The Daily Sign-Out

November is Lung Cancer Awareness Month

Sometimes I can't help but feel, especially as one with a steadfast interest in lung pathology (and lung cancer, in particular), that attention and funding for lung cancer research is the neglected ugly sister to breast cancer.

Well, November is Lung Cancer Awareness Month!

The numbers are staggering and worth considering: lung cancer is the most frequent cause of cancer deaths in the U.S. It is estimated in 2010 that about 222,000 men and women will be diagnosed with lung cancer and about 157,000 will die from the disease.  Compare these numbers with breast cancer (207,000 diagnosed, 40,000 deaths), prostate cancer (218,000 diagnosed, 32,000 deaths), and colon cancer (143,000 diagnosed, 53,000 deaths).  In other words, more people will die from lung cancer this year than breast, prostate and colon cancer combined. This from SEER Stat Fact Sheets.

Moreover, only 15% of lung cancer patients are diagnosed with early stage, localized disease compared to 60% of breast cancer patients, 80% of prostate cancer patients, and 39% of colon cancer patients.  The overall relative survival of lung cancer patients is 15.8% at 5 years (89% breast, 99.1% prostate, 65.0% colon).  Clearly, despite admirable improvements in outcomes for other common cancers, there has been grudgingly little progress--so far!--in improving the outcomes for lung cancer patients.  Finally, the historically poor treatment outcomes and the inimical tendency to blame lung cancer patients for their disease have created an atmosphere of nihilism amongst the medical community, the public and the media, as Dr. Fred Hirsch points out currently in an editorial from November 2010 issue of Journal of Thoracic Oncology.

Also, there are significant sex, racial/ethnic and geographic differences in the incidence in lung cancer.  The Morbidity & Mortality Weekly Report just last week released a report detailing these differences.  The incidence of lung cancer in black men is scandalous.  In addition, despite the fact that lung cancer kills more women than breast cancer, lung cancer involving women is virtually ignored as a "women's issue."  Why is this?!  There is ripe material here to explore the differences in the ways breast cancer and lung cancer are perceived and treated as metaphors, hmm?

In spite of the above, I believe that we are turning the corner on fighting this disease and there are significant albeit incremental findings being reported almost every week.  Unfortunately, the proportion of lung cancer patients who are enrolled in clinical trials is lower than that for other cancers, perhaps as a consequence of the attitudes expressed above.  Folks, we--doctors, nurses, other health care providers, patients, the public--we all can certainly do better than this!  Advocate, teach, donate, research--whatever it takes. 

Genetic changes and risk of lung cancer and COPD

Clipped an interesting item from FierceBiotech but haven't tracked down the main paper yet.  Specifically, it appears differences in a gene on chromosome 15 coding for a nicotine receptor contributes to nicotine addiction, which subsequently influences risk of COPD and lung cancer:

Your DNA influences how much you smoke and whether you will develop lung cancer or chronic obstructive pulmonary disease (COPD), according to researchers led by Washington University School of Medicine in St. Louis and published in the journal Public Library of Science (PLoS) Genetics.

In what they called the first large-scale effort to match genetics with smoking, lung cancer and COPD combined, researchers studied 38,000 smokers and found that two groups of gene variants on chromosome 15 influence risk for all three problems.

Read more: Not all smokers are created equal; it's in the DNA - FierceBiotech Research http://www.fiercebiotechresearch.com/story/not-all-smokers-are-created-equal-its-dna/2010-10-25#ixzz13US9VCzD

New data challenges assumptions about smoking and lung cancer

Data presented at the recent 11th International Lung Cancer Congress challenges the commonly accepted notion that most lung cancer patients are current smokers or only recently quit after the onset of lung cancer-related symptoms.  A retrospective study of 626 lung cancer patients treated at a tertiary care center reported that 77% of patients had a smoking history--but only 14.7% were smoking at the time of diagnosis.  Moreover, 60% of the remaining patients with a smoking history had not smoked for a mean of 18 years--and the other 40% had stopped smoking within 10 years of diagnosis.  The research team was led by Dr. Cindy Mong from UCLA-David Geffen School of Medicine.

In addition, a relationship between the time interval of smoking cessation and tumor histologic type was identified: patients were significantly more likely to have adenocarcinoma if more than 21 years had elapsed since they last smoked, while squamous cell carcinoma was more common in current smokers.  Interestingly, the prevalence of ACa varied inversely with the number of pack-year history.

