CLINICALLY SPEAKING
Merkel Cell Carcinoma of the Lower Extremity A Case Report Dominic J. Roda, DPM* Brian Albano, DPM† Bharti Rathore, MD* Linda Zhou, MD* Merkel cell carcinoma is a rare, often fatal, neuroendocrine cutaneous malignancy with a highly variable clinical presentation. Due to the rapid progression of the disease, early detection and treatment is vital to survival. Here, we report the case of a 45-year-old woman whose podiatrist noticed an unusual lesion on her lower left leg and referred her to a dermatologist for work-up. A diagnostic excisional biopsy confirmed the diagnosis and was followed by treatment that included wide local excision of the primary lesion with subsequent chemotherapy and radiation. At the time of diagnosis, sentinel lymph node biopsy was positive. Due to the increasing prevalence of Merkel cell carcinoma in the past decade and its propensity to present on the lower extremity, podiatric physicians need to be aware of the clinical presentation and treatment guidelines for this elusive disease. (J Am Podiatr Med Assoc 104(4): 422-425, 2014)
Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous malignancy that was first described by Toker in 1972.1 Found in the basal cell layer, Merkel cells derived from the neural crest are thought to be primarily involved in sensory perception as chemoreceptors or mechanoreceptors.2,3 Although the pathogenesis of MCC is not fully understood, risk factors including UV light exposure, sun-related skin malignancies, and immunosupression are well documented in the literature.1,2,4 Today, 950 to 1,300 cases of MCC are diagnosed per year in the United States, with an annual incidence of 0.23 and 0.01 per 100,000 for white individuals and African Americans, respectively. The mean age at the time of diagnosis is 69 to 75 years old, with little to no male or female preponderance, according to current research.2,5 Clinically, MCC has a highly variable presentation and can appear relatively benign for such an invasive neoplasm. This often leads to a delay of a timely diagnosis and initiation of a treatment plan. This neoplasm typically presents as a rapidly growing, dome-shaped, red or bluish intradermal mass.4 The lesion is most often painless and not *Roger Williams Medical Center, Providence, RI. †Private Practice, Providence, RI. Corresponding author: Dominic J. Roda, DPM, Roger Williams Medical Center, 825 Chalkstone Avenue, Providence, RI 02908. (E-mail: [email protected])
422
tender, which may further the patient’s and physician’s neglect. Confirmation of diagnosis is made by excisional biopsy. Diagnosis is based on typical histologic representation on hematoxylin and eosin–stained slides together with the results of immunohistochemistry. The histology is similar to that of small round cell tumors, such as small-cell lung carcinoma, malignant lymphoma, Ewing’s sarcoma, and rhabdomyosarcoma.1,6 A typical histologic finding in MCC is the presence of small round tumor cells within the dermis with repeated extensions to underlying subcutaneous tissue. The epidermis, papillary dermis, and adnexal structures are not usually involved.2 In a review of 1,024 patients, the primary tumor was found in the head and neck in 40%, in the extremities in 33%, and in the trunk in 23% of those patients. At presentation, lymph nodes are involved in approximately 25% of cases.5 In a study done by Heath et al,6 the five most common clinical features were used to create an acronym: AEIOU (Asymptomatic/lack of tenderness, Expanding rapidly ( 3 months), Immunosuppression, Older than 50 years of age, and location on a UV-exposed site). Once a suspicious lesion has been detected, excisional biopsy is extremely important because of the aggressive nature of the disease.
