The Daily Sign-Out

Hypersensitivity Pneumonitis: recent updates

There have been two recent papers reviewing hypersensitivity pneumonitis (HP) that I had to summarize for myself and am sharing with you. While idiopathic pulmonary fibrosis/usual interstitial pneumonitis (IPF/UIP) may be the prototype for interstitial lung disease, I think that hypersensitivity pneumonitis is more frequently encountered or strongly considered in the differential diagnosis as a non-neoplastic lung biopsy specimen in “the daily sign-out,” at least in community-based general surgical pathology practice, and especially since the majority of IPF cases are now diagnosed by high-resolution CT scans without biopsy. Thus, being a practical sort, I suggest that a solid appreciation for the clinical, radiographic and pathological features of HP would help resolve many cases you might encounter in practice.

The paper by Selman, Pardo and King in the August 15, 2012 Am J Respir Crit Care Med (abstract) is more clinically oriented, while the paper by Herbst and Myers in the August 2012 Arch Pathol Lab Med (abstract) focuses on the role of surgical biopsy in the diagnosis of HP. I refer (defer?) to the Dail and Hammar Pulmonary Pathology textbook for the definitive description of the pathological findings in HP. (I also suggest that curling that textbook--volume 1--with 10 reps for each arm will give you beastly biceps in a few weeks’ time (hey--Kindle version anytime soon?).

One of the interesting aspects of the AJRCCM paper is the discussion on pathogenesis. The authors review the “2-hit” hypothesis: that there is a pre-existing genetic susceptibility and/or environmental factors, followed by exposure to one of the many antigens associated with HP. The antigens can be roughly divided into 3 groups: 1) thermophilic actinomycetes (Saccharopolyspora rectivirgula) as well as a variety of other fungi (Aspergillus, Penicillium spp); 2) a complex mixture of high- and low-molecular weight proteins from avian serum, feces, and feathers; 3) water-borne non-tuberculous mycobacteria. Importantly, no genetic factors have been consistently associated with HP. But certain polymorphisms have been identified that are associated with increased risk, including HLA-DR and -DQ polymorphisms, polymorphisms in the genes coding for TAP transport peptides MHC molecules for presentation to cytotoxic T cells, and polymorphisms in β type 8 (PSMB8)--an immunoproteasome catalytic subunit that participates in degradation of ubiquinated proteins to generate peptides for antigen presentation by class I MHC molecules. Finally, the authors discuss the role of cigarette smoking in HP. It is somewhat curious but known clinically that HP is less frequent in smokers compared to non-smokers. It is hypothesized that nicotine blunts the response to antigen exposure by its effects on decreasing macrophage activation, decreasing lymphocyte proliferation, and impairing T-cell function. However, when HP does occur in smokers, they tend to develop a chronic clinical course characterized by more recurrent episodes of disease and have a poorer survival rate compared with HP in non-smokers.

Classically (“”), HP is divided into acute, subacute, and chronic forms. However, there are no accepted clinical criteria that distinguish the various forms. Moreover, there is little information regarding the latency period between antigen exposure and disease onset. Indeed, it is uncertain that these divisions truly represent different stages of the disease.

Recently, cluster analysis studies suggest a two-cluster model for HP that correlates with observed clinical profile and the type of antigen exposure. Cluster 1 corresponds to the clinically “acute” form of HP. It is associated with an influenza-like syndrome occurring a few hours after a substantial exposure, more recurrent systemic symptoms, and a normal chest xray. Cluster 1 tends to occurs in individuals exposed to thermophilic actinomyces or fungi (≈”farmer’s lung”). Cluster 2 corresponds to the clinically “chronic” form of HP. It is associated with more features of severe, chronic disease (e.g. digital clubbing, hypoxemia, restrictive pattern by PFTs, fibrosis on HRCT scans) as well as slowly progressive chronic respiratory disease. This cluster tends to occur in individuals with bird antigen exposure. As pointed out by Herbst and Myers, this is the form one would be more likely to encounter in a biopsy situation as it mimics IPF/UIP or fibrotic NSIP. Of note, HRCT features that would favor HP over UIP/NSIP include lobular areas with decreased attenuation and air trapping, centrilobular nodules, and lack of lower zone predominance. The cluster analysis by 