This is intriguing (albeit somewhat discouraging) data, although it is unclear how representative these results are compared to the general population or to other areas of the U.S.  There is a referral bias toward non-smokers in this study compared to information about the general U.S. population (23% non-smokers in this study versus 9% in general) as well as an overrepresentation of lower stage patients in this study.  According to 2008 data from the CDC, only 16% of patients in the U.S. were diagnosed with localized disease compared to 59% in this study.

Nevertheless, these data are striking and, if generalized to the entire population, have long-term consequences for patients and oncology care--not to mention important health care policy implications.  Too bad we burned through all that tobacco litigation money.  We will have to do a massive education effort for patients who have ever smoked that they will be at risk for cancer for years after they quit.

Review of Granulomatous Lung Disease: a few highlights

Drs. Mukhopadhyay and Gal have written an excellent review of granulomatous lung disease in the May 2010 issue of Archives of Pathology and Laboratory Medicine, which has a "Special Section" featuring non-neoplastic lung disease.

One of their points, that cannot be emphasized enough IMHO, is the crucial importance of trying to identify an organism since infection is the most common cause of pulmonary granulomas.  This is tedious work and requires a certain grim determination.  It often feels like trying to "find a needle in a haystack."  But I can also say that it is very rewarding to identify an organism so that proper therapy can be administered to the patient.  Re-emphasizing a point made by Ulbright and Katzenstein (1980), examination of additional blocks or sections showing necrosis with special stains is indicated when the histologic appearance suggests infection.  The authors also provide some helpful guidance in reporting situations when the stains are still negative.

Another very helpful item is in Table 2. which lists key diagnostic features of major non-infectious causes of granulomatous inflammation in the lung.  Keep this in your vade mecum.

Keep in mind the distribution of the granulomas.  I find this to be very helpful in generating a differential diagnosis, especially when special stains for organisms are negative.  The authors nicely reiterate this point.

Another important point is to be aware of PCR and other immunohistochemical and molecular methods for identifying organisms in FFPE tissue, especially for suspected mycobacterial infection.  It is worth considering ordering these additional tests when tissue was not obtained for culture or when mycobacterial infection is suspected clinically but routine ZN stains are negative.

The descriptions of the various major non-infectious entities associated with pulmonary granulomatous disease are as good as found in the major specialty textbooks and are a great reference.  I mean, 196 references, are you serious?!

Digital Case Challenge: Pleuropulmonary amyloidosis

A 68-year-old man presents with a history of recurrent bilateral pleural effusions over the past six months and recent CT scan of the chest showing persistent small bilateral effusions ground-glass opacities in the superior segment of the left lower lobe and surrounding atelectasis.  The patient underwent thoracoscopy and local pleurectomy and wedge biopsy of the left lower lobe.  Additional history obtained post hoc disclosed a 5-year history of Waldenstrom's macroglobulinemia.

Typical area showing interstitial thickening and thickened vessel walls without significant interstitial inflammation

A more solid nodular area with marked distortion of the alveolar architecture

High power view showing thickened interstitium with amorphous eosinophilic material.  Note lack of interstitial inflammation.

Congo red stain with and without polarization.  Note the apple-green birefringence characteristic of amyloid.

Prominent perivascular accumulation with eosinophilic material (above) confirmed as amyloid with Congo red and polarization (below).

Long-term pulmonary complications from stem cell transplantation

Medscape(4/30, Chustecka) reports on a study from the journal Cancer (abstract) that pediatric leukemia patients who undergo allogeneic hematopoietic stem cell transplantation (HSCT) are often cured of their leukemia, but have significant pulmonary complications as measured by pulmonary function tests.  In contrast, patients with leukemias who are not treated with HSCT and the related treatments do not show an increase in pulmonary problems notes the study's lead researcher, Hiroto Inaba, MD, PhD. Medscape adds, "The problems affecting the lungs arise from the transplant and the related treatments involved in preconditioning, which include high-dose chemotherapy and total body irradiation."  The following pulmonary function values declined significantly with time: FEV₁/FVC, forced mid-expiratory flow (FEF_25%-75%), total lung capacity (TLC), diffusion capacity corrected for hemoglobin (DLCO_corr), RV, FRC, and RV/TLC which suggests a progressive restrictive type defect.  I'm not aware of any studies looking at the radiographic or histologic lesions associated with post-alloHSCT but it bears further investigation.

Updates on respiratory bronchiolitis/interstitial lung disease

Churg, Muller and Wright published a superb update on RB/ILD in the January 2010 Arch Pathol Lab Med which is essential background to Katzenstein's article in Human Pathology on "occult interstitial fibrosis in smokers."  Do yourself a favor and just read my summary of the Katzenstein paper (skip the original) in light of the excellent update by Dr. Churg.

