

As in ARDS, the presence of hyaline membranes is both a marker for alveolar injury, and a further barrier to gas exchange.

{11427} hyaline membrane disease, newborn
{20014} hyaline membrane disease, newborn
{20015} hyaline membrane disease, newborn

Hyaline membrane disease WebPath Photo

Hyaline Membrane Disease Text and pictures From "Big Robbins"

To test for maturity of an unborn child's lungs, check the lecithin-to-sphingomyelin (L/S) ratio in amniotic fluid obtained by amniocentesis -- should be 1.5 or more.

Until recently, treatment was limited to ventilatory support and oxygen, plus * drugs to dilate the pulmonary arterioles.

During the last decade, administering surfactant into the lungs, before the first breath, has become standard. This is not a panacea.

A significant number of low-birth-weight kids do suffer brain damage from hyaline membrane disease hypoxemia: NEJM 325: 276, 1991.

* The extracorporeal membrane oxygenator (ECMO) is a modified heart-lung machine for preemies. The economic-ethical nightmares still happen.

Big doses of oxygen cause further alveolar damage, resulting in fibrosis, which is given the unfortunate name of bronchopulmonary dysplasia (it is neither incipient cancer, nor a birth defect). Today it is better to call it chronic lung disease of infants.

* An attempt to prevent bronchopulmonary dysplasia by administering inhaled glucocorticoids was a flop: NEJM 340: 1036, 1999.

Bronchopulmonary "dysplasia"
WebPath Photo


Some of these kids get better in a few months, but the outcome is usually bad for both lung and brain (Pediatrics 77: 345, 1986). Many of these babies spend months or years on ventilators before finally dying.

* Other problems of preemies: patent ductus arteriosus, meconium aspiration, necrotizing enterocolitis, cerebral hemorrhages from the germinal zone of the subependymal plate, preemie retinopathy (oxygen, bright lights).

* In genetic absence of surfactant, babies born at term are unable to inflate their lungs. The disease is fatal: NEJM 350: 1296, 2004.

Newborn aspiration WebPath Photo

Newborn aspiration WebPath Photo

ATELECTASIS

Atelectasis From Chile In Spanish

Collapse (or incomplete expansion) of pulmonary acini from any cause.

Obstructive atelectasis (Baby Robbins and others call it absorption atelectasis) results from non-ventilation of alveoli that are still perfused; the alveolar gas is carried away by the bloodstream.

Seen distal to tumors, foreign bodies, mucus blobs, post-surgical discomfort preventing cough, enlarged hilar nodes (cancer, TB -- producing "the right middle lobe syndrome") etc. Before antibiotics, this was a setup for bronchiectasis.

If an airway is obstructed, expect that over time the alveoli will fill with surfactant, which will mostly be engulved by macrophages. This is the "obstructive pneumonia" or "golden pneumonia", and often is the first x-ray sign of lung cancer.

Compressive atelectasis results from something in the pleural cavity (blood, exudate, tumor, air.)

If extensive and unilateral, obstructive and compressive atelectasis can be distinguished by the direction in which the mediastinum is shifted on x-ray (think about it).

A deficiency of surfactant produces "patchy atelectasis" in both hyaline membrane disease ("fetal atelectasis" -- * a term also used for lungs of stillborns who never breathed) and ARDS (see below.)

Atelectasis
This was from a hemothorax
WebPath

{10228} atelectasis (left lung of a baby whose left bronchus failed to form)

* Round atelectasis ("folded lung", "shrinking pleuritis"): a vanishing coin lesion, resulting when normal lung parenchyma is crunched into a little ball beneath a shrinking pleural scar. Familiar to radiologists, sometimes operated for diagnosis.

Regardless of cause, atelectatic lung appears redder than inflated lung at autopsy, because the blood vessels are compacted. (In life, these vessels might not have been so well perfused, thanks to the hypoxic vascular response.)

SUDDEN INFANT DEATH SYNDROME ("SIDS", "crib death", "cot death", "today, the most common cause of death during infancy" -- Br. Med. J. 298: 689, 1989; "the seventh leading cause of years of potential life lost before age 65, commensurate with AIDS" -- MMWR 37: 644, 1988, etc., etc.). The following will upset you.

Sudden death in an apparently healthy baby, less than one year old, with no explanation even after autopsy. Sources in the 1970's and 1980's claimed that this affected 2-3 per 1000 live births, "the single most common cause of infant death" (Baby Robbins, etc., etc.) -- slightly more common than baby death due to birth defects.

There is no question that genuine SIDS cases exist, i.e., some babies do die from disturbed pathophysiology without any environmental or anatomic explanation. A few causes are known (i.e., channelopathy) or suspected (actual problems with respiratory drive; these must be rare). But to understand "sudden infant death", we first need to sort out deaths that aren't "SIDS" at all. Thankfully, this is now happening.

During the 1960's, mostly because of the militancy of a single pediatrician-activist, certain anti-common-sense ideas about the sudden deaths of infants were suddenly and uncritically accepted, both by the medical community and by the public. Looking back, this had a lot to do with the "feel good / no blame / flower power" mentality of the times. It was dogma that:

• A baby supposedly could not possibly smother to death by being placed face-down on a mattress.
• A parent falling asleep on top of a baby, or a large toy in the crib, supposedly could not possibly asphyxiate the baby.
• Sudden death of a baby supposedly resulted in almost all cases from a mysterious failure of the respiratory drive. To prevent this from happening, babies spent their first years attached to elaborate machines to alert the parents should breathing stop.
• And of course, SIDS cases are not the result of anyone's negligence or actual malice. That would be unthinkable.

That this was wishful thinking should have been obvious, even at the time.

The classical autopsy finding in SIDS is petechiae over the thymus, lungs, and heart, without other abnormalities... or with nasal hemorrhages too. And this is exactly what you'd expect to find in a baby who has been suffocated -- accidentally, intentionally, on the bedclothes, or against the mattress (JAMA 263: 2865, 1990; Arch. Dis. Child. 85: 116, 2001).

And it was already well-known that "higher rates are encountered in many developing countries" (Baby Robbins), and especially among the underclass in industrial countries (Practitioner 232: 577, 1988; Arch. Dis. Child 65: 830, 1990; risk for First Americans correlates with underclass risk factors rather than genes J. Ped. 121: 242, 1992; also & JAMA 288: 2717, 2002). Some classic reported SIDS death rates:

0.04%... Rich New York suburbanites

0.4%... Poor New York slum dwellers (both from NEJM 315: 100 & 126, 1986)

0.35%... North Plains Indian reservations (JAMA, above)

2% (!!) Children of British criminal offenders (Arch. Dis. Child. 62: 146, 1987.

near zero... Hong Kong -- attributed to zero privacy and many helpers for mothers, no junk in the cribs, "nobody lets her baby sleep prone", "no unwanted babies": Lancet 2: 1346, 1985; Br. Med. J. 298: 721, 1989.

It is now obvious that many (if not most) deaths signed out as "SIDS" during the decades of ignorance were the results of negligence or abuse by family members. This was substantiated in the 1980's by careful death-scene investigators (filicide Arch. Dis. Child. 60: 505, 1985; NEJM, above; Lancet 1: 313, 1986; Lancet 1: 199, 1989; J. Ped. 117: 351, 1990.)

There was never any basis for believing that overlying cannot kill a baby. (King Solomon's judgement; Yeats's Moll Magee; most cultures historically have simply accepted that overlying kills babies.) See also Am. J. Forensic Med. & Path. (8): 256, 1987; when we stop kidding ourselves, overlying turns out to be common: Am. J. Dis. Child. 146: 968, 1992.) Sharing a bed with a parent as a risk for SIDS: Br. Med. J. 319: 1457, 1999; Arch. Path. Lab. Med. 126 343, 2002; J. Ped. 147: 32, 2005; Arch. Dis. Child. 88: 1058, 2003; Lancet 363: 185, 2004 (painfully obvious), sofas are worse and so is sleeping with Mom when she is drunk or on drugs (go figure; Arch. Dis. Child. 88: 112, 2003).

Drug use by Mom ("during pregnancy", and of course most likely continuing after) is a very powerful risk factor for SIDS, especially when the drug is heroin or methadone, and when other risk factors (poverty, smoking, and so forth) are controlled-for (J. Ped. 123: 120, 1993). A classic observation is a higher incidence (+ 60% or so) of "SIDS" on weekends (Aust. N.Z. J. Med. 18: 861, 1988; still true Arch. Dis. Child. 89: 670, 2004), when Mom and Dad/current boyfriend are more likely to be drunk or stoned. This is every bit as true today as before the "back to sleep" campaign (Arch. Dis. Child. 89: 670, 2004 -- no surprise). And children of schizophrenic mothers have around five times the risk of "SIDS" (Arch. Gen. Psych. 58: 674, 2001).

The fact that "SIDS is more than ten times more frequent if a sibling has already died of SIDS" (Arch. Dis. Child. 64: 179, 1989) hardly proves that "bad genes" are responsible. (No adoption studies are available yet....) The fact that SIDS rates are more than double for very young parents (J. Ped. 116: 520, 1990) hardly proves that some mysterious intra-uterine factor is involved. Nor does the fact that SIDS rates are double if the parents smoke (Am. J. Pub. Health 80: 29, 1990) prove that the cause is subtle irritation of the airways.

And the fact that twins used to die of "SIDS" at exactly the same time invites an obvious conclusion (Am. J. Forens. Med. Path. 10: 200, 1989; AJFMP 19: 195, 1998). The fact that this no longer happens (Arch. Ped. Adol. Med. 153: 736, 1999) just says to me that pathologists are no longer stupid enough to call these "SIDS".

The traditional wisdom that "SIDS" typically follows a minor illness now seems to be unfounded (Lancet 300: 1237, 1990). The claims about immunization being a risk factor are clearly untrue; statistically, children actually seem protected (Br. Med. J. 322: 822, 2001; the role of coincidence Pediatrics 115: e643, 2005).

And the familiar junk-science claim by breast-feeding militants that SIDS is due to bottle feeding simply isn't true: Br. Med. J. 310: 88, 1995. At best, the relationship is statistical, and it's weak. However, the SIDS organizations still tell people that breast-feeding protects children from SIDS, which must put a terrible burden of guilt on people whose babies died of the real thing.

Possibly a few infants do die from failure of respiratory drive during sleep. "Near-miss" apnea and related respiratory rhythm disturbances are demonstrable in some siblings, though the findings are notoriously un-reproducible.

* I was impressed only by Hum. Genet. 73: 39, 1986 -- a family with very little myelin in the respiratory centers of their medullas). Since this hasn't been replicated, I wonder about the neuropathologist's myelin stain. Finding hypoplasia of the arcuate (CO₂ sensor) nucleus of the medulla in a subset of SIDS is interesting: J. Neuropath. 51: 394, 1992; I'd bet these brains are those that don't respond to having the mouth and nose up against the mattress. An Italian group claims to have found "frequent alterations, mainly cogenital, of the autonomic nervous system" (Am. J. Clin. Path. 124: 259, 2005; also J. Clin. Path. 58: 77, 2005). Stay tuned.

Otherwise, "near-miss apnea seen in siblings" is peculiarly non-lethal: Science 264: 197, 1994. I suspect that, in most cases, "near-miss SIDS" is Cheyne-Stokes respirations (as a junior med student sharing a call room, I was told I do this while asleep) or transient obstructive sleep apnea.

It is now obvious that some cases of SIDS result from laying babies prone (Pediatrics 93: 814, 1994; Pediatrics 105: 650 2000; JAMA 273: 783, 1995, lots more). Most plausibly, sleeping babies might simply fail to move when their faces lie flat against mattress, and smother in this way.... (gee whiz) ... or rebreathe carbon dioxide, which is pretty much the same thing (Am. J. Dis. Child. 147: 642, 1993; J. Ped. 122: 874, 1993). This is consistent with some studies which strongly suggest prolonged hypoxia has occurred prior to death in many SIDS cases (Pediatrics 87: 306, 1991, others).

There has been about a 50% reduction in "SIDS" in countries where there's been a campaign to get parents not to place their babies prone. The impact is extremely obvious (Lancet 363: 185, 2004). In the U.S., where "SIDS activists" insisted for two decades that "SIDS is not your fault and a child cannot smother against the mattress", the campaign was delayed. Figure out yourself how many children died as a result. "Suffocated prone: the iatrogenic tragedy of SIDS": Am. J. Pub. Health 90: 527, 2000. Strangely, in the US, breast-feeding militants are still pressuring women to sleep with their infants.

* "Swaddling clothes" (remember these from the Christmas story?) are an ancient custom designed to keep children lying on their backs, perhaps to prevent SIDS: J. Ped. 141: 398, 2002.

There's some interesting work on facial morphology in these kids -- their upper and lower jaws seem to be, on average, farther back, and perhaps this makes it easier for them to smother on their mattresses (Lancet 317: 293, 1998). The relationship with obstructive sleep apnea -- which this group claims is more common in SIDS families -- is going to take more study to work out.

SIDS
Instructional material
WebPath Photo


When you are working in the neonatal intensive care unit, you will frequently see preemies that have trouble breathing or even stop breathing ("apnea of prematurity") or suffer cardiac rhythm disturbances. These have nothing to do with SIDS (Pediatrics 77: 811, 1986; Pediatrics 78: 787, 1986).

Public awareness of "SIDS" resulted in a huge "apnea monitor" industry (racket, or "expensive cover-your-butt stuff", as almost everybody will tell you nowadays). Today, the people who really know about SIDS laugh at the idea that monitors save lives (see, for example, Chest 91: 898, 1987; Can. Med. Assoc. J. 140: 1072, 1989), but they did keep parents from staying up all night watching their babies breathe. "Consensus document" on home monitoring: Pediatrics 79: 292, 1987; noncompliance or worse: Am. J. Dis. Child. 142: 1037, 1988. By 1994, the idea that apnea is an important cause of SIDS is dismissed by almost the entire scientific community, though still believed by physicians (Science 264: 197, 1994); however it's still routinely prescribed (Arch. Dis. Child. 84: 270, 2001). To clinch the matter, Waneta E. Hoyte, the mother whose "tragic story" led to the paper (Ped. 50, 646, 1972) that spawned the apnea monitor business confessed in 1994 to having smothered her five children. ("Their screaming made her feel useless": Ped. 93: 944, 1994).

Some "clever" parents learn to stop their kid from crying by smothering it into unconsciousness; this will load the lungs with hemosiderin-laden macrophages (why?). Eventually, these kids are likely to die. Pathologists are now routinely signing "SIDS" cases with lots of these macrophages as "manner of death undetermined" (J. Clin. Path. 52: 581, 1999) and staining all infant lungs to see hemosiderin (Am. J. For. Med. Path. 23: 360, 2002.

The British put kids with near-miss SIDS on secret video in two hospitals, and videoed THIRTY of them being intentionally suffocated or strangled by a parent to quiet them (Pediatrics 100: 735, 1997). The conclusion was the understatement of the year: "When parents have failed to acknowledge that they have deceived health professionals, partnership with them in seeking to protect their children may be neither safe nor effective." Nowadays, even when the death certificate might originally have said "SIDS" or some other natural cause, many perpetrators are being successfully prosecuted: Arch. Dis. Child. 80: 7, 1999.

* Believe it or not, some "ethicists" got very upset over the invasion of the British parents' privacy and "breach of trust" between the medical community and the abusers (Med. J. Aust. 160: 352, 1994).

The British estimate that 1 in every 10 SIDS cases is a covert homicide (Arch. Dis. Child. 89: 443, 2004); whatever you think of the estimate, common-sense tells you when to suspect murder. SIDS "research" and political agendas: Arch. Dis. Child 88: 1085, 2003.

Before you write "SIDS" on a death certificate, try to rule out:

• upper respiratory infection (especially winter cases, when "SIDS" is most common)
• long QT interval syndrome (channelopathy, I predicted this one; NEJM 338: 1709, 1998; Circ. 104: 1158, 2001; Lancet 358: 1342, 2001; JAMA 286: 2264, 2001 shows it's about 2% of SIDS cases)
• streptococcus B infections (newborns)
• epilepsy resulting in apnea
• adrenal insufficiency (you couldn't have missed this at autopsy, however...; J. Ped. 145: 178, 2004)
• botulism (ask about the baby having been fed raw honey)
• obstructive sleep apnea (newly described -- there is at least one familial small-throat syndrome, see Lancet 1: 402, 1986; Arch. Dis. Child. 61: 1039, 1986), and probably more (Pediatrics 83: 647, 1989). Huge tonsils: For. Sci. Int. 53: 93, 1992. NOTE: Many monitor-detected "apparent life-threatening events" precede the development of classic sleep apnea when these kids get older (Chest 102: 1065, 1992, no surprise).
• malformations of the brain stem and/or base of the skull (one example is achondroplasia: Am. J. Dis. Child. 142: 989, 1988)
• inborn errors of fatty-acid breakdown -- these children will have fatty liver and are likely to be misdiagnosed as Reye's syndrome at autopsy (Lancet 2: 1073, 1986; Pediatrics 78: 1052, 1986; Br. Med. J. 296: 11, 1987; this is rare, and you don't find the defect in ordinary SIDS J. Ped. 122: 715, 1993; Arch. Dis. Child. 66: 1315, 1991).
• absence or anomalous origin of one or more coronary arteries (Pete Maravich made it to his 40's with no left main coronary artery, but many don't)
• other cardiac malformation (J. Ped. 141: 336, 2002) -- in these cases, the child is usually awake when he/she falls over dead
• "ectodermal dysplasia" with no sweat glands
• * vertebral artery occluded at the junction of the occiput and C1 by turning the head: Pediatrics 103: 460, 1999 (still hypothetical...)
• carbon monoxide poisoning (how's that home heater working?)
• early pertussis infection (whooping cough is rampant in Europe thanks to the anti-immunization movement; link with SIDS Pediatrics 114: e9, 2004)

• unnatural death (including overlying by parent, suffocation by toys, bedclothes, or the waterbed (NEJM 319: 1415, 1988) or beanbag chair (NEJM 324: 1858, 1991), hyperthermia, shaken-baby syndrome without subdural bleeds -- contrary to popular (and groundless) "no-guilt" claims, all of these can and do kill babies -- and of course, murder by smothering, i.e., Mary Beth Tinning / Waneta Hoyte syndrome; see Pediatrics 91: 423, 1993.)

