shows the summary for pathological diagnosis of MCC. Fine needle aspiration cytology (FNAC) enables an early noninvasive diagnosis of this aggressive tumor to facilitate early planning of surgery. FNAC can be easily performed in elderly patients compared to excisional biopsy. The cytological features in aspirate (stained with Pappenheim and Papanicolaou staining) include increased cellularity, noncohesive groups of small-to-medium size malignant cells with uniform, round-to-oval nuclei with moulding effect, fine chromatin, multiple micronucleoli, and scanty cytoplasm [30
]. Since this tumor has a highly malignant potential for local recurrence, nodal and distant spread, and very often is combined with other tumors, it is important to perform FNAC or biopsy of different lesions in the same patient. Collision tumors
have been reported in which MCC coexists with other skin malignancies [31
Pathologists should follow standard protocol for the examination of MCC specimens [32
]. Definitive diagnosis is made by histological, especially immunohistochemical methods (detection of intermediate filaments and neuroendocrine markers) [2
Histologically, MCC arises in dermis and extends into the subcutis. The epidermis is infrequently involved, and the overlying skin is rarely ulcerated. The tumor can consist of isolated cells, loose cohesive sheets, and rosette-like structures.
The 3 main histologic patterns are (1) solid type—most common type, composed of irregular groups of tumor cells interconnected by strands of connective tissue, (2) trabecular type—well-defined cords of cells that form invading columns or cords, and (3) diffuse type—exhibits poor cohesion and a lymphoma-like diffuse type of growth.
Neoplastic cells in MCC are round to ovoid and very uniform. Finely granular chromatin and frequent mitotic figures are observed. Under close scrutiny small faintly stained juxtanuclear “caps” were seen. The paranuclear globular coexpression of cytokeratin and neurofilaments by an undifferentiated dermal tumor is of significant help in diagnosing MCC and differentiating it from small-cell carcinoma [33
]. The electron microscopy demonstrates the pathognomonic features for this tumour: dense-core neurosecretory granules with diameter of 100–250
nm surrounded by whorls of intermediate filaments [34
]. Under the scanning electron microscope, numerous finger-like processes, ranging from 0.1–0.25
micron in diameter and 2.5
micron in length, had been described by Yamashita et al. [35
Immunocytochemical results are universally positive for cytokeratin [36
]. Antibodies associated with epithelial derivation include antikeratin monoclonal antibody AE1/AE3, polyclonal anti-keratin, and monoclonal anticytokeratin cocktail (MAK-6), as well as a monoclonal antibody against epithelial membrane antigen (EMA). Positive keratin labeling (AE1/AE3, MAK-6) of filaments arranged in paranuclear aggregates, with presence of cytoplasmic synaptophysin helps to make the diagnosis [37
]. Neuron-specific enolase (NSE) positivity is diffuse, although a weak dot-like positivity is seen in some cells. Leukocyte common antigen is universally negative. There could be conflicting immunostaining results. An example of positivity for chromogranin in the primary tumor but negative in the cytologic material was described by Gupta and Teague [38
]. Other positive markers include Ber-EP4, an immunohistochemical marker used to identify carcinoma. Thyroid transcription factor-1 had been reported to be positive in MCC [39
], so it is unreliable by itself to differentiate from metastastic small-cell carcinoma of the lung metastasizing to the skin.
Recent studies demonstrate chromosomal abnormalities in chromosomes 1, 11, and 13 [40
]. Comparative genomic hybridization analysis revealed a pattern of gains and losses that closely resembles that seen in small-cell lung cancer. Losses were seen for chromosomes 3p (46%), 5q (21%), 8p (21%), 10 (33%), 11q (17%), 13q (33%), and 17p (25%). Significant gains were seen for chromosomes 1 (63%), 3q (33%), 5p (38%), 8q (38%), 19 (63%), and X (41%), with smaller numbers having gains for chromosomes 6, 7, 20, and 21 [42
Diagnostic pitfalls include the following.
- Coexistence of primary cutaneous MCC in association with squamous and basal-cell carcinoma . This has the implication that an ordinary squamous or basal cell carcinoma should be sectioned thoroughly to avoid missing the aggressive MCC component.
- Presence of desmoplasia may mask the diagnosis of MCC .
- Malignant lymphoma is an important differential diagnosis of cutaneous small round blue cell tumors. Immunohistochemistry and, if necessary, polymerase chain reaction and sequencing are useful tools to differentiate them .
The Johns Hopkins School of Medicine applied molecular techniques to detect Merkel cell virus (MCV) in sentinel lymph node (SLN) [46
]. Eight out of 25 (32%) samples had detectable MCV without microscopic disease. This may identify a subset of patients who would benefit from adjuvant nodal treatment.