July/August 2014 Vol 104 No 4 Journal of the American Podiatric Medical Association
The prognosis of patients with MCC is highly associated with the extent of the disease at presentation. Typically MCC has a tendency to progress rapidly, and in just a few months, the tumor may attain a large diameter.2 Several reports show strong correlations between tumor size and survival rates. Lemos et al7 evaluated 2,856 patients and found a 5-year survival rate of 66% when tumors were 2 cm or smaller and a 51% 5-year survival rate when the tumor was larger than 2 cm (P , 0.0001). Metastatic state has also been shown to correlate with survival rates. In the same study by Lemos et al,7 the overall population 5-year survival rate was 54%; for those with local, nodal, and distant disease at presentation, these values were 64%, 39%, and 18% respectively. Due to the rapidly decreasing survival rate with disease progression, a timely diagnosis and treatment course is essential. All questionable cases should be referred to a dermatologist as soon as possible. Because of the rarity of the tumor, there are many treatment protocols described in the literature; however, surgical treatment is most often a firstline therapy. Early, radical surgery with margins of 2 to 5 cm is the recommended procedure for the treatment of primary MCC.2 As mentioned earlier, a sentinel lymph node biopsy is an important prognostic factor and is strongly advocated in the treatment and staging of individual tumors. Merkel cell carcinoma is a highly radiosensitive tumor and many authors have recommended postoperative radiotherapy based on outcomes comparisons, which report longer survival rates among patients treated with adjuvant radiotherapy as opposed to surgery alone.2 Chemotherapy is generally reserved for stage III cases of MCC, and there are no standard protocols reported in the literature, though the standard treatment approaches involve treatment as for poorly differentiated neuroendocrine carcinoma such as small-cell lung cancer.
significant for Barrett’s esophagus, chronic obstructive pulmonary disease, mitral valve prolapse, and fibromyalgia. The patient had a 25-pack-year smoking history but quit 10 years earlier. The patient was referred to a dermatologist who scheduled an excisional biopsy with the differential diagnosis of lipoma, erythema nodusm, or neoplasm. The initial pathology report of the biopsy came back as small-cell carcinoma with features favoring MCC. The patient underwent a computed tomography (CT) scan of the chest and abdomen that revealed multiple nonspecific nodes throughout the chest and abdomen. The patient was also found to have small external iliac chain lymph nodes and inguinal adenopathy. The patient was scheduled for staging work-up with positron emission tomography (PET)/CT and also to see a surgical oncologist for wide reexcision of the primary tumor and sentinel lymph node biopsy. Due to stage III disease, chemotherapy and radiotherapy were discussed with the patient. The patient underwent reexcision of the primary tumor with 2-cm margins. A skin graft was used to cover the wound once a healthy granular base had been attained. The pelvic lymph node biopsy was positive, and the patient was treated with chemoradiotherapy using carboplatin and etoposide (CE regimen). The patient achieved complete remission lasting for approximately 15 months and eventually had disease recurrence in 2009, presenting with adenopathy in the iliac region for which she received six cycles of chemotherapy with cyclophosphamide, doxorubicin, and vincristine (CAV regimen). The patient subsequently has undergone alternating annual PET and CT scans to monitor for disease recurrence. She did not need to undergo any further surgical procedures. To this date the patient remains in remission and is asymptomatic and pain free.
Discussion Case Report A 45-year-old woman presented to her podiatrist’s office in June, 2007, for follow-up on a recent ankle sprain. During her examination, the physician noted an odd lesion on her left anterior leg. The patient reported noticing the lesion approximately 6 months earlier and due to its painlessness and benign appearance, she had ignored it thinking might be a bug bite. The lesion was described as a faintly pink, firm nodule measuring approximately 1.3 cm. The patient’s past medical history was
At the time of diagnosis, our patient was quite young (45 years of age) compared with the mean age of most patients diagnosed with MCC (69–75 years of age). Merkel cell carcinoma is extremely rare before the age of 50, after which the incidence increases steeply with age, suggesting accumulation of oncogenic events. Although our patient was not known to be immunocompromised, MCC incidence increases approximately 11-fold for people with AIDS and five-fold for people with organ transplantation.3