  * Kids with febrile seizures are not at increased risk for SIDS, so it is probably unacceptable to invoke a seizure as causal: Arch. Dis. Child. 86: 125, 2002.

But after you've done all this, can your autopsy rule out smothering or all other forms of lethal trauma? In a word, "No" (Am. J. Dis. Child. 144: 137, 1990). The SIDS autopsy: J. Clin. Path. 45(S-11): 11, 1992.

* The pathology lab has nothing to offer for the differential diagnosis of "near-miss SIDS" (Am. J. Dis. Child. 140: 484, 1986). Protocol for the SIDS autopsy: J. Clin. Path. 40: 481, 1987.

When a second SIDS death takes place in a home, the pathologist's task is especially difficult. One big study concluded that most of these are natural, and that many are homicides, and that sorting them out definitively is impossible (Lancet 365: 29, 2005). Probably you have to call the child protection folks (Arch. Dis. Child. 88: 699, 2003).

CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD, chronic air flow obstruction, * COAD, * CAWO, * chronic airway obstruction): The most common cause of activity-restricting disability in the U.S. Morphology and pathophysiology review: Lancet 364: 709, 2004. Clinical review (no surprises): Lancet 362: 1053, 2003.

Chronic Obstructive Pulmonary Disease Queen's U., Kingston Thanks Dr. Boag

"Obstructive lung disease" is a traditional and irrational grouping of four illnesses:

1. chronic bronchitis
2. emphysema
3. asthma
4. bronchiectasis.

The term generates tremendous confusion, and I urge you not to use it.

"COPD" includes two very common "diseases" that typically occur together.

Chronic bronchitis causes obstruction to air flow because of edema, necrosis, fibrosis, and recurring infections in the bronchial tree.

The walls do get thicker and this narrows the bronchial lumens. This has been confirmed by some good pathology studies (Am. Rev. Resp. Dis. 143: 1152, 1991; Chest 97(S2): 6S, 1990), and now we see it on high-resolution imaging studies.

Although narrowing of the bronchial lumens ("thickening of the bronchial walls") interferes some with breathing, it's usually the severity of the co-existing emphysema that really disables these people.

Increased mucous secretions and hyperplasia of mucous-secreting glands by themselves, though typical of chronic bronchitis, are now thought not to contribute significantly to obstruction (i.e., it's not prolonged suffocating on hockers). Am. Rev. Resp. Dis. 128: 491, 1983; Am. Rev. Resp. Dis. 133: 942, 1986.

* Constrictive bronchiolitis" is a striking lesion seen in a minority of smokers, and in some other lung diseases. It's dense fibrosis around bronchioles with serious compromise of the lumens.

Emphysema causes obstruction to air flow because loss of the lung's elastic recoil allows small airways to collapse at the beginning of expiration. We all lose some elasticity as we age, but smokers and people who are alpha-1 antitrypsin deficient lose it much more, and also have some destruction of their septa, which is not part of normal aging.

NOTE: Some people include all asthma cases as COPD, but regular asthma has a much better prognosis. Today, even chronic "asthmatic bronchitis" is distinguished from other forms of chronic bronchitis, which are much more lethal: NEJM 317: 1309, 1987.

Both emphysema and chronic bronchitis are most commonly caused by cigaret smoking. Most smokers with one have the other, too.

Smokers should be prepared for:

• tobacco pigment in the lungs (brown stuff)
• carbon pigment in the lungs ("anthracosis"; more than non-smokers)
• loss of ciliary motility (maybe; these people don't get problems so severe as people with congenital immotile cilia do)
• goblet cell proliferation in remaining columnar epithelium
• hypertrophy and hyperplasia of mucous glands
• thickening of the respiratory epithelial basement membrane ("subepithelial collagen deposition")
• increased numbers of polys in the lungs
• increased numbers of alveolar macrophages (x6 or so)
• impaired ability of alveolar macrophage to function usefully
• increased neutrophil and macrophage elastase production and release
• impaired ability of alveolar macrophage to function usefully
• squamous metaplasia of respiratory epithelium (contrary to what others may have told you, this is the exception rather than the rule)
• loss of elasticity of alveolar walls
• eventual destruction of alveolar walls

Baby Robbins's estimate of "10,000 to 20,000 deaths in the U.S." yearly due to COPD is much too low. COPD probably contributes in a major way to around 100,000.

* Supposedly the neuropathies seen in these patients are due to hypoxemia itself.

* Not a trivial problem -- advising the COPD patient about air travel: Ann. Int. Med. 111: 362, 1989.

EMPHYSEMA

Emphysema
Lung pathology series
Dr. Warnock's Collection

Emphysema I From Chile In Spanish

Emphysema II From Chile In Spanish

Emphysema Good blebs WebPath

Emphysema Supposedly centrilobular WebPath

"Types of emphysema" Lung pathology series Dr. Warnock's Collection

Centrilobular emphysema Formalin-inflated lung KU Collection

Emphysema Supposedly centrilobular WebPath

Emphysema Trashed, overstretched alveoli WebPath

Emphysema Australian Pathology Museum High-tech gross photos

{11506} emphysema
{20239} emphysema
{20993} emphysema
{29153} emphysema
{38362} emphysema
{38365} emphysema
{49068} "pan-acinar emphysema"
{49069} "centrilobular emphysema"

The old-fashioned anatomists define "emphysema" as an abnormal, permanent dilatation of part of all of the acinus, with eventual destruction of many of the alveolar walls.

I predict that the definition will eventually be changed to reflect the true sine qua non -- loss of elasticity of the lung. The new definition may also include the requirement that there be some destruction of the alveoli.

You'll diagnose emphysema on lung function tests by noting prolongation of the time required for a full forced expiration, in the absence of asthma.

Two common forms are distinguished:

Centrilobular (centriacinar) emphysema shows more dilatation of the respiratory bronchioles and their alveoli.

Traditionally, this is seen in early smoker's emphysema "because cigaret smoke exposure is heaviest in the centers of the acini". And "it is worse in the upper lobes, because they get more smoke exposure" (why?).

Panlobular (panacinar) emphysema involves the acinus uniformly.

Traditionally, this is caused by alpha₁-protease inhibitor ("antitrypsin") deficiency "because the blood brings neutrophils to all of the lung uniformly". And "it is worse in the lower lobes, because they get more blood" (why?)

By the time emphysema patients come to autopsy, the damage is so severe that you won't be able to make the distinction, and it's not really something that matters to the clinician, radiologist, or patient.

There are about 2 million diagnosed emphysema patients in the U.S. at any time, and the real prevalence of this disease is much higher.

The pathogenesis is pretty clear.

Emphysema is not caused by air trapping behind inflamed bronchioles (asthmatics don't develop emphysema from it) or playing wind instruments (Chest 88: 201, 1985).

The problem is damage to the elastic fibers of the lung by elastases from polys, monos, possibly pancreas. Of course, smoking cigarets brings lots of polys to the lung.

* The elasticity explanation for emphysema probably was first stated by Laennec, inventor of the stethoscope: Lancet 335: 1372, 1990.

Deficiency of serum alpha-1-antitrypsin (our major * "serpin" -- serine protease inhibitor) is an inborn error of metabolism in which severe panacinar emphysema develops in non-smokers.

This results from inability to efficiently release an abnormal anti-protease from the hepatocytes. Inclusions develop in the cells. The defects is the result of alleles at the Pi ("protease-inhibitor") locus -- "M" is the common allele, while "S", "Z", and others result in less product getting into the bloodstream. Homozygous patients may also get cirrhosis. Whether heterozygotes are more at risk for emphysema if they smoke is the subject of much discussion, as they have intermediate levels of anti-protease. Replacement therapy with the enzyme ("Prolastin", watch for "Respitin") is now in use for these patients, at a cost of around $36,000 per year (Chest 119: 745, 2001; third-party payers are of course balking and estimates of the cost of a year of life saved vary widely: Chest 117: 875, 2000).

* Social factors in disease: The Swedes screened all newborns for SZ and ZZ and warned all parents of these children to stop smoking. They discovered that none of the parents complied (Thorax 43: 505, 1988).

Tobacco smoke augments elastases, inhibits anti-proteases, and promotes infection with further release of elastases. We do not know why some smokers get much worse emphysema than others.

Because of loss of elastic recoil, small airways collapse during forced expiration.

The classic "emphysema" patient is a "pink puffer", with normal P_aCO₂, barrel chest, pursed lips, dyspneic, tachypneic, thin (he's working hard all the time), miserable. The only consistent finding on physical exam is slowing of forced expiration ("Can you blow out a match at six inches with your mouth wide open?").

Pink puffers learn to keep their lungs hyperinflated to keep the respiratory bronchioles from collapsing, and this eventually changes the shape of the chest itself ("barrel chest", "increased AP diameter", "increased total lung volume").

These people eventually start getting bacterial lung infections, and die of cor pulmonale, pneumothorax, or pneumonia.

At autopsy, the lungs are hyperinflated and relatively bloodless. Eventually, broken alveolar septa dangle in the breeze, and many of the capillaries in the septa are gone (we don't really know why the latter occurs).

In 1996, the NEJM (334: 1095, 1996) published an article showing that the newly-popular "lung reduction surgery" (lung-lift, like face lift or certain other cosmetic procedures to reverse sagging, $75,000) produces improved exercise ability for a while. Just as you'd expect from what you've learned about emphysema, people who have little inspiratory resistance (i.e., wide open larger airways) do nicely, while those with really badly-narrowed bronchi are not benefited (NEJM 338: 1181, 1998). Update NEJM 343: 239, 2000 (better exercise tolerance, no proof of longer survival). It is now very common and the benefits are obvious (Chest 123: 1838, 2003). Changing times: Medicaid decided every smoker on welfare did not have a "right" to this surgery, and surprisingly few people were outraged.

Bullous emphysema produces air-filled blebs (if >2 cm, you can call them "bullae") containing little or no lung tissue, usually at the apices, sometimes (but by no means always) at the sites of old TB scars.

Most cases probably result from common emphysema, with the inelastic lung "collapsing under its own weight" (Thorax 44: 533, 1989); the upper lobes have more contact more tobacco smoke because they are better ventilated.

The blebs may be removed surgically, with improvement in the "pink puffer"'s puffing.

Blebs are also prone to rupture, causing pneumothorax and sudden death. Iatrogenic disease: "IPPB breathing treatments" are irrational therapy for uncomplicated emphysema, and kill patients by blowing out blebs.

{10778} blebs in emphysema

Emphysema patient
Barrel chest
Well-developed arms

Other forms of "emphysema":

* Paraseptal (distal acinar): rare, blamed for spontaneous pneumothorax in young people. I suspect this is a mythical process.

Compensatory (i.e., following removal of a lobe of a lung, the other lobes expand; this is a misnomer, as there is no destruction of alveoli, and no loss of elasticity.)

"Irregular" or "tractional" (i.e., after scarring, etc.; another misnomer.)

"Senile" (loss of elasticity without loss of lung substance, from "old age")

"Interstitial emphysema" doesn't even refer to lung. It means air has been forced into the fibrous tissues of the body, often as the result of tearing of the lung itself (by real emphysema, by severe coughing, by a respirator, by a broken rib, by barotrauma). Listen for the "milkman's crunch" sign as the heart beats, palpate the little bubbles under the skin, and reassure the patient that it will reabsorb.

CHRONIC BRONCHITIS ("smoker's cough" -- never trivial)

Defined clinically, as persistent cough with sputum production for at least three months in at least two consecutive years. (Worth committing to memory.)

It's not the cough
That carries you off,
It's the coffin
They carry you off in.

-- Ogden Nash

Again, the usual cause is cigarets. Marijuana isn't exactly good for the lungs either (gee whiz, JAMA 259: 966, 1988; NEJM 318: 547, 1988) but so far hasn't produced wards full of respiratory cripples.

The "classic chronic bronchitis patient" is a "blue bloater", with increased P_aCO₂, obese, edematous (cor pulmonale), cyanotic, producing much sputum, happy (CO₂ narcosis.)

The distinguishing feature of this kind of patient is an acquired tolerance for the hypercarbia that poor ventilation (i.e., from emphysema) ultimately causes. Unlike "pink puffers" (who retain their hypercarbic drive), these patients no longer really struggle to breathe, so long as they have adequate oxygen.

Because of the poorer alveolar ventilation, (*  and perhaps with a contribution from scarring around airways and vessels, and the fact that they present later in the course of their disease), pulmonary hypertension supervenes earlier in "chronic bronchitis" patients than in emphysema patients.

Exacerbations and death often follow infection with S. pneumoniae or H. influenzae.

Death may also result from cor pulmonale or from apnea brought about by breathing oxygen (remember, hypercarbia no longer stimulates respiration in these patients.)

Many clinicians today are treating chronic bronchitis with glucocorticoids "to control the component of bronchospasm, as in asthma". I suspect they're actually making the walls of the inflamed large bronchi thinner, with even a little bit of widening the lumens helping a lot. As an autopsy pathologist in the 1980's, I was very impressed with the ability of systemic glucocorticoid side effects to kill these people. Today's pulmonologists are switching to inhaled glucocorticoids (Lancet 351: 773, 1998).

Genetic factors seem to determine whether a smoker becomes a "pink puffer" or a "blue bloater." See Am. Rev. Resp. Dis. 129: 207, 1984. The onset of "chronic bronchitis" is supposed to be earlier than emphysema, which is understandable since it will be diagnosed by hearing the patient rattle all those hockers, while emphysema is diagnosed only when shortness of breath becomes profound.

At autopsy we find copious secretions in the airways, even in the absence of pneumonia. The trachea itself may be almost filled with yellow slime.

Microscopically, we see thickening of the bronchial basement membrane (seen also in asthma), proliferation of goblet cells, hypertrophy and hyperplasia of mucous glands, more of the various inflammatory cells, more lymphoid aggregates and follicles than usual, and often a considerable amount of scarring (histopathology update on "smoker's small airways disease": NEJM 350: 2645, 2004).

"Reid index" is ratio of thickness of submucosal mucous glands to entire submucosa. Normal is up to .4; increased in chronic bronchitis.

* In the worst cases, we see widespread obliteration of the lumens of the terminal bronchioles (i.e., bronchiolitis obliterans or denser scarring).

{08761} chronic bronchitis (chronic inflammation, missing epithelium)

Chronic Bronchitis From Chile In Spanish

Chronic bronchitis
Lung pathology series
Dr. Warnock's Collection

* "Coarse breath sounds" / "coarse rhonchi" are hockers moving around in the big airways. Make the patient cough, and they'll perhaps go away or at least change.

Despite elaborate systems of testing pulmonary function, the ultimate diagnosis of "COPD" is made on history and physical exam. This applies to most other disease, too (Am. J. Med. 94: 188, 1993).

BRONCHIAL ASTHMA (some lump it with "small airways disease"; BMJ 314: 45, 1997; NEJM 325: 425, 1991)

Common syndrome (10% of kids, 5% of adults) in which the small bronchi are abnormally responsive to various stimuli which cause constriction and/or are considerably inflamed (usually both). This produces episodes of dyspnea, wheezing, cough.

You'll hear plenty of wheeze sounds through your stethoscope; the sound is air rushing through narrow airways, making noises like the wind section of the orchestra playing out of tune.

Asthma kills around 3000 people in the U.S. each year. Very few of these people took good care of themselves (no-nonsense article: Thorax 44: 97, 1989); and asthma death is primarily an underclass phenomenon (NEJM 331: 1542, 1994). Likewise, the asthmatic children who die are for the most part the underclass ones, as a result of smoky homes and "disease mismanagement": Ped. Clin. N.A. 50: 65, 2003.

Lately there's been much interest in chlamydia TWAR, as a chronic infection, as cause of asthma -- and six months on a macrolide to effect a cure. Update AJRCCM 171: 1083, 2005 (many childern harbor it); AJRCCM 167: 406, 2004 (but few adults); Chest 121: 1782, 2002 (macrolides help if and only if chlamydia are present).

Mast cell factors appear to mediate the bronchoconstriction regardless of what triggers the attack.

These factors include histamine, bradykinin, leukotrienes ("SRS-A", etc.), prostaglandins (must be present: Science 287: 2013, 2000), probably others. We're still learning what's in those mast cells.

* If you actually look inside (rather than below) the epithelium, asthmatics actually average ten times as many intraepithelial mast cells as their non-asthmatic counterparts (Am. Rev. Resp. Dis. 148: 80, 1993).

All about arachidonic acid metabolites in lung disease: Am. Rev. Resp. Dis. 143: 188, 1991. Leukotrienes are of course notorious for being chemotactic for inflammatory cells, and for tightening smooth muscle.

Asthmatic attacks are often triggered by:

• type I hypersensitivity, from IgE-mediated mast-cell degranulation resulting from exposure to pollen, dander (what's that?), cockroach detritus (NEJM 336: 1382, 1997), other potent allergens

* "I wasn't surprised": Allergy shots offer no benefits for asthmatic kids getting appropriate medical treatment: NEJM 336: 324, 1997

• viral infections ("non-reaginic asthma"; "non-aspirin-induced intrinsic asthma")
• pollution, cigaret smoke (we don't know why, but it's potent; a smoking parent greatly exacerbates a child's asthma), inhaling heroin
• "strong odors" (fresh paint triggers some asthmatics; I suspect this is actually a chemical effect that we do not yet understand; Chest 116: 1780, 1999)
• aspirin; other NSAIDS, tartrazine yellow (see below)
• "stress"
• gastric acid reflux ("heartburn")
• exercise, especially in the cold (drying and/or chilling of the airways; some people get this even without "classic asthma")
• chlamydia TWAR. This is BIG news and I suspect that this bug underlies the burst in new cases of asthma, and the success of anti-chlamydials in treating it. See below.