Pathology of HP

As one may have surmised already, “acute” HP is just not biopsied very often so it is not very well-characterized. When specimens have been examined in which patients were diagnosed clinically with acute HP, the histologic findings resemble acute fibrinous organizing pneumonia. The “chronic” form of HP is much better studied and characterized as consists of a histologic triad of chronic interstitial inflammation, nonnecrotizing granulomas, and cellular bronchiolitis.  While this triad is seen in around 80% of patients with the clinical diagnosis of HP, it is not specific for HP.

The chronic interstitial infiltrate consists of a patchy and variably intense lymphoplasmacytic interstitial infiltrate that is frequently most intense around small bronchi and bronchioles. A salient point by Herbst and Myers (that I have noticed myself as well) is that this infiltrate may be accompanied by alveolar macrophages in adjacent alveoli with occasional aggregates of foamy macrophages suggesting lipid pneumonia. They also note that large numbers of foamy macrophages are frequently seen in pigeon-breeder’s disease. Importantly, necrosis and vasculitis are not seen. Nonnecrotizing granulomas may be found around respiratory bronchi or bronchioles as well as in the interstitium or in alveoli (so basically anywhere). These are “poorly-formed” (cf. sarcoidal granulomas) and composed of epithelioid histiocytes and Langhans’ giant cells. One helpful tip is the use of cathepsin K by IHC to help identify microgranulomas, particularly in “subacute” cases, but I think it would probably be helpful when granulomas don’t pop out at you. Another notable point is that the giant cells frequently contain cholesterol clefts, Schaumann bodies, and/or birefringent oxalate crystals. The cellular bronchiolitis is somewhat self-explanatory btu is primarily lymphocytic and extends into adjacent alveolar interstitium.

Herbst and Myers also point out some other significant “soft” findings that can be valuable in the diagnosis of HP. Small foci of organizing pneumonia pattern are found in up to 60% of patients diagnosed with HP. Small airways involvement may be found (more frequently in farmer’s lung than pigeon breeder’s disease) and adds an obstructive component. Mast cells are a constant finding and are frequently found in areas of interstitial fibrosis. And last but not least--interstitial fibrosis. Significant intersitial fibrosis is frequently found in patients who are biopsied months to years after the onset of symptoms as well as in those who have repetitive or persistent exposure to the putative antigen. Histologically, the fibrosis may have a UIP-like pattern identical to IPF.

As a personal note, I have found that the diagnosis of HP is typically made by carefully correlating the biopsy findings with the patient’s clinical history and radiographic findings in collaboration with the pulmonologist and radiologist. The paper by Selman, Pardo and King highlights important clinical findings of which we should be aware in consideration of the histological findings and the paper by Herbst and Myers emphasizes those histological features that might lead one to consider HP perhaps with less than adequate or preliminary clinical information. Both papers are timely and highly recommended but I hope I’ve been able to summarize them adequately for you.

Evidence for lung regeneration in an adult: case report

The conventional view is that lung growth and development ends around age 7 but a fascinating article in last week's NEJM (N Engl J Med 2012; 367:244-247July 19, 2012) suggests that lung growth can occur in adults.

Abstract

 A 33-year-old woman underwent a right-sided pneumonectomy in 1995 for treatment of a lung adenocarcinoma. As expected, there was an abrupt decrease in her vital capacity, but unexpectedly, it increased during the subsequent 15 years. Serial computed tomographic (CT) scans showed progressive enlargement of the remaining left lung and an increase in tissue density. Magnetic resonance imaging (MRI) with the use of hyperpolarized helium-3 gas showed overall acinar-airway dimensions that were consistent with an increase in the alveolar number rather than the enlargement of existing alveoli, but the alveoli in the growing lung were shallower than in normal lungs. This study provides evidence that new lung growth can occur in an adult human. 

