The patient is an elderly woman with rheumatoid arthritis who was evaluated in our multidisciplinary cutaneous oncology clinic for a new diagnosis of Merkel cell carcinoma.
This 74-year-old Caucasian female noted a red nodule on her left forearm approximately 4 months prior to diagnosis. She stated that the lesion started as a small, raised papule and slowly grew in size. Because the lesion was enlarging, the patient sought evaluation by her dermatologist. A biopsy was performed and revealed Merkel cell carcinoma. Positron-emission tomography/computed tomography (PET/CT) scan was performed and did not show evidence of metastatic disease. The patient subsequently underwent wide excision with concurrent sentinel lymph node evaluation. The reexcision specimen revealed an undifferentiated small-cell carcinoma most consistent with Merkel cell carcinoma, with clear margins. One sentinel lymph node harvested from the left axilla was negative for metastatic disease.
The patient then presented for a second opinion regarding further treatment options and follow-up plans. Of note, the patient has a 20-year history of rheumatoid arthritis. She has been treated with oral steroids for approximately 15 years, and at the time of her initial evaluation was on 2 mg of prednisone(Drug information on prednisone) daily. She was also being treated with infliximab(Drug information on infliximab) (Remicade) for her rheumatoid arthritis for approximately 2 years prior to her diagnosis of Merkel cell carcinoma.
Her past medical history is also significant for hypertension, which is well controlled on low-dose lisinopril(Drug information on lisinopril). Her family history is significant for a daughter who died of leukemia in her early 30s. There is no family history of merkel cell carcinoma or melanoma. Her review of systems was pertinent for arthritis pain, mainly in her wrists. The rest of her review of systems was unremarkable.
Physical exam revealed a well-appearing female in her usual state of health. The patient’s cardiac, pulmonary, and abdominal exam were unremarkable. Her left forearm had a 2 × 2 × 2 cm red, exophytic tumor (see Figure 1). There was no palpable cervical, supraclavicular, axillary, or inguinal lymphadenopathy. Examination of her joints revealed ulnar deviation of her right hand and thickening and limited range of motion of her wrists bilaterally. There was no active synovitis.
This patient is a 74-year-old female with a stage IB MCC on her left forearm. Her lesion is confined to the skin, and there is no evidence of distant or regional metastasis.
Dr. Ragini Kudchadkar: The incidence of Merkel cell carcinoma is low compared to other cutaneous malignancies; however, the number of cases has been steadily rising. Almost 500 new cases are seen in the United States each year. The steady increase in incidence has been attributed to the aging population in the United States. MCC is primarily a disease of the elderly and is extremely rare in those under age 50 (less than 5% of cases). Whites are affected more commonly than blacks. Most tumors primarily occur in the sun-exposed areas of the skin, with almost half the cases occurring on the face or neck. The majority of patients present with localized disease. Regional lymph node involvement at the time of diagnosis occurs in 10% to 30% of cases, while distant metastases occur in only 1% to 4% of cases at initial presentation. The most common sites of distant disease are the liver, lung, and bones.
Dr. Kudchadkar: Dr. Fitzpatrick, will you review the pathology for us?
Dr. James Fitzpatrick: This specimen demonstrated features consistent with MCC on routine hematoxylin and eosin (H&E) stains, with a normal epidermis overlying nodular dermal aggregates of small, round cells, and no evidence of vascular or lymphatic extension (see Figure 2). On high power, the nuclei were relatively uniform in appearance, with round hyperchromatic nuclei that demonstrate one to several small nucleoli. Scattered atypical mitotic figures were present. Some of the cells demonstrated scant lightly eosinophilic cytoplasm at one edge of the nucleus (see Figure 2).
In sum, the histologic features are those of a “small blue-cell carcinoma” of the skin. In addition to MCC, the differential diagnosis on H&E for this pattern also includes small-cell carcinoma of the lung, lymphoma, Ewing’s sarcoma, and small-cell melanoma.
Dr. Fitzpatrick: Since it is very difficult to distinguish between some of the tumors in the “small blue-cell carcinoma” differential, a panel of immunoperoxidase stains should always be done. In our laboratory, if MCC is suspected, the initial immunoperoxidase panel consists of a cytokeratin 20 (CK20), neuron-specific enolase (NSE), and thyroid transcription factor-1 (TTF-1).
Merkel cell carcinomas express CK20 in 90% of cases, often with a characteristic perinuclear dotlike pattern. A positive CK20 is also useful because it excludes lymphoma, Ewing’s sarcoma, and small-cell melanoma, as these lesions do not express this cytokeratin; however, about one-third of small-cell carcinomas of the lung express CK20. The TTF-1 is ordered to exclude small-cell carcinoma of the lung, as it is uniformly negative in MCC and positive in more than 90% of small-cell carcinomas of the lung. Although CK20 is most commonly ordered, other cytokeratin stains including pancytokeratin and CAM5.2 are positive in most cases. The NSE is ordered as a confirmatory stain and is usually positive in more than 80% of cases (see Figure 3). In cases that do not coexpress cytokeratin and NSE, we order additional confirmatory stains such as CD117, CD56, epithelial membrane antigen (EMA), chromogranin A, or synaptophysin.
Dr. Rene Gonzalez: Will you review how the sentinel lymph node should be processed and evaluated? Is it evaluated differently than a specimen from a patient with melanoma?
Dr. Fitzpatrick: There is far less experience in evaluating sentinel lymph nodes in patients with MCC, as compared to melanoma, and there is no uniformly agreed on standard for processing them. In general, everyone agrees that sentinel lymph nodes should be bisected and multiple step sections examined by routine H&E. What is not agreed upon is how many step sections should be examined and whether the step sections should be consecutive or cut with skip regions so that different areas of the lymph node can be examined. Intuitively, the latter approach would likely provide the most accurate assessment, although there are no studies to support this.
I think that it would be reasonable to bisect the lymph node and do one H&E and four unstained sections every 1 mm as you step in the block. The H&E stains are examined, and any areas that are suspicious for MCC should be confirmed with a CK20 stain done on one of the adjacent sections. If the initial tumor is CK20-negative, then another stain that is known to be positive for NSE can be used. In sum, a positive sentinel lymph node in MCC should demonstrate cells consistent with Merkel cell carcinoma on routine H&E, and it should be supported a by an immunoperoxidase stain that is consistent with the lineage of the primary tumor.