Allergic asthma is said to be present when the patient's attacks are typically triggered by IgE-mediated hypersensitivity.

This often is severely disabling in childhood, though it generally gets better in adult life. An old misnomer is "extrinsic asthma".

Remember both the familiar inhalants and food allergy (J. Allerg. Clin. Imm. 112: 168, 2003).

Remember histamine, leukotrienes, prostaglandin D₂, and platelet activating factor as the major contributors to this kind of wheezing, with leukotrienes perhaps most important.

Industrial asthma is a serious problem. The worst offenders are cedar wood platinum salts, anhydrides (epoxy hardeners) and isocyanates, followed by proteolytic enzymes, epoxy resins themselves, lab animals, vinyl chloride used in meat packing, flour, crab processing, oil mists, and penicillin. Formaldehyde asthma is a problem for a few unlucky pathologists.

* Platelet-activating factor antagonists are on the way: Chest 108: 529, 1995. Montelukast / zafirlukast for leukotriene receptor blockade (JAMA 279: 455 & 1181, 1998) -- works wonders for exercise-induced bronchoconstruction (chilling and drying?) and mild allergic asthma (NEJM 339: 1998).

We believe that some of the longstanding epithelial havoc is wrought by major basic protein of eosinophils recruited to the sites of the reaction. Be this as it may, another eosinophil protein crystallizes as "Charcot-Leyden crystals" in the sputum of allergic asthmatics.

If a chronic aspergillus infection gets established in an asthmatic's lungs, allergy to this fungus is likely to make the asthma much worse). As many as 15% of severe cases get this. In "allergic bronchopulmonary aspergillosis", the fungi actually find safe haven inside the plugs, creating a vicious cycle.

Idiosyncratic asthma is said to be present when the patient's attacks are typically triggered by exposure to aspirin (Chest 88: 387, 1985), another cyclo-oxygenase inhibitor, and/or tartrazine yellow. These people's small airways are teeming with eosinophils and mast cells (Am. J. Resp. CCM. 153: 90, 1996, NEJM 346: 1699, 2002), the obvious source for the extra leukotrienes.

This is more likely to begin in adult life. An old misnomer is "intrinsic asthma". (Look for nasal polyps in the aspirin-sensitive patient.)

Reactive airways disease is a current concept (some might say a fad) in which asthma follows a single noxious exposure of the bronchial mucosa to something hurtful (i.e. poison or hot gas, poisonous fumes). Other folks use the term as a synonym for triggerable asthma.

Regardless of cause, the pathology in asthma is inflammation of the bronchial mucosa, with eosinophils, and (probably also, maybe as a result) increased fragility of the epithelium. Review Chest 124: 32, 2003.

The smooth muscle is also likely to be hyperplastic. This (and some increase in collagenization) is the principal histologic feature correlating with severity (AJRCCM 167: 1360, 2003).

Part of the trouble, we may reasonably think, is irritation of the C-fibers that travel up the vagus nerve and mediate bronchospasm by an autonomic reflex.

The worse the asthma, the worse the inflammation (Am. J. Resp. CCM. 154: 24, 1996). No surprise. Anatomy of asthma, with a focus on the long term "repair" changes which actually make things worse: J. Allerg. Clin. Imm. 98: S278, 1996.

Only a small percent of asthmatics lack eosinophils, and it's not clear whether this is the same disease: Am. J. Med. 115(S-A3): 49S, 2003. In the animal model, the airways do not undergo much fibrous thickening if the animal has no eosinophils (Science 305: 1776, 2004).

* According to one group, the lungs of asthmatics lack T-bet⁺ lymphocytes which produce gamma-interferon which modulates the immune response here, and T-bet⁺ knockout mice have histological and clinical asthma (NEJM 346: 857, 2002).

Fatal cases ("status asthmaticus") show mucosal edema, many eos, polys, mucous secretions, desquamation, and obvious basement membrane thickening (see Thorax 87: 152-S, 1985).

A study of non-fatal asthma cases showed that all had thick bronchiolar epithelial basement membranes. Non-asthmatic controls had no mast cells or eosinophils, while these were present in most of the asthmatics. Asthmatics also showed more of a tendency for the epithelium to fragment. See Am. Rev. Resp. Dis. 145: 922, 1992.

The thickening of the basement membrane, hyperplasia of smooth muscle, increase in goblet cells, and hyperplasia of bronchial glands is now called "remodelling" and is the most-studied phenomenon in asthma (Am. J. Resp. CCM 164: S46 & S52, 2001); the causes remain as mysterious as always.

Sputum from most asthmatics with type I immune injury shows Charcot-Leyden crystals (eosinophil alkaline proteins), Curschmann's spirals (coily strings of altered goo from little airways).

Chest deformities (barrel, pigeon, Harrison's sulcus) often result from severe childhood asthma (JAMA 259: 1722, 1988).

Asthma Text and pictures From "Big Robbins"

Asthma, great pictures Lung pathology series; follow the arrows Dr. Warnock's Collection

Asthma Australian Pathology Museum High-tech gross photos

Asthma Hyperinflated lungs WebPath

Asthmatic mucus plugs WebPath

Asthmatic airway WebPath

Asthmatic airway The kind with the eosinophils WebPath

Asthma Plug and wall changes KU Collection

Asthma Lung pathology series Dr. Warnock's Collection

{08228} asthma, hyperinflated lungs (notice that they completely cover the heart in front)
{08231} asthma, mucus plugging airways
{08234} asthma, plugs
{29236} asthma, plugs
{07564} asthma, thick basement membrane
{08240} asthma, thick basement membrane, lots of smooth muscle, lots of epithelial cells lying around
{08243} asthma, thick basement membrane, mucus plug (trichrome stain)
{09899} Curschmann's spirals
{25999} Curschmann's spirals
{27492} occupational asthma; isocyanates are infamous

The mainstay of treating asthma is inhaled glucocorticoids, which (when not abused) are incredibly safe (NEJM 332: 868, 1995; Thorax 49: 1185, 1995). Best used in low doses daily; they actually prevent the anatomic pathology (inflammatory cells, cytokine production, even basement membrane thickening) which allow acute attacks to occur (Am. J. Resp. CCM. 150: 17, 1994).

* Did you know that glucocorticoids cause eosinophils to undergo apoptosis? (Am. J. Resp. CCM. 154: 237, 1996)

* Acupuncture totally fails when tested as a treatment for asthma: Chest 121: 1396, 2002.

* Although I have not seen this in the current literature, I was told twice in the 1990's, both times by members of "conservative-religious-family-values" identity-groups, that children are only wheezing to get attention and should be punished for it. If I'm hearing this, then so are at least some of your patients. I urge you to call this what it is -- one more stupid, ugly lie. I've taught you how to deal with these things ("If that were true, then wouldn't you be able to observe....?")

* Regular spinal manipulation is heavily promoted to the public by many chiropractors for childhood asthma. Since childhood asthma almost always gets better by itself, a controlled study would seem to be indicated -- and finally has been done (no measurable benefit: NEJM 339: 1013, 1998 -- in an issue with two positive studies of the value of manipulation for low back pain.)

"All that wheezes is not asthma." Wheezing may also result from:

• foreign body or tumor in the upper airway
• pulmonary edema (especially left-sided congestive heart failure; see Lancet 335: 693, 1990)
• pulmonary embolus
• chronic bronchitis
• carcinoid syndrome

* This might be a good place to mention pepper spray, used by law enforcement and private citizens. You may hear it alleged that this has killed people; I find this hard to believe and so do the more scientifically-minded reviewers (Am. J. For. Med. Path. 16: 1995).

BRONCHIOLITIS OBLITERANS ("cryptogenic organizing pneumonitis", "bronchiolitis obliterans organizing pneumonia", "BOOP")

This is a histopathologist's word for a lesion in which nubbins of loose connective tissue develop and plug the respiratory bronchioles and alveolar ducts and spaces. Air flow is obstructed, and lung expansion restricted.

BOOP
Very nice pictures and
discussion by Dr. Epler


This unhealthy situation can be seen in any of the following:

• organizing pneumonias from any cause (including eosinophilic pneumonias)
• asbestosis
• organic pneumoconiosis
• autoimmune diseases of the lung (lupus, rheumatoid arthritis, Sjogren's; Am. J. Resp. CCM. 154: 1531, 1996)
• rejection of a transplanted lung (extremely important in lung transplantation nowadays; Lancet 339: 1649, 1992, AJRCCM 170: 1022, 2004; lots more)
• GVH disease
• * amiodarone lung; acebutolol lung (Thorax 44: 711, 1989)
• idiopathic bronchiolitis obliterans -- a mysterious illness that responds well to treatment with glucocorticoids
• some of the occupational diseases in which a volatile chemical, rather than a dust, is inhaled (for example, microwave-popcorn-packer's lung, from artificial butter-flavor: NEJM 347: 33, 2002)

* Researchers are presently looking at platelet-derived growth factor as a major player in the pathogenesis of this process (Am. J. Resp. CCM. 155: 676, 1997). Another group reports finding mast cells in the alveoli of BOOP patients, but none in controls, contradicting a traditional teaching of histologists: Chest 110: 383, 1996.

Bronchiolitis
Lung pathology series
Dr. Warnock's Collection

BRONCHIECTASIS ("ectasia", or "pulling wide" of the bronchi)

Defined to be the permanent cylindrical dilatation and ulceration of part of the bronchial tree.

The clinical picture is chronic cough with sputum production, up to many cups daily. (Bronchiectasis is on a continuum with chronic bronchitis.)

The dilatation ("-ectasis") results from contraction of scar surrounding the bronchus, and from surrounding atelectasis.

Bronchiectasis I From Chile In Spanish

Bronchiectasis II From Chile In Spanish

Bronchiectasis Lung pathology series Dr. Warnock's Collection

Cystic fibrosis Bronchiectasis KU Collection

Bronchiectasis WebPath

Bronchiectasis WebPath

Bronchiectasis WebPath

Bronchiectasis WebPath

Bronchiectasis WebPath

Bronchiectasis WebPath Photo

Bronchiectasis WebPath Photo

Bronchiectasis Photo and mini-review Brown U.

{5762} bronchiectasis
{10787} bronchiectasis
{24542} bronchiectasis
{27242} bronchiectasis
{38383} bronchiectasis
{38389} bronchiectasis

Bronchiectasis complicates respiratory infections (severe, or those in the immunosuppressed), asthma, cigaret smoking, inherited disease (especially cystic fibrosis and primary ciliary dyskinesis/immotility, including Kartagener's.

In older days when bronchiectasis was much more common, it often followed measles, staphylococcal or pertussis pneumonia. This is very rare nowadays.

Regardless of the predisposing lesion, the proximate cause is a bacterial infection ("normal throat flora", H. influenzae, S. pneumoniae, anaerobes). Once established, bronchiectasis will persist due to a vicious cycle of exudation and infection.

Bronchiectasis results in serious social problems in many cases; it may lead to amyloidosis, brain abscesses, cor pulmonale, and so forth.

The anatomic pathologists sees bronchi pulled wide by contraction of scar surrounding the ulcerated airways. (Ignore the quaint subclassification of "saccular", "cylindroid", and "fusiform" bronchiectasis).

Modern medical and surgical treatment has improved the outlook for these patients greatly.

OBSTRUCTIVE SLEEP APNEA: NEJM 347: 498, 2002

A common (1-5% of adults, and some kids), serious, long-neglected health problem, characterized by many episodes of upper airway obstruction each night.

Sleep apnea victims all snore famously (snoring correlates with excessive daytime sleepiness and other quality-of-life issues: Chest 110: 659, 1996). Most are overweight (more fatty tissue in the upper airway) or have huge tonsils or jaw deformities. Most sleep in the supine position. Most have "thick necks" and/or drink a lot (Am. Rev. Resp. Dis. 141: 1228, 1990; Thorax 46: 86, 1991). For some reason, premenopausal women are seldom affected.

* Worth remembering in treating patients: Obstructive sleep apnea often accounts for deterioration in patients with hypothyroidism (myxedema) and Down syndrome (Br. Med. J. 296: 1618, 1988).

As the victim starts to go into deep sleep, his upper airway closes (physiology: JAMA 266: 1384, 1991), he thrashes, snorts, partly wakes up, and re-opens the airway with a gasp. The cycle repeats every few minutes through the night, and the patient never gets to sleep soundly.

Sleep apnea results in morning headaches, daytime somnolence, "narcolepsy", cognitive and behavioral changes, school and job failure, "psychiatric disease", divorce ("She refused to sleep with me any longer"), auto accidents (infamous, "I fell asleep with no warning" or "I blacked out": Arch. Int. Med. 151: 1451, 1991; NEJM 340: 847, 1999), "near-miss SIDS", sudden "cardiac" death, snooze angina (Lancet 345: 1085, 1995), hypertension (Br. Med. J. 320: 479, 2000, lots more), etc.

* It is doubtful that sleep apnea takes many years off life expectancy, but it does have a very negative impact on quality of life (Chest 94: 531, 1988). Neglected, it exacerbates the common cardiovascular diseases (JAMA 290: 1906, 2003). Occasionally it does kill people (Chest 94: 9, 1988), and is now being "linked to dementia" (Chest 95: 279, 1989).

Most cases seem to involve subtle abnormalities of throat anatomy and mechanics: Lancet 337: 597, 1991 (*  more type IIa muscle fibers in these people's throats), as well as problems with the reflexes which keep the throat open (Am. Rev. Resp. Dis. 143: 810, 1991).

* A higher-than-expected percentage also have lung damage from smoking, making the clinical picture more complex.

The hypoxemia, hypercarbia, and/or straining against a closed upper airway may produce deadly cardiac arrhythmias ("fatal heart attack while sleeping", maybe even "SIDS"). However, the large majority of people with sleep apnea do die while awake (Chest 94: 531, 1988).

For documentation, call the sleep lab and have them do polysomnography on your patient (*  $1200).

Treatments:

Have the patient sleep on one side, so the uvula flops out of the way (South. Med. J. 79: 1061, 1986). If you like, duct-tape a tennis ball to the back of his neck.

The drug protriptyline helps the brain maintain a patent airway.

Uvulopalatopharyngoplasty (an operation) and/or tonsillectomy is moderately useful.

* Missionary physician-hero Dr. David Livingstone ("I presume?") cured himself of sleep apnea by cutting off his own uvula while in Africa.

Machines that provide continuous positive airway pressure work wonders for most victims ($1000) -- Am. Rev. Resp. Dis. 137: 1238, 1988.

Tracheostomy is the last resort but cures sleep apnea. * Mini-tracheostomy for this disorder: Thorax 44: 224, 1989.

Pickwickian syndrome: severe sleep apnea resulting in loss of hypercarbic drive (sleep-apnea's blue bloater). Patients are very obese. I have wondered whether these patients have already suffered some brain damage from the hypoxic episodes, and hence overeat. * The name comes from Joe, the sleepy fat boy in Charles Dickens's "Pickwick Papers".

Central sleep apnea is like obstructive sleep apnea, except that victims do not snore or struggle.

It is probably the same disease as obstructive sleep apnea, except that the struggle to breathe is delayed.

In others (notably some folks with CHF), one might breathe super-hard after a brief rise in P_aCO₂, and stop breathing for a while after it's (over)corrected (NEJM 341: 949, 1999).

Patients complain of daytime somnolence, etc., but are easier to sleep with. * Treatment with CPAP reportedly works well, though it's hard to explain why.

* We used to "call respiratory arrests" and do CPR on these patients ("saved lots of lives").

The ondine's curse or central [alveolar] hypoventilation is a serious situation in which there is diminished respiratory drive from the brain. You'll learn about this in the ICU. There is a genetic form (* homeobox mutation, Nat. Genet. 33: 440 & 459, 2003).

* Cheyne-Stokes respiration can be normal variant. Do not confuse it with central sleep apnea or death.

Systemic high blood pressure and sleep apnea: Long-known, now well-demonstrated, but nobody knows why it happens. NEJM 342: 1378, 2000.

* I predicted in these notes in the 1980's that "Gaisbock's primary idiopathic polycythemia" (long-noted to be a disease of heavy, middle-aged men) would prove to be due to sleep apnea. Anyway, this diagnosis is almost never made any more, and sleep apnea is now a well-recognized cause of polycythemia. So I think that's the explanation.

LUNG INFECTIONS

The airways of non-smokers are normally sterile below the vocal cords, but almost any organism capable of causing disease has caused pneumonia, infection of the lung substance.

Smoker bronchi tend to contain a few H-flu and pneumococci.

Infections by the common bacteria most often cause exudation (edema fluid, then polys and maybe macrophages) into the alveolar spaces ("I'm coughing up icky stuff").

If the bacterial infection is confined to patches within individual lobes, it is called bronchopneumonia.

If the bacteria spread aggressively ("through the pores of Kohn"), stopping only for interlobar fissures, it is called lobar pneumonia.

Lobar pneumonia Gray hepatization KU Collection

Pneumonia Tom Demark's Site

Lobar Pneumonia Australian Pathology Museum High-tech gross photos

Pneumonia WebPath Photo

Middle lobe pneumonia This was nocardiosis WebPath

Nocardiosis Acid fast stain WebPath

Pneumonia, going chronic This was nocardiosis WebPath

Viral and mycoplasma infections most often cause mild edema confined to the interstitium, and infiltration of the interstitium by lymphs and macrophages ("I've got a dry, hacking cough").

TB, pneumocystis, and fungal pneumonias each have distinctive pathology.

