The Journal of Foot & Ankle Surgery 53 (2014) 219–225
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Merkel Cell Carcinoma: Case Study and Literature Review Danae L. Lowell, DPM 1, Jerry Roberts, DPM 2, Prema Gogate, MD 3, Rose Goodwin, DPM 4 1
Staff Surgical Podiatrist, Department of Podiatry Surgery, and Assistant Residency Director, Cleveland Louis Stokes Veterans Affairs Medical Center, Cleveland, OH Submitted during 3rd Year of PMSR/RRA, Cleveland Louis Stokes Veterans Affairs Medical Center, Cleveland, OH 3 Staff Pathologist, Cleveland Louis Stokes Veterans Affairs Medical Center, Cleveland, OH 4 Submitted during 4th Year at Kent State University College of Podiatric Medicine, Kent, OH 2
a r t i c l e i n f o
a b s t r a c t
Level of Clinical Evidence: 4
Merkel cell carcinoma is a rare, aggressive, highly metastatic, often fatal, primary neuroendocrine tumor typically located on sun-exposed skin. It is frequently found in white males aged 60 to 70 years. The somewhat typical benign clinical appearance of the lesion can result in a delayed diagnosis, leading to a less than optimal outcome. Ó 2014 by the American College of Foot and Ankle Surgeons. All rights reserved.
Keywords: cancer cutaneous trabecular carcinoma lower extremity neuroendocrine carcinoma polyomavirus primary cutaneous tumor
According to data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program from 1973 to 2006, the incidence of Merkel cell carcinoma (MCC) was 0.41 per 100,000 for men and 0.18 per 100,000 for women, and 94.9% of those patients were caucasian (1). The incidence of MCC, most often found on the head and neck regions, tripled from 1986 to 2001, with approximately 1500 cases annually reported in the United States. It is believed that the increased incidence observed during the past 2 decades has been associated with improved diagnostic techniques and an aging population with an overall increased ultraviolet (UV) exposure. Investigators found a 75%, 59%, and 25% 5-year relative survival rate for 1034 patients with localized, regional, and distant MCC disease, respectively (2–4). Before 2007, little was known about this highly malignant skin cancer, which has an age-adjusted incidence of mortality of 0.031/100,000 (5). Since then, significant research and reviews have contributed to the current body of knowledge surrounding MCC. The differential diagnosis for MCC includes lesions that are more common, including basal B-cell carcinoma, squamous cell carcinoma, cutaneous metastatic small cell carcinoma of the lung, small cell cutaneous lymphoma, anaplastic small cell melanoma, Ewing’s sarcoma, neuroblastoma, rhabdomyosarcoma, epidermoid cyst, amelanotic melanoma, and atypical fibroxanthoma (6–9). In an effort to review the published data related to MCC, the MEDLINE database was searched for relevant studies. The term Financial Disclosure: None reported. Conflict of Interest: None reported. Address correspondence to: Danae L. Lowell, DPM, Department of Podiatry Surgery, Cleveland Louis Stokes Veterans Affairs Medical Center, 10701 East Boulevard, Cleveland, OH 44106. E-mail address: [email protected] (D.L. Lowell).
“Merkel cell carcinoma” was used as the basis for the searches, and references were included according to their relevance. In 1875, Friedrich Sigmund Merkel originally described the mechanoreceptors we now know as Merkel cells (10). He demonstrated the existence of nondendritic, nonkeratinocyte, touch-sensitive cells (tastzellen) in the skin and suggested that the cells were receptors and transducers of mechanical stimuli to neural impulses (10). After microscopic confirmation of the existence of these cells, the term Merkel cell was coined; and Toker (9) first described MCC in 1972 from his case review. His morphologic description included anastomosing trabeculae, cell nests, and cytoplasmic dense core granules that led to him to describe it as a “trabecular carcinoma of the skin” that he surmised arose from the Merkel cells. The term MCC came from Rywlin (11), who, in 1982, associated the tumor with Merkel cells in the basal layer of the epidermis. Since then, MCC research has led to a better understanding, classification, and treatment of this deadly carcinoma. MCC typically presents as a singular, “reddish glassy,” rapidly growing, pale to violaceous, firm, smooth, nonpainful, shiny nodular dermal lesion that arises 81% of the time in areas of chronic sun (UV radiation) exposure owing to the increased UV exposure to certain areas of the body. Telangiectasia has frequently been noted. Variations exist in which plaque-like lesions are exhibited. Ulcerations are rarely encountered but can be found in more advanced cases (12,13). MCC is rarely found on the oral and genital mucous membranes, where UV exposure is significantly lower. When encountered in these areas, the prognosis has typically been poor (14,15). Satellite metastases occur early and frequently in cases of MCC and have been found in the skin in 28% of cases, lymph nodes in 27%, liver in 13%, lung in 10%, bone in 10%, and brain in 6% (13). In 2010, Ng et al
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(16) presented the fifth documented case of metastatic MCC to the spine. After resection of the primary lesion in that case, the patient returned with neurologic deficits related to the metastasis. However, postoperative wound healing complications and aspiration pneumonia developed, and the patient died. They also reported occasions in which MCC spinal metastatic lesions were noted, and no primary lesion was ever found. A review of these cases demonstrated similar results and the aggressive nature of MCC (16). Epidemiologic analysis has suggested that the pattern distribution of MCC indicates an association with UV radiation exposure. Of 2384 cases of MCC reviewed by Paulson et al (17), involvement of the left side of the body, predominantly the arm and face, occurred in 52.7% of the cases. An even (50%) distribution was noted on the lower extremities in 571 of the 2384 cases. Their results suggested that driver-side UV exposure might be a contributing factor in the development of MCC. The results from a review of 171 patients with MCC by Koljonen et al (18), in 2012, confirmed left-sided asymmetry in 56% of the cases in sun-exposed areas of the body, although the distribution was equal (symmetrical) in areas typically shaded from the sun. Although UV exposure might be an etiologic culprit in the development of MCC, nonexposed areas are also at risk. In 2011, Iavazzo et al (19) reported a case of vulvar MCC in a 63-year-old female. At the diagnosis, the lesion was 9 cm, and inguinal lymph node metastasis was noted. Fewer than 20 cases of vulvar MCC have been reported. In addition to UV exposure, immunosuppression has also been determined to be key in the development of MCC. Organ transplant patients receiving immunosuppressive medications and patients with lymphoma, diabetes, or human immunodeficiency virus (HIV) all have a greater incidence of MCC. Engels et al (20) collected data from 309,365 patients with HIV and found 6 cases of MCC, a relative risk of 13.4 (95% confidence interval 4.9 to 29.1) compared with the general population. The results of a study by Tolstov et al (21), in 2011, found no direct correlation between HIV or acquired immunodeficiency syndrome and MCC. This supports the hypothesis that immunocompromise as an associated co-infection transformation was likely. It also suggested that MCC infection, although highly prevalent among adults, is often asymptomatic, indicating that transmission is common but that the actual clinical identification of the carcinoma is rare. The symptoms were similar between patients with HIV who were seropositive and those who were seronegative (21). This research not only supported that immunosuppressive therapy was found to be associated with an increased incidence of MCC but also led to generally a poorer prognosis (22). Using this information, Heath et al (23) described the mnemonic AEIOU for use when describing the clinical appearance and demographic data associated with MCC. AEIOU stands for an asymptomatic lesion expanding rapidly in a patient with immune suppression, age older than 50 years, with a history of UV exposure to the area. In their study of 195 patients with MCC, 88% were found to be asymptomatic despite rapid growth of the lesion, leading to a median 3-month delay between the initial presentation and diagnosis. Early lymphovascular invasion might be 1 key to understanding the very aggressive nature of MCC. Kukko et al (24) reviewed 126 MCC samples and found that 93% had intravascular invasion, of which 66% were solely lymphovascular and 3% were only vascular. Although the tumors lacking invasion were typically smaller, lymphovascular invasion was noted in the smallest lesion (0.3 cm in diameter) (24). Possibly contributing to early lymphovascular invasion, Werchau et al (25) investigated the process of lymphangiogenesis in MCC. They found a threefold increase in the mean density of small lymphatic capillaries and a more than eightfold increase in the median ratio of the number of small to large lymphatics compared with the controls (25). The increased lymphangiogenesis occurring with MCC supports
a connection between MCC and early lymphovascular invasion and the aggressive nature of MCC. The morphologic features include an asymmetric dermal distribution in sheets, nests, and serpiginous, diffuse, or trabecular and anastomosing patterns, with frequent subcutis involvement. Small round or oval blue cells, necrosis, nuclei with significant mitotic activity, pagetoid growth, and scant cytoplasm with argyrophil granules have commonly been described (26,27). The papillary dermis, epidermis, and adnexa are usually spared. Three histologic patterns exist, based on the arrangement and appearance of the tumor cells, trabecular, intermediate, and small cell, with intermediate constituting 80% of the 3 types. Although the trabecular pattern has the best prognosis and small cell the worst, frequent mixed and transitional types have been noted, making the histologic prognostic indicators unreliable (28–30). The typical prognostic factors for determining low, intermediate, and high risk, such as diameter, nodal status, and metastasis, have not held true for MCC (31). Poor prognostic indicators also include the presence of a secondary malignancy such as squamous cell carcinoma or chronic lymphocytic leukemia (32). Other adverse prognostic indicators include disease stage at presentation and male gender. Kaae et al (33) also showed the existence of shared risk factors for MCC and squamous cell carcinoma and chronic lymphocytic leukemia. Electron microscopy, enzyme, and immunohistochemical assays are used to confirm the expression of chromogranin, synaptophysin, and other neuropeptides. Because a variety of neoplasms display similar characteristics, specific markers for MCC have been determined to distinguish MCC from others. Cytokeratin (CK)20 positivity is specific for MCC