Over the 15 year follow-up following right pneumonectomy, spirometry showed a 50% increase in FEV₁ and 35% increase in FVC (versus a predicted age-related decrease in both parameters). In addition, serial surveillance CT scans over the same period showed a gradual increase in tissue volume in the left lung, nearly doubling after surgery. I know it sounds like I'm gushing but the 3-dimensional CT reconstructions of the remaining left lung are just COOL!

But what is really orbital about this brief report is the use of a diffusion MRI study with "hyperpolarized helium-3 gas" to derive a quantitative estimate of acinar microstructure--and thus the development of new septae and evidence for lung regeneration. It took when a couple passes through this section to unwrap the radiology technique and how it relates to a microanatomical dimension (I'm somewhat embarassed to admit)--but check this out. The references on this technique are only a couple of years old, so this is some really cutting edge stuff.

Whether this unique case can be generalized would be an interesting study. The patient was very young when she was diagnosed with lung cancer and apparently had a robust daily exercise regimen--certainly not the typical lung cancer patient. But the evidence presented here is a credible challenge to a long-held assumption that adult lungs do not grow.

The new IASLC/ATS/ERS Lung Adencarcinoma Classification is a Stage-Independent Predictor of Survival

 I blogged on this new classification over a year ago when it was first published, but now papers are rolling out showing its utility.  My take on this recent paper below is that it confirms the idea of histologically grading lung ADC according to the predominant different subtypes (lepidic predominant grade 1 "well-differentiated" versus solid predominant being grade 3 "poorly-differentiated".  Moreover, it asserts that it is sufficient to regard only the predominant histologic type with regard to survival--which is a relief from going through the tedious task of estimating percentages of different minor subtypes after complete histologic examination.  Get this article--good for discussion with surgeons, oncologists, tumor conference, etc. 

The Novel Histologic International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society Classification System of Lung Adenocarcinoma Is a Stage-Independent Predictor of Survival.

Possible false positive interpretation of Napsin A staining in evaluating lung non-small cell carcinomas

Dr. Nelson Ordonez (MD Anderson Cancer Center, Houston) published a brief and very helpful article in the March 2012 American Journal of Surgical Pathology (abstract) that addresses a very practical issue of using IHC staining for Napsin A in evaluating primary lung NSCLC for confirmation of adenocarcinoma type.

Napsin A is normally expressed in type II alveolar pneumocytes but may also be localized immunohistochemically in intraalveolar macrophages presumably from phagocytosis.  The expression of both Napsin A and pro-surfactant protein B (ProSP-B) are regulated by thyroid transcription factor-1 (TTF-1), which is one of the common IHC stains initially performed on NSCLC not diagnostic for adenocarcinoma on routine H&E.  Napsin A is localized to lamellar bodies with ProSP-B and is thought to be involved in post-translational processing of ProSP-B.

This paper must be understood in the context of new IASLC lung adenocarcinoma classification and the algorithm recommended to histological type NSCLC.  Napsin A has emerged as a useful adjunct IHC stain, such as, in those cases in which a tumor is negative or equivocal for initial screening markers for both adenocarcinoma (ADC) and squamous cell carcinoma (SQC).  Until recently, Napsin A was found to be highly specific for lung ADC.  But, as Dr. Ordonez points out, several recent publications have found Napsin A positivity in lung squamous cell carcinomas and, thus, cast doubt over the high degree of specificity of Napsin A for lung adenocarcinoma and utility of this marker in this context.

Dr. Ordonez studied Napsin A expression by IHC in 90 primary lung SQC, including whole section and biopsy specimens, and 64 non-pulmonary SQC.  None of the primary lung SQC or the non-pulmonary SQC showed Napsin A positive staining in the malignant cells.

