Application of Immunohistochemistry to the Diagnosis of Primary and Metastatic Carcinoma to the Lung

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1 Application of Immunohistochemistry to the Diagnosis of Primary and Metastatic Carcinoma to the Lung Jaishree Jagirdar, MD Context. Immunohistochemistry is a very valuable and often used tool in the differential diagnosis of lung carcinomas whether primary or secondary to the lung. The most useful application is in distinguishing primary lung tumors from metastatic tumors to the lung from common sites (colon, breast, prostate, pancreas, stomach, kidney, bladder, ovaries, and uterus). Immunohistochemistry also aids in the separation of small cell carcinoma from non small cell carcinoma and carcinoids particularly in small biopsy specimens limited by artifact. Although there is no lung-specific tumor marker, with the help of a relatively restricted marker, thyroid transcription factor 1, it is possible to separate a lung primary from a metastasis with a reasonable degree of certainty. Another lung-specific marker on the horizon is napsin A, which appears to complement thyroid transcription factor 1 in defining a lung primary. Objective. To present a practical review and to critique commonly used markers in the differential diagnosis of lung neoplasms and to list valuable immunohistochemical prognostic markers that the pathologist is called on to perform and interpret. Data Sources. A comprehensive PubMed data search and personal practical experience. Conclusions. With a panel of immunohistochemical markers, it is possible to distinguish or narrow down most lung neoplasms and separate them into meaningful therapeutic categories. In the future as more proteomic and genomic data surface, immunohistochemical markers to newly discovered antigens may become a routine part of prognostication. (Arch Pathol Lab Med. 2008;132: ) LUNG-SPECIFIC MARKERS The quest has been to find lung-specific tumor markers, but we have not yet identified any marker that has high fidelity for the lung such as prostate-specific antigen for the prostate. Perhaps one does not exist, but we will not know that unless an exhaustive search is made. Recently, a unique lung carcinoma microrna molecular profile has been identified showing promise in both diagnosis and prognosis. 1 A novel antibody, ES1, is claimed to stain lung carcinomas that are not picked up by thyroid transcription factor 1 (TTF -1) such as poorly differentiated lung carcinomas including large cell carcinoma, whereas nonlung carcinomas are negative or show weak staining. It is a single domain antibody raised against lung carcinoma cell line A549. ES1 antibody recognizes a variant form of carcinoembryonic antigen related adhesion molecule 6. However, ES1 is not ready for prime-time diagnostic use. Surfactant is exclusively produced by the lung and appears, intuitively, to be a good lung-specific marker. However, this has not been the case. Although displaying some specificity for lung and lung tumors, antibodies to surfactants used for immunohistochemistry lack sensitivity and specificity. 2 4 In fact according to some authors, only 63% Accepted for publication November 9, From the Department of Pathology, University of Texas Health Science Center at San Antonio. The author has no relevant financial interest in the products or companies described in this article. Reprints: Jaishree Jagirdar, MD, Department of Pathology, University of Texas Health Science Center, 7703 Floyd Curl Dr, San Antonio, TX ( of primary lung carcinomas stain with surfactant protein A and B. Conversely, 46% of metastatic carcinomas, including primary breast cancers, stain with surfactant A and B antibodies. 5 Enteric type of lung adenocarcinomas pose yet other problems because they tend to aberrantly express colonic-type markers. In the enteric type of pulmonary adenocarcinomas, lung-specific markers such as surfactant proteins, TTF -1, and napsin A (see later) tend to be lost, whereas the enteric-type (colonic) markers, CDX-2, cytokeratin (CK) 20, and MUC3, are aberrantly expressed. Cytokeratin 7 is retained in these primary enteric-type lung adenocarcinomas and in this context it appears to be most valuable in distinguishing lung cancer from colon cancer, which is CK7 negative. 6 Another lung-specific marker worth considering is napsin A. Napsin A is a functional aspartic proteinase that is expressed in the normal lung parenchyma in type II pneumocytes and the proximal and convoluted tubules of the kidney. 7 It is present in the lysosomes of type II pneumocytes and alveolar macrophages (probably secondary to phagocytosis) and to a lesser degree in pancreatic acini and ducts. 8 Napsin A is first detected at the outset of embryogenesis of type II pneumocytes and continues to be expressed on mature type II cells. 8 Napsin may be involved in maturation of the biologically active SP-B peptide. 9 In the lung, napsin A is identical to the protein spots TAO1 and TAO2 detected by 2-dimensional gel electrophoresis of lung adenocarcinoma. 10 It is expressed in the cytoplasm and is strongly positive in up to 80% of primary lung adenocarcinomas by immunohistochemistry. The poorly differentiated cancers do not stain as well as the well-differentiated ones. Squamous cell carcinomas 384 Arch Pathol Lab Med Vol 132, March 2008 Immunohistochemistry Diagnosis of Lung Carcinoma Jagirdar