and distinguishes it from other small round blue cell tumors. CK20 expression of a paranuclear plaque, a dot-like pattern, has been found in 87% of MCC cases (34,35). Pertinent exclusionary markers for thyroid transcription factor 1 and leukocyte common antigen will largely be diagnostic for MCC (36,37). Thyroid transcription factor-1 and leukocyte common antigen are found in small cell lung carcinoma and lymphoma, respectively, but will be absent in MCC. Neurofilament protein is not found in small cell lung carcinoma and is usually positive in MCC. Endothelial and neuroendocrine markers, including chromogranin and synaptophysin, which are found with differing frequency and intensity, can be used for confirmation (34). The current recommendations are that once the diagnosis has been confirmed, the next step is to obtain sentinel lymph node biopsy to assist with guiding treatment. Ruan and Reeves (38) in 2009 and Bichakjian et al (39) in 2007 developed treatment algorithms from the highest levels of available published data. Wide local surgical resection, determining the sentinel lymph node status, radiotherapy, chemotherapy and close follow-up to monitor for recurrence have been outlined as methods to evaluate and treat this aggressive carcinoma using multidisciplinary care (38,39). Experts have agreed that wide local excision with 2- to 3-cm margins is recommended (40–43). Yiengpruksawan et al (43) reported on 70 patients from Sloan-Kettering Cancer Center from 1969 to 1989 and found an overall survival rate of 64% for 5 years. The surgical margins were evaluated in 38 specimens and ranged from 1 to 5 cm, depending on the location. They observed margins of 3 cm or less in 27 (71%) and more than 3 cm in 11 (29%) specimens. Local recurrence was found in 4 of the 27 patients with margins of 3 cm or less compared with none in the 11 patients with surgical margins greater than >3 cm, supporting the recommendation for wide local excision with clear lateral margins greater than 3 cm. However, recurrence and metastatic spread can occur even with larger than recommended excisions, stressing the importance of early recognition and close long-term follow-up. Recurrence rates of 30% to 45% for local disease, 40% to 70% for nodal involvement, and 30% to 50% for distant metastases have been noted (2,44). Medina-Franco et al (45)
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reviewed 1024 cases from 20 series. Of those, 11 series had reported local recurrence rates of 10.5% with, and 52.6% without, adjunctive radiotherapy. Adjunctive or concurrent chemotherapy or radiotherapy can be considered for high-risk patients. MCC staging, developed by the American Joint Committee on Cancer and published in 2010, has led to a reliable predictor of relative mortality of 30% at 2 years and 50% at 5 years after confirmation of the diagnosis. Although similar to other classifications, AJCC staging starts with the tumor size and further substages the lesions according to the pathologic nodal evaluation (46). Lesions less than 1.0 cm in diameter have been found to be unlikely to be associated with regional lymph node metastasis (47). The 5-year survival rate for patients with stage I has been approximately 81%; however, for stage II, it has been 67%, and for stage III, 52%. Stage IV disease has had an 11% 2-year survival rate (48). Sentinel lymph node biopsy has been determined to be the best predictor of survival. Pathologic diagnosis of negative lymph node involvement predicts a 5-year survival rate of approximately 97%; however, positive lymph node involvement predicts a 5-year survival rate of 52% (49). Histologic parameters, including nodular or infiltrative architecture, thickness, and lymphovascular infiltration, have been noted to predict survival (50). Doyle (51) reported primary lower extremity MCC in 1986. That account described multiple recurrences of MCC in the form of nodular lesions that appeared 6 months after excision of a solitary lesion in the same area of the leg. After a second excision and skin grafts were performed, as well as radiotherapy, a new lesion presented on the foot, requiring additional surgery and lymph node biopsy. The lymph node biopsy was positive, and amputation of the foot was considered but abandoned. New lesions presented at 6, 8, and 12 months, and each was excised when noted. After admission for wound complications and subsequent surgical intervention, chemotherapy was initiated, and some improvement was noted. However, after additional lesion recurrence was noted in the lower extremity, the patient was lost to follow-up. In 2007, O’Rourke et al (52) published another report of a case of pedal MCC and described preoperative magnetic resonance imaging, needle biopsy, and bone scan results before wide resection and local flap reconstruction. Postoperatively, the patient received radiotherapy and underwent repeat magnetic resonance imaging at 7 months and 1, 2, and 5 years, with no evidence of recurrence. These cases demonstrate the lesion’s tendency to recur and successful surgical management of MCC. Since these publications, advancements in diagnostic and therapeutic strategies have led to a greater understanding of the lesion and its treatment. One of the most important findings related to MCC was its association with polyomavirus. Because immunosuppression has been associated with MCC, a viral component was suspected (53,54). Polyomaviruses are small, double-stranded DNA viruses that were first identified in mice. To date, 9 human polyomaviruses have been identified. In 2007, Feng et al (55) developed the process of digital transcriptome subtraction, thereby jump-starting research that focused on MCC. This screening method, which has been used to discover viral nucleic acids, would eventually be used to discover Merkel cell polyomavirus (MCPyV), in 2008, by Feng et al (56). They found that MCPyV infection and DNA integration occur before replication of tumor cells, suggesting (but not proving) that MCPyV has a causal role in the oncogenesis of MCC (56). They showed that MCPyV was a contributing factor in 80% of cases of MCC. MCPyV-negative MCCs have greater nuclear irregularity and more abundant cytoplasm than do MCPyV-positive MCCs, which have uniformly round nuclei and scant cytoplasm (57). Several studies have shown the presence of MCPyV DNA in MCC specimens (58–64). Furthermore, Shuda et al (65) showed that the MCPYV T-antigen gene was mutated in the presence of MCC but that the mutation was absent in
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nontumorigenic MCPyV strains in humans, making the MCPyV T antigen a good genetic marker for MCC (65). In 2009, Goh et al (66) identified the presence of MCPyV in respiratory secretions, suggesting a route of transmission. That same year, Kean et al (67) examined the seroprevalence of a small number of viruses, including MCPyV strains 350 and 339, and noted these 2 strains in 67% of the specimens, suggesting that primary exposure occurred in childhood. By developing a specific MCPyV virus-like particle enzyme-linked immunoassay and testing patients with MCC and control groups, Tolstov et al (68) found that patients without MCC had evidence of previous MCPyV exposure and that previously unrecognized infection was widespread. Carter et al (69) tested the prevalence of antibodies against MCPyV in the general population and the association between these antibodies and MCC and found that MCPyV was common, that it appeared to be associated with MCC, and that it did not appear to have antibodies cross reactive against other polyomaviruses. In 2010, Loyo et al (70) compared MCPyV levels in MCC specimens and other tissues and showed MCPyV to be highest in the cases of MCC and that it was also present in other tissues. After MCC tissue, greater levels of MCPyV were found in the upper aerodigestive tract, digestive system, and saliva than in the lung and genitourinary system, suggesting a fecaloral transmission. However, it seems that only neuroendocrine skin cells are susceptible to transformation by MCPyV (70). Schowalter et al (71) developed an improved rolling circle amplification technique to isolate circular DNA viral genomes from skin swabs and found that 3 polyomavirus species, including MCPyV, were shed from the skin in the form of virions. Foulongne et al (72) obtained multiple cutaneous and mucosal swabs from 46 participants, 5 of whom had MCC, 16 of whom had other skin diseases, and 25 of whom were clinically healthy. MCPyV DNA was found in 44 of the 46 volunteers. Summarizing these findings, MCPyV appears to be ubiquitous, with likely early onset exposure and multiple routes of transmission (72). The immunologic responsiveness of MCC, owing to its viral association, might provide options for future treatment of lesions associated with the polyomavirus. Proof of this can be offered by the spontaneous regression of disseminated MCC lesions (73). Paulson et al (74) found that patients with MCC had high IgG antibody reactivity to specific MCPyV large T and small T antigen oncoproteins, allowing T-antigen antibodies to be accurate predictors of tumor burden. However, this was not found to be protective against disease progression despite its use as a monitor of disease status (74). In 2011, Paulson et al (75) sought to determine whether a prognostic biomarker for MCC could be established. They determined that intratumoral CD8þ lymphocyte infiltration was associated with significantly better survival rates of MCC (75). Currently, standard therapies for MCC are lacking, especially in cases of advanced disease. Excision and radiotherapy have been well described for the treatment of MCC in its initial stages (76–79). Boyer et al (80) showed that wide, local resection was preferred if Mohs was performed, and adjunctive radiotherapy was suggested. Of 25 patients treated using Mohs surgery only, 4 (16%) had recurrence compared with no recurrence in a group of 20 patients who had undergone Mohs surgery and radiotherapy. However, high-level clinical evidence is not available for review to determine effectiveness. Adjunctive radiotherapy has also been determined to be beneficial. The American Joint Committee on Cancer (2010) showed a difference between patients with positive sentinel lymph nodes who received adjunctive therapy and those who did not. The 3-year disease-free survival rate was 50% with therapy versus 0% without adjunctive therapy. Adjunctive therapy has been described as a dose of 40 to 50 Gy, administered in 2-Gy daily fractions, to the primary or regional basin (81–83). Single and multiagent chemotherapy for local advanced and metastatic MCC using anthracycline, 5-fluorouracil, cisplatin, etoposide, cyclophosphamide, doxorubicin, and vincristine, among others, have been used. These
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Fig. 1. Clinical picture of suspicious lesion showing a singular 10 mm 15 mm 5 mm raised violaceous nodule on the anterior lateral aspect of the right lower extremity 2 in. above the ankle.
