Merkel cell carcinoma.
Merkel cell carcinoma is a cutaneous neoplasm most commonly presenting in white males, in their 7th or 8th decade of life. (2,5,6) In a study of 195 patients with MCC by Heath et al, (2) the median patient age was 69; 97.9% of patients were white, with the percentage of males and females at 58.5% and 41.5%, respectively. Merkel cell carcinoma has a nonspecific clinical appearance. It most commonly presents as a persistent asymptomatic red/ pink cystic lesion, smaller than 2 cm, which rapidly increases in size over a period of weeks to months on chronically exposed, sun-damaged skin. (2) Other dermatologic presentations include acneiform lesions; blue or red firm, solitary, dome-shaped nodules; or plaque-like growths. (6) The most common clinical features of MCC have been summarized by the acronym AEIOU: (1) A for asymptomatic/lack of tenderness; (2) E for expanding rapidly (<3 months); (3) I for immunosuppression; (4) O for older than age 50; and (5) U for UV-exposed sites (location). Up to 89% of patients with MCC in 1 study (2) met 3 or more of the AEIOU criteria.
The most common site of presentation is the head and neck region, with up to 53% of MCC cases located in this region according to 1 study; other affected sites include the extremities (35%), trunk, and rare cases (less than 10%) occurring in the oral and genital mucosa. (2,6,7) Ultraviolet exposure has been found to be directly proportional to the risk of MCC. Patients with psoriasis who were treated with UVA radiation and methoxsalen were found to be associated with a 100-fold increase in the incidence of MCC as compared with the general population. A relationship between MCC and immunosuppression has also been demonstrated in various studies. Patients who were immunosuppressed had a higher incidence of MCC, and at a younger age, than the general population. (5)
Histologically, MCC presents predominantly as a dermal-based lesion composed of strands or nests of uniform, small round cells with scanty cytoplasm, round to oval nucleus with powdery dispersed chromatin, and inconspicuous nucleoli (Figure 1). The tumor spreads to the reticular dermis and subcutis, generally sparing the papillary dermis, epidermis, and adnexa. However, occasional epidermal involvement has been reported in 5% to 30% of tumors. (6)
Irregular nested groups of infiltrating cells with an Azzopardi effect, single-cell necrosis, frequent mitoses, vascular invasion, perineural invasion, and epidermal involvement via pagetoid spread may also be present. (5-7) A desmoplastic response is often present in the surrounding dermis, and ulceration of the epidermis overlying the lesion has also been described in more advanced lesions. (6,7) The 3 histologic subtypes, though clinically insignificant, need to be recognized so as not to be mistaken for another entity. The intermediate variant is the most common subtype of MCC. This variant shows large, solid nodules made of diffuse sheets of basophilic cells with the characteristic round to oval nucleus, powdery chromatin, and inconspicuous nucleoli. The small cell variant has small round cells with scant cytoplasm, oval hyperchromatic nuclei, and prominent nucleoli. The tumor cells form a solid sheet or clusters, often with crush artifact and nuclear molding. Finally, the least common trabecular variant has round to polygonal cells with abundant cytoplasm; round, centrally located vesicular nuclei; and inconspicuous nucleoli arranged in an organoid, trabecular, or ribbonlike arrangement. (7) Merkel cell carcinoma may also express squamoid, eccrine, glandular, and melanocytic differentiation. Cases of MCC in association with invasive squamous cell carcinoma and melanoma have also been described. (6,8)
[FIGURE 1 OMITTED]
Merkel cell carcinomas are unique in that they possess both neuroendocrine and epithelial features. The malignant cells express epithelial markers such as AE1/AE3, CAM 5.2, pan-cytokeratin, epithelial membrane antigen, and Ber-EP4. Cytokeratin (CK) 20 is a fairly specific and sensitive marker for MCC, with a characteristic paranuclear dotlike positivity (9,10) (Figure 2). Although most MCCs reported have been CK20 positive and CK7 negative, a few cases of CK7-positive and CK20-negative MCCs have been described. (11) Merkel cell carcinoma expresses a wide range of neuroendocrine markers such as neurofilaments, neuron-specific enolase, chromogranin, synaptophysin (Figure 3), bombesin, somatostatin, vasoactive intestinal peptide, and proconvertases PC1/ PC3 and PC2.7. (7,9,10,12) Merkel cell carcinoma may also express CD117, CD56, rarely CD99 and terminal deoxynucleotidyl transferase (TdT); however, it is negative for thyroid transcription factor 1 (TTF-1), S100, and leukocyte common antigen/CD45. (9,13)
HISTOGENESIS AND PATHOGENESIS
Merkel cells were first described in 1875 by Friedrich Sigmund Merkel as large, clear, oval cells found in the basal epidermal layer of skin, hair follicles, and oral mucosa. Merkel cells are derived from the neuroectoderm and function as type I mechanoreceptors by forming synapselike contacts with the tactile hair discs of Pinkus. (7) These cells are considered part of the diffuse neuroendocrine system or amine precursor uptake and decarboxylation system and are believed to originate from an asymmetric cell division of basal keratinocytes. (14) Ultrastructurally, Merkel cells have fingerlike protoplasmic protrusions and cytoplasmic dense neuroendocrine granules. (5) Their origin from neural crest cells have been confirmed in transgenic mouse models. (10) Merkel cell carcinoma is believed to be derived from Merkel cells, since they both possess dense core neuroendocrine granules, neurofilament, and CK20 expression. However, the cell origin of MCC is still in debate because epidermal involvement of MCC is so rare.