2 and small cell carcinomas of the lung have been negative for napsin A (personal observation, September 2007). In our laboratory, a preliminary evaluation of more than 1000 cases suggests that napsin A is superior to TTF -1 in that its expression is stronger, more diffuse, and more sensitive (Figure 1, A through D). The strongest staining is seen in lung carcinoma and appears to be specific for a lung primary. However, 10% of renal cell carcinomas and thyroid carcinomas are also positive. Unlike lung adenocarcinomas, many renal and thyroid cancers end up being false positives most likely because of the presence of intrinsic biotin, which can be readily detected on negative controls (Figure 1, E and F). Less than 5% of assorted adenocarcinomas including those from the breast, pancreas, biliary tract, and colon stain with napsin A. Expression, when present, in breast and colonic adenocarcinomas, appears to be granular unlike that in the lung. In a handful of studies conducted by Japanese and Swedish workers, metastatic carcinomas except for renal cell carcinoma have been negative for napsin A In our study, napsin A stained 11% more lung adenocarcinomas than did TTF -1. Napsin B, another isoform of napsin, is transcribed exclusively in cells related to the immune system and lacks an in-frame stop codon and is believed to be a pseudogene. 10 Thyroid Transcription Factor 1 Thyroid transcription factor 1 was identified in 1989 as a nuclear tissue specific protein with DNA-binding activity that interacted with the thyroglobulin gene in the rat. 14 It is a 40-kd member of NKx2 family of homeodomain transcription factors. Thyroid transcription factor 1 regulates gene expression in the thyroid, lungs, and diencephalon during embryogenesis. In the lung, TTF -1 regulates the expression of surfactant proteins SP-A, SP-B, and SP-C and Clara cell secretory protein genes. Thyroid transcription factor 1 expression is highly specific for thyroid (follicular tumors and medullary carcinomas) and lung tumors, particularly lung adenocarcinomas. It has been widely used to detect the primary site of tumor For more details on the expression in thyroid neoplasms, please see the article by Fischer and Asa, Application of Immunohistochemistry to Thyroid Neoplasms, in this special issue. Newer keratins have been used to subclassify primary lung carcinomas such as CK5 and CK8 in a panel along with TTF -1. These are not as popular as CK7 and CK20 yet (see later). Most squamous cell carcinomas of the lung have the immunophenotype of CK5 /TTF -1. Many nonepidermoid lung carcinomas have the lung-specific phenotype CK5 /TTF -1 ; most small cell carcinomas of lung have the phenotype CK5 /CK8 /TTF -1, many adenocarcinomas ( 72%) are CK5 /TTF -1, and more than 50% of large cell carcinomas are CK5 /TTF -1. Thus, more than 50% of large cell carcinomas are of the same phenotype as adenocarcinomas. 15 Immunoreactivity for TTF -1 is detected in pulmonary neuroendocrine (NE) tumors and less frequently in small cell carcinomas from other sites such as the urinary bladder, prostate, cervix, vagina, and esophagus (Table 1). Anti TTF -1 antibody is particularly very useful in distinguishing pulmonary adenocarcinoma from other primary carcinomas, distinguishing mesothelioma (TTF -1 negative) from pulmonary adenocarcinoma (TTF -1 positive), and distinguishing small cell carcinoma (TTF -1 positive, CK20 negative) of the lung from Merkel cell carcinoma (TTF -1, CK20 positive). The above panel may also be useful in distinguishing NE tumors of the lung from welldifferentiated NE tumors from other sites, such as the intestine. However, TTF -1 is positive in 2% of intestinal carcinoids and between one third to one half of small cell carcinomas from other sites such as the uterine cervix and the prostate (Tables 1 and 2). ADENOCARCINOMA, PRIMARY IN THE LUNG VERSUS METASTATIC Table 3, A through G, shows how by using a profile of 3 markers, TTF -1, CK7, and CK20, it is possible to narrow the primary site of a metastatic adenocarcinoma in the lung. The immunohistochemical profile should always be used in conjunction with the clinical presentation, distribution of the lesions, and the morphology. When the tumor has the appropriate morphology and is positive for all 3 markers, namely TTF -1, CK7, and CK20, primary bronchioloalveolar carcinoma either mucinous or mixed type should be considered. Seldom the enteric type of primary lung adenocarcinoma, which has the morphologic features resembling intestinal type of carcinoma, may be in the differential diagnosis and is positive for all 3 markers listed here (Table 3, A). Most primary adenocarcinomas except mucinous carcinomas are positive for 2 of the 3 markers, namely TTF -1 and CK7 (Table 3, B). Most nonlung adenocarcinomas are positive for either CK7 or CK20 or both and negative for TTF -1 (Table 3, C and E; Figure 2, A and B; Figure 3, A through D). A small proportion of mucinous bronchioloalveolar lung carcinomas also carry this last profile and mimic metastases from a gastrointestinal primary. In this situation, a knowledge of the tumor distribution and additional markers is very useful. For more details on CK7 and CK20 profiles of other nonlung tumors, please see Figure 9 in the article by Bahrami et al, Undifferentiated Tumor: True Identity by Immunohistochemistry, in this special issue. Of the primary lung carcinomas, small cell carcinoma is the only cancer that is positive for TTF -1 and negative for both CK7 and CK20 (Table 3, D). We use monoclonal antibody 8G7G3/ 1 to TTF -1 from DakoCytomation (Glostrup, Denmark) and an automated Ventana system (Tucson, Ariz). It works well in our hands. The staining is crisp and nuclear. However, nonspecific cytoplasmic staining may be observed particularly in the liver and should not be interpreted as positive. Using polyclonal antibodies, Bejarano et al 5 have found focal TTF -1 staining in colonic and gastric carcinomas. See Tables 1 and 2 for a listing of nonlung tumors that are positive for TTF -1. METASTATIC BREAST CARCINOMA VERSUS PRIMARY LUNG ADENOCARCINOMA This is a common problem so it is mentioned separately. In this differential diagnosis, TTF -1 is the most specific marker with approximately 72% of lung adenocarcinomas being positive for TTF -1 and none of the breast tumors being positive. Estrogen receptor is positive in 72% of breast carcinomas and far less frequently positive in lung carcinoma ( 4%). Gross cystic disease fluid protein 15 is positive in 53% of breast carcinomas and 2% of lung adenocarcinomas. 16 Mammaglobin is positive in approximately 85% of breast carcinomas (Table 3, F) and less frequently positive in lung adenocarcinoma (17%). However, Arch Pathol Lab Med Vol 132, March 2008 Immunohistochemistry Diagnosis of Lung Carcinoma Jagirdar 385