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Merkel cell carcinoma usually occurs on sunexposed areas of skin, which correlates with the highest incidence occurring on the head and neck, followed by partially protected areas such as the extremities, as was the case with our patient. Merkel cell carcinoma often appears benign at initial presentation, with the common presumptive diagnosis of a cyst or acneiform lesion, which may lead to a delay in diagnosis (Fig. 1). Our patient attributed the lesion to a bug bite when asked about it at initial presentation. Differentiating MCC from other small-cell tumors can be difficult, and specialized stains are often used to rule out other malignancies.4 The initial pathology report on this patient’s biopsy was identified as a small-cell–type carcinoma based on typical findings (Fig. 2). The final diagnosis of MCC was only made after the use of immunohistochemical dyes. Immunohistochemically, the tumor cells are usually positive for cytokeratin 20 (CK20) in a characteristic paranuclear, dot-like pattern (Fig. 3). This particular feature has become pivotal in the distinction of MCC from histologically similar malignancies.3 There is no single treatment protocol described in the literature for MCC, and treatment often involves several modalities. In general, early surgical resection with wide margins is the initial approach. Our patient underwent excision of the 1.3-cm primary lesion with 2-cm margins. As mentioned earlier, radiotherapy has been shown to increase survival rates when combined with surgical resection. Chemoradiotherapy was used and the patient
Figure 2. Typical presentation of Merkel cell
carcinoma consisting of small round cells with a round nucleus, powdery chromatin, and scanty cytoplasm. Normal subcutaneous tissue is seen to the right. (Obtained from a case at our institution.) (H&E x200). achieved remission for 15 months. Scheduled PET scans and CT scans were used to monitor for reoccurrence, which did occur in 2009. Six cycles of chemotherapy alone were used, and the patient has been in remission since then. Given that regional lymph nodes were positive at initial diagnosis, this patient’s prognosis was not favorable. Now in remission, it is vital that she receive close monitoring and the necessary action be taken for new symptoms. There are no set parameters for follow-up once the patient is in remission, although routine examination at the
Figure 1. A photograph of the actual lesion was
unavailable; this photograph is representative of the general appearance of a Merkel cell carcinoma and is a case from our institution.
424
Figure 3. A characteristic paranuclear dot-like staining with cytokeratin 20 (CK20). (Obtained from a case at our institution.)
July/August 2014 Vol 104 No 4 Journal of the American Podiatric Medical Association
discretion of the oncologist is recommended. Our patient sees her oncologist every 4 months, and imaging is performed as needed for new symptomatology.
Conclusions Merkel cell carcinoma is 100 times less common than melanoma but twice as deadly. The overall 5year survival rate for patients with MCC is 50% to 68%.4 With an increase in the imunocompromised and elderly population, the rates of MCC have increased in recent years. Podiatric physicians play an integral role in patient survival rates with MCC and many other neoplasms that present on the skin of the lower extremities by performing biopsies and making appropriate consultations. Despite the aggressiveness of MCC, early diagnosis, optimal resection, and postoperative radiotherapy can achieve long-term survival rates.4 The patient reported in this case was given a 5-year survival rate of less than 39% given her stage at presentation. At nearly 5 years after diagnosis, she remains in remission and has a good quality of life, which can be attributed to the rapid diagnosis, treatment, and follow-up care she received.
Financial Disclosure: None reported. Conflict of Interest: None reported.
References 1. DUPRAT JP, LANDMAN G, SALVAJOLI JV, ET AL: A review of the epidemiology and treatment of Merkel cell carcinoma. Clinics 66: 1817, 2001. 2. KOLJONEN V: Merkel cell carcinoma. World J Surg Oncol 4: 7, 2006. 3. ROCKVILLE MERKEL CELL CARCINOMA GROUP: Merkel cell carcinoma: recent progress and current priorities on etiology, pathogenesis, and clinical management. J Clin Oncol 27: 4021, 2009. 4. PAPAMICHAIL M, NIKOLAIDIS I, NIKOLAIDIS N, ET AL: Merkel cell carcinoma of the upper extremity: case report and an update. World J Surg Oncol 6: 32, 2008. 5. CHEUNG M, LEE H, PURKAYASTHA S, ET AL: Ileocaecal recurrence of Merkel cell carcinoma of the skin: a case report. J Med Case Reports 4: 43, 2010. 6. HEATH M, JAIMES N, LEMOS B, ET AL: Clinical characteristics of Merkel cell carcinoma at diagnosis in 195 patients: the AEIOU features. J Am Acad Dermatol 58: 375, 2008 7. LEMOS BD, STORER BE, IYER JG, ET AL: Pathologic nodal evaluation improves prognostic accuracy in Merkel cell carcinoma: analysis of 5823 cases as the basis of the first consensus staging system for this cancer. J Am Acad Dermatol. 63: 751, 2010.