agents were chosen owing to their effectiveness treating small cell lung carcinoma, because of the histologic similarities to MCC. However, the studies have mainly included small groups and have been retrospective. The results have been limited and have not led to promising consistent MCC treatment. Donepudi et al (84) have provided an excellent review of the available data on the chemotherapeutic options. Regarding the prevention of MCC, Iyer et al (85) noted that MCC tumors often developed when T cells for MCPyV T-antigen oncoproteins were present; thus, peptide-specific vaccines and immunotherapies should be possible. Pastrana et al (86), in 2009, studied the seroresponsiveness. They and found that although most elderly people have been exposed to MCPyV, the magnitude of the serologic responsiveness had wide variability, with MCPyV and MCC patients displaying the greatest titer humoral response (86). This suggests that a virus-like particle-based vaccine might be effective in preventing primary MCPyV infection. Rollison et al (87), in 2011, suggested that another potential target for vaccination was the involvement of MCPyV in squamous cell carcinoma carcinogenesis. The antibody survivin, found sevenfold in virus-positive MCC, and p53/p63 suggest a poorer prognosis. In addition to survivin being used as a prognostic indicator, it has been evaluated as a potential target for therapy. Pathways involving survivin can be identified and used to target viralinduced cancers for treatment or prevention (88,89).
Fig. 2. Clinical picture of 4-mm punch biopsy procedure.
The physical examination at his presentation failed to reveal ipsilateral inguinal or popliteal lymphadenopathy. Inspection of the lesion revealed an approximately 1 1.5 cm in diameter by 0.5-cm, raised violaceous lesion located on the anterior lateral lower extremity approximately 2 in. proximal to the level of the ankle joint (Fig. 1). The lesion was firm and fixed within the skin and did not blanch on compression. It did not transilluminate. Appropriate discussion transpired, and consent was obtained to perform a biopsy in an effort to accurately identify the lesion. The area adjacent and deep to the lesion was infiltrated with 3 mL of plain 1% lidocaine for anesthesia, and sterile preparation of the area was performed with povidone iodine. After verifying anesthesia, a 4-mm diameter by 8mm deep punch biopsy specimen was taken from the central aspect of the lesion (Figs. 2 and 3). The specimen consisted of thick, solid, white fibrous tissue. Once hemostasis was obtained, a single 4-0 nylon simple suture was used for closure, followed by application of adhesive skin strips and a light dry sterile dressing. The excised specimen was fixed in formalin and sent to pathology for analysis. Subsequent clinical inspections at the follow-up visits showed the biopsy site to have healed uneventfully. Histopathologic review confirmed the diagnosis of a neuroendocrine carcinoma, namely MCC. The diagnosis of MCC was determined
Case Report In early January 2011, a 78-year-old white male presented to the Louis Stokes Cleveland Department of Veterans Affairs Medical Center outpatient podiatry clinic for diabetic foot care. The patient’s dermatology, vascular, and neurologic examination findings were unremarkable relative to the foot. However, a nodular lesion was noted on the anterior aspect of his lower right leg. On questioning, the patient stated he had first noticed it about 3 months earlier and that it occasionally opened and drained. In addition, he noted that it had been much smaller and had quickly become larger within a short period. He denied pain associated with the lesion. He did not recall trauma, knowledge of foreign body penetration, or an insect or arachnid bite. Also, he had no history of contact with a thermal surface. He had no knowledge or history of similar lesions elsewhere on his body. His medical history was significant for both diabetes and rosacea.
Fig. 3. Another view of 4-mm punch biopsy procedure.
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Fig. 4. Low magnification showing tumor under the skin surface and uninvolved epidermis.
using specific staining techniques. Merkel cells exhibit both epithelial and neuroendocrine markers, which stain positive for low-molecularweight CK8, CK18, CK19, and CK20. CK20 in particular is specific for Merkel cell identification. Normally, CK20 stains diffusely. However, in the case of MCC, a paranuclear dot-like pattern will be seen. Approximately 80% to 90% of all MCCs will stain positive for CK20 in the paranuclear pattern (22). In the present case, the immunostains were positive for CK8, CK18, and CK20 and for chromogranin, synaptophysin, and CD56, which are also useful diagnostic markers for MCC. The immunostains were negative for CD45 and CD117 (Figs. 4 to 8). The patient was referred to both the general and plastic surgery services and hematology and oncology for continued care. Shortly thereafter, a staging computed tomography scan of the chest, abdomen, and pelvis with contrast and a positron emission tomography scan were performed. Both were negative for any evidence of metastasis. The general surgery service excised 2 sentinel lymph nodes using sulfur colloid for imaging and performed a 5.0-cm 5.0cm diameter by 1.0-cm deep wide local excision around the original
Fig. 5. Medium magnification showing diffuse infiltration of dermis by small cells, slightly larger than lymphocytes. No organoid or trabecular arrangement was seen. The cells had round to slightly irregular nuclei and scant cytoplasm. The nuclei were pale with inconspicuous nucleoli and frequent mitoses. No necrosis was present.
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Fig. 6. Magnification at 40 revealing many mitotic figures.
lesion. The specimen was oriented by the surgeon with a short suture designating the superior aspect and a long suture designating the lateral border and was submitted for review. Reconstruction of the excision site was concurrently performed by the plastic surgery service. The surgical sites healed without complications. The pathologist confirmed that the lymph nodes were negative for evidence of malignancy. A review of the original lesion wide-resection specimen revealed no evidence of residual neoplasm. The patient was seen by the hematology and oncology service and his case was discussed at the tumor board conference. The MCC was staged as T1N0M0 by the initial size of the lesion, negative lymph node involvement, and negative metastatic findings. A recommendation of surveillance and no chemotherapy or radiotherapy was made. Shave biopsies of 4 lesions noted on the back and flank in June and August 2011 were benign. Surveillance computed tomography scans in September 2011 and April 2012 were completed. The results of the April 2012 imaging studies revealed new subcutaneous nodules at the anterior abdominal wall. A positron emission tomography scan was performed in April 2012, and hypermetabolism was noted. In May 2012, a computed tomography-guided biopsy of the lesions was performed, and no evidence of malignancy was found. Since then, shave biopsies of 5 lesions on the chest, flank, and back have been performed, with
Fig. 7. Immunostain for chromogranin (synaptophysin stain was similar).
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Fig. 8. Immunostains for cytokeratins (CK8/CK18 and CK20) and neuroendocrine markers (chromogranin, synaptophysin, and CD56) show diffuse cytoplasmic staining in the tumor cells.
benign processes only found. At 34 months of follow-up, he has had no new lesions or disseminated disease noted. Discussion The patient described in the present report presented with a benign-appearing lesion of unknown etiology. His age, race, and lifetime UV accumulative exposure, the location and presentation of the lesion, and his history of diabetes, all placed him in a subset of patients in which MCC is likely. In the present case, a high index of suspicion of a seemingly benign lesion and quick referral led to the early recognition and successful multidisciplinary treatment of a rare, aggressive, malignant tumor with a relatively high mortality rate. The main purpose of the present case report and published data review was to bring MCC to the attention of foot and ankle surgeons and to offer guidance to the clinicians who might be the first to observe such a lesion. Clinical suspicion should arise when a rapidly growing, red or violaceous plaque, papule, or nodule of unknown origin is encountered in a patient with known relative risk factors for MCC. Lesional biopsy, wide local excision, sentinel lymph node inspection, and timely referrals should be the standard of care in determining treatment and will likely decrease the incidence of metastasis. In addition, long-term follow-up surveillance is recommended for early recognition of the potential recurrence of the carcinoma. Acknowledgments Special thanks to Donna Perzeski, Director Library Services, Kent State University College of Podiatric Medicine for her assistance with obtaining literature. References 1. Albores-Saavedra J, Batich K, Chable-Montero F, Sagy N, Schwartz AM, Henson DE. Merkel cell carcinoma demographics, morphology, and survival based on 3870 cases: a population based study. J Cutan Pathol 37:20–27, 2010. 2. Agelli M, Clegg LX. Epidemiology of primary Merkel cell carcinoma in the United States. J Am Acad Dermatol 49:832–841, 2003. 3. Pan D, Narayan D, Ariyan S. Merkel cell carcinoma: five case reports using sentinel lymph node biopsy and a review of 110 new cases. Plast Reconstr Surg 110:1259– 1265, 2002.