The etiology of MCC has remained much of a mystery despite substantial research. Various defects in the molecular pathways have been shown to play a role in the pathogenesis of MCC. Tumorigenesis has been found to be associated with the inhibition of apoptosis via the intrinsic as well as the extrinsic pathways. Overexpression of anti-apoptotic molecule Bcl-2 was found in three-fourths of MCCs in 1 study, (14) and in vivo inhibition of Bcl-2 in a SCID (severe combined immunodeficiency) mouse/human MCC xenograft model resulted in tumor shrinkage. (15) However, a phase II trial16 using a bcl-2 antisense agent (G3139, Genasense) showed very limited efficacy in patients with MCC. The presence of another anti-apoptotic molecule, survivin, has also been found to be associated with a more aggressive clinical course. (14)
The rapid growth seen in MCC has been suggested to be associated with dysregulation of various normal growth factor receptors. A single heterozygous base change in exon 10 of the platelet-derived growth factor receptor [alpha] gene, leading to an amino acid substitution at codon 478, was present in 3 of 9 MCCs (33.3%) in 1 study. (14) A heterozygous loss of band 10q23 has also been reported. This is also the location of another tumor suppressor, phosphatase and tensin homologue. (14,17)
Multiple chromosomal abnormalities have been found in MCC, the most common of which is the deletion of the short arm of chromosome 1 (1p36), a structural aberration found in up to 40% of MCCs. Deletions in chromosome 1 have also been found in cases of malignant melanoma and neuroblastoma. (18) It is speculated that a tumor suppressor gene is present on 1p, and its loss plays a role in the pathogenesis of MCC. Aberrations in other chromosomes, such as loss of heterozygosity in band 3p21--an abnormality also reported in small cell carcinoma--10q23, and chromosome 13 have also been reported in cases of MCC. (18,19) Other abnormalities also found in MCC include trisomy 1, trisomy 6, trisomy 11, trisomy 18, and deletion of chromosome 7. (20) Despite the multiple cytogenetic anomalies and the mutations in the growth regulatory and apoptotic pathways that have been discovered in MCC, the precise pathogenesis remains largely unclear.
