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Precision medicine for lung cancer: role of the surgical pathologist.

The Houston Lung Symposium highlights exciting innovations in the practice of medicine, particularly pathology, in this age of precision medicine. Although pathologists must embrace molecular testing methodologies and advanced imaging techniques, in this article we illustrate how a more-traditional role of the surgical pathologist, using conventional techniques and familiar equipment, juxtaposes these technologic advances. Our illustration is for one predictive biomarker of lung cancer, but it is instructive about the role of surgical pathologists generally in the near future.


Lung cancer is a major focus of recent developments in precision medicine in the eyes of physicians, other medical professionals, and the lay public. Lung cancer is the leading cause of cancer deaths in the United States, and the estimated number of deaths from lung cancer in the United States for 2012 is 160 340, more than the total number of deaths from the next 3 most common causes of cancer deaths (colon, breast, and prostate cancers) combined. (1) About 29% of all cancer deaths among men and 26% of all cancer deaths among women in the United States in 2012 are estimated to be due to lung cancer. (1) Globally, lung cancer accounted for 18% (1 400 000) of all cancer deaths in 2008 and, worldwide, was the leading cause of cancer deaths in men and the second leading cause of cancer deaths in women. (2) Although significant improvements in survival have been achieved for other forms of cancer in recent years, the survival rate for lung cancer has remained largely unchanged for decades with 5-year survival for patients with lung cancer ranging from 6% to 14% for men and from 7% to 18% for women. (3)

The traditional role of the surgical pathologist caring for patients with lung cancer was limited before the advent of precision medicine. In standard therapy of lung cancer, (1) small cell carcinomas are treated by chemoradiation; (2) early stage, operable non-small cell carcinomas (adenocarcinomas, squamous cell carcinomas, and large cell carcinomas) are treated by surgical resection; and (3) advanced, nonoperable non-small cell carcinomas are treated by doublet chemotherapy. (4-6) World Health Organization classifications of cell types have been based on resection specimens of early stage cancers, which provide generous quantities of tumor for histologic examination by the pathologist. (7) On the other hand, more than two-thirds of lung cancers present in advanced stages, and typically, only limited tumor samples are examined on small biopsies and/ or cytology specimens, which may be subject to crush or other artifacts. (7) In 1993, a Lung Cancer Working Party of the United Kingdom Coordinating Committee for Cancer Research reported that inaccuracies were introduced when pathologists attempted to diagnose specific World Health Organization cell types of non-small cell carcinomas on small biopsies, although differentiation of small cell carcinoma from the non-small cell carcinomas was more reliable. Therefore, it suggested the use of non-small carcinoma, not otherwise specified when cell type was equivocal to reduce the inaccuracies of specific cell-type diagnoses. (8) Because the treatment options depended on whether or not the lung cancer was small cell carcinoma versus any of the non-small cell carcinoma cell types, a diagnosis by the pathologist of non-small cell carcinoma, rather than a specific cell-type of the latter, was acceptable clinically in many situations. Thus, it became the standard in many practices to default to the less-specific term and, eventually, the diagnosis of non-small cell carcinoma, not otherwise specified, became a frequent diagnosis on small biopsies and cytology specimens. (9) Therefore, for treatment selection, the traditional role of the pathologist has been to differentiate small cell carcinoma from non-small cell carcinoma without a requirement to further classify cell type. (4,5)