RB/ILD can be described as a clinicopathologic entity characterized by clinically evident interstitial lung disease (originally described by Myers et al. as restrictive pattern of changes by PFTs and/or bilateral, poorly defined centrilobular nodules and ground-glass opacities mainly involving lower lung fields by HRCT) and histologic changes listed below with specific exclusion other forms of ILD.  Morphologic changes include:

• clusters of pigmented alveolar macrophages in respiratory bronchiolar lumens--the fundamental requirement for diagnosis
• mild chronic interstitial inflammation, mild interstitial fibrosis and type 2 pneumocyte hyperplasia in bronchioles and adjacent alveolar walls

But since RB/ILD is a disease of cigarette smokers (and heavy smokers at that--reported mean pack-years between 29 to 54), these patients also are at risk for COPD--"a process that potentially confounds the diagnois of RBILD pathologically, radiologically, and on pulmonary function testing."

Can we separate RBILD from RB?  Based on their review, the authors find that there are no histologic features that separate RBILD from RB.  Moreover, although some authors have contended that clinical RBILD is associated with a greater degree of fibrosis histologically, this point is in doubt since many lungs from smokers also show some (usually mild) alveolar wall fibrosis (thus see comments about the Katzenstein article below).

What is the relationship between RB/RBILD and centrilobular emphysema?  The authors note that emphysematous foci are (as one would expect) a common finding in patients with RB/RBILD and that foci of centrilobular emphysema can be associated with fibrosis.  Which begs the question "whether some of the descriptions of alveolar wall fibrosis associated with RB/RBILD may really be misclassifications of fibrotic emphysematous foci."  In addition, previous studies including careful evaluation and grading of fibrosis and grading respiratory and membranous bronchioles and correlation with PFTs showed a correlation with obstructive PFT abnormalities related to COPD.

Since many of these patients have clinical, functional and histologic features of COPD, the authors argue that "only restrictive or mixed restrictive/obstructive patterns, or (less certainly) a markedly reduced diffusing capacity in the absence of significant airflow obstruction, allow the diagnosis of RBILD."  (with the presence of RB histologic features described above on biopsy).

Churg A, Muller NL, Wright JL.  Respiratory bronchiolitis/interstitial lung disease.  Arch Pathol Lab Med 2010;134:27-32.

Genetic variation and susceptibility to COPD

The Dec. 17 New England Journal of Medicine has an interesting article exploring genetic susceptibility to COPD.   Having just recently finished my lung pathology course to second-year medical students, I can confess to the awkward feeling I have when the inevitable question arises as to why doesn't everyone who smokes get COPD (or lung cancer, for that matter).  My (somewhat feeble) reply is to ascribe this to "individual differences" or "genetic variation."  This paper tries to investigate specifically how genetic variation might be with associated with susceptibility to COPD.

The rationale for the study is that matrix metalloproteinase-12, produced by alveolar macrophages, is essential for the development of emphysema in mouse models and is increased by up to a factor of 9 in alveolar macrophages from smokers compared to non-smokers.  Further, production of MMP12 in lower airways leads to destruction of elastic fibers in alveolar walls--the resulting increase in elastin fragments recruits more macrophages thus setting up a reinforcing feedback loop that amplifies this process.  The authors' hypothesis is that MMP12 variants influence lung function and the development of COPD.  Their study tested for an association between SNPs in MMP12 and lung function test (FEV1) in different cohorts including children with asthma and adults with and without COPD.

They found a positive association between the minor allele of SNP rs2276109 and FEV1 in all cohorts and, in adult cohorts, a 35% reduction in the risk of developing COPD in smokers.  Conversely, they observed a 54% increased in risk of COPD in smokers in the absence of the minor allele (i.e. homozygous for the major allele).  It is noted that the minor allele of SNP rs2276109 is a functional polymorphism is associated with decreased promoter activity through less efficient binding of AP-1 in murine and human monocytic cell lines.  Further, deletion of the AP-1 binding site abrogates both baseline and stimulated MMP12 expression.  There are some important limitations to this study but this is a fascinating insight into "individual variation" due to genetic variability in SNPs and an association between smoking and the development of COPD.

Pink puffer versus blue bloater

One of the students wished for clarification between the clinical phenotypes of "pink puffer" versus "blue bloater" in COPD.