4. Hodgson NC. Merkel cell carcinoma: changing incidence trends. J Surg Oncol 89:1– 4, 2005. 5. Ascoli V, Minelli G, Kanieff M, Frova L, Conti S. Merkel cell carcinoma: a population-based study on mortality and the association with other cancers. Cancer Causes Control 22:1521–1527, 2011. 6. Andres C, Puchta U, Flaig MJ. Detection of Merkel cell polyomavirus DNA in atypical fibroxanthoma in correlation to clinical features. Am J Dermatopathol 32:799–803, 2010. 7. Pectasides D, Pectasides M, Economopoulos T. Merkel cell cancer of the skin. Ann Oncol 17:1489–1495, 2006. 8. Nghiem P, McKee PH, Haynes HA. Merkel cell (cutaneous neuroendocrine) carcinoma. Book of the American Cancer Society Atlas of Clinical Oncology: Skin Cancer Chapter 8.2:127–141, 2001. 9. Toker C. Trabecular carcinoma of the skin. Arch Dermatol 105:107–110, 1972. 10. Merkel F. Tastzellen und Tastkorperchen bei den Haustieren und beim Menschen. Arch Mikrosk Anat 11:636–652, 1875. 11. Rywlin AM. 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J Am Acad Dermatol 58:375–381, 2008. € hling TO. Vascular invasion is an 24. Kukko HM, Koljonen VSK, Tukiainen EJ, Haglund CH, Bo early event in pathogenesis of Merkel cell carcinoma. Mod Pathol 23:1151–1156, 2010. 25. Werchau S, Toberer F, Enk A, Dammann R, Helmbold P. Merkel cell carcinoma induces lymphatic microvessel formation. J Am Acad Dermatol 67:215–225, 2012. 26. Calder KB, Smoller BR. New insights into Merkel cell carcinoma. Adv Anat Pathol 17:155–161, 2010. 27. Plaza JA, Suster S. The Toker tumor: spectrum of morphologic features in primary neuroendocrine carcinomas of the skin (Merkel cell carcinoma). Ann Diag Pathol 10:376–385, 2006. 28. Schrama D, Peitsch WK, Zapatka M, Kneitz H, Houben R, Eib S, Haferkamp S, €hler C, Scolyer RA, Becker JC. Moore PS, Shuda M, Thompson JF, Trefzer U, Pfo Merkel cell polyomavirus status is not associated with clinical course of Merkel cell carcinoma. J Invest Dermatol 131:1631–1638, 2011. 29. Asioli S, Righi A, Volante M, Eusebi V, Bussolati G. p63 Expression as a new prognostic marker in Merkel cell carcinoma. Cancer 110:640–647, 2007. 30. Tucci MG, Lucarini G, Giangiacomi M, Zizzi A, Criante P, Ricotti G, Biagini G. Immunohistochemical study of apoptosis markers and involvement of chemokine CXCR4 in skin Merkel cell carcinoma. J Eur Acad Dermatol Venereol 20:1220–1225, 2006. 31. Zager JS, Rollison DE, Messina J. Prognostication in Merkel cell carcinoma. Expert Rev Anticancer Ther 11:665–667, 2011. 32. Brenner B, Sulkes A, Rakowsky E, Feinmesser M, Ykelson A, Bar-Haim E, Katz A, Edelevich E, Neuman A, Barhana M, Fenig E. Second neoplasms in patients with Merkel cell carcinoma. Cancer 91:1358–1362, 2001. 33. Kaae J, Hansen AV, Biggar RJ, Boyd HA, Moore PS, Wohlfahrt J, Melbye M. Merkel cell carcinoma: incidence, mortality, and risk of other cancers. J Natl Cancer Inst 102:793–801, 2010. 34. Bobos M, Hytiroglou P, Kostopoulos I, Karkavelas G, Papadimitriou CS. Immunohistochemical distinction between Merkel cell carcinoma and small cell carcinoma of lung. Am J Dermatopathol 28:99–104, 2006. rezt JL. Merkel cell 35. Acebo E, Vidaurrazaga N, Varas C, Burgos-Bretones JJ, Dıaz-Pe carcinoma: a clinicopathological study of 11 cases. J Eur Acad Dermatol Venereol 19:5046–5051, 2005. €cker EB, Houben R. Merkel cell carci36. Becker JC, Kauczok CS, Ugurel S, Eib S, Bro noma: molecular pathogenesis, clinical features and therapy. J Dtsch Dermatol Ges 6:709–720, 2008. 37. Becker J, Mauch C, Kortmann RD, Deilholz U, Bootz F, Garbe C, Hauschild A, Moll I. Short German guidelines: Merkel cell carcinoma. J Dtsch Dermatol Ges 6(Suppl 1):S15–S16, 2008.
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38. Ruan JH, Reeves M. A Merkel cell carcinoma treatment algorithm. Arch Surg 144:582–585, 2009. 39. Bichakjian CK, Lowe L, Lao CD, Sandler HM, Bradford CR, Johnson TM, Wong SL. Merkel cell carcinoma: critical review with guidelines for multidisciplinary management. Cancer 110:1–12, 2007. 40. O’Connor WJ, Roenigk RK, Brodland DG. Merkel cell carcinoma: comparison of Mohs micrographic surgery and wide excision in eighty-six patients. Dermatol Surg 23:929–933, 1997. 41. Ott MJ, Tanabe KK, Gadd MA, Stark P, Smith BL, Finkelstein DM, Souba WW. Multimodality management of Merkel cell carcinoma. Arch Surg 134:388–393, 1999. 42. Gillenwater AM, Hessel AC, Morrison WH, Burgess MA, Silva EG, Roberts D, Goepfert H. Merkel cell carcinoma of the head and neck: effect of surgical excision and radiation on recurrence and survival. Arch Otolaryngol Head Neck Surg 127:149–154, 2001. 43. Yiengpruksawan A, Coit DG, Thalaer HT, Urmacher C, Knapper WK. Merkel cell carcinoma: prognosis and management. Arch Surg 126:1514–1519, 1991. 44. Giannotti G, Lazzeri D, Viacava P, Barbieri B, Colizzi L, Fanelli G, Pagnini D, Massei A. Merkel cell carcinoma of the lower extremity: report of four cases and new considerations. Ann Plast Surg 62:83–86, 2009. 45. Medina-Franco H, Urist MM, Fiveash J, Heslin MJ, Bland KI, Beenken SW. Multimodality treatment of Merkel cell carcinoma: case series and literature review of 1024 cases. Ann Surg Oncol 8:204–208, 2001. 46. American Joint Committee on Cancer. AJCC Cancer Staging Handbook. Merkel Cell Carcinoma. New York: Springer; 2010, pp. 377-386. 47. Stokes JB, Graw KS, Dengal LT, Swenson BR, Bauer TW, Slingluff CL, Ledesma EJ. Patients with Merkel cell carcinoma tumors 1.0 cm in diameter are unlikely to harbor regional lymph node metastasis. J Clin Oncol 27:3772–3777, 2009. 48. Allen PJ, Bowne WB, Jaques DP, Brennan MF, Busam K, Coit DG. Merkel cell carcinoma: prognosis and treatment of patients from a single institution. J Clin Oncol 23:2300–2309, 2005. ~ as PF, Gellenthin M, Lee SJ, Nghiem P. Sentinel lymph node 49. Gupta SG, Wang LC, Pen biopsy for evaluation and treatment of patients with Merkel cell carcinoma: the Dana-Farber experience and meta-analysis of the literature. Arch Dermatol 142:685–690, 2006. 50. Andea AA, Coit DG, Amin B, Busam KJ. Merkel cell carcinoma: histologic features and prognosis. Cancer 113:2549–2558, 2008. 51. Doyle MA. Merkel cell carcinoma. JFAS 25:374–377, 1986. 52. O’Rourke H, Meyers SP, Katzman PJ. Merkel cell carcinoma of the foot: case report and review of the literature. JFAS 46:196–200, 2007. 53. Wang TS, Byrne PJ, Jacobs LK, Taube JM. Merkel cell carcinoma: update and review. Semin Cutan Med Surg 30:48–56, 2011. 54. Rockville Merkel Cell Carcinoma Group. Merkel cell carcinoma: recent progress and current priorities on etiology, pathogenesis, and clinical management. J Clin Oncol 27:4021–4026, 2009. 55. Feng H, Taylor JL, Benos PV, Newton R, Waddell K, Lucas SB, Chang Y, Moore PS. Human transcriptome subtraction by using short sequence tags to search for tumor viruses in conjunctival carcinoma. J Virol 81:11332–11340, 2007. 56. Feng H, Shuda M, Chang Y, Moore PS. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science 319:1096–1100, 2008. 57. Kuwamoto S, Higaki H, Kanai K, Iwasaki T, Sano H, Nagata K, Kato K, Kato M, Murakami I, Horie Y, Yamamoto O, Hayashi K. Association of Merkel cell polyomavirus infection with morphologic difference in Merkel cell carcinoma. Hum Pathol 42:632–640, 2011. 58. Andres C, Belloni B, Puchta U, Sander CA, Flaig MJ. Prevalence of MCPyV in Merkel cell carcinoma and non-MCC tumors. J Cutan Pathol 37:28–34, 2010. €hler C, Schrama D. MC polyomavirus is 59. Becker JC, Houben R, Ugurel S, Trefzer U, Pfo frequently present in Merkel cell carcinoma of European patients. J Invest Dermatol 129:248–250, 2009. 60. Foulongne V, Kluger N, Dereure O, Brieu N, Guillot B, Segondy M. Merkel cell polyomavirus and Merkel cell carcinoma, France. Emerg Infect Dis 14:1491–1493, 2008. 61. Garneski KM, Warcola AH, Feng Q, Kiviat NB, Leonard JH, Nghiem P. Merkel cell polyomavirus is more frequently present in North American than Australian Merkel cell carcinoma tumors. J Invest Dermatol 129:246–248, 2009. € pflin A, Diaz C, Weyers W, Stickeler E, Werner M, Zur Hausen A. 62. Kassem A, Scho Frequent detection of Merkel cell polyomavirus in human Merkel cell carcinomas and identification of a unique deletion in VP1 gene. Cancer Res 68:5009–5013, 2008. €hling T, Joensuu H. Clinical factors 63. Sihto H, Kukko H, Koljonen V, Sankila R, Bo associated with Merkel cell polyomavirus infection in Merkel cell carcinoma. J Natl Cancer Inst 101:938–945, 2009. 64. Mangana J, Dziunycz P, Kerl K, Dummer R, Cozzio A. Prevalence of Merkel cell polyomavirus among Swiss Merkel cell carcinoma patients. Dermatology 221:184–188, 2010. 65. Shuda M, Feng H, Kwun HJ, Rosen ST, Gjoerup O, Moore PS, Chang Y. T antigen mutations are a human tumor-specific signature for Merkel cell polyomavirus. Proc Natl Acad Sci U S A 105:16272–16277, 2008.