3 Figure 1. Expression of napsin A (A and C) in lung adenocarcinoma compared with thyroid transcription factor 1 (TTF -1). Note that the TTF -1 is weaker (B) or absent (D) and less diffusely expressed as compared with napsin A. Expression of napsin A in renal (E) and thyroid (F) tumors is primarily a false-positive probably because of intrinsic biotin because the negative control in the picture shows brown staining. 386 Arch Pathol Lab Med Vol 132, March 2008 Immunohistochemistry Diagnosis of Lung Carcinoma Jagirdar

4 TTF-1 Table 1. Lung-Specific Markers Available for Immunohistochemistry Antibody Antigen Sensitivity Specificity Thyroid transcription factor 1 For lung cancer: adenocarcinoma 75%, squamous carcinoma 11%, large cell carcinoma 50% ES1 CEACAM6 Undifferentiated lung cancer, large cell and poorly differentiated adenocarcinoma are positive, which do not stain well with TTF-1 Surfactant A and B Napsin A (new) Surfactant protein A and B Functional aspartic proteinase Lung and thyroid tissue and tumor arising in these organs stain; small cell carcinomas from other organs are positive Other cancers show weak immunoreactivity 63% of primary lung cancers 46% of metastatic carcinomas to lung are positive including breast carcinoma 90% of lung adenocarcinomas express diffuse strong staining. Compared with TTF-1, napsin A appears to be superior in sensitivity and probably comparable in specificity CEACAM6 indicates carcinoembryonic antigen related adhesion molecule 6. Normal lung type II pneumocytes and alveolar macrophage lysosomes; proximal renal tubules in our hands stain. Thyroid carcinomas and renal cell carcinomas express napsin A. However, the majority of the expression appears to be false-positive in the latter, probably because of intrinsic biotin in these nonlung tumors using the same clone (304-1A5, Dako, Copenhagen, Denmark) another group from Japan, in their study of 238 breast cancers, found that mammaglobin 1 stained only 48% of breast carcinomas, significantly reducing its value as a routine positive marker for detection of primary breast carcinoma. 17 In addition, mammaglobin is positive in approximately 10% of endometrial carcinomas. 18 Cytokeratin 7 is not useful because both primary lung carcinomas and metastatic breast carcinomas are positive for CK7. Recommended panel for primary lung carcinoma versus metastatic breast carcinoma: TTF -1, estrogen receptor, gross cystic disease fluid protein 15, and/or mammaglobin. SMALL CELL CARCINOMA VERSUS SQUAMOUS CELL CARCINOMA WITH SMALL CELL FEATURES In small biopsy specimens with crush artifact, separating small cell carcinoma from poorly differentiated squamous cell carcinoma with or without small cell features is a problem. The markers that have been used are TTF -1 and p63 (a nuclear basal cell marker and a member of the p53 family involved in development of epithelial tissues) 19 and CK5 and CK8. 15 Small cell carcinomas are predominantly TTF -1 positive ( 90%), p63 negative, CK5 negative, and CK8 positive, and squamous cell carcinomas are typically TTF -1 negative ( 90%), p63 positive, CK5 positive, and CK8 negative. However, in another article by Au et al, 20 p63 staining using monoclonal antibody 4A4 was found to have a wider distribution with 96.9% of squamous cell carcinomas and 77% of small cell carcinomas expressing p63. Moreover, in this study they found p63 staining was proportional to the tumor grade in NE carcinomas and had an impact on the prognosis. 20 In our laboratory, we use TTF -1, chromogranin, and CK5. For practical purposes if the tumor is TTF -1, chromogranin, and CK8 negative but CK5 positive, in all likelihood it is a squamous cell carcinoma. Recommended panel for small cell carcinoma versus poorly differentiated squamous cell carcinoma: TTF -1, chromogranin, CK5, and/or CK8. SMALL CELL CARCINOMA VERSUS ATYPICAL CARCINOID This can be a diagnostic dilemma on small biopsy specimens with major prognostic and therapeutic impact on the patient. The key diagnostic features used to distinguish the two may not be present such as number of mitoses ( 10 mitoses/1 high-power field for small cell carcinoma; atypical carcinoid 2 10 mitoses/10 high-power fields), presence of obvious areas of necrosis on small biopsies, and nuclear molding with salt and pepper chromatin pattern. However, in this differential diagnosis, morphology is still the gold standard. In ambiguous cases as recommended by Pelosi et al, 21 Ki-67 (MIB-1) immunostaining is most helpful in which most small cell carcinomas reveal more than 50% labeling. Carcinoids including atypical carcinoids do show more frequent staining for NE markers such as chromogranin and synaptophysin than small cell carcinomas. However, this finding may not be helpful in small specimens suffering from sampling errors. 21 In this differential diagnosis, TTF -1 cannot be used as carcinoids, like small cell carcinomas, show TTF -1 staining, which can be quite variable in the carcinoids (0% 95%). 14 SQUAMOUS CELL CARCINOMA OF HEAD AND NECK VERSUS PRIMARY SQUAMOUS CELL CARCINOMA OF LUNG The reported incidence of pulmonary malignancy in patients with head and neck cancer ranges from 4.5% to 14%. 22,23 In the set of patients who develop a second malignancy in the lungs, as many as 31% will be synchronous. 24 Second malignancies of the lung are most frequently associated with primary laryngeal tumors, followed by pharynx. The risk of developing a metachronous second malignancy, when the larynx is the index tumor, is approximately 0.6% per year. Most second malignancies in the lung are squamous cell carcinoma, followed by adenocarcinoma, large cell lung cancer, and small cell lung cancer. Primary squamous cell carcinoma of the lung is difficult to distinguish from metastatic head and neck squamous cell carcinoma. Thyroid transcription factor 1 is positive in 7% to 10% of squamous cell carcinomas of lung Arch Pathol Lab Med Vol 132, March 2008 Immunohistochemistry Diagnosis of Lung Carcinoma Jagirdar 387