Aspergillus Fungus ball in the making WebPath

Aspergillus Fungus ball in the making WebPath

Aspergillus Fungus ball WebPath

Aspergillus Fungus hyphae WebPath

Aspergillus Fungus hyphae WebPath

Coccidioides granuloma WebPath

Coccidioides Nice spherule WebPath

Aspergilloma Lung pathology series; follow the arrows Dr. Warnock's Collection

Aspergilloma Lung pathology series; follow the arrows Dr. Warnock's Collection

Chronic necrotizing aspergillosis Lung pathology series; follow the arrows Dr. Warnock's Collection

Chronic necrotizing aspergillosis Lung pathology series; follow the arrows Dr. Warnock's Collection

Aspergillus tracheobronchitis Lung pathology series Dr. Warnock's Collection

{11435} cryptococcal pneumonia

Cryptococcosis
Photo and mini-review
Brown U.

The terminology for all this is a little confused. Often "pneumonia" is used for inflammation in the alveolar air spaces, and "pneumonitis" is used for inflammation limited to the interstitium.

Lung infections are a common pathway out of life for people with disabling diseases of all sorts.

BRONCHOPNEUMONIA ("lobular pneumonia")

This patchy lung infection is ubiquitous in the hospital, and you will spend much of your time diagnosing and treating "pneumonia".

Why sick people get bronchopneumonia:

• Many of them don't cough and clear their lungs like they should because of medications, old age, physical weakness, pulmonary fibrosis, other disease, or whatever;
• Many of them have poor mucociliary elevator function from smoking, infection, other disease, or whatever;
• Many of them have poor alveolar macrophage function from smoking, oxygen therapy, alcoholism, or whatever;
• Pulmonary edema from whatever cause is a great culture medium;
• Glop in the lungs (cystic fibrosis, airway obstruction, "chronic bronchitis", etc., etc.) helps get the lungs infected.

The anatomic pathology is nodules of edematous to hemorrhagic-purulent, patchy infected areas in the lung substance. Often easy to see, they are always easier to feel, being distinctly firmer than normal lung. You can even hear that there is less air.

Microscopically, the lesion is polys and fibrin nets in the air spaces. There is seldom much fibrin. (Important exception: E. coli pneumonias are mostly interstitial.)

Bronchopneumonia used to be a common complication of measles and whooping cough. Secondary bronchopneumonia caused by staph was a major killer in the 1918 influenza pandemic.

Bronchopneumonia WebPath

Bronchopneumonia Inflated lung WebPath

Bronchopneumonia I From Chile In Spanish

Bronchopneumonia II From Chile In Spanish

Bronchopneumonia Formalin-inflated lung WebPath

Bronchopneumonia WebPath

Pneumonia WebPath

Pneumonia WebPath

Pneumonia WebPath

Necrotizing pneumonia WebPath

Necrotizing pneumonia WebPath

Necrotizing bacterial lung infection WebPath

Bronchopneumonia
Photo and mini-review
Brown U.

{10148} bronchopneumonia (patchy)
{49076} bronchopneumonia

Though common, bronchopneumonia is an opportunistic infection, and patients are already sick with something that allows bacteria to gain a foothold.

Many people with bronchopneumonia have deficient gag and/or cough reflexes, from old age, anesthesia, drugs, pain, wasting diseases, paralysis.

If the cilia are not functioning (hereditary dyskinesis, squamous metaplasia, cigaret smoking, gas exposure, viral chest cold), it is hard to clear bacteria.

Alcohol and tobacco are noted for interfering with the ability of the alveolar macrophages to kill bacteria, and even oxygen therapy is supposed to be able to do this.

When secretions pool in the chest (bad chronic bronchitis, cystic fibrosis, or behind an obstructing cancer), bacteria have a great place to grow.

Edema fluid is a good culture medium, and it is common for a single clinical episode of bronchopneumonia to be series of infections by different organisms. It may begin as a pneumococcal infection, which is replaced by a H. 'flu infection, which is replaced by a klebsiella infection, which is replaced by a serratia infection. This probably explains most "antibiotic failures".

Aspiration pneumonia follows aspiration of gastric contents (or sometimes just food; in the newborn it can be meconium). Chemical injury plus mixed bacteria (from the mouth -- worst is a mouth is full of rotten teeth) cause a fulminant disease.

Aspiration Foreign body reaction WebPath

Aspiration pneumonia Lung pathology series; follow the arrows Dr. Warnock's Collection

Actually most bronchopneumonia cases are caused by bugs aspirated from the mouth.

The large majority of aspiration pneumonias are on the right side, and most often the right upper lobe is involved (why?).

* Fears that the "back to sleep" campaign for SIDS prevention would result in an increase in deaths from aspiration have proved unfounded (Pediatrics 109: 661, 2002).

* If you perform pulmonary lavage on a child with lung disease, you may be given the "lipid-laden macrophage index". This has been promoted recently as a marker for chronic aspiration; I am more willing to believe that it's less specific and just as likely to be the result of some alveoli being chronically obstructed (Eur. Resp. J. 18: 790, 2001).

Special cases:

• Staphylococcus: Complicating influenza (depending on the staph, this may include toxic shock)
• Mixed flora in the unborn child: Chorioamnionitis (Am. J. Ob. Gyn. 185: 173, 2001)
• Streptococcus B: newborns
• Gram negative rods: nosocomial, or after GI tract surgery (remember that the meanest bugs are the ones that live in the hospital)
• Anaerobic pneumonia: alcoholics with bad (but still present) teeth

{12638} vicious case of staph pneumonia

Pneumonia
never mind the exotic bug...
Pittsburgh Illustrated Case

LOBAR PNEUMONIA

As noted above, this is an infection of an entire lobe produced by a virulent micro-organism.

By far the most common etiologic agent has always been Streptococcus pneumoniae ("pneumococcus", a gram-positive diplococcus called "captain of the men of death", "the old man's friend", etc.), which struck down healthy people in their prime (Chest 99: 2, 1991). But this organism is still easy to handle with antibiotics, epidemics have become rare, there's the vaccine, and few people die today of pneumococcal pneumonia.

{27689} pneumococci in sputum; gram stain

Pneumococcal pneumonia Sputum gram stain KU Collection

Pneumonia I
From Chile
In Spanish

Pneumonia II
From Chile
In Spanish

Klebsiella pneumoniae ("Friedlander's pneumonia", named by German pathologist Carl Friedlander whose relationship if any to your lecturer remains unknown) causes lobar pneumonia in deteriorated alcoholics. This gram-negative rod is coated by a thick slimy capsule, and victims cough up sticky slime ("cranberry sauce").

Abscessing pneumonia

WebPath Photo

* Staphylococcus (after influenza), H. 'flu, pseudomonas, and others are notable causes of lobar pneumonia in those with damaged lung defenses.

In the era when huge numbers of people died of pneumococcal pneumonia, the classical anatomic pathologists distinguished four successive stages of lobar pneumonia:

1. Hyperemia and edema: the bugs divide like crazy, and the blood vessels dilate and leak fluid in response to injury. "Congestion", given in traditional accounts of pneumonia, is an obvious misnomer.

2. Red hepatization: the inflammation progresses, and the damaged vessels now leak fibrinogen, which forms fibrin meshworks in the alveoli. Some red cells are released by damage to the blood vessels, and polys come in to fight the bacteria. The alveolar exudate becomes "rusty sputum".

3. Gray hepatization: fibrin dominates the picture, while polys and red cells break down ("gray" because hemorrhage is no longer taking place and the red cells have lysed)

4. Resolution: plasmin clears out the fibrin, and the lung returns to normal (hopefully).

COMPLICATION: The pleural surfaces overlying the infection are almost always involved, accounting for the pain of lobar pneumonia. There will be fibrinous adhesions, which may resolve or turn into scars.

COMPLICATION: In Klebsiella, staph, or pseudomonas lobar pneumonia, there is often necrosis and abscess formation, which greatly complicates healing. Necrosis is rare in pneumococcal pneumonia (exception: the slimy type 3). More on this below.

Lung Abscess From Chile In Spanish

Lung abscess WebPath

Lung abscesses WebPath

Lung abscesses
WebPath

{12641} staph producing abscess

COMPLICATION: If the infection gets really bad in the pleural space, it will fill with pus ("empyema") and this will need to be drained. (This was the most helpful thing that a doctor could do for pneumococcal pneumonia before penicillin.)

Suppurative pleuritis
Not quite empyema
WebPath

{49077} empyema

COMPLICATION: Sometimes the fibrin in the alveoli mostly organizes instead, leaving a scar.

{39530} organizing pneumonia; balls of fibrin in the alveoli

COMPLICATION: The bacteria often spread to other structures (pericardial sac, meninges)

Today, uncomplicated lobar pneumonias are easily treated with antibiotics once the etiologic agent is identified.

Lobar pneumonia WebPath

Lobar pneumonia WebPath

{11431} lobar pneumonia
{11732} lobar pneumonia
{11733} lobar pneumonia
{11734} streptococci in lobar pneumonia, gram stain
{12464} lobar pneumonia
{17565} lobar pneumonia
{17567} lobar pneumonia

LEGIONNAIRE'S DISEASE (legionellosis, "Pontiac fever", etc.)

This is a special form of bronchopneumonia named for a lethal outbreak at an American Legion convention at a hotel in Philadelphia.

The etiologic agent is Legionella pneumophila. You need special stains (immunostain or silver) to see it.

The organism is common in standing water, especially in air-conditioning systems.

Most healthy people merely experience a bad "chest cold", but in older people who drink and smoke heavily, it is likely to be fatal if untreated.

{08179} legionella demonstrated with a silver stain

NOTE: We are now recognizing that many cases of tough-to-treat community acquired pneumonias are due to CHLAMYDIA (Arch. Int. Med. 148: 1425, 1988), notably the TWAR strain ("Chlamydia pneumoniae", Chest 95: 664, 1989; NEJM 323: 1546, 1990). These infections have long been recognized in newborns, who acquire the more familiar sexually-transmitted pathogen from the birth canal. It's now a notorious, chronic, hard-to-eradicate infection of the airways (J. Inf. Dis. 182: 1678, 2000; Am. J. Resp. CCM 164: 536, 2001).

PNEUMOCYSTIS PNEUMONIA

This is a curious lung infection caused by a protozoan (?) organism, Pneumocystis carinii.

It was originally identified as the cause of plasma-cell pneumonia in malnourished children in Europe at the end of World War II.

It is now familiar as a cause of pneumonia in AIDS patients and people on cancer chemotherapy.

Instead of a plasma-cell pneumonia, these people show no visible cellular reaction to the infection. The organism and its cysts grow in the foamy exudate.

* As junior medical students, we used to go to the airport to pick up the pentamidine the CDC shipped in every time we suspected pneumocystis. It was the only thing that we knew worked.

If you spend any time on the oncology service, you will probably meet pneumocystis (i.e., you will develop antibodies), but it can't hurt you as long as your T-cells are working properly.

Future pathologists: You still need silver stains if you want to identify pneumocystis with confidence.

{0456} pneumocystis pneumonia

Pneumocystis carinii H&E, see the froth KU Collection

Pneumocystis
Lung pathology series, great photos
Dr. Warnock's Collection

Pneumocystis
Photo and mini-review
Brown U.

LUNG ABSCESS

Polys plus necrosis in a confined space (i.e., walled off by granulation tissue) within the lung. Mechanisms (after Baby Robbins):

1. Aspiration of bacteria (bad teeth, tonsils), as when drunk or unconscious.

2. Complication of necrotizing pneumonia (staph, klebsiella, pseudomonas, legionella) or bronchiectasis

3. Obstructed bronchus (as, behind a cancer)

4. Infection within a lung cancer itself

5. Septic pulmonary embolus (leg vein infection, endocarditis, and now an extremely common problem of IV drug abusers -- Chest 94: 251, 1988)

6. Infarction of a pre-existing infection (as when a pulmonary embolus hits an area of bronchopneumonia)

Anaerobic bacteria are often present, and aerobes may also be involved.

Sooner or later, the enlarging abscess ruptures into an airway. The patient gets a worse cough and bad breath, while the radiologist looks for air-fluid levels.

VIRAL AND MYCOPLASMAL PNEUMONIA ("primary atypical pneumonia", "chest cold", etc.)

A family of infections by micro-organisms smaller than familiar bacteria, all causing interstitial pneumonitis.

A while back, a group biopsied a bunch of folks with colds, and found what you'd expect -- inflammation, mostly lymphocytes, in the bronchial mucosa (Am. J. Resp. Crit. Care Med. 151: 879, 1995).

Viral lung infection
Lymphocytes
WebPath Photo

Many annoying chest-colds are caused by Mycoplasma pneumoniae (check blood for cold agglutinins).

Viral infection of the lungs can be seen in measles (major killer worldwide), influenza (all strains), chicken pox, adenovirus infection (look for "smudge cells"; this can cause serious pneumonia even in healthy people, Am. J. Med. Sci. 325: 285, 2003).

Respiratory syncytial virus, once considered merely the usual cause of "bronchiolitis" in toddlers, is now known to be prevalent and lethal among older adults.

* Interestingly, a vaccine was tried in the late 1960's and proved to make the disease worse instead of rendering the kids immune (J. Inf. Dis. 167: 553, 1993). Puzzle that one out.

Metapneumovirus, a cause of wheezing mostly in youngsters, was discovered in 2001 (Lancet 360: 1393, 2002; NEJM 350: 443 & 451, 2004).

Lethal influenza infection without staph superinfection presents diffuse alveolar damage and necrosis along the epithelium of the bronchi and bronchioles.

Herpes simplex can present as an ulcerative tracheobronchitis in moderately immunocompromised hosts. Alternatively, herpes simplex and herpes zoster can both present as miliary hemorrhagic areas in the lung parenchyma if immunosuppression is severe. Look for "herpes cells" with a single intranuclear inclusion surrounded by a clear halo. (*  In contrast to skin and cervix, these viruses seldom produce multinucleation in the lung.)

The nastiest infectious pneumonitis in the U.S. is the new hantavirus, from inhaled mouse droppings ("Navajo pneumonia"; anatomic pathology Am. J. Path. 146: 552, 1995; review NEJM 330: 949, 1994). The virus specifically damages the endothelial cells, producing an extreme pulmonary edema. Distinctive for this infection is an abundance of immunoblasts in lung and peripheral blood.

SARS is a coronavirus: NEJM 348: 1977 & 1995, 2003. The origin remains unknown; the original claim that it was a zoonosis from eating wild animals didn't work out (Science 301: 1031, 2003). The epidemic: Lancet 362: 1353, 2003. Thankfully only about 1000 people died (follow-up Nat. Med. 9(s): S-88, 2004). The pathology (Lancet 361: 1773, 2003; Am. J. Clin. Path. 121: 574, 2004; Hum. Path. 36: 303, 2005) features:

• coronaviruses reproducing in, and destroying, the type II pneumocytes, which look foamy and purple ...
• a preponderance of macrophages in the inflammatory infiltrate, and ...
• diffuse alveolar damage in persons dying later in the course of the illness

* The receptor for the virus in the lung is angiotensin converting enzyme-2 (Nat. Med. 11: 875, 2005).

* Nobody knows how many nasty chest-colds are really zoonotic Q-fever (Coxiella). Probably underdiagnosed. Pathologists look for "ring / donut granulomas". "Poker player's pneumonia", the scourge of one town, was Q-fever traced to a cat's placenta (NEJM 319: 354, 1988).

In most cases of viral pneumonitis that come to autopsy, the pathologist sees edema and inflammatory cells, and the process is confined to the interstitium.

The lungs are heavy but not airless (why?) The inflammatory infiltrate is mostly lymphs and macrophages.

In severe cases, an ARDS picture supervenes, with hyaline membranes.

* Lymphoid interstitial pneumonitis is a dense, polyclonal ("pseudolymphoma") infiltration of lymphocytes strictly confined to the pulmonary interstitium, usually in kids with AIDS or adults with Sjogren's. Don't confuse it with a virus. Some patients have a low-grade clonal lymphomas which look identical; it's a spectrum (Chest 122: 2150, 2002).

Respiratory syncytial virus Bad pneumonitis WebPath

Respiratory syncytial virus Syncytia WebPath

{38402} bad viral pneumonia; the lung is nearly solid from all the inflammatory stuff in the alveolar septa

Lymphocytic interstitial pneumonia Pittsburgh Pathology Cases

Most patients recover without treatment. The most worrisome thing about chest viruses for healthy adults is that they predispose the lung to bacterial superinfection.

You're already familiar with Kaposi's virus infection ("Kaposi's sarcoma") of the lung (Radiology 195: 545, 1995).

Kaposi's in the lung
Lung pathology series
Dr. Warnock's Collection

TUBERCULOSIS ("TB", "the white plague" -- covered twice in R&F).

Tuberculosis Autopsy lung KU Collection

Tuberculosis WebPath Photo

Pathology of TB WebPath Tutorial

You are already familiar with how TB causes tissue injury. (Click here for a review.)

Primary tuberculosis occurs when the TB bacillus first infects a person.

A single lesion (the Ghon focus) occurs just under the pleura in the midportion (midway between apex and base -- the best-ventilated area) of one lung.

Tuberculosis
Very large Ghon focus
WebPath Photo

The bacilli find their way to the regional lymph nodes, and in a few weeks, granulomas have walled off the bacilli in both locations. (The combination of lesions in the lung and node is called the Ghon complex). Viable bacilli remain in the Ghon focus/complex for life.

{08333} TB, lymph node
{08336} TB, lymph node

Much primary TB is asymptomatic, i.e., you discover you're turned your TB skin test.

Progressive primary tuberculosis is the name given to overwhelming primary infection, which is not so rare as we used to teach.

The classic dogma is that almost all progressive adult TB represents reactivation of a latent primary focus. I have never understood why people believed this, and it turns out that it's clearly not true: NEJM 330: 1697, 1703 & 1710, 1994 (at least in America's slums; confirmed NEJM 346: 1453, 2002; TB in immigrants does often seem to be reactivation). Only in 2002 did we get molecular proof that one patient's TB had reactivated: J. Inf. Dis. 185: 401, 2002. Primary or re-activated, the pathology of bad TB is that of classic "secondary tuberculosis"....

Secondary tuberculosis ("active TB", "postprimary tuberculosis", "adult tuberculosis", "reinfection tuberculosis", "cavitary tuberculosis") occurs when bacilli escape the original Ghon focus or more bacilli enter the body from outside.