This traditional role of the pathologist in lung cancer treatment began to change with the advent of successful, new therapies for lung cancer that required a specific diagnosis of cell type, rather than the traditional non-small cell, not otherwise specified, diagnosis. The antifolate drug pemetrexed proved effective in patients with adenocarcinoma but not patients with squamous cell carcinoma. (10,11) Bevacizumab, an anti-VEGF monoclonal antibody, was approved only for patients with advanced, nonsquamous, non-small cell lung cancers when patients with squamous cell carcinomas developed pulmonary hemorrhage, which was sometimes life-threatening. (12,13) The need for pathologists to be more specific in their diagnosis of cell type, in addition to other new roles in care of patients with lung cancer, have emerged from the introduction of successful new targeted molecular therapies for lung cancer. (4,5) Identification of predictive biomarkers for targets of molecular therapy, of which, epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements are currently validated clinically, is the most reliable basis for selecting patients with lung cancer who are likely to respond to these targeted therapies. Evidence so far indicates that adenocarcinomas should be selected for EGFR and ALK biomarker testing, whereas testing of pure squamous cell carcinomas or pure small cell carcinomas for these biomarkers is unlikely to be productive. (14-21) Today, the surgical pathologist is expected to provide a diagnosis of small cell carcinoma, adenocarcinoma, or squamous cell carcinoma on small biopsies/cytology specimens of lung cancer whenever feasible, including with the use of histochemical and/or immunohistochemical stains, and to avoid the diagnosis non-small cell carcinoma, not otherwise specified, if possible.


The unique skill of the surgical pathologist to diagnose specific cell types is now a cornerstone of precision medicine for patients with lung cancer. However, does the role of the surgical pathologist in precision medicine of lung cancer end with the diagnosis of cell type? We believe that the surgical pathologist will make a larger contribution, beyond identifying cell type, using conventional techniques and tools. We will illustrate this by examining the potential role of the surgical pathologist in diagnosing [ALK.sup.+] lung cancers.

The ALK gene is activated through chromosomal rearrangements, most notably with echinoderm microtubuleassociated proteinlike 4 (EML4) forming an aberrant fusion gene. Because only a minority of lung cancers are [ALK.sup.+], features identifying which lung cancers should be selected for ALK testing has been the subject of much debate. Although [ALK.sup.+] lung cancers are associated with certain clinical features, such as a light or never smoker history, there are sufficient exceptions to these clinical features to exclude patients from ALK testing who might otherwise benefit from ALK inhibitor treatment. (22) Therefore, clinical features, while possibly suggestive, are not generally preferred for selecting patients for ALK testing. (21)

The ALK rearrangements are associated with adenocarcinoma cell type, which is a diagnosis that is made by the surgical pathologist and is currently a basis for sending tissue for ALK testing. However, can the surgical pathologist further stratify patient selection for testing using routine histology? In multiple reports, ALKrearrangements are also associated with specific adenocarcinoma subtypes and variant features, most often solid adenocarcinoma pattern with signet ring features. (23-29) Yoshida et al (28) found that the most powerful histologic indicator of ALK rearrangement by multivariate analysis was the presence of solid signet-ring cell pattern and a mucinous cribriform pattern, which they found to be at least focally present in 78% of [ALK.sup.+] tumors and only 1% of [ALK.sup.-] tumors. However, the use of histologic subtypes and variants is not currently considered sufficient to select patients for ALK testing because a substantial number of patients who might benefit from treatment but whose tumors lack these features would once again be excluded. (21) In addition, as already mentioned, most lung cancers are diagnosed only on the basis of small biopsies and/or cytology specimens, which may not sample all of the histologic subtypes or variants within a tumor. Therefore, the merits, if any, of subclassification of adenocarcinomas for test-selection purposes remain to be confirmed but are tantalizing for the future.

The ALK chromosomal rearrangements are readily identified by cytogenetic methods and fluorescence in situ hybridization (FISH) has been recommended as the test for ALK rearrangements, including the decision by the US Food and Drug Administration to approve a specific companion test (Vysis ALK Break-Apart FISH Probe Kit, Abbott Molecular Inc, Abbott Park, Illinois) to select patients for therapy with the US Food and Drug Administration approved ALK inhibitor Xalkori (Pfizer, New York, New York). (30,31) False-negative results are a risk for reverse transcription-polymerase chain reaction (RT-PCR), which is used in some laboratories because there are multiple variants of the ALK-EML4 fusion structure and the ALK fusion with other partners has been reported. (32-36) Of course, FISH requires darkfield microscopy with special equipment and is not a routine procedure for many surgical pathologists. Therefore, beyond diagnosing the cell type, which is a crucial step, and sending tissue off for molecular testing the surgical pathologist might seem excluded from further direct participation in precision medicine employing knowledge of histopathology and the familiar tool, the light (brightfield) microscope.