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66. Goh S, Lindau C, Tiveljung-Lindell A, Allander T. Merkel cell polyomavirus in respiratory tract secretions. Emerg Infect Dis 15:489–491, 2009. 67. Kean JM, Rao S, Wang M, Garcea RL. Seroepidemiology of human polyomaviruses. PLoS Pathog 5:1–10, 2009. 68. Tolstov YL, Pastrana DV, Feng H, Becker JC, Jenkins FJ, Moschos S, Chang Y, Buck CB, Moore PS. Human Merkel cell polyomavirus infection: II. MCPYV is a common human infection that can be detected by conformational capsid epitope immunoassays. Int J Cancer 125:1250–1256, 2009. 69. Carter JJ, Paulson KG, Wipf GC, Miranda D, Madeleine MM, Johnson LG, Lemos BD, Lee S, Warcola AH, Iyer JG, Nghiem P, Galloway DA. Association of Merkel cell polyomavirus-specific antibodies with Merkel cell carcinoma. J Natl Cancer Inst 101:1510–1522, 2009. 70. Loyo M, Guerrero-Preston R, Brait M, Hoque MO, Chuang A, Kim MS, Sharma R, geois MJ, Koch WM, Califano J, Westra WH, Sidransky D. Quantitative detection Lie of Merkel cell virus in human tissues and possible mode of transmission. Int J Cancer 126:2991–2996, 2010. 71. Schowalter RM, Pastrana DV, Pumphrey KA, Moyer AL, Buck CB. Merkel cell polyomavirus and two novel polyomaviruses are chronically shed from human skin. Cell Host Microb 7:509–515, 2010. s J, Guillot B, Segondy M. 72. Foulongne V, Kluger N, Dereure O, Mercier G, Mole Merkel cell polyomavirus in cutaneous swabs. Emerg Infect Dis 16:685–687, 2010. 73. Vesely MJ, Murray DJ, Neligan PC, Novak CB, Gullane PJ, Ghazarian D. Complete spontaneous regression in Merkel cell carcinoma. J Plast Reconstr Aesthet Surg 61:165–171, 2007. 74. Paulson KG, Carter JJ, Johnson LG, Cahill KW, Iyer JG, Schrama D, Becker JC, Madeleine MM, Nghiem P, Galloway DA. Antibodies to Merkel cell polyomavirus Tantigen oncoproteins reflect tumor burden in Merkel cell carcinoma patients. Cancer Res 70:8388–8397, 2010. 75. Paulson KG, Iyer JG, Tegeder AR, Thibodeau R, Schelter J, Koba S, Schrama D, Simonson WT, Lemos BD, Byrd DR, Koelle DM, Galloway DA, Leonard JH, Madeleine MM, Argenyi ZB, Disis ML, Becker JC, Cleary MA, Nghiem P. Transcriptome-wide studies of Merkel cell carcinoma and validation of intratumoral CD8þ lymphocyte invasion as an independent predictor of survival. J Clin Oncol 29:1539–1546, 2011. 76. Haag ML, Glass LF, Fenske NA. Merkel cell carcinoma: diagnosis and treatment. Dermatol Surg 21:669–683, 1995. 77. Eng TY, Boersma MGK, Fuller CD, Cavanaugh SX, Valenzuela F, Herman TS. Treatment of Merkel cell carcinoma. Am J Clin Oncol 27:510–515, 2004. 78. Hitchcock CL, Bland KI, Laney RG III, Franzini D, Harris B, Copeland EM III. Neuroendocrine (Merkel cell) carcinoma of the skin: its natural history, diagnosis, and treatment. Ann Surg 207:201–207, 1988. 79. Cotlar AM, Gates JO, Gibbs FA Jr. Merkel cell carcinoma: combined surgery and radiation therapy. Ann Surg 52:159–164, 1986. 80. Boyer JD, Zitelli JA, Brodland DG, D’Angelo G. Local control of primary Merkel cell carcinoma: review of 45 cases treated with Mohs micrographic surgery with and without adjuvant radiation. J Am Acad Dermatol 47:885–892, 2002. 81. Queirolo P, Gipponi M, Peressini A, Disomma CF, Vecchio S, Raposio E, Guenzi M, Sertoli MR, Cafiero F. Merkel cell carcinoma of the skin: treatment of primary, recurrent and metastatic disease: review of clinical cases. Anticancer Res 17:2339– 2342, 1997. 82. Westgate SJ. Radiation therapy for skin tumor. Otolaryngol Clin North Am 26:295– 309, 1993. 83. Fenig E, Lurie H, Klein B, Sulkes A. The treatment of advanced Merkel cell carcinoma: a multimodality chemotherapy and radiation therapy treatment approach. J Dermatol Surg Oncol 19:860–864, 1993. 84. Donepudi S, DeConti RC, Samlowski WE. Recent advances in the understanding of the genetics, etiology, and treatment of Merkel cell carcinoma. Semin Oncol 39:163–172, 2012. 85. Iyer JG, Afanasiev OK, McClurkan C, Paulson K, Nagase K, Jing L, Marshak JO, Dong L, Carter J, Lai I, Farrar E, Byrd D, Galloway D, Yee C, Koelle DM, Nghiem P. Merkel cell polyomavirus-specific CD8þ and CD4þ T-cell responses identified in Merkel cell carcinomas and blood. Clin Cancer Res 17:6671–6680, 2011. 86. Pastrana DV, Tolstov YL, Becker JC, Moore PS, Chang Y, Buck CB. Quantitation of human seroresponsiveness to Merkel cell polyomavirus. PLoS Pathog 5:e1000578, 2009. 87. Rollison DE, Giuliano AR, Messina JL, Fenske NA, Cherpelis BS, Sondak VK, Roetzheim RG, Iannacone MR, Michael KM, Gheit T, Waterboer T, Tommasino M, Pawlita M. Case-control study of Merkel cell polyomavirus infection and cutaneous squamous cell carcinoma. Cancer Epidemiol Biomarkers Prev 21:74–81, 2012. 88. Kim J, McNiff JM. Nuclear expression of survivin portends a poor prognosis in Merkel cell carcinoma. Mod Pathol 21:764–769, 2008. 89. Arora R, Shuda M, Guastafierro A, Feng H, Toptan T, Tolstov Y, Normolle D, €mling A, Brodsky JL, Chang Y, Moore PS. Survivin is a Vollmer LL, Vogt A, Do therapeutic target in Merkel cell carcinoma. Sci Transl Med 4:133ra56, 2012.