A "pink puffer" is a person where emphysema is the primary underlying pathology. As you recall, emphysema results from destruction of the airways distal to the terminal bronchiole--which also includes the gradual destruction of the pulmonary capillary bed and thus decreased inability to oxygenate the blood.  So, not only is there less surface area for gas exchange, there is also less vascular bed for gas exchange--but less ventilation-perfusion mismatch than blue bloaters.  The body then has to compensate by hyperventilation (the "puffer" part).  Their arterial blood gases (ABGs) actually are relatively normal because of this compensatory hyperventilation.  Eventually, because of the low cardiac output, people afflicted with this disease develop muscle wasting and weight loss.  They actually have less hypoxemia (compared to blue bloaters) and appear to have a "pink" complexion and hence "pink puffer".  Some of the pink appearance may also be due to the work (use of neck and chest muscles) these folks put into just drawing a breath.

A "blue bloater" is a person where the primary underlying lung pathology is chronic bronchitis. Just a reminder, chronic bronchitis is caused by excessive mucus production with airway obstruction resulting from hyperplasia of mucus-producing glands, goblet cell metaplasia, and chronic inflammation around bronchi.  Unlike emphysema, the pulmonary capillary bed is undamaged. Instead, the body responds to the increased obstruction by decreasing ventilation and increasing cardiac output. There is a dreadful ventilation to perfusion mismatch leading to hypoxemia and polycythemia.  In addition, they also have increased carbon dioxide retention (hypercapnia).  Because of increasing obstruction, their residual lung volume gradually increases (the "bloating" part).  They are hypoxemic/cyanotic because they actually have worse hypoxemia than pink puffers and this manifests as bluish lips and faces--the "blue" part.

More notes from PPS 2009: Small airways disease

Here are more of my notes from the Pulmonary Pathology Society meeting recently held in Portland, OR.  Dr. Jeffrey Myers gave us an update on small airways disease on Thursday, June 25.
First a definition of "small airways":  bronchioles with internal diameter less than 2 mm.

Small airways disease = bronchiolitis + airflow limitation

The small airways have been recognized for 40+ years as the primary site of disease for COPD where there is a marked increase in airflow resistance due to luminal occlusion by inflammatory mucous exudates and expansion of all compartments of the airway wall by remodeling and inflammation.  Remodeling and inflammation occur in both asthma and COPD, although there are differences in the pattern of inflammation, structures affected, and primary site of involvement.  However, with disease progression and corticosteroid treatment, these patterns become more similar.  Summation point: in the future, the pattern of inflammation and remodeling may be more important than clinically catagorizing a patient as having either asthma or COPD.

Clinicopathologic Classification of Bronchiolitis

1. Primary bronchiolitis
2. Interstitial lung disease with prominent bronchiolitis
   1. Hypersensitivity pneumonitis
   2. Respiratory bronchiolitis-ILD
   3. Cprytogenic organizing pneumonia
   4. "Airway-centered" interstitial fibrosis
3. Bronchiolitis with large airways disease

2 and 3 are not associated with airflow limitation (so are not small airways disease).

Primary bronchiolitis includes:

1. Constrictive (obstructive) bronchiolitis
2. Acute bronchiolitis
3. Diffuse panbronchiolitis
4. Respiratory bronchiolitis
5. Mineral dust airway disease
6. Follicular bronchiolitis

The latter three are not associated with airflow limitation.

Constrictive bronchiolitis and diffuse panbronchiolitis are histologically distinctive and occur in characteristic clinical contexts.

Constrictive bronchiolitis occurs in a patchy distribution and consists of an early "acute bronchiolitis" pattern (acute inflammation and epithelial necrosis) and a late "bronchiolitis obliterans" pattern (peribronchiolar fibrosis and obliteration of the lumen).  This pattern may be idiopathic but is also associated with a variety of conditions, including collagen vascular diseases, drugs, inhaled or ingested toxins, lung or bone marrow transplantation, post-infection, and neuroendocrine cell hyperplasia.  Women are affected more than men and patients usually present in their 50s with progressive dyspnea and dry cough.  The CXR may be normal or show hyperinflation but HRCT shows mosaic attenuation.

Diffuse panbronchiolitis has been reported mainly in Japan, in non-smokers from the 4th to 7th decades.  Patients have chronic sinusitis, productive cough, dyspnea on exertion, and wheezing.  Prognosis has been reported as poor with 50% survival at 5 years.

FInal caveat from Dr. Myers: "acute (and chronic) bronchiolitis is frequently a completely nonspecific histologic finding that sometimes occurs in specific clinical settings."