The key observation is the identification of entrapped type 2 pneumocytes and/or intraalveolar macrophages in desmoplastic areas adjacent to the tumor and in small clusters within the tumor--which could be a source of false-positive interpretation in SQC.  Dr. Ordonez found 5 biopsies in which these entrapped cells were difficult to distinguish from malignant cells and CK 5/6 was used in 2 of these cases to rule out the possibility that these were Napsin A-positive malignant squamous cells.

This is a critical distinction and very welcome contribution to the lung cancer pathology literature.  The reader should keep point this in mind, especially when evaluating biopsy material.  The illustrations are excellent in demonstrating these points and should also be kept close at hand.  Congratulations to Dr. Nelson Ordonez for an excellent paper.

Biomarkers in COPD

Chronic obstructive lung disease (COPD) is defined functionally as airflow limitation that is not fully reversible.  It is a MAJOR cause of morbidity and mortality in the U.S. and worldwide.  COPD has two distinct major, but often coexisting, forms that represent different manifestations of COPD: emphysema and chronic bronchitis.  Emphysema can be defined morphologically, either by radiography or pathology, while chronic bronchitis is defined clinically based upon the duration of productive cough and exclusion of other causes.  Treatment is focused on preventing progression of disease and the development of acute exacerbations, which are a major cause of hospitalizations, morbidity and mortality.  Common to both major forms is small airways inflammation and an abnormal inflammatory response either in large airways (chronic bronchitis) or in alveoli (emphysema).

COPD is also associated with low-grade systemic inflammation and biomarkers that could predict increased risk for mortality from progressive disease or acute exacerbations might be greatly beneficial in providing more intesive surveillance and treatment of this group.  A team of researchers led by Tufts University School of Medicine screened blood samples from people in the ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) to see if inflammatory biomarkers could predict disease outcome (abstract).  The study included 1843 patients who were followed for 3 years.  168 of the 1843 patients (9.1%) died.  Serum or plasma levels of fibrinogen, chemokine ligand 18, surfactant protein D, C-reative protein, Clara cell secretory protein-16, interleukin-6, IL-8, and tumor necrosis factor-alpha were measured at recruitment and at subsequent visits.

The addtion of a panel of biomarkers significantly improved predictive power and was able to better predict outcomes compared with current clinical variables, including age, BODE index, and hospitalization history. The addition of IL-6 provided the most improvement of discriminatory power, but this was improved further with the addition of all biomarkers measured.

Aberrant Wnt1 and beta-catenin expression in NSCLC

This month's April 2011 Journal of Thoracic Oncology has an interesting paper by Xu and colleagues (abstract) that examines Wnt1 expression in non-small cell lung cancer (NSCLC) in relation to downstream Wnt signaling molecules, including beta-catenin, and correlates different marker expression with traditional clinicopathological parameters.

This is an immunohistochemical study of a tissue microarray composed of 262 NSCLC resected specimens.    The authors define aberrant beta-catenin expression as: 1) decreased membranous pattern in less than 70% of tumor cells, 2) cytoplasmic pattern of expression, or 3) nuclear pattern of expression.  As expected, the majority of patients are stage 1 or 2 but nearly 36% of the study population are never-smokers--over 50% in the adenocarcinoma histology group (!).  The authors found that Wnt1 overexpression was significantly associated with never-smoker status and ADC histology; aberrant beta-catenin expression was associated with SQC histology.  While each Wnt1 overexpression and aberrant beta-catenin expression were independently associated with decreased OS regardless of TNM stage, patients that demonstrated both had worse OS than other combinations of Wnt1/beta-catenin expression.  Further, Wnt1/beta-catenin expression was also an independent factor adjusted by stage, pleural invasion, lymphatic invasion, ECOG PS or stage, age, gender, histology, and p53 expression.

