Immunohistochemical Distinction Between Merkel Cell Carcinoma and Small Cell Carcinoma of the Lung

Merkel cell carcinoma is a rare and aggressive form of skin cancer of neuroendocrine origin. Its treatment involves wide excision and radiotherapy but no effective therapy exists for advanced disease. Upregulation of the platelet-derived growth factor receptor family of tyrosine kinases, PDGFRA and KIT, has a crucial role in cancer development. Several studies have shown expression of the tyrosine kinase receptor KIT (CD117) in Merkel cell carcinoma. In this study, we examined the expression and mutational status of KIT and PDGFRA in 14 primary and 18 metastatic Merkel cell carcinoma. The expression of KIT and PDGFRA and their respective ligands, stem cell factor (SCF) and PDGFA, was assessed by immunohistochemistry. In addition, we analyzed KIT exons 9, 11, 13 and 17, and PDGFRA exons 10, 12 and 18 for the presence of activating mutations. We found that only 53% of cases of Merkel cell carcinoma expressed KIT, which was mostly seen as diffuse weak staining, and SCF expression was observed only in 31% of cases. In contrast, 87 and 81% of cases expressed PDGFRA and PDGFA, respectively. We observed coexpression of SCF and KIT in only 5 of 32 cases (16%) whereas 25 of 31 cases (81%) showed coexpression of PDGFRA and its ligand PDGFA. While we documented silent mutations in exon 17 of KIT and exons 10, 12 and 18 of PDGFRA, we were not able to identify any known activating mutations. Our results indicate that there is no correlation between positive immunostaining and occurrence of activating mutations in KIT and PDGFRA. Moreover, the presence of KIT/SCF and PDGFRA/PDGFA coexpression in a proportion of cases may indicate an autocrine/paracrine stimulation loop. We think therefore that imatinib mesylate is less likely to be an effective therapy for Merkel cell carcinoma, unless activating mutations exist in other exons of these receptor kinases.

Section: Discussionsupporting

confidence: 90%

Silent mutations in KIT and PDGFRA and coexpression of receptors with SCF and PDGFA in Merkel cell carcinoma: implications for tyrosine kinase-based tumorigenesis

Kartha

Sundram

2008

“…Eventually 763 cases of cutaneous Merkel cell carcinoma were retrieved from the English literature and included in our review. 15,[18][19][20][21][22][23][24][25][26][27][28][29] …”

Section: Case Selectionmentioning

confidence: 99%

Merkel cell carcinoma of lymph node with unknown primary has a significantly lower association with Merkel cell polyomavirus than its cutaneous counterpart

Pan

Chen

et al. 2014

Rare cases of Merkel cell carcinoma have been encountered in lymph nodes with unknown extranodal primary, which exhibit similar morphologic and immunophenotypic features to those in primary cutaneous Merkel cell carcinomas. However, it is uncertain whether the nodal Merkel cell carcinoma is a primary tumor of the lymph node or represents a metastasis from an occult or regressed extranodal lesion. To establish an accurate diagnosis of the nodal Merkel cell carcinoma can be challenging because of significant morphologic mimics, including lymphoblastic lymphoma and metastatic small cell carcinoma. Moreover, there is no consensus for a diagnostic term, and many different terms have been used, which can be confusing and may not fully reflect the nature of nodal Merkel cell carcinoma. In this study, we investigated the detailed clinicopathologic features of 22 nodal Merkel cell carcinomas, with comparison to 763 primary cutaneous cases retrieved from the literature. Overall, the nodal and cutaneous Merkel cell carcinomas shared similar clinical presentations, morphologic spectrum, and immunophenotype; both were mostly seen in elderly male with a typical neuroendocrine morphology. Most of cases expressed CK20, synaptophysin, and chromogranin A; and PAX5 and TdT were also positive in majority of cases. However, nodal Merkel cell carcinomas had a significantly lower association with Merkel cell polyomavirus than cutaneous cases (31% vs 76%, P ¼ 0.001). Therefore, these two entities may arise from overlapping but not identical biological pathways. We also recommend the use of the diagnostic term 'Merkel cell carcinoma of lymph node' to replace many other names used.

“…14 Because neuroendocrine carcinoma subtyping for site of origin is critical for clinical management, research has been dedicated to finding site and subtype-specific diagnostic markers. [15][16][17][18] Several biomarkers have been utilized to determine tumor subtype. eg, calcitonin is expressed by a majority of medullary thyroid carcinomas, and CK20 is characteristically expressed in Merkel cell carcinoma.…”

mentioning

confidence: 99%

“…eg, calcitonin is expressed by a majority of medullary thyroid carcinomas, and CK20 is characteristically expressed in Merkel cell carcinoma. 15,16 Some authors have proposed a panel of immunohistochemical stains (CDX-2, PDX-1, NESP-55, TTF-1, PAX8) to distinguish between differentiated gastrointestinal, pancreatic, and pulmonary neuroendocrine carcinoma with some success in tumor specificity; 17,18 however, this approach has seen limited utility in clinical practice due to relatively low sensitivities. Functional neuroendocrine carcinoma may have characteristic serology results and clinical presentation (eg, gastrinoma, insulinoma, etc.).…”

mentioning

confidence: 99%

A 92-gene cancer classifier predicts the site of origin for neuroendocrine tumors

Kerr

Schnabel²,

Sullivan

et al. 2014

A diagnosis of neuroendocrine carcinoma is often morphologically straight-forward; however, the tumor site of origin may remain elusive in a metastatic presentation. Neuroendocrine tumor subtyping has important implications for staging and patient management. In this study, the novel use and performance of a 92-gene molecular cancer classifier for determination of the site of tumor origin are described in a series of 75 neuroendocrine tumors (44 metastatic, 31 primary; gastrointestinal (n ¼ 12), pulmonary (n ¼ 22), Merkel cell (n ¼ 10), pancreatic (n ¼ 10), pheochromocytoma (n ¼ 10), and medullary thyroid carcinoma (n ¼ 11)). Formalinfixed, paraffin-embedded samples passing multicenter pathologist adjudication were blinded and tested by a 92-gene molecular assay that predicts tumor type/subtype based upon relative quantitative PCR expression measurements for 87 tumor-related and 5 reference genes.