Journal of the American Podiatric Medical Association Vol 104 No 4 July/August 2014
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Merkel Cell Carcinoma of the Lower Extremity A Case Report Dominic J. Roda, DPM* Brian Albano, DPM† Bharti Rathore, MD* Linda Zhou, MD* Merkel cell carcinoma is a rare, often fatal, neuroendocrine cutaneous malignancy with a highly variable clinical presentation. Due to the rapid progression of the disease, early detection and treatment is vital to survival. Here, we report the case of a 45-year-old woman whose podiatrist noticed an unusual lesion on her lower left leg and referred her to a dermatologist for work-up. A diagnostic excisional biopsy confirmed the diagnosis and was followed by treatment that included wide local excision of the primary lesion with subsequent chemotherapy and radiation. At the time of diagnosis, sentinel lymph node biopsy was positive. Due to the increasing prevalence of Merkel cell carcinoma in the past decade and its propensity to present on the lower extremity, podiatric physicians need to be aware of the clinical presentation and treatment guidelines for this elusive disease. (J Am Podiatr Med Assoc 104(4): 422-425, 2014)
Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous malignancy that was first described by Toker in 1972.1 Found in the basal cell layer, Merkel cells derived from the neural crest are thought to be primarily involved in sensory perception as chemoreceptors or mechanoreceptors.2,3 Although the pathogenesis of MCC is not fully understood, risk factors including UV light exposure, sun-related skin malignancies, and immunosupression are well documented in the literature.1,2,4 Today, 950 to 1,300 cases of MCC are diagnosed per year in the United States, with an annual incidence of 0.23 and 0.01 per 100,000 for white individuals and African Americans, respectively. The mean age at the time of diagnosis is 69 to 75 years old, with little to no male or female preponderance, according to current research.2,5 Clinically, MCC has a highly variable presentation and can appear relatively benign for such an invasive neoplasm. This often leads to a delay of a timely diagnosis and initiation of a treatment plan. This neoplasm typically presents as a rapidly growing, dome-shaped, red or bluish intradermal mass.4 The lesion is most often painless and not *Roger Williams Medical Center, Providence, RI. †Private Practice, Providence, RI. Corresponding author: Dominic J. Roda, DPM, Roger Williams Medical Center, 825 Chalkstone Avenue, Providence, RI 02908. (E-mail: [email protected])
422
tender, which may further the patient’s and physician’s neglect. Confirmation of diagnosis is made by excisional biopsy. Diagnosis is based on typical histologic representation on hematoxylin and eosin–stained slides together with the results of immunohistochemistry. The histology is similar to that of small round cell tumors, such as small-cell lung carcinoma, malignant lymphoma, Ewing’s sarcoma, and rhabdomyosarcoma.1,6 A typical histologic finding in MCC is the presence of small round tumor cells within the dermis with repeated extensions to underlying subcutaneous tissue. The epidermis, papillary dermis, and adnexal structures are not usually involved.2 In a review of 1,024 patients, the primary tumor was found in the head and neck in 40%, in the extremities in 33%, and in the trunk in 23% of those patients. At presentation, lymph nodes are involved in approximately 25% of cases.5 In a study done by Heath et al,6 the five most common clinical features were used to create an acronym: AEIOU (Asymptomatic/lack of tenderness, Expanding rapidly ( 3 months), Immunosuppression, Older than 50 years of age, and location on a UV-exposed site). Once a suspicious lesion has been detected, excisional biopsy is extremely important because of the aggressive nature of the disease.