Contents lists available at ScienceDirect
The Journal of Foot & Ankle Surgery journal homepage: www.jfas.org
Merkel Cell Carcinoma: Case Study and Literature Review Danae L. Lowell, DPM 1, Jerry Roberts, DPM 2, Prema Gogate, MD 3, Rose Goodwin, DPM 4 1
Staff Surgical Podiatrist, Department of Podiatry Surgery, and Assistant Residency Director, Cleveland Louis Stokes Veterans Affairs Medical Center, Cleveland, OH Submitted during 3rd Year of PMSR/RRA, Cleveland Louis Stokes Veterans Affairs Medical Center, Cleveland, OH 3 Staff Pathologist, Cleveland Louis Stokes Veterans Affairs Medical Center, Cleveland, OH 4 Submitted during 4th Year at Kent State University College of Podiatric Medicine, Kent, OH 2
a r t i c l e i n f o
a b s t r a c t
Level of Clinical Evidence: 4
Merkel cell carcinoma is a rare, aggressive, highly metastatic, often fatal, primary neuroendocrine tumor typically located on sun-exposed skin. It is frequently found in white males aged 60 to 70 years. The somewhat typical benign clinical appearance of the lesion can result in a delayed diagnosis, leading to a less than optimal outcome. Ó 2014 by the American College of Foot and Ankle Surgeons. All rights reserved.
Keywords: cancer cutaneous trabecular carcinoma lower extremity neuroendocrine carcinoma polyomavirus primary cutaneous tumor
According to data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program from 1973 to 2006, the incidence of Merkel cell carcinoma (MCC) was 0.41 per 100,000 for men and 0.18 per 100,000 for women, and 94.9% of those patients were caucasian (1). The incidence of MCC, most often found on the head and neck regions, tripled from 1986 to 2001, with approximately 1500 cases annually reported in the United States. It is believed that the increased incidence observed during the past 2 decades has been associated with improved diagnostic techniques and an aging population with an overall increased ultraviolet (UV) exposure. Investigators found a 75%, 59%, and 25% 5-year relative survival rate for 1034 patients with localized, regional, and distant MCC disease, respectively (2–4). Before 2007, little was known about this highly malignant skin cancer, which has an age-adjusted incidence of mortality of 0.031/100,000 (5). Since then, significant research and reviews have contributed to the current body of knowledge surrounding MCC. The differential diagnosis for MCC includes lesions that are more common, including basal B-cell carcinoma, squamous cell carcinoma, cutaneous metastatic small cell carcinoma of the lung, small cell cutaneous lymphoma, anaplastic small cell melanoma, Ewing’s sarcoma, neuroblastoma, rhabdomyosarcoma, epidermoid cyst, amelanotic melanoma, and atypical fibroxanthoma (6–9). In an effort to review the published data related to MCC, the MEDLINE database was searched for relevant studies. The term Financial Disclosure: None reported. Conflict of Interest: None reported. Address correspondence to: Danae L. Lowell, DPM, Department of Podiatry Surgery, Cleveland Louis Stokes Veterans Affairs Medical Center, 10701 East Boulevard, Cleveland, OH 44106. E-mail address: [email protected] (D.L. Lowell).
“Merkel cell carcinoma” was used as the basis for the searches, and references were included according to their relevance. In 1875, Friedrich Sigmund Merkel originally described the mechanoreceptors we now know as Merkel cells (10). He demonstrated the existence of nondendritic, nonkeratinocyte, touch-sensitive cells (tastzellen) in the skin and suggested that the cells were receptors and transducers of mechanical stimuli to neural impulses (10). After microscopic confirmation of the existence of these cells, the term Merkel cell was coined; and Toker (9) first described MCC in 1972 from his case review. His morphologic description included anastomosing trabeculae, cell nests, and cytoplasmic dense core granules that led to him to describe it as a “trabecular carcinoma of the skin” that he surmised arose from the Merkel cells. The term MCC came from Rywlin (11), who, in 1982, associated the tumor with Merkel cells in the basal layer of the epidermis. Since then, MCC research has led to a better understanding, classification, and treatment of this deadly carcinoma. MCC typically presents as a singular, “reddish glassy,” rapidly growing, pale to violaceous, firm, smooth, nonpainful, shiny nodular dermal lesion that arises 81% of the time in areas of chronic sun (UV radiation) exposure owing to the increased UV exposure to certain areas of the body. Telangiectasia has frequently been noted. Variations exist in which plaque-like lesions are exhibited. Ulcerations are rarely encountered but can be found in more advanced cases (12,13). MCC is rarely found on the oral and genital mucous membranes, where UV exposure is significantly lower. When encountered in these areas, the prognosis has typically been poor (14,15). Satellite metastases occur early and frequently in cases of MCC and have been found in the skin in 28% of cases, lymph nodes in 27%, liver in 13%, lung in 10%, bone in 10%, and brain in 6% (13). In 2010, Ng et al
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(16) presented the fifth documented case of metastatic MCC to the spine. After resection of the primary lesion in that case, the patient returned with neurologic deficits related to the metastasis. However, postoperative wound healing complications and aspiration pneumonia developed, and the patient died. They also reported occasions in which MCC spinal metastatic lesions were noted, and no primary lesion was ever found. A review of these cases demonstrated similar results and the aggressive nature of MCC (16). Epidemiologic analysis has suggested that the pattern distribution of MCC indicates an association with UV radiation exposure. Of 2384 cases of MCC reviewed by Paulson et al (17), involvement of the left side of the body, predominantly the arm and face, occurred in 52.7% of the cases. An even (50%) distribution was noted on the lower extremities in 571 of the 2384 cases. Their results suggested that driver-side UV exposure might be a contributing factor in the development of MCC. The results from a review of 171 patients with MCC by Koljonen et al (18), in 2012, confirmed left-sided asymmetry in 56% of the cases in sun-exposed areas of the body, although the distribution was equal (symmetrical) in areas typically shaded from the sun. Although UV exposure might be an etiologic culprit in the development of MCC, nonexposed areas are also at risk. In 2011, Iavazzo et al (19) reported a case of vulvar MCC in a 63-year-old female. At the diagnosis, the lesion was 9 cm, and inguinal lymph node metastasis was noted. Fewer than 20 cases of vulvar MCC have been reported. In addition to UV exposure, immunosuppression has also been determined to be key in the development of MCC. Organ transplant patients receiving immunosuppressive medications and patients with lymphoma, diabetes, or human immunodeficiency virus (HIV) all have a greater incidence of MCC. Engels et al (20) collected data from 309,365 patients with HIV and found 6 cases of MCC, a relative risk of 13.4 (95% confidence interval 4.9 to 29.1) compared with the general population. The results of a study by Tolstov et al (21), in 2011, found no direct correlation between HIV or acquired immunodeficiency syndrome and MCC. This supports the hypothesis that immunocompromise as an associated co-infection transformation was likely. It also suggested that MCC infection, although highly prevalent among adults, is often asymptomatic, indicating that transmission is common but that the actual clinical identification of the carcinoma is rare. The symptoms were similar between patients with HIV who were seropositive and those who were seronegative (21). This research not only supported that immunosuppressive therapy was found to be associated with an increased incidence of MCC but also led to generally a poorer prognosis (22). Using this information, Heath et al (23) described the mnemonic AEIOU for use when describing the clinical appearance and demographic data associated with MCC. AEIOU stands for an asymptomatic lesion expanding rapidly in a patient with immune suppression, age older than 50 years, with a history of UV exposure to the area. In their study of 195 patients with MCC, 88% were found to be asymptomatic despite rapid growth of the lesion, leading to a median 3-month delay between the initial presentation and diagnosis. Early lymphovascular invasion might be 1 key to understanding the very aggressive nature of MCC. Kukko et al (24) reviewed 126 MCC samples and found that 93% had intravascular invasion, of which 66% were solely lymphovascular and 3% were only vascular. Although the tumors lacking invasion were typically smaller, lymphovascular invasion was noted in the smallest lesion (0.3 cm in diameter) (24). Possibly contributing to early lymphovascular invasion, Werchau et al (25) investigated the process of lymphangiogenesis in MCC. They found a threefold increase in the mean density of small lymphatic capillaries and a more than eightfold increase in the median ratio of the number of small to large lymphatics compared with the controls (25). The increased lymphangiogenesis occurring with MCC supports
a connection between MCC and early lymphovascular invasion and the aggressive nature of MCC. The morphologic features include an asymmetric dermal distribution in sheets, nests, and serpiginous, diffuse, or trabecular and anastomosing patterns, with frequent subcutis involvement. Small round or oval blue cells, necrosis, nuclei with significant mitotic activity, pagetoid growth, and scant cytoplasm with argyrophil granules have commonly been described (26,27). The papillary dermis, epidermis, and adnexa are usually spared. Three histologic patterns exist, based on the arrangement and appearance of the tumor cells, trabecular, intermediate, and small cell, with intermediate constituting 80% of the 3 types. Although the trabecular pattern has the best prognosis and small cell the worst, frequent mixed and transitional types have been noted, making the histologic prognostic indicators unreliable (28–30). The typical prognostic factors for determining low, intermediate, and high risk, such as diameter, nodal status, and metastasis, have not held true for MCC (31). Poor prognostic indicators also include the presence of a secondary malignancy such as squamous cell carcinoma or chronic lymphocytic leukemia (32). Other adverse prognostic indicators include disease stage at presentation and male gender. Kaae et al (33) also showed the existence of shared risk factors for MCC and squamous cell carcinoma and chronic lymphocytic leukemia. Electron microscopy, enzyme, and immunohistochemical assays are used to confirm the expression of chromogranin, synaptophysin, and other neuropeptides. Because a variety of neoplasms display similar characteristics, specific markers for MCC have been determined to distinguish MCC from others. Cytokeratin (CK)20 positivity is specific for MCC