{08459} cavitary TB
{10230} TB in the lung, good cavity
{21151} disseminated, miliary TB in liver

Miliary TB WebPath Photo

Miliary TB WebPath Photo

TB

WebPath Photo

Miliary TB See millet seed also! Dr. Warnock's Collection

Tuberculosis; white pneumonia Lung pathology series; follow the arrows Dr. Warnock's Collection

The bacilli may be released from the Ghon focus by invading cancer or "by immunosuppression" of some sort.

The infection usually reappears at the apex of one or both lungs ("Simon's foci" -- the TB bacilli actually entered the bloodstream, but grow best in the lung apex where oxygen is most abundant.) This is one cause of "white pneumonia" ("pneumonia alba"; the other is syphilis).

The better the patient's cell-mediated immunity, the more classic the granulomas.

In other words, the worst TB cases in America today have very few, if any, granulomas! For example, an AIDS patient can have lungs teeming with "red snappers" with only a sprinkling of macrophages trying to fight them. (This patient may not even be very sick, but his ability to transmit the infection is impressive.)

Polys are most abundant when the caseum has eroded into the large airways (why?). Also remember that TB tends to calcify (handy for radiologists who want to tell it from cancer).

{05949} TB eroding through the chest wall
{08187} TB, kidney
{08188} TB, lung
{08190} TB, lung
{08193} TB, lung

Arrested TB is secondary TB that has "calcified" and/or been largely replaced by collagen.

{11423} old TB

By contrast, progressive pulmonary tuberculosis spreads throughout the lungs and can produce a "tuberculous empyema" by involving the pleural cavities.

When a large portion of the lung has undergone caseous necrosis, extension into a large airway causes all the debris to be coughed up -- exactly what the TB bacillus "wants", since this is how it is transmitted to other people. The result is a cavity. (* Howler in R&F: "coin lesions" are lone granulomas, not cavities.)

TB is also prone to infect the larynx and larger airways ("tracheobronchial TB") and, because bacilli are swallowed, to affect the intestine (* look for Peyer's patches with ulcers having their long axes perpendicular to the long axis of the bowel).

Miliary TB results when many TB bacilli enter the bloodstream but the granulomatous response is good. It is supposedly named for millet seed (parakeet seed -- * would anyone prefer "milli-", meaning "thousands" of little granulomas?).

When TB ruptures into a pulmonary artery, there is miliary involvement of part of a lung, while rupture into a vein results in miliary involvement of the rest of the body.

* WHEN I HAVE FEARS When I have fears that I may cease to be Before my pen has gleaned my teeming brain, Before high-piled books, in charactery, Hold like rich garners the full-ripened grain; When I behold, upon the night's starred face, Huge cloudy symbols of a high romance, And think that I may never live to trace Their shadows, with the magic hand of chance; And when I feel, fair creature of an hour, That I shall never look upon thee more, Never have relish in the faery power Of unreflecting love! -- then on the shore Of the wide world I stand alone, and think Till Love and Fame to nothingness do sink. -- John Keats

*  Keats went to medical school for a year and was licensed as a physician and surgeon. He quit to devote his life to writing poetry. * In this sonnet, he shares his fear that he may die before had has time to get all his ideas into writing. * With his medical training, he had good reason to be afraid. A few days before he wrote the poem, he had experienced his first episode of hemoptysis. Three years later he was dead of tuberculosis.

TB granulomas

WebPath Photo

* Also good: Alexander Dumas Jr.'s Camille (TB is glamorous), Eugene O'Neill's Long Day's Journey Into Night (TB and drug addiction aren't glamorous), 1970's Italian film A Brief Vacation (TB as social-political-feminist problem). I didn't understand Thomas Mann's The Magic Mountain.

Reminder: In most chronic inflammatory diseases of lung, clubbing of the nails ("Hippocratic change") often develops because megakaryocytes embolize through the new vascular channels formed in the lungs.

Tuberculosis WebPath

Tuberculosis WebPath

Tuberculosis WebPath

TB How cavities form WebPath

TB Urbana Pathology

TB How cavities form WebPath

TB Ghon complex WebPath

TB Granulomas, not very good caseation WebPath

TB Granulomas, low power WebPath

TB Good caseation WebPath

TB granuloma Joke also WebPath

TB Acid fast bugs WebPath

Miliary TB Bad pneumonitis WebPath

TB Miliary WebPath

Pulmonary tuberculosis
Photo and mini-review
Brown U.

INTERSTITIAL RESTRICTIVE LUNG DISEASE ("stiff lung"; "fibrosing alveolitis"; "honeycomb lung")

Interstitial Lung Disease Notes on processing tissue; great photos Dr. Warnock's Collection

A generic term for longstanding inflammatory damage leading to fibrosis of the alveolar walls. Pulmonary compliance decreases, a mechanical barrier to oxygen exchange comes into existence ("diffusion barrier", "alveolar capillary block"), and pulmonary blood pressure goes up (leading to cor pulmonale and death).

It seems to reasonable to think, as "Big Robbins" does, that the initial stimulus to inflammation is the presence of an unknown antigen.

Fibrosis finally wipes out groups of alveoli. In most of these entities, the process is uneven throughout the pulmonary parenchyma, with some less-involved airways (especially respiratory bronchioles) stretched wide by scar contraction -- hence the radiographic and autopsy diagnosis of "honeycomb lung".

* The actual histopathology is very complex. There is always some inflammation. There may also be nodules of smooth muscle, vascular changes, etc., etc. In many cases, the honeycombing is worst just under the pleura. Elastin and proteoglycans also accumulate.

* Regardless of cause, most fibrosing lung diseases are worst in the lower lobes, where there is ordinarily less air and more vasculature. (Asbestosis, a pneumoconiosis, can be an exception -- why?)

Honeycomb Lung
Great gross photos
Dr. Warnock's Collection


* Clinicians hear distinctive dry "velcro crackles" in pulmonary fibrosis.

The known etiologies of diffuse pulmonary fibrosis:

Rheumatoid lung, scleroderma lung, and Sjogren's lung: secondary to autoimmune disease.

The histopathology in rheumatoid lung is widely variable: Chest 127: 2019, 2005.

Rheumatoid lung, capillaritis
Lung pathology series
Dr. Warnock's Collection


Asbestosis, berylliosis, hard metal (i.e., cobalt & maybe nickel), and rare cases of longstanding farmer's lung ("hypersensitivity pneumonitis": T-cell havoc Chest 104: 38, 1993): due to pneumoconiosis

Asbestosis
Photo and mini-review
Brown U.


Histiocytosis X ("Langerhans' cell histiocytosis" is a better name for this family)

Desquamative interstitial pneumonitis: ("DIP") in addition to fibrosis, the alveoli clog with lipid- and mucin-laden macrophages. Some cases supposedly turn into Hamman-Rich syndrome; the relationship is dubious (Thorax 52: 333, 1997). The response to steroids in this disease is generally good.

Nonspecific interstitial pneumonitis also responds well to glucocorticoids. It is distinguished from UIP/Hamman-Rich by the uniformity of the histologic changes, with all septa involved about equally, and no "honeycomb cysts". Chest 125: 522, 2004.

Desquamative interstitial pneumonitia
Lung pathology series
Dr. Warnock's Collection


Radiation lung, amiodarone lung, cytoxan lung, busulfan lung, bleomycin lung (Am. J. Path. 147: 352, 1995), and GVH disease lung: fibrosis due to cancer therapy

* Some people are super-sensitive to the fibrosing effects of bleomycin. This is now yielding up its secrets, thanks to a mouse model of bleomycin sensitivity with scrambled pulmonary interstitial matrix remodelling (Am. J. Path. 152: 821, 1998).

Paraquat ingestion -- patients who drink this herbicide die of rapidly-developing, severe fibrosis of the lungs.

Despite the selective indignation, nobody got sick from smoking marijuana sprayed with paraquat.

Sarcoid lung: see below

Polymyositis-dermatomyositis: Especially when antibodies against t-RNA synthetases (anti-Jo, etc.) are present.

Idiopathic pulmonary hemosiderosis: usually-mild, not-very-serious illness of young people with recurring microhemorrhages into the alveolar spaces

* Acute idiopathic pulmonary hemorrhage occurs in babies and can be fatal. It's presently being worked-out (MMWR 50: 494, June 15, 2001; Am. J. For. Med. Path. 22: 188, 2001. There was a flap about about a mold in the homes of these children as the cause of a supposed epidemic in Cleveland (Pediatrics 99: E5, 1997); I'm undecided.

* Angiosarcoma metastatic to the lung is a hard-to-diagnose cause of diffuse pulmonary hemorrhage: Arch. Path. Lab. Med. 125: 1562, 2001.

Wegener's you know. Pulmonary capillaritis has been described in anti-myeloperoxidase disease (Am. Rev. Resp. Dis. 146: 1326, 1993; the histopathology is the same as pulmonary Wegener's) and generally in systemic vasculitis (fibrinoid precedes neutrophils: Arch. Path. Lab. Med. 121: 144, 1997). Am. J. Clin. Path. 104: 7, 1995.

Wegener's granulomatosis Lung pathology series; follow the arrows Dr. Warnock's Collection

Wegener's granulomatosis Lung pathology series; follow the arrows Dr. Warnock's Collection

Wegener's granulomatosis Lung pathology series; follow the arrows Dr. Warnock's Collection

Wegener's granulomatosis Lung pathology series; follow the arrows Dr. Warnock's Collection

Wegener's with capillaritis Lung pathology series; follow the arrows Dr. Warnock's Collection

Busulfan lung Lung pathology series Dr. Warnock's Collection

Interstitial fibrosis is one component of ARDS and "bronchopulmonary dysplasia" (the latter follows oxygen treatment of neonatal RDS)

Diffuse pulmonary amyloidosis, part of the systemic disease in a few cases

Nodular amyloidosis
Lung pathology series; follow the arrows
Dr. Warnock's Collection


Lymphangioleiomyomatosis: a rare disease with marked proliferation of the smooth muscle throughout the lung. Patients are women in the childbearing years, and the mainstay of therapy is hormonal manipulation (Am. J. Med. Sci. 321: 17, 2001). This is indistinguishable from the lesions of tuberous sclerosis, and since these usually develop only in young female TS patients, probably they are the same disease.

Lymphanioleiomyomatosis
Lung pathology series
Dr. Warnock's Collection


Pulmonary lymphangiomyomatosis
Great photos
Pittsburgh Pathology Cases


Alveolar proteinosis: surfactant and proteinaceous goop fills the alveoli (same as in acute silicosis) -- listed here by "Robbins", but rarely includes fibrosis.

Patients have shortness of breath and may note that they cough up "white jello".

Most cases are idiopathic, and probably result from some loss of ability of the type II pneumocytes and/or alveolar macrophages to dispose of surfactant.

Infectious agents (notably mycobacteria, but a host of others have been mentioned) are often present; no one knows whether they interfere with surfactant processing and/or simply grow well in this culture medium.

* Certain amphophilic drugs can induce alveolar proteinosis, perhaps by interacting with the soapy surfactant itself.

* Mouse model Am. J. Path. 146: 1017, 1995.

There is a congenital form with surfactant protein B absent (NEJM 328: 406, 1993).

Regardless of cause, bronchial lavage is the mainstay of therapy.

Alveolar proteinosis from silicosis
Lung pathology series
Dr. Warnock's Collection


Amyloid and proteinosis
Lung pathology series
Dr. Warnock's Collection


Cases in which the etiology is totally obscure are called idiopathic pulmonary fibrosis / Hamman-Rich syndrome. See below.

* NOTE: The "Loeffler's" family of eosinophilic pneumonias seldom produce fibrosis.

Clinicians: "Restrictive lung disease" (sort of the opposite of "obstructive lung disease") exists when the airways are widely patent but there is a problem ventilating the lungs. ("Restrictive" and "obstructive" lung disease give contrasting patterns on spirometry. Other causes of "restrictive lung disease" include large pleural effusions or cancers in the pleural spaces, pneumothorax, chest wall and spinal column problems, lungs full of tumor, boa constrictor attack, metastatic calcification, massive obesity -- don't overlook this one Am. J. Med. 116: 58, 2004-- etc, etc.)

Farmer's lung Trust me WebPath

IDIOPATHIC PULMONARY FIBROSIS ("Hamman-Rich syndrome"; "cryptogenic (idiopathic) fibrosing alveolitis", "usual interstitial pneumonitis" and its kindred: CMAJ 171: 153, 2004)

Pulmonary fibrosis, most often occurring in middle-aged and older people, and progressing to death.

"Usual interstitial pneumonia", or "UIP" is the most common and most deadly of several different processes in which pulmonary fibrosis appears. It is recognized by uneven fibrosis of the alveolar septa themselves, with overlying cuboidalization of the epithelium.

The alveoli are thickened, though some areas are always spared. Focal areas of hyperplastic fibroblasts have overlying type II pneumocytes. Contraction of the fibrous tissue causes dilation of some of the air spaces ("honeycomb cysts"). The involved alveoli show obvious chronic inflammation, but no pathogenic micro-organism or other etiology has been forthcoming.

Part of the problem seems to be factors produced by malfunctioning alveolar macrophages and/or epithelial cells, notably platelet-derived growth factor (PDGF -- NEJM 317: 202, 1987; J. Clin. Invest. 86: 1055, 1992, interleukin 8 Am. Rev. Resp. Crit. Care 151: 1604, 1995), the proto-oncogene product which is the major factor that turns fibroblasts on in normal wound healing. There are reports of several others, but so far no common mechanism.

Survival times are improving, with as long as 5 years being relatively common.

Honeycomb lung Ed Uthman's Pathology Gallery

Fibrosing alveolitis Lung pathology series Dr. Warnock's Collection

Hamman-Rich WebPath

Hamman-Rich Trichrome WebPath

Honeycomb lung WebPath

Usual interstitial pneumonitis Lung pathology series Dr. Warnock's Collection

Restrictive Lung Disease Queen's U., Kingston Thanks Dr. Boag

{40688} Hamman-Rich, gross, remember scar is white
{40685} Hamman-Rich, histology, the alveoli are slits

Glucocorticoids are notoriously ineffective for UIP, though they work well for its clinical mimics (desquamative, lymphoid, and nonspecific interstitial pneumonias). So far, no other medication has been shown to improve survival for UIP.

* There's an accelerated form (?) called "acute interstitial pneumonia". It follows a cold, gets worse over days or weeks, involves only the lungs, and looks like ARDS under the microscope. It is evidently curable most of the time with glucocorticoids (Chest 124: 554, 2003).

SARCOIDOSIS ("sarcoid", "Boeck's sarcoid"; * "sarcoid" literally means "the fleshy disease"): "A multi-system disorder of unknown etiology characterized by formation of noncaseating granulomas" (Baby Robbins) in many organs of the body, with variable clinical course. Review Lancet 361: 1111, 2003.

Sarcoidosis might even be a reaction pattern rather than one disease.

Most sarcoid patients are young adults. In the US, women and blacks are more often affected, but no group is immune.

There is only a slight familial tendency.

The majority of people with sarcoidosis never become symptomatic. Those that do are likely to have:

• Fever, malaise (much of this is due to interleukin-1 production)
• Enlargement of the hilar lymph nodes (bilateral, very characteristic, seen on chest x-ray -- the nodes are packed with granulomas; "potato nodes")
• Palpable lymph nodes in many areas (biopsy the right scalene nodes)
• Inflammation of the walls of the alveoli ("interstitial alveolitis"). This progresses to fibrosis in bad cases, which causes most of the disability in sarcoidosis. Interleukin 1 probably mediates this, but the molecular biology is still being worked out.
• Abnormalities of the plasma proteins, especially an acute phase reaction plus a polyclonal hypergammaglobulinemia. This produces the famous "sarcoid steps" on serum protein electrophoresis:
• Hypercalcemia -- for some obscure reason, the alveolar macrophages of sarcoid patients synthesize calcitriol (1,25-(OH)₂-D₃, see Lancet 1: 1186, 1985). The resulting hypercalciuria is likely to cause kidney stones.
• Cutaneous anergy, a sign of defective cell-mediated immunity (patients have no response to intradermal antigens to which everybody is immune -- mumps, candida, athletes' foot fungus, etc., etc.) This happens despite markedly increased T4-cell activity in the sarcoid granulomas themselves.
• Elevated serum levels of angiotensin converting enzyme ("ACE" -- produced by the granuloma cells, helpful in making the diagnosis and monitoring the course of the disease -- Arch. Int. Med. 145: 677, 1985. (Other important causes of much-elevated ACE: Gaucher's disease and pneumocystosis; Chest 95: 803, 1989).
• Facial and/or auditory nerve palsies and/or a neuropathy (Lancet 359: 2085, 2002);
• Sicca syndrome (granulomas, not lymphocytes, destroy the parotid and lacrimal glands)
• Granulomatous uveitis (inflammation of the iris, ciliary apparatus, and/or choroid) which may progress to glaucoma and blindness
• Arthritis
• A characteristic rash (groups of granulomas in the dermis, "lupus pernio", not to be confused with systemic or discoid lupus)
• Erythema nodosum -- painful red bumps on the front of the legs, mysterious and nonspecific -- and an indicator of good prognosis

• Cardiac sarcoidosis is rare but lethal, when granulomas in the AV node cause 3rd-degree heart block and sudden death (CMAJ 136: 1064, 1987; Thorax 44: 371, 1989). Suspect it whenever a young person has heart block or * focal echo abnormalities of the ventricular wall (Br. Heart. J. 57: 256, 1987).

  * In one variant of cardiac sarcoidosis, the heart is massively involved, with minimal involvement of other organs (Br. Med. J. 292: 1095).

• Sarcoidosis of the nervous system: Granulomas and/or vasculitis. A great imitator. See Arch. Int. Med. 151: 1317, 1991.
• * Curious "sarcoid variants" in the lung, especially necrotizing granulomas around the airways

The "cause" of sarcoidosis continues to elude us.

