Case of the Month: Inguinal Lymph Node

This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2013, case 14, and is Merkel cell carcinoma.

The tumor grows in solid sheets and broad bands and extends into perinodal adipose tissue without desmoplastic response. Scattered minute foci of coagulative necrosis are identified. The neoplastic cells display minimal cytoplasm, vague cytoplasmic borders, and have uniform nuclei with small nucleoli. Mitoses are numerous. By immunohistochemistry, the neoplastic cells display peri-nuclear dot-like positivity for cytokeratin 20 and are diffusely positive for synaptophysin. Prostate specific antigen, S100, and TTF-1 are negative. The pattern of cytokeratin 20 expression is one of the most helpful features confirming the diagnosis of Merkel cell carcinoma (MCC). Small cell carcinoma of the lung is practically excluded by the results of immunohistochemical studies (TTF-1 negative and cytokeratin 20 positive). Melanoma and lymphoma are cytokeratin negative.

MCC is a neuroendocrine cutaneous carcinoma with mortality higher than that of melanoma. Although MCC is rare, its incidence is rising, most likely due to ultraviolet exposure (including ultraviolet A phototherapy) and immunosuppression (e.g., organ transplant or HIV patients). MCC most commonly occurs in sun-exposed skin, especially on the head and neck. A minority of patients presents with nodal or visceral disease with occult primary site. The lack of clinically apparent cutaneous disease is generally regarded to be the result of tumor regression at the primary site or of a primary nodal carcinoma.

Although several histological types of MCC (i.e., small cell type, trabecular type) were described, these have no prognostic significance. However, cutaneous MCCs with a nodular growth pattern have a better prognosis than those with an infiltrative morphology and this parameter is part of the CAP cancer protocol for MCC.

The most important recent development in our understanding of MCC was the identification of a novel polyomavirus—Merkel cell polyomavirus (MCV)—in up to 80% of MCCs. Several reports showed MCV to be a part of the normal cutaneous flora: MCV infection occurs in early childhood and the highest MCV DNA levels are detected in MCC patients. The transforming activity of MCV depends on MCV integration into host genome and mutation of the MCV large T antigen. The lack of these two events distinguishes MCV in MCC from MCV in healthy skin.

The potential clinical or morphologic differences between MCV-positive and MCV-negative MCC cases are presently unknown; however, some data indicate a more favorable prognosis for MCV-positive cases. Although viral capsid protein-1 (VP1) antigen could not be detected immunohistochemically even in MCV-positive MCC, in some studies, higher titers of anti-VP1 antibody in the serum were associated with longer progression-free survival.

Until recently, several different staging systems were used. For the first time, the 7th edition of the AJCC Cancer Staging Manual has a chapter dedicated specifically to MCC. (Note: the TNM criteria for MCC involving eyelids are distinct from those for MCC affecting other sites). The current AJCC staging system is based on prognostic analysis of over 5,800 patients from the National Cancer Data base with median follow-up of more than 5 years.The (T) staging depends on the primary tumor size (with cut-offs of 2.0 cm and 5.0 cm) and extracutaneous (e.g., bone or muscle) invasion.

Pathologic regional lymph node status at the time of presentation is a better prognostic parameter than lymph node examination by clinical inspection or radiologic imaging. In fact, routine sentinel lymph node biopsy is recommended for MCC patients. Once regional lymph node involvement is identified, relative survival of MCC patients can be further stratified by the nodal "tumor burden". For instance, patients with negative lymph nodes by clinical inspection, palpation, or imaging studies and with histologically proven nodal metastasis are categorized as "N1a", also referred to as "micrometastasis". Although size of tumor nests metastatic to lymph nodes represents one of the prognostic factors recommended for collection by the National Cancer Data Base, it is not included in the definition of "micrometastasis". "Macrometastasis/N1b" is defined as a lymph node metastasis that is apparent clinically and is confirmed histologically. "In transit metastasis/N2" is defined as focus of MCC distinct from the primary lesion and located "distal to the primary lesion" or between the primary lesion and the draining regional lymph node.

1. WHICH TUMOR TYPICALLY DISPLAYS A PERI-NUCLEAR DOT-LIKE CYTOKERATIN 20 POSITIVITY?
   
   1. Melanoma
   2. Merkel cell carcinoma
   3. Mesothelioma
   4. Prostate adenocarcinoma
   5. Small cell carcinoma of the lung
2. WHAT IS THE DEFINITION OF NODAL MICROMETASTASIS OF MERKEL CELL CARCINOMA?
   
   1. Clinically identifiable lymph node metastasis confirmed by histological examination
   2. Clinically negative lymph node with histological evidence of Merkel cell carcinoma
   3. Focus of metastatic carcinoma that can be identified only by immunohistochemical studies
   4. Presence of fewer than 300 neoplastic cells in a lymph node
   5. Smaller than 2.0 cm focus of metastatic carcinoma
3. HISTOLOGIC TYPES OF MERKEL CELL CARCINOMA HAVE PROGNOSTIC SIGNIFICANCE.
   
   1. True
   2. False

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2. Andea AA, Coit DG, Amin B, Busam KJ. Merkel cell carcinoma: Histologic features and prognosis. Cancer. 2008;113(9): 2549-58.
3. Assouline A, Tai P, Joseph K, Lian JD, Krzisch C, Yu E. Merkel cell carcinoma of skin-current controversies and recommendations. Rare tumors. 2011;3(2):e23.
4. Feng H, Shuda M, Chang Y, Moore PS. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science. 2008;319(5866):1096-1196.
5. Kuwamoto S. Recent advances in the biology of Merkel cell carcinoma. Hum Pathol. 2011;42(8):1063-1077.
6. Lemos BD, Storer BE, Iyer JG, et al. Pathologic nodal evaluation improves prognostic accuracy in Merkel cell carcinoma: analysis of 5823 cases as the basis of the first consensus staging system. J Am Academy of Dermatol. 2010;63(5):751-761.
7. Schowalter RM, Pastrana DV, Pumphrey KA, Moyer AL, Buck CB. Merkel cell polyomavirus and two previously unknown polyomaviruses are chronically shed from human skin. Cell Host & Microbe. 2010;7(6):509-515.
8. Edge SB, Byrd DR, Compton CC, et al. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2009.
9. Touze A, Le Bidre E, Laude H, et al. High levels of antibodies against merkel cell polyomavirus identify a subset of patients with merkel cell carcinoma with better clinical outcome. J Clin Oncology. 2011;29(12):1612-1619.

2012
Simion I. Chiosea, MD
Surgical Pathology Committee
University of Pittsburgh Medical Center
Pittsburgh, PA

1. Merkel cell carcinoma (b). 
2. Clinically negative lymph node with histological evidence of Merkel cell carcinoma (b). 
3. False (b).