July/August 2014 Vol 104 No 4 Journal of the American Podiatric Medical Association
The prognosis of patients with MCC is highly associated with the extent of the disease at presentation. Typically MCC has a tendency to progress rapidly, and in just a few months, the tumor may attain a large diameter.2 Several reports show strong correlations between tumor size and survival rates. Lemos et al7 evaluated 2,856 patients and found a 5-year survival rate of 66% when tumors were 2 cm or smaller and a 51% 5-year survival rate when the tumor was larger than 2 cm (P , 0.0001). Metastatic state has also been shown to correlate with survival rates. In the same study by Lemos et al,7 the overall population 5-year survival rate was 54%; for those with local, nodal, and distant disease at presentation, these values were 64%, 39%, and 18% respectively. Due to the rapidly decreasing survival rate with disease progression, a timely diagnosis and treatment course is essential. All questionable cases should be referred to a dermatologist as soon as possible. Because of the rarity of the tumor, there are many treatment protocols described in the literature; however, surgical treatment is most often a firstline therapy. Early, radical surgery with margins of 2 to 5 cm is the recommended procedure for the treatment of primary MCC.2 As mentioned earlier, a sentinel lymph node biopsy is an important prognostic factor and is strongly advocated in the treatment and staging of individual tumors. Merkel cell carcinoma is a highly radiosensitive tumor and many authors have recommended postoperative radiotherapy based on outcomes comparisons, which report longer survival rates among patients treated with adjuvant radiotherapy as opposed to surgery alone.2 Chemotherapy is generally reserved for stage III cases of MCC, and there are no standard protocols reported in the literature, though the standard treatment approaches involve treatment as for poorly differentiated neuroendocrine carcinoma such as small-cell lung cancer.
significant for Barrett’s esophagus, chronic obstructive pulmonary disease, mitral valve prolapse, and fibromyalgia. The patient had a 25-pack-year smoking history but quit 10 years earlier. The patient was referred to a dermatologist who scheduled an excisional biopsy with the differential diagnosis of lipoma, erythema nodusm, or neoplasm. The initial pathology report of the biopsy came back as small-cell carcinoma with features favoring MCC. The patient underwent a computed tomography (CT) scan of the chest and abdomen that revealed multiple nonspecific nodes throughout the chest and abdomen. The patient was also found to have small external iliac chain lymph nodes and inguinal adenopathy. The patient was scheduled for staging work-up with positron emission tomography (PET)/CT and also to see a surgical oncologist for wide reexcision of the primary tumor and sentinel lymph node biopsy. Due to stage III disease, chemotherapy and radiotherapy were discussed with the patient. The patient underwent reexcision of the primary tumor with 2-cm margins. A skin graft was used to cover the wound once a healthy granular base had been attained. The pelvic lymph node biopsy was positive, and the patient was treated with chemoradiotherapy using carboplatin and etoposide (CE regimen). The patient achieved complete remission lasting for approximately 15 months and eventually had disease recurrence in 2009, presenting with adenopathy in the iliac region for which she received six cycles of chemotherapy with cyclophosphamide, doxorubicin, and vincristine (CAV regimen). The patient subsequently has undergone alternating annual PET and CT scans to monitor for disease recurrence. She did not need to undergo any further surgical procedures. To this date the patient remains in remission and is asymptomatic and pain free.
Discussion Case Report A 45-year-old woman presented to her podiatrist’s office in June, 2007, for follow-up on a recent ankle sprain. During her examination, the physician noted an odd lesion on her left anterior leg. The patient reported noticing the lesion approximately 6 months earlier and due to its painlessness and benign appearance, she had ignored it thinking might be a bug bite. The lesion was described as a faintly pink, firm nodule measuring approximately 1.3 cm. The patient’s past medical history was
At the time of diagnosis, our patient was quite young (45 years of age) compared with the mean age of most patients diagnosed with MCC (69–75 years of age). Merkel cell carcinoma is extremely rare before the age of 50, after which the incidence increases steeply with age, suggesting accumulation of oncogenic events. Although our patient was not known to be immunocompromised, MCC incidence increases approximately 11-fold for people with AIDS and five-fold for people with organ transplantation.3