* Mycobacteria, clay dust, and pine pollen have been suggested, but never demonstrated, as "antigens". More recently, interferon therapy has apparently caused "sarcoidosis": Cancer 59: 896, 1987, and it may appear in response to immune reconstitution in patients receiving HAART for HIV.

The immune disturbance seems central.

There are lots of T4-helper cells at sites of inflammation, very few in the circulating blood.

Further, the body's B-cells are hyperactive (polyclonal gammopathy) -- it seems likely they are getting bad advice from the T4-cells.

Lymph nodes draining a cancer occasionally exhibit a morphologic reaction identical to sarcoidosis (Cancer 68: 1845, 1991) that may stay around after the cancer is cured (Chest 98: 1300, 1990).

* Sarcoidosis is infamous for popping up in its victims' tattoos (Arch. Derm. 141: 869, 2005).

Sarcoid granulomas are sharply circumscribed, tend to occur adjacent to lymphatic vessels, usually do not caseate, and contain giant cells. (You may hear that foreign-body giant cells are most characteristic of sarcoidosis, but actually Langhans cells are just as common.)

Sarcoidosis Great discussion Rockford Case of the Month

Sarcoid Classic x-ray WebPath

{08756} sarcoid in the lung
{11417} sarcoid in a node, asteroid body
{11464} sarcoid, odd stain
{11774} sarcoid, lymph node
{12376} lupus pernio
{10976} sarcoid granuloma
{10979} sarcoid granuloma
{14427} sarcoid granuloma
{15474} brain sarcoid
{20220} sarcoid, lymph node
{23380} sarcoid, granulomas
{34913} sarcoid, lung
{35945} sarcoid, muscle
{38416} gross, sarcoid
{42030} sarcoid, marrow

* "Asteroid bodies" (probably wreckage from the cytoskeleton) and "Schaumann's conchoid bodies" (laminated calcium and iron, refractile) can turn up inside the giant cells, but have no diagnostic utility.

The diagnosis of sarcoidosis is usually made by finding noncaseating granulomas on biopsy of some organ, in the absence of infectious organisms, foreign body, or other explanation.

* Every writer on sarcoid seems to have a favorite organ to biopsy first. Right scalene node is standard, but you'll hear about biopsy of the lip (minor salivary gland), liver, bone marrow, and even fine-needle aspiration of the spleen, all in a search of noncaseating granulomas.

Serum angiotensin converting enzyme (ACE) is a useful adjunct test (elevated more often than not), to make the diagnosis and monitor disease activity.

* For following the course of severe disease, the gallium-67 lung scan seems to be preferred nowadays (over sed rate, lung function tests, ACE).

You'll hear about the Kveim test, which involves taking ground-up spleen from someone with sarcoidosis and injecting it into the dermis. If a granuloma forms, the living patient supposedly has sarcoidosis (80% sensitive, 95% specific). Long considered outdated, there is now a resurgence of interest in the material, especially among researchers who need to decide who really does and does not have the disease (Clin. Chest Med. 18:799, 1997; Mount Sinai Journal of Medicine 63:335, 1996; J, Imm. 154: 1450, 1995). To date, nobody knows what's in Kveim reagent, except that it's supposedly not bacteria: AJRCCM 159 1981, 1999.

Making the diagnosis is important, because immunosuppression using a few weeks on glucocorticoids is often helpful. Longer therapy is much more dubious; the side-effects of the drugs are noxious, and you're not going to clear up scar tissue.

* Thalidomide for sarcoidosis: Chest 122: 227, 2002. Also watch infliximab and pentoxifylline.

* Sarcoidosis is a common, lethal disease in horses. Oddly, amyloidosis almost never complicates sarcoidosis (Thorax 43: 422, 1988).

* Treatment of cutaneous sarcoidosis using tetracycline: Impressive. Is this really a bacterial disease after all? Arch. Derm. 137: 69, 2001.

* "Giant cell interstitial pneumonitis" is a recognizable reaction pattern almost always caused by inhalation of hard metal dust.

GOODPASTURE'S DISEASE: Antibodies against the basement membranes of lung and kidneys -- type II immune injury.

Pulmonary hemorrhage is seldom severe, but a few patients do exsanguinate or drown in blood. More about this under "Kidney" -- these patients die of renal involvement.

Not all of these patients have renal involvement clinically: Thorax 46: 68, 1991.

{24848} Goodpasture's, lung
{29104} Goodpasture's, lung, iron stain
{29581} Goodpasture's
{29584} Goodpasture's

Lupus and Goodpasture's
Lung pathology series
Dr. Warnock's Collection

Remember that intra-alveolar hemorrhage may not produce massive hemoptysis, and instead mimic pneumonia (why?) You can also see intra-alveolar pulmonary hemorrhage with lupus (Chest 118: 1083, 2000; Arch. Path. Lab. Med. 125: 475, 2001), small-vessel polyarteritis or cryoglobulin vasculitis, abciximab (anti-platelet antibody) therapy (Chest 120: 126, 2001), crack cocaine (don't miss this one, Doc: Chest 121: 1231, 2002) and so forth.

EOSINOPHILIC PNEUMONIAS ("Loeffler's", etc.)

A grab-bag of illnesses ("idiopathic", drug-related, and caused by worms) that feature many eosinophils in the blood and sputum and in the pulmonary alveolar walls. Patients usually have pulmonary infiltrates and increased eosinophils in the blood.

In the U.S., the disease is most often due to aspergillus colonizing the airways of an asthmatic. But there are many other causes, including ascaris worms migrating through the lungs, and plenty of "idiopathic" cases.

In "tropical eosinophilia", microfilaria worms are trapped in the lungs and break down, producing a similar syndrome.

* While we are on the subject of worms in the lungs, remember that dirofilariasis, the dog heartworm, is prone to die in human lungs and produce a "coin lesion" simulating lung cancer. I suspect this accounts for a few cases of "surgically cured squamous cell carcinoma of the lung."

Among drugs, the best-known offender is nitrofurantoin.

Some of these patients will have Loeffler's eosinophilic endocarditis.

* Churg-Strauss vasculitis may feature an "eosinophilic pneumonia" -- future pathologists, look hard for granulomas before making your diagnosis of "idiopathic Loeffler's" (Am. J. Clin. Path. 114: 767, 2000).

Do not confuse these with eosinophilic granuloma, a member of the "histiocytosis X" family of quasi-neoplastic proliferations of Langerhans histiocytes, seen mostly in older smokers.

Future pathologists: All forms of "histiocytosis X" feature "Birbeck tennis-racket granules" and the histiocytes of eosinophilic granuloma show "coffee bean nuclei". Since "eosinophilic granuloma" occurs just under the pleura, it's blamed for causing pneumothorax.

Histiocytosis X with Birbeck granules Lung pathology series Dr. Warnock's Collection

Eosinophilic granuloma Lung pathology series, follow the arrows Dr. Warnock's Collection

LIPID PNEUMONIA

{38464} lipid pneumonia

Exogenous lipid pneumonia: the lung's reaction to aspirated oil.

Causes include oily nose drops, mineral-oil laxatives, and forcing children to take cod-liver oil (the latter must have been an important killer of children, whose pitiful deaths were due to "pneumonia"). Don't give this stuff to your patients.

The more unsaturated the oil, the worse the inflammation. Mineral oil disease is usually mild. Polyunsaturated vegetable oils are worst.

The pathologist sees yellow patches grossly. The microscopic picture features lipid-laden macrophages and fibroblasts laying down scar tissue.

* "Fire eater's pneumonia" is actually due to aspiration of petroleum products, though it mimics an infection clinically (Chest 124: 398, 2003).

Endogenous lipid pneumonia ("golden pneumonia"): buildup of surfactant (in macrophages) behind an obstructed major airway (i.e., lung cancer) or many small airways ("bronchiolitis obliterans" family), or in amiodarone lung (interferes with surfactant processing: Chest 112: 1068, 1997).

Lipid pneumonia WebPath

Lipid pneumonia This was exogenous WebPath

Lipid pneumonia Endogenous, golden surfactant pneumonia WebPath

Lipid pneumonia Lung pathology series Dr. Warnock's Collection

Amiodarone lung
Lung pathology series
Dr. Warnock's Collection

* MISCELLANEOUS LESIONS

Bronchocentric granulomatosis: A reaction pattern, most often seen with infection by Aspergillus fungus, in which the bronchi break down into caseating granulomas.

A similar histologic pattern has been reported in "hot tub lung", in which immunocompetent people get an overwhelming infection with Mycobacterium avium complex (Am. J. Clin. Path. 115: 755, 2001; Arch. Int. Med. 163: 845, 2003).

The cystic adenomatoid lesion is a fortunately rare and dangerous hamartoma seen in infants.

Cystic adenomatoid malformation

Virtual Hospital


A bronchopulmonary sequestrum is a portion of lung tissue, inside or outside the healthy lung, with airways unconnected to the main bronchial tree, and therefore unaerated. It is prone to become infected, or to cause problems because of its mass.

Pulmonary interlobar sequestrum is a birth defect in which part of the lung is supplied by a branch of the aorta instead of by the pulmonary artery. This is only a problem later when it gets infected.

Several types of congenital cysts of the respiratory tree also occur and can cause problems (hemorrhage, infection, rupture, etc.) at any age.

Remember that most lung diseases will tend to be exacerbated by gastric reflux

Congenital lobar emphysema

Virtual Hospital

LUNG CANCER

Lung Cancer From Chile In Spanish

Lung Cancer Queen's U., Kingston Thanks Dr. Boag

The vast majority of primary malignant neoplasms of the lungs are some form of BRONCHOGENIC CARCINOMA. Easy review Lancet 355: 479, 2000.

In 2005, the US had around 184,800 new cases of bronchogenic carcinoma (102,420 men, 82,380 women) -- CA, in loc. There were around 168,140 deaths.

Bronchogenic carcinoma is the leading cancer killer of US men, although age-adjusted rates have been dropping for men since 1980 (NEJM 321: 1197, 1989), and the total absolute number is now decreasing; the total percent of people dying of lung cancer is way down.

It surpassed breast cancer as the leading cancer killer of women in 1985. The rates in women have just started to drop (2004).

Most lung cancers are silent until they've become inoperable. Those lucky patients whose cancers are of operable subtype and are detected very early have a reasonably good prognosis (maybe 60% long survival with stage I, 40% stage II: Ann. Thorac. Surg. 60: 466, 1995).

Bronchogenic carcinoma is a disease of older people, and is unusual under age 30. The incidence increases with age and "pack-years smoked".

Lung cancer exhibits Nowell's law in action, with mutations in the surrounding "normal" epithelium. Prognosticating lung cancer using genetic markers has been underway since the mid-1990's, and centers now look at around 100 genes (Am. J. Resp. CCM. 170: 167, 2004); clinical decisions are not yet based on the genetic profile, but probably will be within a decade.

Risk factors are well-established (Chest 103-S1: 20-S, 1993)

Cigaret and cigar smoking: This is the overriding risk factor.

The danger is proportional to the amount of smoke inhaled every day and the duration of smoking, and is measured in "pack-years." After ten pack-years the increased risk is measurable, and after fifteen pack-years, there is clear-and-present danger. After quitting, the risk decreases slowly and approaches normal after ten or fifteen years. (Cigar smokers inhale less smoke overall than cigaret smokers, but contrary to what you may hear, their risk for lung cancer is still greatly increased.)

"Passive smoking" seems to be of some importance, but much less than active smoking (Am. J. Pub. Health 82: 1525, 1992). Pipe smoking and tobacco chewing are much less risky than cigaret smoking, at least as far as the lungs are concerned.

The other risk factors are synergistic (i.e., more than just additive) with cigaret smoking.

* By the way, former smokers filling out research forms will often say they never smoked. Remember this when you're evaluating research articles (Chest 101: 19, 1992).

Radiation: uranium miners (powerful effect, all histologies Cancer 89: 2613, 2000), atomic bomb survivors, after radiation therapy (mild effect; Cancer 71: 3054, 1993), radon in homes ("if you say so....": NEJM 330: 159, 1994.)

* During the 1980's and early 1990's, there was a hoopla over radon from the ground building up in our energy-efficient homes. The claim, advanced by the Environmental Protection Agency, was that it caused 5-20 thousand lung cancers yearly, multiplicative with tobacco smoking. Was it just junk science? I wasn't the only one to say so... Lancet 337: 1329, 1991; Arch. Int. Med. 151: 674, 1991 (AMA council report). It does seem possible that smokers are at increased risk if there's radon in their homes. Most of the epidemiologic studies have come back negative, one controversial study found a negative correlation (as if radon protected you: Health Phys. 72: 623, 1997), the last big paper to find a link was Am. J. Pub. Health 89: 1042, 1999 and even the authors admit it's really weak, and even Br. J. Cancer 84: 134, 2001, which did a study of radon and lung-cancer in nonsmoking men, couldn't quite get a statistically significant correlation. There seems to be agreement that non-smokers aren't at serious risk, and that smokers can protect themselves much less expensively by stopping smoking (Am. J. Pub. Health 88: 811, 1998).

As you would expect, the nucleic acid damage from radiation is more random than in tobacco smokers. See Lancet 339: 576, 1992.

Asbestos inhalation: Notorious cause of lung cancer. More than half of asbestos workers who smoke have died of lung cancer (more: Br. Med. J. 306: 1503, 1993).

Certain metal dusts (nickel, silver, chromate ion as in dyestuffs)

Coal tar fumes, carbon black (Lancet 358: 562, 2001) and other chemicals (*  notably vinyl chloride, chloromethyl ethers) Occupational lung cancer: Mayo Clin. Proc. 68: 183. 1993.

Urban pollution: a minor risk factor compared with the others, with which it may be synergistic (JAMA 287: 1132, 2002)

* In one study which generated a hoopla, the investigators failed to take into account the fact that people living near the steel mill smoked much, much more than did their rural counterparts. When somebody noticed this, the "cancer risk" from the steel mill disappeared (Arch. Env. Health 48: 184, 1993).

In the poor nations, living in a coal-heated dwelling that's not ventilated clearly causes a great deal of lung cancer (Lancet 362: 849, 2003; JNCI 94: 826, 2002).

* I think that silica / sand exposure, made "official" in 1997 by the International Agency for Research on Cancer, is a crock. The numbers are very soft and there's no credible mechanism. See Am. J. Epidemiol. 153: 695, 2001.

* Pigeon keeping: Possible promoter, but not a mega-risk factor (Br. Med. J. 305: 986 & 989, 1992). A 1992 flap about keeping a canary or parakeet being a risk factor for lung cancer was laid to rest by a bunch of negative studies (Br. Med. J. 313: 1218, 1996).

* Right there is a hoopla about carotenoids (there are at least five kinds) as protecting people (smokers, non-smokers) from lung cancer. Given that a high level of blood carotenoids strongly suggests an overall healthy-lifestyle, and that today's "pop wisdom" is that vegetables protect from cancer, it's hard to do reliable studies. Protection by dietary carotenoids: Am. J. Clin. Nutr. 72: 990, 2000; Am. J. Ep. 156: 536, 2002 (about a whopping 15%, and based on self-reports); no protection Canc. Causes Contr. 13: 231, 2002; more confusion Br. J. Cancer 84: 728, 2001 (something's going on but it can't all be the tomato sauce).

NOTE: We know who is at risk. The traditional wisdom is that screening (routine x-rays, exfoliative cytology) is a waste of time and money (Ann. Int. Med. 111: 232 & 239, 1989). With today's improved low-radiation scanning, we may be putting all smokers into the machine yearly: Cancer 89(S-11): 2474, 2000, curing 60-80% of the early cancers we find.

Classification scheme:

The classification was updated in 1999, but most bronchogenic carcinomas still get assigned to one of the four light-microscopic categories of the old WHO classification (1967):

Tumor Type "Features" (find one....)

Squamous Cell...keratin, squamous pearls, "bridges" (desmosomes); EM: tonofilaments, diffuse keratin; IP: high MW keratin

* Subtypes ("glycogen-loaded sugar-tumor", "adenosquamous with a little bit of mucin production". "polypoid sticking-up rather than invading much") exist but don't matter much.

Adenocarcinoma... glands, papillae, mucin; EM: microvilli, secretory granules, gland formation; IP: low MW keratin, CEA

The new WHO 1999 classification rightly places bronchioloalveolar cell carcinoma in its own category.

* Other adenocarcinoma subtypes exist and except as noted below are of no known significance.

Large Cell Undifferentiated... none of the above, plenty of cytoplasm

Small Cell Undifferentiated... "small blue cells" (i.e., very little cytoplasm to stain pink); EM: "neurosecretory" (dense-core, APUD) granules, fine chromatin, little cytoplasm; IP: neuron-specific enolase, bombesin

These categories (especially the first three--"squamous", "adeno", and "large cell undifferentiated") are difficult to distinguish unless the tumor is very well-differentiated. (*  The new WHO system ignores tiny areas with "squamous" or "adeno" features taking up less than 10% of a resected tumor; so the number of "large cell undifferentiated" tumors will increase). The treatment (surgery, palliative radiation, maybe some chemotherapy) and prognosis (bad) are the same anyway.

"Subtypes exist, of course" but making the distinctions is not all that useful. Reported relative frequencies vary widely. For this course, remember that bronchogenic carcinomas of all four types are about equally common. Adenocarcinoma the most common if you are asked on somebody's exam (won't be mine). Squamous cell carcinoma used to be easily the commonest, now it's probably a close race between adenocarcinoma (listed as "most common" in a few recent reviews; "because smoke from filtered cigarets goes deeper into the lungs") and small-cell ("increasing in frequency").

The trend still seems to be "men get more squamous cells, women get more adenocarcinomas" (Cancer 69: 86, 1992; Cancer 103: 2566, 2005; we may suppose us very macho men cannot inhale our non-filtered cigs as deeply as the ladies inhale their filtered cigs).

* Or maybe filtered cigs produce smaller particles that get farther in the lungs. Cancer 77: 1278, 1996.