5 Table 2. Thyroid Transcription Factor 1 Expression in Tumors % Diagnosis Positive Adenocarcinoma, thyroid* 100 Alveolar adenoma 100 Carcinoid tumor, atypical, lung 100 Sclerosing hemangioma of lung cuboidal cells and polygonal cells 100 Adenocarcinoma, bronchioloalveolar, mixed 91 Carcinoma, oat cell, pulmonary 88 Adenocarcinoma, bronchioloalveolar, nonmucinous 87 Signet ring cell carcinoma, lung 85 Carcinoid tumor, metastatic, lung primary 80 Adenocarcinoma, lung and metastases 77 Carcinoma, adenosquamous, lung 75 Adenocarcinoma, mucinous, lung 73 Adenocarcinoma, enteric differentiation, lung 70 Carcinoma, large cell, metastatic 63 Carcinoma, small cell, prostate 58 Carcinoid tumor, lung 57 Carcinoma, rhabdoid features, lung, nonrhabdoid component 56 Carcinoma, small cell, metastatic to lung 50 Carcinoma, large cell, neuroendocrine 46 Carcinoma, small cell, bladder 34 Carcinoma, small cell, esophageal 34 Carcinoma, small, cell, vaginal 34 Carcinoma, undifferentiated type, metastatic 34 Carcinoid, atypical 26 Carcinoid, NOS 24 Adenocarcinoma, bronchioloalveolar, mucinous 21 Carcinoma, small cell, cervix 20 Synovial sarcoma 20 Carcinoma, large cell, NOS 20 Carcinoma, small cell, gastrointestinal 17 Adenocarcinoma, peritoneal, primary 8 Carcinoma, squamous cell, lung 7 Sarcoma, NOS 6 Adenocarcinoma, endometrial 6 Adenocarcinoma, colorectal, metastatic 4 Carcinoid tumor, intestinal 2 Cystadenocarcinoma, ovarian 2 Adenocarcinoma, colorectal 2 Mesothelioma, all types 0 * Anaplastic carcinomas of thyroid are less frequently positive. For more details on the expression in thyroid neoplasms, please see the article by Fischer and Asa, Application of Immunohistochemistry to Thyroid Neoplasms, in this special issue. This table was created from the ImmunoQuery Web site, now STATdx PathIQ. 27 NOS indicates not otherwise specified. and negative in head and neck carcinoma. So in this instance, TTF -1 is helpful but lacks sensitivity. Currently, there is no immunohistochemical marker that will help in that differential. Difference in clonality between the 2 lesions may be helpful. At the present time it is not practical to use clonality for diagnostic purposes, although it is feasible. Most cases are sorted out clinically. The current clinical recommendation is that whether a second malignant lesion is simultaneous (1 in head and neck and 1 in the lung), synchronous (2 primary cancers in the lung appearing within 6 months), or metachronous (2 primary lesions of the lung with the second one appearing after 6 months), it should be approached with a curative intent, because a 20% to 47% 5-year survival can be obtained. 25 Resection of a second malignant lesion in appropriate candidates should be performed in metastasis and second primaries, with or without a significant diseasefree interval, because an improvement in survival can be gained. SMALL CELL CARCINOMA OF LUNG VERSUS MERKEL CELL CARCINOMA Merkel cell carcinoma is an uncommon primary NE carcinoma of the skin first described as a trabecular carcinoma in 1972 by Cyril Toker. 26 It is generally categorized in the group of small round blue cell tumors together with small cell carcinoma, malignant lymphoma, Ewing sarcoma, rhabdomyosarcoma, and neuroblastoma and occurs in older men or women. It may pose a problem in patients who have metastases because it has a very varied morphology that includes small cell, plasmacytoid, large cell/pleomorphic, spindle cell, and multinucleated type. When it is the small cell type, it can closely mimic small cell carcinoma of the lung. However, the morphology is somewhat different from that in small cell carcinoma of the lung. In Merkel cell carcinoma, the nuclei may be vesicular as compared with salt and pepper in small cell carcinoma (Figure 4, A). Molding is not quite as prominent as in small cell carcinoma. The Merkel cell carcinoma is CK20 positive (in a dotlike fashion, Figure 4, B) and TTF -1 negative. Rarely, small cell carcinoma can be CK20 positive (Table 3, G). However, Merkel cell carcinomas are not TTF -1 positive. Other markers in this differential diagnosis are TIMP-2 and keratin 35 11, both of which are strongly positive in small cell carcinoma and negative in Merkel cell carcinoma. 27 Other markers positive in Merkel cell carcinoma that confirm its NE nature are chromogranin, synaptophysin, neurofilament protein, and CD56. Fli-1 and CD99 are also positive in Merkel cell carcinoma with potential confusion with Ewing sarcoma. Recommended panel in the differential diagnosis of small cell carcinoma of lung and Merkel cell carcinoma: TTF -1 and CK20. SMALL CELL CARCINOMA VERSUS PRIMARY BASALOID CARCINOMA OF THE LUNG Basaloid carcinomas are rare and composed of small undifferentiated round cells and may be confused with high-grade NE carcinoma and are presumed to arise from the bronchial basal cell. However, basaloid carcinomas, whether primary or metastatic to the lung, do not have NE features. Primary basaloid carcinoma of the lung is positive for both high- and low-molecular-weight keratins, whereas small cell carcinoma is positive for the low-molecular-weight keratin only and chromogranin. Recommended panel in the differential diagnosis of small cell carcinoma of lung versus basaloid carcinoma of lung: chromogranin, AE1 (low molecular weight) or 35 11, AE3 (high molecular weight) separately. METASTATIC MELANOMA, CHORIOCARCINOMA, THYMIC CARCINOMA, AND OTHER TUMORS Only select metastatic tumors are discussed here. For complete immunohistochemical profiles of other tumors, please see Figure 4 and Table 2 in the article by Bahrami et al, Undifferentiated Tumor: True Identity by Immunohistochemistry, in this special issue. Metastatic melanoma needs to be distinguished from the rare primary melanoma of the lung and from other more common primary carcinomas of the lung. The distribution of the lesion and prior history of melanoma is key in this differential diagnosis. There are no markers to 388 Arch Pathol Lab Med Vol 132, March 2008 Immunohistochemistry Diagnosis of Lung Carcinoma Jagirdar