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Merkel cell carcinoma usually occurs on sunexposed areas of skin, which correlates with the highest incidence occurring on the head and neck, followed by partially protected areas such as the extremities, as was the case with our patient. Merkel cell carcinoma often appears benign at initial presentation, with the common presumptive diagnosis of a cyst or acneiform lesion, which may lead to a delay in diagnosis (Fig. 1). Our patient attributed the lesion to a bug bite when asked about it at initial presentation. Differentiating MCC from other small-cell tumors can be difficult, and specialized stains are often used to rule out other malignancies.4 The initial pathology report on this patient’s biopsy was identified as a small-cell–type carcinoma based on typical findings (Fig. 2). The final diagnosis of MCC was only made after the use of immunohistochemical dyes. Immunohistochemically, the tumor cells are usually positive for cytokeratin 20 (CK20) in a characteristic paranuclear, dot-like pattern (Fig. 3). This particular feature has become pivotal in the distinction of MCC from histologically similar malignancies.3 There is no single treatment protocol described in the literature for MCC, and treatment often involves several modalities. In general, early surgical resection with wide margins is the initial approach. Our patient underwent excision of the 1.3-cm primary lesion with 2-cm margins. As mentioned earlier, radiotherapy has been shown to increase survival rates when combined with surgical resection. Chemoradiotherapy was used and the patient
Figure 2. Typical presentation of Merkel cell
carcinoma consisting of small round cells with a round nucleus, powdery chromatin, and scanty cytoplasm. Normal subcutaneous tissue is seen to the right. (Obtained from a case at our institution.) (H&E x200). achieved remission for 15 months. Scheduled PET scans and CT scans were used to monitor for reoccurrence, which did occur in 2009. Six cycles of chemotherapy alone were used, and the patient has been in remission since then. Given that regional lymph nodes were positive at initial diagnosis, this patient’s prognosis was not favorable. Now in remission, it is vital that she receive close monitoring and the necessary action be taken for new symptoms. There are no set parameters for follow-up once the patient is in remission, although routine examination at the
Figure 1. A photograph of the actual lesion was
unavailable; this photograph is representative of the general appearance of a Merkel cell carcinoma and is a case from our institution.
424
Figure 3. A characteristic paranuclear dot-like staining with cytokeratin 20 (CK20). (Obtained from a case at our institution.)
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discretion of the oncologist is recommended. Our patient sees her oncologist every 4 months, and imaging is performed as needed for new symptomatology.
Conclusions Merkel cell carcinoma is 100 times less common than melanoma but twice as deadly. The overall 5year survival rate for patients with MCC is 50% to 68%.4 With an increase in the imunocompromised and elderly population, the rates of MCC have increased in recent years. Podiatric physicians play an integral role in patient survival rates with MCC and many other neoplasms that present on the skin of the lower extremities by performing biopsies and making appropriate consultations. Despite the aggressiveness of MCC, early diagnosis, optimal resection, and postoperative radiotherapy can achieve long-term survival rates.4 The patient reported in this case was given a 5-year survival rate of less than 39% given her stage at presentation. At nearly 5 years after diagnosis, she remains in remission and has a good quality of life, which can be attributed to the rapid diagnosis, treatment, and follow-up care she received.
Financial Disclosure: None reported. Conflict of Interest: None reported.
References 1. DUPRAT JP, LANDMAN G, SALVAJOLI JV, ET AL: A review of the epidemiology and treatment of Merkel cell carcinoma. Clinics 66: 1817, 2001. 2. KOLJONEN V: Merkel cell carcinoma. World J Surg Oncol 4: 7, 2006. 3. ROCKVILLE MERKEL CELL CARCINOMA GROUP: Merkel cell carcinoma: recent progress and current priorities on etiology, pathogenesis, and clinical management. J Clin Oncol 27: 4021, 2009. 4. PAPAMICHAIL M, NIKOLAIDIS I, NIKOLAIDIS N, ET AL: Merkel cell carcinoma of the upper extremity: case report and an update. World J Surg Oncol 6: 32, 2008. 5. CHEUNG M, LEE H, PURKAYASTHA S, ET AL: Ileocaecal recurrence of Merkel cell carcinoma of the skin: a case report. J Med Case Reports 4: 43, 2010. 6. HEATH M, JAIMES N, LEMOS B, ET AL: Clinical characteristics of Merkel cell carcinoma at diagnosis in 195 patients: the AEIOU features. J Am Acad Dermatol 58: 375, 2008 7. LEMOS BD, STORER BE, IYER JG, ET AL: Pathologic nodal evaluation improves prognostic accuracy in Merkel cell carcinoma: analysis of 5823 cases as the basis of the first consensus staging system for this cancer. J Am Acad Dermatol. 63: 751, 2010.
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