EM and immunohistochemistry have further complicated things.

Clinicians consider it most important that the pathologist distinguish small cell undifferentiated carcinoma ("small cell" carcinoma) from the others.

"Small cell" carcinoma is not a surgical disease, and usually had a nice initial response to chemotherapy. See below.

The other types are treated surgically if feasible, radiated ("spot-welded") as needed, and seldom respond well to chemotherapy. My own favorite article from 1998 was BMJ 317: 771, 1998: People who had been given chemotherapy for advanced non-oat-cell carcinoma of the lung would NOT have accepted it if they'd been told the truth beforehand. And a comparison of four expensive, horrific protocols which showed that none gave better than 20% transient responses ended with the frank admission that it's not right to do this (NEJM 346: 92, 2002).

* Adjuvant chemotherapy after surgery does seem to help some (NEJM 350: 353, 2004).

* Managed-care comes to the pathology lab. Appropriate handling of lung cancer specimens: Arch. Path. Lab. Med. 119: 695, 1995.

Lung cancer Large hilar tumor, emphysematous lung KU Collection

SQUAMOUS CELL CARCINOMA ("Epidermoid carcinoma")

Squamous Lung Cancer From Chile In Spanish

Squamous Cell Lung Cancer Australian Pathology Museum High-tech gross photos

Squamous cell carcinoma Lung pathology series Dr. Warnock's Collection

Squamous Lung Cancer Photo and mini-review Brown U.

Squamous cell carcinoma Big central lesion WebPath

Squamous cell carcinoma Big central lesion WebPath

Squamous cell carcinoma Big central lesion WebPath

Squamous cell carcinoma WebPath

Squamous cell carcinoma Nice desmosome prickles WebPath

Squamous cell carcinoma Nice squamous pearl WebPath

{17520} squamous cell carcinoma of lung, large mass at hilum
{20994} squamous cell carcinoma of lung, find the cavity
{20996} squamous cell carcinoma of lung, gross
{17525} squamous cell carcinoma of lung, poorly differentiated
{15401} tonofilaments
{15402} desmosome

Tobacco smoking is the major risk factor (90-99%, estimates vary).

Tumors arise anywhere in the bronchi, often near hilum. Large squamous cell carcinomas tend to cavitate. Often hemorrhage into the cavity and out the mouth is the final event (exsanguination, drowning in blood).

Generally the pathologist can find squamous metaplasia and dysplasia (and even carcinoma in situ) in the bronchi surrounding a squamous carcinoma. ("Nowell's law" triumphant.)

Squamous cell carcinomas very commonly produce a parathyroid-hormone-like substance that may cause elevated serum calcium even in the absence of bone metastases -- "humoral hypercalcemia of malignancy". (Production of other ectopic hormones is unusual.)

The protein is PTHrP, parathormone-related peptide, required for proper development of teeth and bones (Proc. Nat. Acad. Sci. 95: 11846, 1998).

The epidermal growth factor receptor, coded by the erbB proto-oncogene, is much over-expressed in this particular cancer (Nature 307: 521, 1984), but adenocarcinomas and large-cell-undifferentiated carcinomas will also stain some for this. Oat-cell is usually negative, and this is another helpful distinction.

Big news: Gefitinib, a pill which inhibits epidermal growth factor receptor, for chemotherapy-resistant non-oat-cell lung cancers that bear the mutation: JAMA 290: 2149, 2003; Science 304: 1497, 2004; NEJM 350: 2129, 2004. Responses have been dramatic but sadly there are probably no cures. Eventually, a further mutation of the gene results in resistance (NEJM 352: 786, 2005).

If the tumor is found when small, and is well-differentiated, the surgical cure rate is reasonably good. Squamous differentiation still remains an independent "good" prognositic sign in a bad disease: Ann. Thor. Surg. 77: 1173, 2004.

* Spontaneous regression of this dread cancer is very rare but happens: Chest 94: 701, 1988.

ADENOCARCINOMA

Adenocarcinoma From Chile In Spanish

Adenocarcinoma of the lung was once thought not to be related to tobacco smoking (Acta Path. Microbiol. Scand. S-157: 1, 1962.) Nowadays 75-90% of these patients in recent studies have been smokers.

Given similar risk factors, women supposedly get more adenocarcinomas and men get more of the other types.

Most adenocarcinomas arise in the periphery beneath the pleura.

Adenocarcinoma This was a scar cancer Tom Demark's Site

Adenocarcinoma Lung pathology series; follow the arrows Dr. Warnock's Collection

Adenocarcinoma Peripheral cancer WebPath

Healthy lungs Freshly-opened at autopsy WebPath

Adenocarcinoma
Photo and mini-review
Brown U.

{20997} peripheral adenocarcinoma

Adenocarcinomas have been said to arise in scars in the lung, including old TB, old infarcts, and physical wounds. These are called "Yokoo tumors", and Dr. Yokoo taught me in residency. I used to think that the the cancer produces the fibrosis, but I've seen several adenocarcinomas at autopsy in non-smokers and these have always been in the setting of scars of known etiology.

The histology correlates with the prognosis for small tumors (Cancer 61: 2083, 1988), while large tumors are very lethal.

Surfactant apoprotein stain is now available and should be handy in telling this tumor from metastatic disease. Other special stains: Am. J. Clin. Path. 92: 150, 1990.

Oddly, about 20% of lung adenocarcinomas arise multicentrically (Chest 95: 151, 1989).

* Molecular biologists again: Mutational activation of the K-ras proto-oncogene (at "hot spot" 12) is involved in many smoking- and occasional non-smoking-related adenocarcinomas, in contrast to other lung cancers.

About 10% (figures vary) of adenocarcinomas are of the BRONCHIOLO-ALVEOLAR CARCINOMA subtype, considered to include cancers of the bronchial goblet cells ("mucin-positive") as well as type II pneumocytes and Clara cells ("mucin-negative"; includes the "sclerosing" sub-subtype).

These malignant cells grow along the alveolar septal framework and (if "mucin positive") secrete mucus into the alveoli, producing "consolidation." This cancer does not invade, but kills by growing as a single layer of thick cells covering over the respiratory membranes.

This type of cancer is getting to be more common (Cancer 68: 1973, 1991). WHO-1999 separates it from other adenocarcinomas. Before 1980 it was thought to be non-cigaret-related; newer studies show a relationship (but less than any of the four "major" types.

* Pathologists distinguish primary bronchioloalveolar cell carcinomas from metastatic colon cancer (which can look identical) because only the latter stains for the villin antigen; this is not 100%. New technique: Cdx2 stain usually does not stain bronchiolo-alveolar carcinomas, but usually does stain colon metastases (Am. J. Clin. Path. 122: 421, 2004). Beyond this, bronchioloalveolar carciomas are a genetically and immunologically heterogeneous lot: Arch. Path. Lab. Med. 128: 406, 2004.

* Future pathologists: the term for this pattern of growth along a surface without invasion is "lepidic".

Bronchioloalveolar carcinoma Freshly-opened at autopsy WebPath

Bronchioloalveolar carcinoma WebPath

Atypical adenomatous hyperplasia Forme fruste of bronchioloalveolar cell carcinoma?

Bronchioloalveolar cell carcinoma, great case Lung pathology series; follow the arrows Dr. Warnock's Collection

Bronchioloalveolar cell carcinoma
Various cell types can give rise to it
Dr. Warnock's Collection

{11454} bronchiolo-alveolar carcinoma; very small cells growing along the alveolar septa
{12608} bronchiolo-alveolar carcinoma; the lung is solidified by mucus in the alveoli

The tumor is slow-growing but very lethal unless it's a small resectable lesion (Ann. Thor. Surg. 71: 971, 2001). A few may be benign, but no one knows how to recognize these.

* Jaagziekte, an infectious disease of South African & other sheep, resembles this tumor histologically and clinically, but there is no good evidence of transmissibility in humans.

* Cigaret-smoking beagles, an animal model for human lung cancer, get mostly bronchioloalveolar carcinoma, and so do scleroderma patients (Arch. Pathol. Lab. Med. 108: 7, 1984.)

* Future pathologists only: Here's a popular system for subdividing the small (2 cm or less) adenocarcinomas that you will get as surgical specimens (Cancer 75 2844, 1995):
• Type A: Localized bronchioloalveolar carcinoma (claras, type II's, or goblet cells), no or minimal scarring, enough atypia to qualify as cancer; expect surgery to be curative


• Type B: As type A, but with foci of alveolar structural collapse / scar contracting; still expect surgery to be curative


• Type C: As type B, but with active fibroblasts; surgery cures about 75%


• Type D: Poorly-differentiated adenocarcinoma, but with a sharp border; about 50% surgical cures


• Type E: Tubular adenomacarcinoma (fron the bronchial glands; looks like salivary gland cancer), acini, tubules, and/or back-to-back glands, sharp border


• Type F: Papillary, expansile growth; not enough cases to prognosticate

LARGE CELL UNDIFFERENTIATED CARCINOMA ("hundred-day cancer")

Oat Cell / Large Cell Anaplastic From Chile In Spanish

Most are related to tobacco smoking (90-99%, estimates vary.) These tumors arise anywhere in lungs. Cures are rare, and death comes quickly.

Large cell and adenocarcinomas
Lung pathology series
Dr. Warnock's Collection

Obviously these tumors are mostly occupied with growth and invasion rather than looking like they did in health. There are no useful tumor markers (hPTH-like substance may be produced) or other clinical behaviors that really show this is a distinct entity.

SMALL-CELL UNDIFFERENTIATED CARCINOMA ("OAT CELL") (Lancet 345: 1285, 1995; treating it Chest 112(4S): 251-S, 1997.)

Oat cell carcinoma KU Collection

Oat cell carcinoma Looks like sushi WebPath

Oat cell carcinoma Follows the bronchi WebPath

Oat cell carcinoma WebPath

Oat cell CA with Azzopardi phenomenon Lung pathology series; follow the arrows Dr. Warnock's Collection

Bronchiolo-Alveolar Carcinoma High magnification KU Collection

Oat cell carcinoma Photo and mini-review Brown U.

Oat cell carcinoma Tom Demark's Site

{11428} oat cell carcinoma, spreading along the bronchi
{10475} oat cell carcinoma, growing down between the cartilage rings
{10435} oat cell carcinoma
{11693} oat cell carcinoma
{12578} oat cell carcinoma
{14076} oat cells, spinal fluid
{12581} oat cells in sputum
{38521} oat cell
{38527} oat cell
{09082} oat cell carcinoma, electron micrograph showing neurosecretory granules

The "cell of origin" is the Kulchitsky (APUD) cell of the bronchial epithelium.

Almost all (99+%) tumors are related to tobacco smoking (rarely, just uranium mining).

Small cell carcinomas arise anywhere in the lung, most often near the hilum, and quickly spread along bronchi.

This cancer is infamous for early and widespread metastases and rapid death of the patient. (Surgery is usually considered futile; a few heroes are trying it again, however.)

The tumor is composed of small (2x size of a lymphocyte) cells with very little cytoplasm ("small blue cells", "oat cells"), with many mitoses and usually a lot of necrosis.

EM shows oval nuclei, finely dispersed chromatin, scanty cytoplasm, usually a few neurosecretory (dense-core, APUD) granules, sometimes squamous and/or "adeno" features.

Future pathologists: The tumor cells stain positive for neuron-specific enolase (NSE) and bombesin/GRP.

Like the K-cells from which they derive, "small cell" carcinoma is also known for secreting a lot of different substances.

Among these are ACTH, hADH, neurophysin, neuron specific enolase, bombesin (and/or the closely-related gastrin-releasing peptide), * bradykinin, * calcitonin, * growth hormone (hGH), * histamine, * hLH, * lipotropin (finding this suggests that elevated ACTH is not of pituitary origin: J. Clin. Endo. Metab. 86: 2997, 2001), * oxytocin, * prolactin, * somatostatin, * several different enzymes, etc., etc. (Bombesin/GRP is the cancer's autocrine growth factor).

IMPORTANT: Of these, the ones most likely to be detected are hADH (hyponatremia / water intoxication) and ACTH (Cushing's syndrome). Each syndrome occurs in 5-10% of "small-cell" patients (and ectopic secretion of the hormone is much commoner); they are seldom very serious but help make the diagnosis.

PTH-like hormone secretion and hypercalcemia are not typical of small-cell tumor patients.

The molecular biology is small cell carcinoma was worked out in the early 1980's.

One of the first genetic signatures discovered in cancer is the deletion at 3p21 in oat cell carcinomas. Actually, some material is lost here in most lung cancers.

At least many small cell carcinomas have amplification (many extra copies) of exactly one member of the myc family of proto-oncogenes. This is more common in relapsed or super-aggressive small-cell carcinoma cases.

* Rb is mutated more often than not. There's a lot more known about the molecular genetics of oat cell and non-oat-cell lung cancers, but little has found clinical usefulness. The surrounding, morphologically normal epithelium bears many of the same mutations.

Oat cell's initial response to chemotherapy is usually very good. Most cases relapse and die, but occasional cures of the early disease are now being claimed (Chest 123: 259-s, 2003; two percent of all patients alive at 5 years Cancer 89: 523, 2000). Second primaries and chemotherapy-induced leukemias may still occur and kill the patient.

* Future pathologists: (1) On biopsy, it's often tough to tell crushed oat cells from crushed lymphocytes, especially if your biopsy instrument is dull. Most helpful is a common leukocyte antigen (Semin. Onc. 20: 153, 1993). (2) On fine needle aspiration, there is a tendency to mistake oat-cell carcinoma for non-oat-cell carcinoma. and carcinoids for oat-cell carcinoma. How not to make these errors: Arch. Path. Lab. Med. 129: 614 & 619, 2005.

PREINVASIVE LESIONS

The World Health Organization (J. Clin. Path. 54: 257, 2001) now recognizes three "in situ" lesions.
• Squamous dysplasia / carcinoma in situ, very familiar to pathologists, now has a grading system, probably not very useful
• * Atypical adenomatous hyperplasia could turn into adenocarcinoma; the dividing line with bronchioloalveolar carcinoma, which is by definition noninvasive, is unknown
• * Diffuse neuroendocrine cell hyperplasia is thankfully rare, and turns into multiple carcinoids
If there is carcinoma in situ at the resection margin, a stump recurrence is likely. If it's down in the glands, it's near-certain (Chest 128: 1736, 2005).

* Autofluorescence bronchoscopy is now in use to find the squamous in-situ lesions. A majority will turn invasive (Chest 117: 1572, 2000).

CLINICAL MANIFESTATIONS OF BRONCHOGENIC CARCINOMA

The onset is notoriously subtle. Patients present with cough, chest pain, shortness of breath, and/or (especially) weight loss. The disease is most often unresectable when the patient comes to the physician.

Extension of the tumor in and near the chest causes many problems:

• Superior vena caval obstruction (often small-cell carcinoma)
• Pain in the shoulder and arm (especially the ulnar nerve distribution) due to invasion of the brachial plexus ("Pancoast tumor" -- often small-cell carcinoma)
• Bronchial obstruction with hyperinflation, atelectasis, and obstructive pneumonia behind a protruding mass.
• Pleural effusions
• Recurrent laryngeal nerve involvement (result in hoarseness)
• Horner's sign (pupillary constriction, droopy eyelid, loss of sweating on surrounding skin; from invasion of the cervical sympathetic chain)

Metastatic disease:

It is very common for lung cancer to present as a brain tumor. Oat-cell is infamous for this, but any common type can do this.

{18764} brain "mets"

Bronchogenic carcinoma often involves the brain, bones, liver, adrenals (why?), kidneys, heart, pleura, and skin; no organ is immune.

{18774} adrenal "mets", this may well have produced adrenal insufficiency
{18778} bone "mets", this hurts

Extrapulmonary, nonmetastatic manifestations of bronchogenic carcinoma are frequently seen. They include:

• Cushing's syndrome (ACTH-producing small-cell tumor)
• Hyponatremia (hADH-producing small-cell tumor)
• Hypercalcemia (squamous-cell carcinoma, less often large-cell, not small-cell) -- this may be "humoral" or due to bone metastases
• Blindness (anti-retina antibodies from small-cell tumors) and dementia (especially with small-cell tumors, autoimmunity once again)
• Myasthenic syndrome (Eaton-Lambert syndrome from small-cell tumors, caused by autoantibodies against calcium channels in nerve cells, and other neurologic syndromes we will encounter in neuropathology.

  "Oat cell carcinoma causes autoantibodies against the nervous system because the cancer cells are of neural crest origin and the body is fighting them." This is probably mostly true.

  

• Clubbing of digits (*  when an x-ray shows extremely severe underlying bony changes it is called "hypertrophic pulmonary osteoarthropathy")
• Acanthosis nigricans, dermatomyositis, marantic thrombi on valves, thrombophlebitis, and other less-common paraneoplastic syndromes. All about the paraneoplastic syndromes in lung cancer: Mayo Clin. Proc. 68: 278, 1993.

* Preoperative staging of lung cancer has long been a challenge; watch for fluorodeoxyglucose PET scanning to become the mainstay (NEJM 343: 254, 2000; Radiology 212: 803, 1999). Nowadays around 40% of non-oat I-A tumors are apparently cured surgically.

BRONCHIAL CARCINOIDS

Most histologically low-grade lung carcinomas are typical carcinoids (Chest 119: 1647, 2001), from Kulchitsky cells.

The only known risk factor for these tumors is MEN-I. Tobacco smoking is not a risk factor.

Typical carcinoids are located in the large bronchi, exhibit a pushing border and are quite vascular (can hemorrhage after biopsy.)

Typical carcinoid by light microscopy (benign-appearing cuboidal cells in rows), immunoperoxidase (chromogranin-positive, neuron-specific-enolase positive), and electron microscopy (APUD granules).

Carcinoid syndrome is seldom produced by these lesions. Only about 10% metastasize, and even these tend to be indolent.

WHO-1999 distinguishes two other neuroendocrine (K-cell derived) lung cancers.