6 Table 3. Differential Expression of Thyroid Transcription Factor 1 (TTF-1), Cytokeratin (CK) 7, and CK20 in the Most Common Primary and Metastatic Tumors of the Lung* Diagnosis TTF-1, % CK7, % CK20, % A. TTF-1 CK7 CK20 Bronchioloalveolar Carcinoma Adenocarcinoma, bronchioloalveolar, mixed Adenocarcinoma, mucinous, lung B. TTF-1 CK7 CK20 Tumors Adenocarcinoma, bronchioloalveolar, nonmucinous Adenocarcinoma, enteric differentiation, lung Adenocarcinoma, follicular, papillary thyroid Adenocarcinoma, lung Adenocarcinoma, lung, metastatic Sclerosing hemangioma of lung Signet ring cell carcinoma, lung C. TTF-1 CK7 CK20 Tumors Adenocarcinoma, ampullary Adenocarcinoma, bronchioloalveolar, mucinous Carcinoma, signet ring cell, stomach Carcinoma, transitional cell, NOS Cystadenocarcinoma, mucinous, ovarian, NOS D. TTF-1 CK7 CK20 Tumors Carcinoma, oat cell, pulmonary E. TTF-1 CK7 CK20 Adenocarcinoma, endometrial Adenocarcinoma, gallbladder Adenocarcinoma, gastric Adenocarcinoma, metastatic Adenocarcinoma, pancreas Adenocarcinoma, peritoneal, primary Carcinoma, breast Carcinoma, breast, metastatic Carcinoma, embryonal, NOS Carcinoma, large cell, NOS Carcinoma, signet ring, breast Carcinoma, squamous cell, cervical Cholangiocarcinoma Cystadenocarcinoma, ovarian Malignant mesothelioma, localized Mesothelioma, NOS Mucoepidermoid carcinoma, lung Neuroendocrine carcinoma, high grade, ampulla of Vater Papillary cystadenocarcinoma metastatic F. Primary Lung Adenocarcinoma Vs Metastatic Breast Carcinoma Immunostain Class Lung Adenocarcinoma, % Positive Breast Carcinoma, % Positive TTF Mammaglobin ERP 4 72 GCDFP G. Small Cell Carcinoma Vs Merkel Cell Carcinoma Immunostain Class Small Cell Carcinoma of Lung, % Positive Merkel Cell Carcinoma, % Positive CK TTF TIMP H11 (keratin 903) 75 0 * NOS indicates not otherwise specified; ERP, estrogen receptor protein; GCDFP-15, gross cystic disease fluid protein 15; and TIMP, tissue inhibitor of matrix metalloproteinase. separate a primary melanoma from a metastatic one to the lung. Occasionally, small cell melanoma variants may mimic small cell carcinoma of the lung. Wilson and Moran 28 reported 8 cases of primary malignant melanoma of the lung that presented as solitary, central endobronchial neoplasms, resulting in a picture that closely resembled carcinoid tumor or poorly differentiated non small carcinoma of the lung. In situ component was present in half the lesions of melanoma. The immunohistochemistry profile is similar to melanomas elsewhere in the body in that they are S100, HMB-45, and Mart-1 positive and mostly negative for keratin. The caveat is that between 2% and 5% of melanomas can be focally keratin positive (CAM 5.2 and AE1/AE3), 2% are epithelial membrane antigen positive, and 3% are S100 negative. Conversely, 11% of lung carcinomas may be S100 positive. Arch Pathol Lab Med Vol 132, March 2008 Immunohistochemistry Diagnosis of Lung Carcinoma Jagirdar 389

7 Figure 2. Low (A) and high (B) magnifications of subpleural mucinous carcinoma growing in a lepidic fashion simulating a primary mucinous bronchioloalveolar carcinoma. The patient had multiple pleural nodules and a mass in the head of the pancreas. Recommended panel in the differential diagnosis of melanoma versus lung carcinoma: pankeratin, S100, TTF -1, and Mart-1. Metastatic choriocarcinoma can be confused with primary lung carcinoma with giant cells. However, if the classic feature of hemorrhage in association with syncytiotrophoblasts and cytotrophoblasts is present, a diagnosis of choriocarcinoma can be made. Human chorionic gonadotropin ( -hcg) is positive in choriocarcinoma. Large cell carcinoma is mostly -hcg negative. On rare occasions, some primary lung carcinomas are -hcg positive. In a recently published article, -hcg was elevated in the serum in up to 22% of large cell carcinomas and was demonstrated in the tumor tissue by immunohistochemistry in 9% to 93% of the cases. In this review, it was proposed that the -hcg expressing tumors were more aggressive because of blockade of the binding site of one of the transforming growth factor (TGF- ) receptor chains, preventing TGF- induced receptor association, intracellular signaling, and apoptosis. 29 In addition, large cell carcinomas may express keratin in less than 50% of the cases, further adding to the confusion. HLA-G (MHC class 1) is Figure 3. Same case as in Figure 2. A panel of immunohistochemical markers reveals the tumor to be cytokeratin (CK) 7 positive (A), CK20 positive (B), and thyroid transcription factor 1 (TTF -1) negative (D). Although mucinous bronchioloalveolar carcinomas of the lung are TTF -1 negative ( 79%) and can acquire CK20 (67%), the CA 19-9 (C) is usually negative. Pancreatic carcinomas on the other hand are usually positive for CA So the above panel along with the distribution of the tumor as pleural nodules is most consistent with a pancreatic primary. 390 Arch Pathol Lab Med Vol 132, March 2008 Immunohistochemistry Diagnosis of Lung Carcinoma Jagirdar

8 Figure 4. A, Hematoxylin-eosin stained section of a Merkel cell carcinoma. Note the vesicular nuclei and lack of molding as contrasted with small cell carcinoma. B, Cytokeratin 20 staining in a Merkel cell carcinoma in a dotlike fashion unlike small cell carcinoma. positive in choriocarcinoma as well as in large cell lung carcinoma and cannot be used in this differential diagnosis. Thyroid transcription factor 1 is positive in up to 50% of large cell carcinomas. In the TTF -1 negative cases, the final diagnosis rests with the clinical presentation and the morphology. Recommended panel in the differential diagnosis of primary large cell carcinoma or pleomorphic carcinoma versus choriocarcinoma: TTF -1 and hcg. THYMIC CARCINOMA AND THYMOMA VERSUS PRIMARY LUNG CARCINOMA This is rarely a problem when there is an infiltrative mediastinal mass with a lesion in the lung. CD5, 67-kd surface glycoprotein receptor and a T-cell marker, is aberrantly expressed in thymic carcinoma. 