[FIGURE 2 OMITTED]
[FIGURE 3 OMITTED]
The discovery by Feng et al (4) in 2008 of MCPyV in 8 of 10 MCC tumors has provided yet another clue to the pathogenesis of MCC. Polyomaviruses are a group of icosahedral, double-stranded DNA viruses that encode a large T-antigen oncoprotein known to cause tumors in animal models. (21) The most studied large T antigen among the polyomaviruses is that of the simian vacuolating virus 40 (SV40), which regulates the life cycle of host cells by interaction with tumor suppressor p53 and retinoblastoma tumor suppressor (Rb) genes. This viral stimulation of the cell cycle by the large T antigen is believed to be the driving force of the oncogenic potential in polyomaviruses. These polyomaviruses express genes in 2 waves: (1) the early genes encode large and small T antigens that bind to host protein and force the cell into the S phase to facilitate viral replication; (2) the late genes encode components of viral coat and enable lysis of the host cell. (14) There are 3 distinct groups of polyomaviruses: avian polyomaviruses, mammalian viruses related to MCPyV, and the mammalian polyomaviruses related to SV40. Within the family of Polyomaviridae are 4 known viruses directly associated with malignancy, namely, Polyomavirus hominis 1 (BK) virus, John Cunningham virus (JCV), KI polyomavirus, and mumps virus. (4)
Merkel cell carcinoma, like Kaposi sarcoma (KS), is more common among immunosuppressed patients; this led to the search for a possible viral link to MCC similar to that between KS and the KS-associated herpesvirus. With the digital transcriptome subtraction method, a 5387-bp polyomavirus genome was identified by using cDNA libraries from 4 different MCC tumors. This genome was named MCPyV because of its association with MCC. Eighty percent (8 of 10) of MCCs showed the presence of MCPyV in comparison to 8% (5 of 59) of normal control tissues and 16% (4 of 25) of non-MCC skin tumors. (4) In a separate study by Garneski et al, (22) 16 of 37 MCC cases (43%) were positive for MCPyV with real-time polymerase chain reaction. Using 3 separate primer sets for MCPyV, Duncavage et al (23) performed polymerase chain reaction studies on MCCs from 29 patients; all cases showed DNA presence of MCPyV. These studies suggest a direct relationship between MCPyV and MCC. (4,21-23)
Merkel cell polyomavirus integrates into band 3p14 at the human protein tyrosine phosphatase, receptor type, G gene, a tumor suppressor gene. When inserted into the host DNA, the viral T antigen is expressed as large T and small T antigens. These T antigens, expressed from viral transcripts, target and alter the behavior of tumor suppressor and cell cycle regulatory proteins, including Rb, p53, protein phosphatase 2A, and Bub1. (21) The study by Shuda et al (21) found that when MCPyV integrates, the full-length large T protein is lost, secondarily to deletion of the carboxyl terminal, an event that prevents autonomous viral genome replication, a feature seen in polyomavirus-mediated carcinogenesis. Two distinct mutagenic steps are believed to be required for MCC development: first, integration of MCPyV into host genome; second, prevention of autonomous viral replication by T antigenmutations. Risk factors, such as increased exposure to UV and ionizing radiation, may be involved in T-antigen mutations. (21) The association of MCC with a virus may explain the higher incidence of MCC in immunosuppressed patients, perhaps in a manner similar to the relationship between KS and the KS-associated herpesvirus. (4) The pathogenesis of MCC still remains unclear; however, the discovery of the first human malignancy with a relatively consistent presence of integrated sequences of a specific type of polyomavirus, MCPyV, in combination with the other known molecular defects, may allow further understanding of this entity and development of more targeted therapies.
The histologic features of MCC are similar to those of various other tumors, such as metastatic small cell carcinoma, the small round cell tumors, blastic hematologic malignancies of skin/soft tissue, and melanoma. The advent of immunohistochemistry, specifically CK20, has significantly assisted in the accurate diagnosis of MCC.
Small cell carcinoma of the lung (SCCL) is a highly aggressive malignant epithelial tumor with neuroendocrine features, and is often not diagnosed until the tumor has already metastasized. Metastatic SCCL can be morphologically identical to the small cell variant of MCC, with sheets of small round cells with a round, ovoid, or spindle nuclei; finely granular chromatin; inconspicuous nucleoli; and scant cytoplasm. Nuclear molding, mitoses, and Azzopardi effect are often present. (24) Until recently, the differentiation of SCCL from MCC was extremely challenging because of the shared neuroendocrine and epithelial features between these 2 entities. Small cell carcinoma of the lung shows up to 90% positivity for thyroid transcription factor 1 (TTF-1) and is positive for CD56, chromogranin, and synaptophysin in two-thirds of cases. (9,25) In a study by Leech et al, (25) the combination of CK20 and TTF-1 showed that 10 of 11 cases of MCC were CK20 positive and 11 of 11 were TTF-1 negative, while all 10 cases of SCCL were positive for TTF-1 and negative for CK20. In a similar study comparing MCC and SCCL, Bobos et al (7) found that the use of CK20, TTF-1, and neurofilament was helpful in separating MCC and SCCL. Small cell carcinoma of the lung showed 100% positivity for TTF-1, 7% positivity for CK20, and no positivity for neurofilament in comparison to MCC, which showed no positivity for TTF-1, 100% positivity for CK20, and 92% positivity for neurofilament. A less helpful stain is CK7, which stains positively in SCCL, but that stains positively in only 20% of MCCs. (9,24,25) The distinction between these 2 entities is important, as prognosis and treatment are vastly different. Despite the success of immunostains in differentiating between MCC and SCCL, a thorough investigation, including physical examination and radiologic studies, can help identify primary small cell lung carcinomas.