So, now we have 2 questions: Can the surgical pathologist contribute additional information to select lung cancers for ALK testing? Can the surgical pathologist actually perform the ALK testing him or herself? Chromogenic in situ hybridization (CISH) and immunohistochemistry offer the potential of involving the surgical pathologist directly in further patient selection for ALK testing and to perform the ALK testing. CISH has been reported as a potential alternative to FISH, which would permit the use of brightfield microscopy and is more applicable to the typical surgical pathologist's circumstances. (37,38) However, CISH is less familiar to most surgical pathologists than immunohistochemistry. Early immunohistochemistry protocols to detect ALK expression in lung cancers had challenges that are now less formidable, and the role of the surgical pathologist in diagnosing [ALK.sup.+] lung cancers may now be much enhanced.

The ALK immunohistochemistry does not detect the ALK fusion gene itself but, rather, expression that is not present in normal tissues without the fusion gene. Because of the low expression of ALK in lung cancers, compared with lymphomas, early studies of ALK immunostaining had the risk of low sensitivity and, hence, false-negative results in lung cancers that were demonstrated to have the ALK fusion genes by FISH or RT-PCR. (21,39-48) Techniques and antibodies that improve sensitivity are able to detect [ALK.sup.+] lung cancers, and an antibody that detects ALK using standard immunostaining techniques has been reported by participants at the Houston Lung Symposium. (39) At least one of the sensitive ALK antibodies is now commercially available in the United States (ALK [D5F3] XP Rabbit mAb [biotinylated] 8936, Cell Signaling Technology, Danvers, Massachusetts). A variety of algorithms whereby the surgical pathologist, using the familiar tools of immunohistochemistry and light microscopy, can prescreen or screen for [ALK.sup.+] lung cancers have been proposed. (40-48)

Therefore, using familiar techniques, the surgical pathologist has the possibility to further screen for, or diagnose, [ALK.sup.+] lung cancers with advantages over FISH, RT-PCR, and other molecular procedures. Immunohistochemistry permits conventional visualization of the tissue, allowing for discrimination between viable cancer cells and necrosis, fibrosis, and nonmalignant cells, including inflammatory cells, fibroblasts, and other normal or reactive cells, which is an advantage over FISH and RT-PCR. In addition, samples not readily amenable to FISH or RT-PCR, can be examined by immunohistochemistry, for example, metastases in bone marrow core biopsies. (39-48) Of course, as with any immunostain, opportunities for false-negative and false-positive results still exist, and confirmation of an equivocal immunostain can be done by FISH. More investigations need to be done to correlate immunostaining results with patient outcomes and specific therapies, but, using this one example, we can see that the role of the surgical pathologist can be much more comprehensive than simply diagnosing cell type and sending tissue off for molecular testing.


As illustrated by this one relevant example, the traditional expertise and tools of the surgical pathologist are not excluded from precision medicine but, rather, are subject to new opportunities. Even as surgical pathologists adopt new technologies described at the Houston Lung Symposium into their practice, their conventional skills will be incorporated into precision medicine to the patient's great advantage.


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Philip T. Cagle, MD; Jeffrey Myers, MD

Accepted for publication June 22, 2012.

From the Department of Pathology and Genomic Medicine, The Methodist Hospital, Houston, Texas (Dr Cagle); and the Division of Anatomic Pathology, The University of Michigan, Ann Arbor (Dr Myers).

The authors have no relevant financial interest in the products or companies described in this article.

Presented at the Houston Lung Symposium; April 28-29, 2012; Houston, Texas.

Reprints: Philip T. Cagle, MD, Department of Pathology and Genomic Medicine, The Methodist Hospital, 6565 Fannin St, Main Building, Room 227, Houston, TX 77030 (e-mail:
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Author:Cagle, Philip T.; Myers, Jeffrey
Publication:Archives of Pathology & Laboratory Medicine
Date:Oct 1, 2012
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