30 CD5 is also aberrantly expressed by neoplastic B cells in lymphoproliferative disorders, small lymphocytic lymphoma/chronic lymphocytic leukemia, and mantle cell lymphoma, which are thought to arise from CD5 perifollicular center lymphocytes. Borderline thymic tumors, with features intermediate between those of thymoma and thymic carcinoma, weakly express immunoreactivity for CD5 similar to that observed for lymphoepithelioma-like carcinomas. Benign and invasive thymomas studied for CD5 immunoreactivity are uniformly negative; NE tumors, including carcinoids and small cell carcinomas, are uniformly negative for CD5. Sixty-one other malignant neoplasms (lung, cervix, thyroid, prostate, mixed germ cell tumors, melanoma, and mesothelioma) likely to occur as primary in or metastasize to the anterior mediastinum are negative for CD5 immunoreactivity. CD99 is positive in immature lymphocytes of the thymus in benign and some borderline thymic lesions and is negative in thymic carcinomas. Thymomas are CK7 negative, whereas lung adenocarcinomas are CK7 positive. Thymomas including thymic carcinomas are TTF -1 negative. Recommended panel of thymic carcinoma versus primary lung carcinoma: CD5, CD99, TTF -1, and CK7. SELECT PROGNOSTIC MARKERS FOR TARGETED CHEMOTHERAPY Select prognostic markers and markers for targeted chemotherapy that show promise are epidermal growth factor receptor (EGFR), c-erb-b2, cell cycle markers p16 INK4A, Ki-67, p53, Bcl-2, vascular endothelial growth factor C, and CD44. Identification of prognostic markers that add value beyond the TNM staging system is a priority in lung cancer, particularly in stage I. Survival for patients with stage I disease is 70% despite curative surgical resection implying that our current staging criteria are imperfect. The use of molecular markers as a strategy to refine risk stratification beyond staging 31 has been validated in retrospective studies and is under evaluation prospectively. The markers effect malignant transformation and the metastatic process through 5 primary oncogenic mechanisms: cell growth stimulation (EGFR, Erb-B2), cell cycle regulation (p16 INK4A, retinoblastoma [Rb], Ki-67), interference with apoptosis (p53, Bcl-2), tumor angiogenesis (factor VIII related antigen, vascular endothelial growth factor C), and invasive cellular adhesion (CD44) So far, the majority of the factors do not show independent prognostic value. Immunohistochemistry is available for these markers. Some markers that show promise and/or are currently in vogue are discussed in the following. EGFR and Erb-B2 The EGFR/Erb-B family of transmembrane receptor tyrosine kinases consists of 4 members: EGFR/human epidermal growth factor receptor 1 (HER-1)/Erb-B1, HER-2/ c-neu/ Erb-B2, HER-3/Erb-B3, and HER-4/Erb-B4. 38 These proteins share 40% to 50% amino acid homology and have a common domain organization. On activation by the ligand, these receptors signal through the RAS RAF mitogen-activated protein kinase and phosphatidylinositol 3 -kinase pathways, which play critical roles in regulating cell proliferation and survival. The overall EGFR expression rate in non small cell lung carcinoma (NSCLC) is 51%. Expression is less frequent in adenocarcinoma (46.2%) than in squamous cell carcinoma (82.6%). 39 In a meta-analysis, three quarters of the studies on NSCLC did not find EGFR expression to be of prognostic significance. EGFR is found to act as a strong prognostic indicator in head and neck, ovarian, cervical, bladder, and esophageal cancers. 40 In these cancers, increased EGFR protein expression is associated with reduced recurrence-free or overall survival rates. EGFR gene amplification occurs in 6% of all NSCLCs and 28% of squamous cell lung cancers. The molecular correlates of a longer survival are emerging with EGFR gene amplification as detected by fluorescence in situ hybridization and are associated with the better response to gefitinib, an EGFR blocker. 41 Advent of oral EGFR tyrosine kinase inhibitor therapy seems to show some promise as it is simple to administer with minimal side effects (diarrhea and rash, which actually predict a Arch Pathol Lab Med Vol 132, March 2008 Immunohistochemistry Diagnosis of Lung Carcinoma Jagirdar 391

9 better response; the rash can be pretreated and is not a serious problem). This would be ideal for underdeveloped countries where cost and ease of administration are of prime importance. Initial studies using one brand of EGFR tyrosine kinase inhibitor, gefitinib, an anilinoquinazolone, have failed to show a survival benefit over best supportive care. Similar findings have been obtained using other brands such as erlotinib. Certain EGFR mutations on exons 19 to 21 and gene amplification have also been implicated in a better prognosis although the jury is still out on this issue. 42 Conversely, K-ras mutations have been associated with a worse prognosis. In a recent publication, 43 it was found that the 2 most common EGFR mutations were identified in 24% of tumors from patients with NSCLC. EGFR mutation was associated with Asian ethnicity and being a never smoker (P.001). Among patients with EGFR mutations, 39% had EGFR L858R, whereas 61% had an EGFR exon 19 deletion. After treatment with erlotinib or gefitinib, patients with EGFR mutations had a median overall survival of 20 months. After treatment with erlotinib or gefitinib, patients with EGFR exon 19 deletions had significantly longer median survival than patients with EGFR L858R (34 vs 8 months; log-rank P.01). These findings warrant confirmation in prospective studies particularly in patients from East Asia, women, and never smokers. The paradigm has now shifted to individualized targeted therapy leaving far greater room for customized therapy rather than response statistics for all NSCLCs. The prevailing belief is that biologic blockers such as EGFR tyrosine kinase inhibitors (gefitnib and erlotinib) will be very useful in a subset of lung cancer patients such as women, nonsmokers, bronchioloalveolar carcinoma, adenocarcinoma, and certain ethnic groups. However, it is likely that the true prognostic significance of the EGFR has been underestimated as the published studies only assess total cellular EGFR levels, rather than the activated form of the receptor, and are not standardized with regard to patient populations or assay methods. Failure to detect a prognostic significance for EGFR in any one cancer type including NSCLC does not necessarily preclude individual patients from benefiting from anti-egfr therapies such as small-molecule EGFR inhibitors gefitinib and erlotinib. Antibodies may be available in the near future to EGFR mutations thus revisiting the value of immunohistochemistry, which is the preferred choice of detection because of its ease of performance. A review of 44 reports on HER-2 expression in NSCLC showed an overall positive staining rate of 35%, using different cutoffs chosen by the various investigators. 