A few comments about this paper.  One significant caveat to the findings is the over-representation of never smokers (35%) in this Asian study population, especially nearly 54% of never smokers in the ADC group, compared to a more typical American population in a community hospital setting (about 10%).  Overexpression of Wnt1 was significantly associated with never-smoking and as well as ADC histology, but, somewhat paradoxically, Wnt1 overexpression was associated with significantly shorter overall survival.  Unfortunately, the authors do not break this further down into Wnt1 overexpression and OS with respect to histological type--perhaps some SQCs showing Wnt1 overexpression and dismal OS are skewing the data here since one would expect never-smokers with ADC to have a better prognosis in general.  Another is the usual issues with using TMAs to represent complex heterogenous tumors.  The authors do not sufficiently describe from where they target obtaining cores for constructing the TMA--are they targeting the invasive margin, the central tumor, wherever?  what about mixed histology tumors?  These are critical methodological issues--especially when extrapolating the data concerning marker expression.  One admirable feature of this paper is the clear definition, supported by appropriate photomicrographs, of "aberrant" beta-catenin expression.  As I am currently working on projects that are similarly assessing beta-catenin expression in NSCLC, I found this very helpful in assessing this paper's findings.

Lymphomatoid granulomatosis: new insights

A great deal has been learned over the past few years about lymphomatous granulomatosis (LG), a rare pulmonary lymphoproliferative disease with a high mortality rate.  The eminent pulmonary pathologist, Anna-Louise Katzenstein, and co-authors, Erika Doxtader and Sonia Narendra, have published an excellent (free!) review e-article in American Journal of Surgical Pathology that I recommend highly.

The pathologic features of LG and post-transplant lymphoproliferative disorder (PTLD) are essentially identical, so the diagnosis of LG should not be made in organ transplant recipients.  Similarly, the pathologic features of LG are so similar to iatrogenic immunodeficiency-associated lymphoproliferative disorder that the latter diagnosis should be given consideration if the patient has a history of receiving methotrexate or other immunosuppresive drugs.

Fetal Lung Interstitial Tumor--report of proposed new entity

So many great articles at the end of the year, it's going to take me 'til Easter to catch up!

The December 2010 issue of American Journal of Surgical Pathology has a fascinating article from Dishop and (multiple) colleagues reporting 10 morphologically distinct tumors from multiple American institutions.  The patients' ages ranged from 0 days to 3 months and imaging in each case revealed a well-circumscribed lobar-based mass.  Lobectomy or wedge resection was performed in each case.

Each tumor was a well-circumscibed intraparenchymal mass with a solid-to-spongelike surface that appeared to be at least partially surrounded by a fibrous capsule.  The microscopic appearance was characterized by an abrupt transition from normal saccular-stage lung to more immature-appearing, variably-sized and -shaped spaces separated by cellular septa with variable width.  The lining epithelium is composed of regularly distributed non-ciliated flattened to cuboidal cells.  The interstitium is composed of a monotonous population of uniformly distributed round-to-ovoid mesenchymal cells.  None of the cases showed any of the malignant features associated with pleuropulmonary blastoma (PPB).

The interstitial cells showed diffuse positivity for vimentin and variable staining for smooth muscle actin and desmin; the epithelial cells were positive for cytokeratin (clone not specified) and EMA but TTF-1 positivity was reported in only 1 case.

Fetal lung interstitial tumor (FLIT) is the term proposed by the authors to describe a lobar-based tumor well-demarcated from surrounding normal lung that presents either prenatally or within the first 3 months of age, is composed of variably sized cysts composed of histologically benign epithelium and interstitial cells, and shows apparently benign clinical behavior.

The authors discuss the possible relationship between "FLIT," type I (cystic) PPB, and congenital peribronchial myofibroblastic tumor (CPMT) and posit a growth disorder in pulmonary interstitial cells as a common histogenesis for these rare, curious tumors.

I realize that this is a highly subspecialized report that is probably of little general interest.  BUT check this: tumors such as these point to the complex interactions between endodermally-derived epithelium and mesodermally-derived mesenchyme during lung development--an interaction which plays itself out again in more common lung diseases, like ILDs and lung cancer!