and distinguishes it from other small round blue cell tumors. CK20 expression of a paranuclear plaque, a dot-like pattern, has been found in 87% of MCC cases (34,35). Pertinent exclusionary markers for thyroid transcription factor 1 and leukocyte common antigen will largely be diagnostic for MCC (36,37). Thyroid transcription factor-1 and leukocyte common antigen are found in small cell lung carcinoma and lymphoma, respectively, but will be absent in MCC. Neurofilament protein is not found in small cell lung carcinoma and is usually positive in MCC. Endothelial and neuroendocrine markers, including chromogranin and synaptophysin, which are found with differing frequency and intensity, can be used for confirmation (34). The current recommendations are that once the diagnosis has been confirmed, the next step is to obtain sentinel lymph node biopsy to assist with guiding treatment. Ruan and Reeves (38) in 2009 and Bichakjian et al (39) in 2007 developed treatment algorithms from the highest levels of available published data. Wide local surgical resection, determining the sentinel lymph node status, radiotherapy, chemotherapy and close follow-up to monitor for recurrence have been outlined as methods to evaluate and treat this aggressive carcinoma using multidisciplinary care (38,39). Experts have agreed that wide local excision with 2- to 3-cm margins is recommended (40–43). Yiengpruksawan et al (43) reported on 70 patients from Sloan-Kettering Cancer Center from 1969 to 1989 and found an overall survival rate of 64% for 5 years. The surgical margins were evaluated in 38 specimens and ranged from 1 to 5 cm, depending on the location. They observed margins of 3 cm or less in 27 (71%) and more than 3 cm in 11 (29%) specimens. Local recurrence was found in 4 of the 27 patients with margins of 3 cm or less compared with none in the 11 patients with surgical margins greater than >3 cm, supporting the recommendation for wide local excision with clear lateral margins greater than 3 cm. However, recurrence and metastatic spread can occur even with larger than recommended excisions, stressing the importance of early recognition and close long-term follow-up. Recurrence rates of 30% to 45% for local disease, 40% to 70% for nodal involvement, and 30% to 50% for distant metastases have been noted (2,44). Medina-Franco et al (45)
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reviewed 1024 cases from 20 series. Of those, 11 series had reported local recurrence rates of 10.5% with, and 52.6% without, adjunctive radiotherapy. Adjunctive or concurrent chemotherapy or radiotherapy can be considered for high-risk patients. MCC staging, developed by the American Joint Committee on Cancer and published in 2010, has led to a reliable predictor of relative mortality of 30% at 2 years and 50% at 5 years after confirmation of the diagnosis. Although similar to other classifications, AJCC staging starts with the tumor size and further substages the lesions according to the pathologic nodal evaluation (46). Lesions less than 1.0 cm in diameter have been found to be unlikely to be associated with regional lymph node metastasis (47). The 5-year survival rate for patients with stage I has been approximately 81%; however, for stage II, it has been 67%, and for stage III, 52%. Stage IV disease has had an 11% 2-year survival rate (48). Sentinel lymph node biopsy has been determined to be the best predictor of survival. Pathologic diagnosis of negative lymph node involvement predicts a 5-year survival rate of approximately 97%; however, positive lymph node involvement predicts a 5-year survival rate of 52% (49). Histologic parameters, including nodular or infiltrative architecture, thickness, and lymphovascular infiltration, have been noted to predict survival (50). Doyle (51) reported primary lower extremity MCC in 1986. That account described multiple recurrences of MCC in the form of nodular lesions that appeared 6 months after excision of a solitary lesion in the same area of the leg. After a second excision and skin grafts were performed, as well as radiotherapy, a new lesion presented on the foot, requiring additional surgery and lymph node biopsy. The lymph node biopsy was positive, and amputation of the foot was considered but abandoned. New lesions presented at 6, 8, and 12 months, and each was excised when noted. After admission for wound complications and subsequent surgical intervention, chemotherapy was initiated, and some improvement was noted. However, after additional lesion recurrence was noted in the lower extremity, the patient was lost to follow-up. In 2007, O’Rourke et al (52) published another report of a case of pedal MCC and described preoperative magnetic resonance imaging, needle biopsy, and bone scan results before wide resection and local flap reconstruction. Postoperatively, the patient received radiotherapy and underwent repeat magnetic resonance imaging at 7 months and 1, 2, and 5 years, with no evidence of recurrence. These cases demonstrate the lesion’s tendency to recur and successful surgical management of MCC. Since these publications, advancements in diagnostic and therapeutic strategies have led to a greater understanding of the lesion and its treatment. One of the most important findings related to MCC was its association with polyomavirus. Because immunosuppression has been associated with MCC, a viral component was suspected (53,54). Polyomaviruses are small, double-stranded DNA viruses that were first identified in mice. To date, 9 human polyomaviruses have been identified. In 2007, Feng et al (55) developed the process of digital transcriptome subtraction, thereby jump-starting research that focused on MCC. This screening method, which has been used to discover viral nucleic acids, would eventually be used to discover Merkel cell polyomavirus (MCPyV), in 2008, by Feng et al (56). They found that MCPyV infection and DNA integration occur before replication of tumor cells, suggesting (but not proving) that MCPyV has a causal role in the oncogenesis of MCC (56). They showed that MCPyV was a contributing factor in 80% of cases of MCC. MCPyV-negative MCCs have greater nuclear irregularity and more abundant cytoplasm than do MCPyV-positive MCCs, which have uniformly round nuclei and scant cytoplasm (57). Several studies have shown the presence of MCPyV DNA in MCC specimens (58–64). Furthermore, Shuda et al (65) showed that the MCPYV T-antigen gene was mutated in the presence of MCC but that the mutation was absent in
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nontumorigenic MCPyV strains in humans, making the MCPyV T antigen a good genetic marker for MCC (65). In 2009, Goh et al (66) identified the presence of MCPyV in respiratory secretions, suggesting a route of transmission. That same year, Kean et al (67) examined the seroprevalence of a small number of viruses, including MCPyV strains 350 and 339, and noted these 2 strains in 67% of the specimens, suggesting that primary exposure occurred in childhood. By developing a specific MCPyV virus-like particle enzyme-linked immunoassay and testing patients with MCC and control groups, Tolstov et al (68) found that patients without MCC had evidence of previous MCPyV exposure and that previously unrecognized infection was widespread. Carter et al (69) tested the prevalence of antibodies against MCPyV in the general population and the association between these antibodies and MCC and found that MCPyV was common, that it appeared to be associated with MCC, and that it did not appear to have antibodies cross reactive against other polyomaviruses. In 2010, Loyo et al (70) compared MCPyV levels in MCC specimens and other tissues and showed MCPyV to be highest in the cases of MCC and that it was also present in other tissues. After MCC tissue, greater levels of MCPyV were found in the upper aerodigestive tract, digestive system, and saliva than in the lung and genitourinary system, suggesting a fecaloral transmission. However, it seems that only neuroendocrine skin cells are susceptible to transformation by MCPyV (70). Schowalter et al (71) developed an improved rolling circle amplification technique to isolate circular DNA viral genomes from skin swabs and found that 3 polyomavirus species, including MCPyV, were shed from the skin in the form of virions. Foulongne et al (72) obtained multiple cutaneous and mucosal swabs from 46 participants, 5 of whom had MCC, 16 of whom had other skin diseases, and 25 of whom were clinically healthy. MCPyV DNA was found in 44 of the 46 volunteers. Summarizing these findings, MCPyV appears to be ubiquitous, with likely early onset exposure and multiple routes of transmission (72). The immunologic responsiveness of MCC, owing to its viral association, might provide options for future treatment of lesions associated with the polyomavirus. Proof of this can be offered by the spontaneous regression of disseminated MCC lesions (73). Paulson et al (74) found that patients with MCC had high IgG antibody reactivity to specific MCPyV large T and small T antigen oncoproteins, allowing T-antigen antibodies to be accurate predictors of tumor burden. However, this was not found to be protective against disease progression despite its use as a monitor of disease status (74). In 2011, Paulson et al (75) sought to determine whether a prognostic biomarker for MCC could be established. They determined that intratumoral CD8þ lymphocyte infiltration was associated with significantly better survival rates of MCC (75). Currently, standard therapies for MCC are lacking, especially in cases of advanced disease. Excision and radiotherapy have been well described for the treatment of MCC in its initial stages (76–79). Boyer et al (80) showed that wide, local resection was preferred if Mohs was performed, and adjunctive radiotherapy was suggested. Of 25 patients treated using Mohs surgery only, 4 (16%) had recurrence compared with no recurrence in a group of 20 patients who had undergone Mohs surgery and radiotherapy. However, high-level clinical evidence is not available for review to determine effectiveness. Adjunctive radiotherapy has also been determined to be beneficial. The American Joint Committee on Cancer (2010) showed a difference between patients with positive sentinel lymph nodes who received adjunctive therapy and those who did not. The 3-year disease-free survival rate was 50% with therapy versus 0% without adjunctive therapy. Adjunctive therapy has been described as a dose of 40 to 50 Gy, administered in 2-Gy daily fractions, to the primary or regional basin (81–83). Single and multiagent chemotherapy for local advanced and metastatic MCC using anthracycline, 5-fluorouracil, cisplatin, etoposide, cyclophosphamide, doxorubicin, and vincristine, among others, have been used. These
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Fig. 1. Clinical picture of suspicious lesion showing a singular 10 mm 15 mm 5 mm raised violaceous nodule on the anterior lateral aspect of the right lower extremity 2 in. above the ankle.