44 HER- 2 overexpression differed significantly between histologic subtypes: 38% in adenocarcinoma, 16% in squamous cell carcinoma, and 18% in large cell carcinoma. Among 20 studies, with data evaluable for meta-analysis, 8 immunohistochemistry studies reported a significant detrimental effect of HER-2 expression on survival, whereas 10 reported no significant prognostic value. A meta-analysis of these studies suggested that HER-2 overexpression is a poor prognostic marker for 3-year and 5-year survival, especially among patients with adenocarcinoma. Two additional studies were published after the meta-analysis. A study on tissue microarray of samples from 284 patients reported that HER-2 expression was a significant predictor of poor survival in patients with lung adenocarcinoma, but only 2 of 80 patients expressed this protein. 45 A second study on 345 patients also included a rather extensive comparative analysis of various scoring criteria but reported no noteworthy association between HER-2 expression and prognosis. 46 Overall, the prognostic significance of HER-2 appears to be controversial. CELL CYCLE REGULATORS AND REGULATORS OF APOPTOSIS Yooetal 47 suggest that p16 INK4A and Bcl-2 are favorable prognostic indicators, independent of the TNM stage in NSCLC. However, Bcl-2 has an antiapoptotic effect leading to tumor cell survival and seems counterintuitive to a favorable outcome when overexpressed. In another study, Mohamed et al 48 recently showed that in pn2 disease, patients with positive p21 and p16 INK4A protein expression in their primary tumors are expected to have a favorable postoperative prognosis in multivariate analysis and may be candidates for primary resection. The loss or inactivation of p16 INK4A results in unchecked activity of cyclin dependent kinase 4 that phosphorylates Rb protein, thus releasing E2F to exert its transcriptional activity in the G 1 phase. p16 INK4A is inactivated in approximately 50% (range, 25% 60%) of NSCLCs. In approximately 30% of tumors, inactivation is by homozygotic deletion. Inactivation by mutation is rare. Promoter hypermethylation also occurs. Among 12 studies that have assessed the clinical effect of p16 INK4A protein expression, 6 reported that retention of staining in tumor cells was a good prognostic marker. 39 Immunohistochemistry is available for all these classes of markers and will be a very important part of the risk stratification for lung cancers in the near future. It will also be important in developing personalized targeted therapy. Pathologists should be in the forefront of such an effort. We are also beginning to realize that the risk factors may be different in women versus men. Among women, 4 factors were found to be associated with increased risk of cancer-specific death: p53, CD44, factor VIII related antigen, and Rb. Among men, there is only 1 significant risk factor, Erb-B2. Among patients with adenocarcinoma, there are 3 significant predictors of cancer-specific death: p53, CD44, and factor VIII related antigen. Among patients with squamous cell carcinoma, Erb-B2 was the only factor with an increased risk. 44 DNA SYNTHESIS AND REPAIR GENES RRM1 AND ERCC1 EXPRESSION AND PROGNOSIS IN LUNG CANCER RRM1, the regulatory subunit of ribonucleotide reductase, is involved in carcinogenesis, tumor progression, and the response of non small cell lung cancer to treatment. RRM1 is involved in DNA synthesis and repair. The expression of RRM1 and ERCC1, an excision repair crosscomplementation group 1 protein, show prognostic value in lung cancer and have been studied in formalin-fixed, paraffin-embedded tissue using immunofluorescence and automated quantitation. RRM1 significantly correlates with the expression of ERCC1. The median disease-free survival is better for the high RRM1 expressors (120 months) as compared with the low expressors (54.5 months). Zeng et al 49 found that RRM1 and ERCC1 were both useful survival markers after surgical treatment of early-stage, non small cell lung cancer. However, the find- 392 Arch Pathol Lab Med Vol 132, March 2008 Immunohistochemistry Diagnosis of Lung Carcinoma Jagirdar

10 Figure 5. A, Hematoxylin-eosin stained section of a sugar tumor. B, HMB-45 positive sugar tumor. Figure 6. Sclerosing hemangioma. A, Thyroid transcription factor 1 positive lining cells and cells in solid areas. B, Epithelial membrane antigen staining the cells in the solid areas and lining cells. Figure 7. A, Hematoxylin-eosin stained section of a meningothelial nodule. B, Progesterone receptor positivity in the nucleus of lesional cells. ings of a better prognosis in early-stage lung cancer are contradictory to the findings in advanced lung cancer in which both proteins RRM1 and ERCC1 serve as markers of chemoresistance and poor survival. Gazdar, 50 in his review article, suggests that the possible explanation for this contradiction is that removal of nucleotide excision pathway drug-dna adducts formed after chemotherapy may lead to drug resistance, hence poor prognosis in advanced lung cancer. Therefore, DNA repair is good for prevention of early mutagenesis (early-stage lung cancer). However, it is bad if excision of drug-dna adducts occurs rendering chemoresistance in advanced lung cancer. Arch Pathol Lab Med Vol 132, March 2008 Immunohistochemistry Diagnosis of Lung Carcinoma Jagirdar 393