The homogenous morphology of MCC may also be confused with that of small round blue cell tumors such as Ewing sarcoma/primitive neuroectodermal tumor (PNET). Ewing sarcoma/PNET is a rare sarcoma, most commonly occurring in the lower extremities of patients who range in age between 10 and 20 years. Histologic examination demonstrates small round cells with round nuclei, finely granular chromatin, inconspicuous nucleoli, and a narrow rim of pale cytoplasm. These malignant cells show expression of CD99, vimentin, and neuron-specific enolase. The most definitive method for diagnosis of Ewing sarcoma/PNET is by gene rearrangement studies, specifically the presence of t(11;22)(q24;q12). (26) Ewing sarcoma is generally negative for CK20, chromogranin, and CD45. (9)
Melanoma is an aggressive cutaneous neoplasm that can be confused morphologically with MCC. In North America, melanoma most often affects whites around the 5th and 6th decade of life--a younger and more diverse age for the patient population as compared to that for MCC--and generally is more common in elderly male patients. The development of melanoma has been associated with environmental factors such as exposure to UV radiation. The melanoma cells originate from activated or genetically altered epidermal melanocytes, either from normal-appearing skin, benign pigmented lesions, or atypical benign nevomelanocytic lesions. (27) Histologically, melanoma is known as the "great mimicker," with a wide spectrum of histologic features similar to those of a variety of tumors such as lymphomas, poorly differentiated carcinomas, neuroendocrine tumors, sarcomas, and germ cell tumors. (28,29) Melanoma can present as predominantly dermal, solitary, well-circumscribed lesions consisting of monomorphic tumor cells with an increased nuclear to cytoplasmic ratio, hyperchromasia, and prominent nucleoli. The tumor cells may be epitheliod, spindled, and occasionally rhabdoid with frequent mitoses and necrosis. They may also lack surface and follicular connections that create histologic features similar to those of MCC. (27-29) The use of immunohistochemistry can assist in the differentiation of melanoma from MCC. S100 is expressed with high sensitivity in melanoma cells; HMB-45, Melan-A, tyrosinase, and microphthalmia transcription factor also have relatively high sensitivity in many melanomas but often with greater specificity. However, melanoma tumor cells have a low reactivity for AE1/AE3, pan-keratin, and low-molecular-weight cytokeratin. They also rarely stain for synaptophysin, with only 12% expression in 1 study, (29) and are generally negative for chromogranin. (27-29)
Many hematologic malignancies can appear morphologically identical to MCC, particularly the blastic hematologic malignancies such as acute lymphoblastic lymphoma, acute myeloid leukemia, cutaneous natural killer/ T-cell lymphoma, and hematodermic [CD56.sup.+]/[CD4.sup.+] neoplasm (also called blastic plasmacytoid dendritic cell neoplasm in the 2008 World Health Organization Classification of Tumours (30)). These hematologic malignancies may present in the form of blasts in the peripheral blood and bone marrow; however, they can also present as a cutaneous lesion with monomorphic, large to intermediate-sized cells with vesicular nuclei, open chromatin, and large nucleoli. The malignant cells can have a background with the classic "starry-sky" appearance and brisk mitotic activity. These lesions may express leukocyte common antigen/CD45, CD34, TdT, CD10, CD3, CD20, myeloperoxidase, and CD117 but lack expression for epithelial markers (AE1/AE3, CAM 5.2, CD7, and CK20) and neuroendocrine markers (neuron-specific enolase, synaptophysin, and chromogranin). Merkel cell carcinoma, however, can express TdT, CD56, CD117, and CD10. In a study by Sur et al, (13) 15 cases of MCC showed 53% expression of TdT, 100% expression of CD56, 53% expression of CD117, and 6% expression of CD10. These findings suggest that a panel of immunohistochemical markers, such as the ones described above, may assist in differentiating MCC from hematologic malignancies. The Table provides a summary of some helpful immunohistochemical stains for distinguishing MCC from its more common differential diagnoses.