agents were chosen owing to their effectiveness treating small cell lung carcinoma, because of the histologic similarities to MCC. However, the studies have mainly included small groups and have been retrospective. The results have been limited and have not led to promising consistent MCC treatment. Donepudi et al (84) have provided an excellent review of the available data on the chemotherapeutic options. Regarding the prevention of MCC, Iyer et al (85) noted that MCC tumors often developed when T cells for MCPyV T-antigen oncoproteins were present; thus, peptide-specific vaccines and immunotherapies should be possible. Pastrana et al (86), in 2009, studied the seroresponsiveness. They and found that although most elderly people have been exposed to MCPyV, the magnitude of the serologic responsiveness had wide variability, with MCPyV and MCC patients displaying the greatest titer humoral response (86). This suggests that a virus-like particle-based vaccine might be effective in preventing primary MCPyV infection. Rollison et al (87), in 2011, suggested that another potential target for vaccination was the involvement of MCPyV in squamous cell carcinoma carcinogenesis. The antibody survivin, found sevenfold in virus-positive MCC, and p53/p63 suggest a poorer prognosis. In addition to survivin being used as a prognostic indicator, it has been evaluated as a potential target for therapy. Pathways involving survivin can be identified and used to target viralinduced cancers for treatment or prevention (88,89).
Fig. 2. Clinical picture of 4-mm punch biopsy procedure.
The physical examination at his presentation failed to reveal ipsilateral inguinal or popliteal lymphadenopathy. Inspection of the lesion revealed an approximately 1 1.5 cm in diameter by 0.5-cm, raised violaceous lesion located on the anterior lateral lower extremity approximately 2 in. proximal to the level of the ankle joint (Fig. 1). The lesion was firm and fixed within the skin and did not blanch on compression. It did not transilluminate. Appropriate discussion transpired, and consent was obtained to perform a biopsy in an effort to accurately identify the lesion. The area adjacent and deep to the lesion was infiltrated with 3 mL of plain 1% lidocaine for anesthesia, and sterile preparation of the area was performed with povidone iodine. After verifying anesthesia, a 4-mm diameter by 8mm deep punch biopsy specimen was taken from the central aspect of the lesion (Figs. 2 and 3). The specimen consisted of thick, solid, white fibrous tissue. Once hemostasis was obtained, a single 4-0 nylon simple suture was used for closure, followed by application of adhesive skin strips and a light dry sterile dressing. The excised specimen was fixed in formalin and sent to pathology for analysis. Subsequent clinical inspections at the follow-up visits showed the biopsy site to have healed uneventfully. Histopathologic review confirmed the diagnosis of a neuroendocrine carcinoma, namely MCC. The diagnosis of MCC was determined
Case Report In early January 2011, a 78-year-old white male presented to the Louis Stokes Cleveland Department of Veterans Affairs Medical Center outpatient podiatry clinic for diabetic foot care. The patient’s dermatology, vascular, and neurologic examination findings were unremarkable relative to the foot. However, a nodular lesion was noted on the anterior aspect of his lower right leg. On questioning, the patient stated he had first noticed it about 3 months earlier and that it occasionally opened and drained. In addition, he noted that it had been much smaller and had quickly become larger within a short period. He denied pain associated with the lesion. He did not recall trauma, knowledge of foreign body penetration, or an insect or arachnid bite. Also, he had no history of contact with a thermal surface. He had no knowledge or history of similar lesions elsewhere on his body. His medical history was significant for both diabetes and rosacea.
Fig. 3. Another view of 4-mm punch biopsy procedure.
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Fig. 4. Low magnification showing tumor under the skin surface and uninvolved epidermis.
using specific staining techniques. Merkel cells exhibit both epithelial and neuroendocrine markers, which stain positive for low-molecularweight CK8, CK18, CK19, and CK20. CK20 in particular is specific for Merkel cell identification. Normally, CK20 stains diffusely. However, in the case of MCC, a paranuclear dot-like pattern will be seen. Approximately 80% to 90% of all MCCs will stain positive for CK20 in the paranuclear pattern (22). In the present case, the immunostains were positive for CK8, CK18, and CK20 and for chromogranin, synaptophysin, and CD56, which are also useful diagnostic markers for MCC. The immunostains were negative for CD45 and CD117 (Figs. 4 to 8). The patient was referred to both the general and plastic surgery services and hematology and oncology for continued care. Shortly thereafter, a staging computed tomography scan of the chest, abdomen, and pelvis with contrast and a positron emission tomography scan were performed. Both were negative for any evidence of metastasis. The general surgery service excised 2 sentinel lymph nodes using sulfur colloid for imaging and performed a 5.0-cm 5.0cm diameter by 1.0-cm deep wide local excision around the original
Fig. 5. Medium magnification showing diffuse infiltration of dermis by small cells, slightly larger than lymphocytes. No organoid or trabecular arrangement was seen. The cells had round to slightly irregular nuclei and scant cytoplasm. The nuclei were pale with inconspicuous nucleoli and frequent mitoses. No necrosis was present.
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Fig. 6. Magnification at 40 revealing many mitotic figures.
lesion. The specimen was oriented by the surgeon with a short suture designating the superior aspect and a long suture designating the lateral border and was submitted for review. Reconstruction of the excision site was concurrently performed by the plastic surgery service. The surgical sites healed without complications. The pathologist confirmed that the lymph nodes were negative for evidence of malignancy. A review of the original lesion wide-resection specimen revealed no evidence of residual neoplasm. The patient was seen by the hematology and oncology service and his case was discussed at the tumor board conference. The MCC was staged as T1N0M0 by the initial size of the lesion, negative lymph node involvement, and negative metastatic findings. A recommendation of surveillance and no chemotherapy or radiotherapy was made. Shave biopsies of 4 lesions noted on the back and flank in June and August 2011 were benign. Surveillance computed tomography scans in September 2011 and April 2012 were completed. The results of the April 2012 imaging studies revealed new subcutaneous nodules at the anterior abdominal wall. A positron emission tomography scan was performed in April 2012, and hypermetabolism was noted. In May 2012, a computed tomography-guided biopsy of the lesions was performed, and no evidence of malignancy was found. Since then, shave biopsies of 5 lesions on the chest, flank, and back have been performed, with
Fig. 7. Immunostain for chromogranin (synaptophysin stain was similar).
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Fig. 8. Immunostains for cytokeratins (CK8/CK18 and CK20) and neuroendocrine markers (chromogranin, synaptophysin, and CD56) show diffuse cytoplasmic staining in the tumor cells.
benign processes only found. At 34 months of follow-up, he has had no new lesions or disseminated disease noted. Discussion The patient described in the present report presented with a benign-appearing lesion of unknown etiology. His age, race, and lifetime UV accumulative exposure, the location and presentation of the lesion, and his history of diabetes, all placed him in a subset of patients in which MCC is likely. In the present case, a high index of suspicion of a seemingly benign lesion and quick referral led to the early recognition and successful multidisciplinary treatment of a rare, aggressive, malignant tumor with a relatively high mortality rate. The main purpose of the present case report and published data review was to bring MCC to the attention of foot and ankle surgeons and to offer guidance to the clinicians who might be the first to observe such a lesion. Clinical suspicion should arise when a rapidly growing, red or violaceous plaque, papule, or nodule of unknown origin is encountered in a patient with known relative risk factors for MCC. Lesional biopsy, wide local excision, sentinel lymph node inspection, and timely referrals should be the standard of care in determining treatment and will likely decrease the incidence of metastasis. In addition, long-term follow-up surveillance is recommended for early recognition of the potential recurrence of the carcinoma. Acknowledgments Special thanks to Donna Perzeski, Director Library Services, Kent State University College of Podiatric Medicine for her assistance with obtaining literature. References 1. Albores-Saavedra J, Batich K, Chable-Montero F, Sagy N, Schwartz AM, Henson DE. Merkel cell carcinoma demographics, morphology, and survival based on 3870 cases: a population based study. J Cutan Pathol 37:20–27, 2010. 2. Agelli M, Clegg LX. Epidemiology of primary Merkel cell carcinoma in the United States. J Am Acad Dermatol 49:832–841, 2003. 3. Pan D, Narayan D, Ariyan S. Merkel cell carcinoma: five case reports using sentinel lymph node biopsy and a review of 110 new cases. Plast Reconstr Surg 110:1259– 1265, 2002.
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