11 Disease Eosinophilic granuloma (Langerhans cell histiocytosis) Intravascular bronchovascular tumor (epithelioid hemangioendothelioma of the lung) Sugar tumor Sclerosing hemangioma Immunohistochemical Markers Cd1a, S100, CD68, CD31 (CD1a is more sensitive and specific than S100) CD31, CD34, factor VIIIR antigen HMB-45, Myo-D1, S100, Leu-7 Solid area: EMA, keratin, TTF-1 Lining cells: keratin, TTF-1 LAM HMB-45, SMA,ER, PR IMT KS Minute pulmonary meningothelial-like nodules SMA, desmin /, LMW keratin, ALK-1 / HHV-8, CD31, factor VIIIR antigen EMA, vimentin, keratin, chromogranin Table 4. Unusual Pulmonary Lesions* Lesional Characteristics Pulmonary Langerhans cell histiocytosis occurs almost exclusively in smokers and younger individuals and has a bronchial distribution, which later involves the interstitium. The cellular phase contains characteristic histiocytes containing kidney bean shaped/convoluted nuclei admixed with variable number of eosinophils, plasma cells, and alveolar macrophages. Characteristic stellate scarring occurs in the later stages. The course is very variable. Name is a misnomer because tumor is of vascular derivation. Staining in vacuoles (primitive vascular lumina) is characteristic. Looks like EH elsewhere in the body with sclerosed papillary structures and chondroid matrix. So named because of clear cell morphology because of glycogen accumulation. Can be confused with metastatic renal cell carcinoma. However, sugar tumors are bland and lack mitoses, necrosis, and thick-walled vessels. They belong to a family of PEComas and include angiomyolipomas, LAM (see later), and others. Name is a misnomer because the tumor is not derived from endothelial cells. Occurs in young women. The lesions are very variegated and display cellular areas along with blood-filled spaces, foam cells, sclerosis, and papillary structures. Rarely, lymph node metastases occur. Abnormal smooth muscle proliferation around the bronchovascular tree and pleura, associated with tuberous sclerosis. It is seen primarily in women of reproductive age. Older synonyms: inflammatory pseudotumor, plasma cell granuloma. The lesion occurs in young adults and 15% occur in children. Pediatric tumors are positive for ALK-1 but not adult tumors. They look like IMTs elsewhere in the body. HHV-8 is a very specific and sensitive marker for KS in the lung in small biopsy specimens. Previously considered as minute chemodectoma-like bodies, the nodules are found incidentally. Perivenular location of bland spindle to rounded cells extending into the interstitium resembling cells seen in meningiomas. These are reactive usually. (May be confused with tumorlets, which are less than 5 mm and are peribronchiolar and chromogranin positive, hence of neuroendocrine derivation.) Cell Derivation and References Langerhans cells that are normally located in the bronchus-associated lymphoid tissue and interspersed between epithelial cells and contain Birbeck granules 58 Endothelial cell PEC 59,60 (Figure 5, A and B) Primitive lung-specific epithelial cell, precursor of type II pneumocyte 61 (Figure 6, A and B) PEC 62,63 Myofibroblasts Lymphatic endothelium; Si et al 64 Meningothelial cell rests (Figure 7, A and B) * EH indicates epithelioid hemangioendothelioma; LAM, lymphangioleiomyomatosis; PEC, perivascular epithelioid cell; EMA, epithelial membrane antigen; TTF-1, thyroid transcription factor 1; SMA, smooth muscle actin; ER, estrogen receptor; PR, progesterone receptor; IMT, inflammatory myofibroblastic tumor of lung; LMW, low molecular weight; KS, Kaposi sarcoma; and HHV-8, human herpesvirus 8. MISCELLANOUS PROGNOSTIC MARKERS OF LUNG CARCINOMA Fascin, an actin bundling protein that induces cell membrane protrusions and increases the motility of both normal and neoplastic cells, was useful in predicting lymph node metastases and was a predictor of aggressiveness in stage I non small cell lung cancer. 51 CD117, a transmembrane tyrosine kinase receptor, made conspicuous by its presence in gastrointestinal stromal tumors, is also expressed predominantly in small cell lung carcinoma and less frequently in other lung cancers. When it is present, it predicts an aggressive behavior STAT-3 is a signal transactivation factor and is at the point of convergence of many transcription factors responsible for proliferation, cell migration, and apoptosis. Recently, we have shown that it is expressed in most lung non small cell carcinomas. Because its value as a potential target has been shown in other tumors via small molecule tyrosine kinase inhibitors, it may also be a valuable target in NSCLC. 56 UNUSUAL TUMORS AND LESIONS OF THE LUNG Immunohistochemistry is valuable in distinguishing and revealing the histogenesis of unusual lung tumors (Table 4). LYMPHOID LESIONS OF THE LUNG A summary of the markers useful in the common lymphoid lesions of the lung is provided in Table For more information on lymphomas, please see the article by Higgins et al, Application of Immunohistochemistry in the 394 Arch Pathol Lab Med Vol 132, March 2008 Immunohistochemistry Diagnosis of Lung Carcinoma Jagirdar

12 Type of Lymphoma Table 5. Immunohistochemical Features of Primary Lymphomas of Lung* Antibody Directed Against CD20 Pax-5 CD79a CD43 CD5 CD10 CD23 CD15 CD30 Cyclin DI BCL-2 BCL-10 EBV Monoclonal Light Chain Marginal zone B cell S N N N N N N N S N S Chronic lymphocytic leukemia/small cell lymphocytic lymphoma S S N N N N S N N S Mantle cell lymphoma S S N N N N S S N N S Follicular lymphoma N N S N N N N S N N S Hodgkin lymphoma S S S N N N N S S N S N S N Lymphomatoid granulomatosis S U U N N N N N N N N U S N Intravascular lymphoma R S U N N N S U U U U Primary effusion lymphoma N N N S N N N N S U U U S N Pyothorax-associated lymphoma S N N N N N U U U S N * EBV indicates Epstein-Barr virus;, reactivity almost always diffuse, strong positivity; S, sometime positive; N, almost always negative; U, uncertain; and R, rare cells positive. Reprinted from Hammar 57 with permission from Elsevier, copyright Diagnosis of Non-Hodgkin and Hodgkin Lymphoma, in this special issue. 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