PROGNOSIS AND TREATMENT
Merkel cell carcinoma is a highly aggressive tumor, with 33% mortality within 3 years of diagnosis. (31) The clinical staging of MCC is based on a 4-tiered system developed at the Memorial-Sloan Kettering Cancer Center (MSKCC) in New York. Stage I disease is defined as localized disease, with tumor smaller than 2 cm; stage II disease shows a tumor that is still localized but greater than 2 cm; stage III disease shows regional metastasis; and stage IV shows distant metastasis. At the time of diagnosis, most patients present with either stage I or II disease (70%). Patients with stage I disease have an 81% survival rate at 5 years as compared with an 11% survival rate for patients with stage IV disease. (5) The newly proposed and soon to be published American Joint Committee on Cancer staging system for MCC remains similar to the MSKCC 4-tiered staging system but with further differentiation of stage III (regional disease) into IIIa in the presence of micrometastasis and IIIb with macrometastasis (clinically detectable disease). (32)
The current literature shows vastly contradictory data regarding the actual utility and importance of the many proposed prognostic indicators. Male sex, age, stage of disease at presentation, location, overexpression of Ki-67, and extent of lymph node disease have been most consistently associated with a poor prognosis. (33) In fact, 1 author (5) proposes that the presence or absence of lymph node disease is the most consistent predictor of survival. Recent studies (33) have also found a direct correlation between p63 expression in MCC and patient survival. Patients whose tumors showed greater than 10% staining for p63 had a worst outcome than patients whose tumors showed less than 10% p63 positivity. Less conclusive, but nonetheless proposed prognostic indicators include absence of an inflammatory reaction, depth of tumor invasion, presence or absence of angioinvasion, presence of mitotic figures, and CD44 positivity. (5,13,33)
Currently, there is no standard protocol for the treatment of MCC, with treatment regimens generally based on the extent of disease. A wide local excision with a tumor-free margin of 2 to 3 cm is recommended for primary lesions smaller than 2 cm, with addition of adjuvant radiation therapy for lesions greater than 2 cm. For patients with regional disease, a wide local excision, along with complete lymph node dissection, radiation therapy of the primary site, and lymph node region, resulted in lower mortality than for patients who received just 1 of the treatments. Although few studies have been performed regarding the utility of chemotherapy in MCC, it is the most common modality used in treatment of distant disease. The most common chemotherapies used in stage IV MCC are cisplatin, doxorubicin, and vincristine or the combination of etoposide and platinum. (5,33)
Merkel cell carcinoma is a highly aggressive tumor with a rapidly increasing incidence and a largely unclear pathogenesis. However, the discovery of the Merkel cell polyomavirus and its association with Merkel cell carcinoma may significantly contribute to further understanding of new insights and developments in the treatment of this neoplasm.
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Hannah H. Wong, MD; Jun Wang, MD
Accepted for publication October 21, 2009.
From the Department of Pathology and Laboratory Medicine, Loma Linda University Medical Center, Loma Linda, California.
The authors have no relevant financial interest in the products or companies described in this article.
Reprints: Hannah H. Wong, MD, Department of Pathology and Laboratory Medicine, Loma Linda University Medical Center, 11234 Anderson St, Room 2151, Loma Linda, CA 92354 (e-mail: HHWong@ llu.edu).
Immunohistochemical Staining Patterns Differentiating Merkel Cell Carcinoma From Its More Common Differential Diagnoses (9-11,13,24,25,28,29) CK20 Chromogranin TTF-1 S100 CD45 Merkel cell carcinoma + + -- -- -- Small cell carcinoma [+ or -] + + -- -- Melanoma -- -- -- + NA Hematologic -- -- -- -- + malignancies (a) Ewing sarcoma/PNET -- -- NA NA CD56 TdT CD99 CD117 NF Merkel cell carcinoma + [+ or -] [+ or -] [+ or -] + Small cell carcinoma [+ or -] NA NA [+ or -] -- Melanoma [+ or -] NA [+ or -] [+ or -] NA Hematologic + + NA + NA malignancies (a) Ewing sarcoma/PNET NA NA + NA NA Abbreviations: NA, not applicable, other stains are more helpful in distinguishing between these entities; NF, neurofilament; TdT, terminal deoxynucleotidyl transferase;TTF-1, thyroid transcription factor 1. (a) Hematologic malignancies such as acute lymphoblastic leukemia, acute myelogenous leukemia, cutaneous natural killer/T-cell lymphoma, and hematodermic [CD56.sup.+]/[CD4.sup.+] neoplasm.
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|Author:||Wong, Hannah H.; Wang, Jun|
|Publication:||Archives of Pathology & Laboratory Medicine|
|Date:||Nov 1, 2010|
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