Uncommon Lung Adenocarcinoma Variants: a mini-review

There are five common types of adenocarcinoma (actually I would say four since "mixed" doesn't seem to me a specific 'type") recognized in the WHO classification of lung cancer.  But this classification also includes five rare but distinctive variants: fetal adenocarcinoma, mucin-producing adencarcinomas (mucinous "colloid" adenocarcinoma, mucinous cystadenocarcinoma, and signet ring adenocarcinoma), and clear cell adenocarcinoma.  

While rare to exceedingly rare as pure tumors, the variant patterns are important to be aware of because they occur much more commonly as a component of mixed type adenocarcinomas, are associated with particular clinicopathologic features, and often require the exclusion of a different primary site.  Another challenging variant is the nonmucinous lung adenocarcinoma which resembles colorectal adenocarcinoma but I'll review this variant in another post.  Hope you all find this of use.

Fetal adenocarcinoma

• Unencapsulated but well-circumscribed composed of closely packed branching tubules with little intervening stroma resembling fetal lung seen between 10 and 16 weeks' development (pseudoglandular stage).
• Cribriform arrangements can be prominent and cells arranged in cords and ribbons with peripheral palisading also described.
• The tubules are lined by "endometrioid" nonciliated pseudostratified columnar cells with frequent subnuclear or supranuclear vacuoles.
• Structures resembling squamous morules as in endometrioid adenocarcinoma are often present and the nuclei in these foci often appear optically clear (nuclear pseudoinclusions) due to biotin accumulation.
• Frequent mitoses.  Variable necrosis--focal to extensive.
• Low-grade and high-grade variants are recognized which differ significantly in clinical and histopathologic parameters:
• • Low-grade: mean age 34 years, about equal M:F, usually present at early stage, associated with a good prognosis; orderly arrangement of glands, focal necrosis (if present at all), small fairly uniform nuclei with inconspicuous nucleoli, morules common; slight to moderate loose fibromyxoid stroma, neuroendocrine differentiation almost always found, occasional AFP-positive cells, p53 protein overexpression uncommon, nuclear and cytoplasmic β-catenin expression
  • High-grade: mean age 64 years, male predominance, usually advanced stage at presentation, associated with poor prognosis (42% DOD@24 mos.); disorderly arrangement of glands, extensive areas of necrosis common, large pleomorphic nuclei with prominent nucleoli, morules absent, abundant desmoplastic stroma, always AFP-positive cells, p53 overexpression common, membranous β-catenin expression

Mucin-producing adenocarcinomas

Morphologically similar to non-pulmonary mucinous carcinomas from GI tract, pancreas, ovary, and breast.

Mucinous (colloid) adenocarcinoma

• Rare as a subtype but mixed tumors frequently show mucinous morphology
• Appears same as in other organs in which it is more frequently encountered: dissecting mucin pools containing islands and strips of mucinous epithelium with malignant cytologic features
• In the lung, mucinous columnar cells can focally line alveoli in a lepidic pattern.
• The neoplastic goblet cells express enteric markers (CDX2, MUC2 and CK20) with inconsistent, focal and weak CK7 and TTF-1 expression--thus, clinical correlation is needed to diagnose this as a pure lung primary.
• • Primary lung mucinous BAC does not show mucin pools invading stroma, is primarily composed of neoplastic mucinous cells lining alveolar walls, and does not show expression of CDX2 or MUC2.
• This neoplasm should be considered a low-grade carcinoma with more favorable survival rates compared to mucinous BAC or conventional mixed adenocarcinoma.