Atypical carcinoids stain for chromogranin but have anaplasia and mitotic figures and often necrosis; about half of these eventually metastasize and some cause death.

Intermediate neuroendocrine carcinomas are neuron-specific-enolase positive but can be chromogranin-negative, and have much larger cells than do classic oat-cell carcinomas. These are almost all fatal. It may not be worth distinguishing them from other large-cell carcinomas: Exp. Mol. Path. 70: 179 2001.

* Proposed reclassification of carcinoids of the lung: Am. J. Clin. Path. 116: S65, 2001. The truly hard-core pathologist can use a gene probe for chromogranin mRNA: Cancer 82: 468, 1998.

OTHER TUMORS

* Tumorlets ("chemodectomas"): little meningioma-like things that are probably hyperplastic chemoreceptor cells.

Tumorlets Lung pathology series Dr. Warnock's Collection

Tumorlet Lung pathology series Dr. Warnock's Collection

Carcinoid and oat cell
Lung pathology series
Dr. Warnock's Collection

* Alveolar adenoma is a benign, multicystic tumor of older women. The cell of origin is the surfactant-producing pneumocyte.

Lymphomas (including "lymphomatoid granulomatosis") are cancers, really-clonal (Am. J. Clin. Path. 103: 341, 1995). Pseudolymphomas (lymphoid hyperplasias -- "Arthur Godfrey's cancer") may turn into lymphomas in some cases. * Ask a hemato-pathologist about lymphomatoid granulomatosis.

Pulmonary hamartoma: A growing nodule of cartilage, with clefts lined by pneumocytes. Future radiologists: recognize the familiar calcified, popcorn-shaped mass. If the radiologist can't call it, then it must be removed for fear of missing a cancer.

Bronchial hamartoma Lung pathology series Dr. Warnock's Collection

Chondroid lung hamartoma WebPath Case of the Week

Hamartoma WebPath

Hamartoma Cartilage and epithelium WebPath

{38506} lung hamartoma, gross

* Pulmonary blastoma: A very rare, mixed epithelial and mesenchymal ("carcinosarcoma") cancer that resembles fetal lung. It occurs at any age, and there are no risk factors.

Metastases to the lung are common in many (if not most) carcinomas and sarcomas. * Taking out lung metastases of sarcoma has long been popular, and nowadays the statistics are quite good for long-term survival (Clin. Orth. Rel. Res. 310: 188, 1995).

Cancer metastatic to lungs "Cannonball metastases" KU Collection

Metastases to the lung WebPath	Metastases to the lung WebPath
Metastases to the lung WebPath

Pulmonary lymphatic carcinomatosis (misnomer: "lymphangitic spread"): Seen in disseminated malignancy. Tumor plugs the pulmonary lymphatics, leading to pulmonary edema and rapid death.

{21001} pulmonary lymphatic carcinomatosis (white strings)

Lymphatic carcinomatosis WebPath

Metastasis on the pleura WebPath

! ! ! ! !

UPPER AIRWAY, LARYNX AND TRACHEA

Larynx Exhibit Virtual Pathology Museum University of Connecticut

Nasopharyngeal teratoma WebPath Photo

Congenital anomalies: The most important is the various forms of tracheo-esophageal fistulas. The newborn chokes and turns blue while eating. Mild forms are easy to treat (*  celebrated in the original M*A*S*H). In the severe forms, the esophagus begins in a blind pouch, and all food ends up in the airways.

Sinusitis

The drainage outlets for some of the sinuses, including the maxillaries, are halfway up the walls, inviting pooling of secretions and hence bacterial infection.

Edema (allergy, infection) around the outlets of the sinuses sets up a vicious cycle, with non-drainage followed by bacterial infection followed by additional obstruction.

The most serious complication is infection of the cavernous sinus and nearby structures. Although sinus trouble is common, serious complications are rare.

Pansinusitis Exotic fungus Pittsburgh Pathology Cases

Frontal sinus cancer Pittsburgh Pathology Cases

Alveocapillary dysplasia Lung pathology series Dr. Warnock's Collection

Infections of the throat and larynx are common:

The common cold and viral laryngitis require no description.

Epiglottitis ("croup") usually results from infection with H. 'flu B. Airway obstruction is the major problem.

Laryngeal papillomatosis is a life-threatening infestation of the larynx with HPV (*  usually strain 1). This time, warts are no laughing matter.

Laryngeal papilloma
Lung pathology series
Dr. Warnock's Collection


Trauma most often results today from intubation (grisly article: Chest 96: 877, 1989). Forensic pathologists look for fractures of the hyoid bone in suspected strangling.

Throat Ed's Histology Notes

Tube pressure ulcers Larynx WebPath Photo

Foreign bodies in the trachea can cause sudden death, especially in toddlers and drunken adults. I've seen a peach section, a roll of ham, and a denture, and a friend lost his two-year-old daughter to a peanut (keep these and popcorn away from toddlers). The "cafe coronary" is usually due to poorly-chewed beef.

Laryngeal nodules ("Justin Timberlake's disease") are benign fibroepithelial polyps on the vocal cords of those who use their voices a lot -- drill sergeants, singers, teachers. They present as hoarseness and are easy to remove.

Angiofibromas
Student case
Galveston

Angiofibroma of the nasopharynx is usually a teenaged boy's tumor. This big white nuisance lesion is best left alone, since it bleeds copiously if biopsied.

Nasopharyngeal carcinoma, usually poorly-differentiated squamous, is rampant in China and seems to be caused by a combination of Epstein-Barr virus (herpes 4) and pickled fish and pickled vegetables. How herpes 4 transforms cells: NEJM 333: 693 & 742, 1995.

* Cancer of the trachea is rare and is usually adenoid cystic carcinoma or mucoepidermoid carcinoma, arising from tracheal glands that are homologous to salivary glands. (These can appear on the bronchi too.)

Mucoepidermoid carcinoma and adenoid cystic carcinoma
Lung pathology series
Dr. Warnock's Collection


Dysplasia of the laryngeal epithelium: Pre-cancerous, more or less aggressive depending on how mean it looks. Cancer 75: 457, 1995.

Metaplasia in a smoker's larynx.
Precedes dysplasia / cancer.
WebPath Photo

TB of the true vocal cords is transmissible by speaking, not just coughing.

Cancer of the larynx is very common, and is almost invariably a squamous cell carcinoma due to cigaret smoking. Ethanol abuse is also a risk factor; nobody knows why. There is usually some nearby carcinoma in situ.

Cancers confined to the true vocal cords (or the region just below them) are usually easy to cure using radiation, saving the voice. Cancers above the true vocal cords usually require laryngectomy.

{11696} laryngeal squamous cell carcinoma, supraglottic

Laryngeal cancer, fatal Ed Lulo's Pathology Gallery

Larynx cancer WebPath Case of the Week

* Subclassifying cancers of the larynx for wiser therapy: Ann. Ot. Rhin. Laryng. 104: 587, 1995.

Tracheobronchopathic osteochondroplastica
Hamartomas in the large airways, usually harmless
Dr. Warnock's Collection

PLEURAL DISEASES

"Devil's grip", or pleurodynia, is a complication of coxsackievirus infection in children who are obviously sick with an acute febrile illness.

Pleural effusion -- fluid in the pleural space -- is a ubiquitous problem in clinical medicine. (Future radiologists: Before you can see it on x-ray, there must be about 700 mL -- a lot of fluid).

Each side can actually hold about 4000 mL if the lung is completely collapsed. Effusions cause atelectasis and restrict lung movement, you can tap them for diagnostic or therapeutic purposes, you can prevent their buildup by sclerosing the pleural space, etc.

Transudates: congestive heart failure, nephrotic syndrome, cirrhosis. All other pleural effusions will probably be exudates.

Hydrothorax: pleural effusion that is a transudate or serous exudate.

Hemothorax: a pleural effusion that is blood

Hemothorax WebPath

Hemothorax Urbana Atlas of Pathology

Hemothorax
Urbana Atlas of Pathology


Pyothorax or empyema: a pleural effusion that is pus

Chylothorax, from injury to the thoracic duct

Chylothorax

WebPath


Pneumothorax: Air in the pleural space, i.e., the lung has collapsed.

This can result from a wound to the chest wall (why?), or from a tear in the visceral pleura. The latter can happen in healthy people ("spontaneous pneumothorax") or from tumor or injury (iatrogenic, pink puffer).

* Catamenial pneumothorax accompanies menstruation, usually in multiparous women. The remedy is to do pleurodesis with talc during the menstrual period.

Pneumothorax is most serious ("tension pneumothorax") if a valve-like flap on the visceral pleura lets air into the chest wall but not out.

Tension pneumothorax X-ray which should not have been obtained -- EMBBS

Pleural plaques of dense collagen are harmless but are a marker for asbestos exposure. They have nothing to do with smoking.

Benign mesothelioma is a pedunculated nubbin made of fibrous tissue. It has nothing to do with asbestos.

Malignant mesothelioma ("Steve McQueen's disease"): cancer of the pleural mesothelium

This extremely lethal cancer almost always results from asbestos exposure.

In most nations, this is industrial.

* Turkey has some asbestos-rich soils and in these regions, blown dust may explain the abundance of asbestos fibers in the lungs and the migh prevalence of mesotheliomas. See Env. Health Perspect. 108: 1047, 2000.

The usual picture is that of a biphasic tumor (why?); histologic subtyping into "epithelioid" and "sarcomatoid" variants is of no use in prognosticating survival (Thorax 44: 496, 1989). Distinguishing mesothelioma from look-alike cancers is difficult. Tips for future pathologists:

• Mesothelial cells and mesothelioma cells often show long "spaghetti" microvilli

Mesothelioma
Electron micrographs
VCU Pathology


• * Mesotheliomas are usually negative for CEA and some of the other popular adenocarcinoma markers.
• * Mesothelioma cells are reliably positive for keratin, even in the "spindle cell" areas. If the spindle-cell areas are negative, think of the uncommon non-asbestos-related "malignant fibrous tumor of mesothelium" if monophasic, metastatic synovial sarcoma if biphasic.
• Mesotheliomas express a lot of keratins of various molecular weights. Old claims that this enabled reliable distinction have not held up.
• There are still no reliable immunostains to distinguish mesothelioma either from adenocarcinoma or from benign mesothelium (Am. J. Clin. Path. 116: 253, 2001).

As a matter of fact, telling mesothelioma from reactive hyperplasia of the mesothelium can be difficult, in biopsies or effusions.

Pathologists can now tell it from metastatic disease most of the time by staining for keratins of various MW's -- a wide range are present in mesothelioma. Autopsy is still helpful in confirming the diagnosis.

Mesothelioma Lung pathology series Dr. Warnock's Collection

Mesothelioma Autopsy specimen KU Collection

Elongated microvilli Mesothelioma Photo from NEJM

Mesothelioma Information Group Resources and advocacy Also asbestosis and bronchogenic CA

Mesothelioma Good gross photo from Bioscience

Mesothelioma Good micro photo from Bioscience

Mesothelioma Network Informational site by lawyers Some pathology

Mesothelioma Immunoperoxidase and electron microscopy

Mesothelioma Good gross photo from some asbestos lawyers

Mesothelioma and asbestosis Nice photos from some asbestos lawyers

Radical mesothelioma resection Amazing photo by radical interventionists

Mesothelioma Autopsy photo Queen's, Canada

Mesothelioma Includes EM of spaghetti UCSF

Oddly, a few percent of mesotheliomas produce insulin-like molecules that cause hypoglycemia.

Treating mesothelioma: Chest 107(S6): 332-S, 1995. Don't get your hopes up for a cure.

* An ultra-inbred community in Turkey in which 50% of the villagers die of mesothelioma, with only a dubious link to environmental carcinogens: Lancet 357: 444, 2001.

Rule: The parietal pleura is very sensitive to pain, far more so than the lung or any but the largest airways. If chest pain accompanies respiratory movements, the cause is probably inflammation or irritation of the parietal pleura. You may have experienced the "stitch", caused by a wrinkle and relieved by super-inflating your lungs.

Mesothelioma WebPath

Mesothelioma WebPath

Asbestos WebPath

Asbestos WebPath

Asbestos, pleural plaques WebPath

Asbestos, pleural plaque WebPath

Mesothelioma Photo and mini-review Brown U.

{27597} mesothelioma, gross

CILIARY DYSKINESIA SYNDROMES (Am. J. Resp. CCM. 151: 1559, 1995).

Too big a topic for the end of "Respiratory", but includes Kartagener's (no dynein arms) and several others. Patients have:

• recurrent respiratory infections (sinusitis, pneumonia, bronchiectasis)

• infertility (almost always in men, sometimes in women; for the latter, see Chest 95: 578, 1989)

• situs inversus (50% of cases; why?)

We will be glad to help you make the diagnosis by electron microscopy.

A transgenic mouse with Kartagener's: Nature 354: 306, 1991.

*  *  * 

* The Fellowship of those who bear the Mark of Pain. Who are the members of this fellowship? Those who have learned by experience what physical pain and bodily anguish mean, belong together all the world over; they are united by a secret bond. Praise God! One and all they know the horrors of suffering to which man can be exposed, and one and all they know the longing to be free from pain. He who has been delivered from pain must not think he is now free again, and at liberty to take life up just as it was before, entirely forgetful of the past. He is now a "man whose eyes are open" with regard to pain and anguish, and he must help to overcome those two enemies (so far as human power can control them) and to bring to others the deliverance which he has himself enjoyed. The man who, with a doctor's help, has been pulled through a severe illness, must aid in providing a helper such as he had himself, for those who otherwise could not have one. He who has been saved by an operation from death or torturing pain, must do his part to make it possible for the kindly anaesthetic and the helpful knife to begin their work, where death and torturing pain still rule unhindered. The mother who owes to medical aid that the child still belongs to her, and not to the cold earth, must help, so that the poor mother who has never seen a doctor may be spared what she has been spared. Where a man's death agony might have been terrible, but could fortunately be made tolerable by a doctor's skill, those who stood around his deathbed must help, that others, too, may enjoy that same consolation when they lose their dear ones.

Such is the Fellowship of those who bear the Mark of Pain.

-- Albert Schweitzer, M.D., Ph.D.
On the Edge of the Primeval Forest

* SLICE OF LIFE REVIEW

{11512} lung, normal
{11739} lung, normal
{14900} epiglottis, normal
{14901} olfactory epithelium, normal
{14902} olfactory epithelium, normal
{14903} trachea (false & true vocal cords)
{14904} trachea (false & true vocal cords)
{14905} trachea, normal
{14906} respiratory epithelium (of trachea)
{14907} respiratory epithelium (of trachea)
{14908} bronchus, normal
{14909} bronchus, normal
{14910} bronchiole, normal lung
{14911} bronchiole, normal lung
{14912} respiratory epithelium, normal
{14913} respiratory bronchiole, normal
{14914} respiratory bronchiole, normal
{14915} alveolar duct, normal
{14916} alveolar duct, normal
{14917} alveolus, normal
{14918} alveolus, normal
{15145} trachea
{15147} trachea
{15148} lung
{15149} lung
{15150} lung, normal
{15151} lung, normal
{15152} lung
{15154} pneumocytes, type ii lung
{15289} trachea, normal
{15290} trachea, normal
{15291} epiglottis, normal
{15292} epiglottis, normal
{15293} epiglottis, normal
{15294} trachea, * seromucous glands
{15295} trachea, normal
{15297} lung, normal
{15298} bronchiole, respiratory bronchiole
{15299} pneumocyte, type ii
{15300} bronchus, normal
{15302} bronchiole, normal
{15303} bronchus, * seromucous gland
{15763} lung, normal
{15764} lung, normal
{15765} lung, normal
{15766} lung, normal
{15767} lung, normal
{15768} lung, normal
{15791} larynx, normal
{15792} larynx, normal
{17521} bronchus, normal
{17566} lung, normal
{20898} trachea
{20899} trachea, seromucous gland
{20900} cilia, tracheal epithelial cells
{20902} epiglottis
{20903} epiglottis
{20904} trachea
{20907} trachea, epithelium
{20909} alveolus, lung
{20910} lung, respiratory duct
{20911} lung, terminal bronchiole ?
{20912} lung, terminal bronchiole ?
{20913} bronchus, lung
{25654} lung, normal
{27215} lung, normal
{27218} lung, normal
{27221} lung, normal
{27224} lung, normal
{27227} lung, normal
{27468} lung, normal
{29168} bronchitis, chronic with normal to compare
{37604} lung, normal
{37619} bronchus, normal
{41517} lung, normal cast of capillary bed
{46452} xerogram laryngeal, norma
{15289} trachea, normal

---

* From far, from eve and morning,
And yon twelve-winded sky,
The stuff of life to knit me
Blew hither: here am I.
Now -- for a breath I tarry
Nor yet disperse apart
Take my hand quick and tell me,
What have you in your heart.
Speak now, and I will answer;
How shall I help you, say;
Ere to the wind's twelve quarters
I take my endless way.

--A.E. Housmann

NOTE: You may not share Mr. Housmann's "scientific" nihilism. I'm always surprised and pleased when such folks at least pay lip service to basic human goodness.

Visitors to www.pathguy.com reset Jan. 30, 2005:

Drop by and meet Ed

Ed says, "This world would be a sorry place if people like me who call ourselves Christians didn't try to act as good as other good people ." Prayer Request

Teaching Pathology

PathMax -- Shawn E. Cowper MD's pathology education links
Ed's Autopsy Page
Notes for Good Lecturers
Small Group Teaching
Socratic Teaching
Preventing "F"'s
Classroom Control
"I Hate Histology!"
Ed's Physiology Challenge
Pathology Identification Keys ("Kansas City Field Guide to Pathology")
Ed's Basic Science Trivia Quiz -- have a chuckle!
Rudolf Virchow on Pathology Education -- humor
Curriculum Position Paper -- humor
The Pathology Blues
Ed's Pathology Review for USMLE I
Part I
Part II

Pathological Chess

Taser Video 83.4 MB 7:26 min