Mucinous cystadenocarcinoma

• Like the ovarian counterparts, this groups of tumors shows a histologic spectrum encompassing benign (mucinous cystadenoma), borderline (mucinous cystic tumor of borderline malignancy) and malignant (mucinous cystadenocarcinoma).
• The cytological and architectural criteria for differentiating these tumors are also similar to those in the ovary, except that invasion of surrounding lung is diagnosed as a mixed subtype of adenocarcinoma (for reasons I'm not quite clear but there it is).
• The mucinous epithelium in all of these cystic lesions differ from the mucinous adenocarcinoma type in that these express CK7 but inconsistently express CK20 and TTF-1.  These are quite rare and have been studied for MUC2 or CDX2.

Signet ring adenocarcinomas

• Rare as a pure subtype and uncommon (around 2%) as a component of mixed adenocarcinomas.
• Younger average age when predominant as a component compared to average age of lung cancer patients in general
• Unlike the other subtypes, this variant is defined by cytology--the classic signet-ring morphology.
• Intracytoplasmic material stains with PAS diastase, mucicarmine, and Alcian blue @ pH 2.7--indicating both neutral and acid mucins
• Over 95% of tumors express CK7 and over 80% express TTF-1 but are negative for CK20; also positive for CEA, MUC1 and MUC5AC--a staining profile that helps distinguish this as a primary lung tumor versus metastasis from breast, gastric and colon primaries.
• This is the most aggressive mucinous-type lung adenocarcinoma.
• Tumors with at least 50% signet-ring component have a poorer 5-year survival rate compared to the typical adenocarcinoma prognosis.

Clear cell adenocarcinoma

• Extremely rare as a pure subtype--but over a third of mixed adenocarcinomas show at least some focal clear cell change.
• Tumor cells form sheets with at least focal tubal formation (the latter required for diagnosis) and may form papillae.
• Intracytoplasmic material is PAS-positive, diastase-sensitive--indicative of glycogen.
• Pure tumors have not been well-studied by IHC--one reported tumor was CK7+/CK20-/TTF-1+.
• Distinguishing primary lung clear cell adenocarcinoma from a renal metastasis requires
• • clinical and radiologic correlation
  • identifying a mixed growth pattern and intracytoplasmic mucin
  • finding IHC markers specific for RCC
     

Mucinous bronchioloalveolar carcinoma of lung and ALK mutation

Last month I received a generous note from a patient who responded to a previous post on molecular markers in lung cancer from the USCAP 2010 meeting.  I made the statement that "every adenocarcinoma should be tested for EGFR mutation (with the exception of mucinous ACa/BAC which are always KRAS mutants)."  This patient's experience should cause us to not be so categorical about such statements.  Moreover, as we develop testing algorithms, we should consider an approach which will allow us to detect "exceptions to the rule."

The patient was diagnosed with mucinous BAC.  But not only was the tumor wild-type for KRAS mutation (i.e., no mutation was detected) but instead an ALK mutation identified in the tumor.  The patient subsequently received the drug crizotinib, an inhibitor of the fusion protein EML4/ALK, and has had a sustained response to treatment.  

This is the drug that generated so much attention at the recent ASCO 2010 meeting in Chicago.  In an international phase I study of advanced, heavily pretreated NSCLC patients selected for ALK protein expression, crizotinib produced a 57% response rate with a 6-month PFS predicted to be 72%.  This data was presented at the Plenary Session.  Moreover, it was noted that the majority of patients showed some kind of response (63% including objective and unconfirmed partial responses), the response often occurred dramatically within the first 2 weeks of treatment, and the responses were often durable.  In this study, 96% of responders had adenocarcinoma histology--primarily signet ring morphology.

This is surely a very exceptional case since mucinous ACa/BAC is a very distinctive histological subtype and has been also characterized at the molecular level as being associated with KRAS mutation.  The point is that histology is not a perfect predictor of potentially druggable molecular pathologies.  If targeted therapy is being contemplated in NSCLC, we should adopt a systematic approach to all NSCLC regardless of histology.  At this point, while we are identifying patients who may potentially benefit from targeted therapy, we are building a database that will allow a more full appreciation of the relationship between histological type and molecular pathology.

Thanks to the patient who took the time to respond to my blog and for helping to edify us all!