(Radiographics. 2002;22:367-376.)
© RSNA, 2002
Imaging of Merkel Cell Carcinoma1
Ba D. Nguyen, MD and
Ann E. McCullough, MD
1 From the Departments of Diagnostic Radiology (B.D.N.) and Laboratory Medicine and Pathology (A.E.M.), Mayo Clinic, 13400 E Shea Blvd, Scottsdale, AZ 85259. Presented as an education exhibit at the 2000 RSNA scientific assembly. Received July 13, 2001; revision requested August 24 and received November 1; accepted November 7. Address correspondence to B.D.N.
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Abstract
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Merkel cell carcinoma (MCC) is a rare, highly malignant cutaneous tumor, primarily of the head and neck, that requires timely diagnosis, adequate staging, and aggressive therapy. MCC tends to be overlooked in the early stage, has a high propensity for invading local and regional nodal basins, and exhibits a high postoperative recurrence rate, with distant thoracic, abdominal, and central nervous system metastases. Conventional radiography and cross-sectional imaging show lesions similar to those originating from other small cell carcinomas. Nuclear medicine procedures such as sentinel node scintigraphy, somatostatin receptor scintigraphy, and positron emission tomography may be used to supplement judicious cross-sectional imaging evaluation, thereby adding diagnostic value in staging and providing therapeutic guidance. Ultimately, however, the diagnosis relies exclusively on pathologic findings at immunohistochemical staining and electron microscopy. The rarity of MCC and the resulting insufficient awareness of this neoplasm often delay correct identification and treatment, which essentially consists of wide-margin surgical excision of the primary tumor and local and regional radiation therapy. To date, clinical information is still insufficient to fully appreciate the role of imaging in MCC management. A better imaging algorithm is expected with increased awareness and improved clinical understanding of this uncommon skin neoplasm.
© RSNA, 2002
Index Terms: Merkel cell carcinoma, 40.39 • Radionuclide imaging, **.12162 • Radionuclide imaging, in diagnosis of neoplasms, **.1216 • Skin, CT, 40.1211 • Skin, neoplasms, **.321
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Introduction
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Merkel cell carcinoma (MCC) is an uncommon tumor of the dermis that is characterized by aggressive regional nodal invasion, distant metastases, and a high rate of recurrence. MCC was first reported by Toker in 1972 (1) as a trabecular carcinoma of the skin and, since then, has also been known as cutaneous APUDoma, neuroendocrine carcinoma of the skin, Merkel cell tumor, primary small cell carcinoma of the skin, primary undifferentiated carcinoma of the skin, anaplastic carcinoma of the skin, and murky cell carcinoma (2). Among these rather complex appellations, all of which are related to tumor characteristics, MCC and neuroendocrine carcinoma of the skin are the most frequently used and best reflect postulated origin and immunocytologic characteristics of this neoplasm. Because of the rarity of MCC, the data and consensus on its epidemiologic characteristics and therapeutic guidelines are constantly being refined.
Radiography and scintigraphy were performed in a series of six patients at our tertiary medical referral center for evaluation of MCC involvement beyond the cutaneous stage. The patients were all adult white males, with an average age of 75 years (range, 69–86 years) and an average clinical follow-up time of 16 months (range, 6–22 months).
In this article, we discuss and illustrate MCC in terms of epidemiologic characteristics, clinical manifestation and diagnosis, and imaging and management.
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Epidemiologic Characteristics
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The most widely accepted origin of MCC is the Merkel cell (3). This clear, oval cell is located within or close to the basal layer of the epidermis and functions as a cutaneous mechanoreceptor (4). Merkel cells are concentrated in acral regions of the human body. The ultrastructural and immunohistochemical similarities between MCC and Merkel cells support the Merkel cell origin of MCC (5–9). However, there is evidence that runs counter to this postulate: MCC and Merkel cells have different locations (dermis and epidermis, respectively), and MCC does not express vasoactive intestinal peptide and metenkephalin specific to Merkel cells (10). An intermediate position holds that the origin of MCC is linked to an immature, totipotential stem cell that acquires neuroendocrine characteristics during malignant transformation (10,11). This same concept of precursor stem cells may explain the coexistence of MCC and squamous cell carcinomas of the skin (12).
MCC occurs predominantly in Caucasians over 65 years old, with no sex predilection reported in most recent series (13,14). MCC is rare in black persons and Polynesians (15). Risk factors include exposure to sunlight and ultraviolet light, association with other ultraviolet light–related skin cancers (eg, squamous cell carcinoma, basal cell carcinoma), previous irradiation, and exposure to radiant infrared heat (12,15,16). Immunocompromise and immunosuppression may represent additional risk factors for MCC, whose prevalence is unusually high in organ recipients compared with the general population (17). A high prevalence of second neoplasms occurring before, concomitant with, or after the diagnosis of MCC (25%–28% of cases) has recently been reported. These neoplasms range from squamous cell carcinoma and hematologic malignancies to adenocarcinoma of the breast and ovary (14). This association with second neoplasms portends a worse outcome for patients with MCC.
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Clinical Manifestation and Diagnosis
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MCC typically manifests as a 2- to 4-cm firm, nontender, dome-shaped red, violaceous, or purple nodule located on areas of the body that have been exposed to sunlight (Figs 1, 2) (18). The overlying skin is smooth and shiny, sometimes exhibiting ulcerative, acneiform, or telangiectatic features (19). MCC involves predominantly the head and neck (>50% of cases) (15,20); it involves the extremities in 40% of cases and the trunk in less than 10%. MCC involving sites not exposed to sunlight (eg, oral mucosa, larynx, esophagus, genitalia) has been documented in a small percentage of cases (21). Its rapid growth may be the only indicator of malignancy, thereby triggering medical attention. Because the early course of MCC is asymptomatic, diagnosis may be delayed until the detection of regional adenopathy and distant metastasis. The working differential diagnosis includes basal cell carcinoma, melanoma, and squamous cell carcinoma, with MCC usually being overlooked (19). The correct identification of MCC is not made until tissue sampling and pathologic evaluation are performed.
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Figure 2. Clinical photograph obtained after wide-margin excision of MCC from a primary head and neck site shows multiple foci of indurated nodules from recurrent MCC in the right temporal and tragus regions (arrows).
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MCC involves the dermis, with exceptional invasion of the epidermis (22). It may be difficult to diagnose on the basis of light microscopic findings because of its similarities with other small cell tumors such as metastatic oat cell carcinoma, metastatic carcinoid tumor, neuroblastoma, eccrine sweat gland carcinoma, and some forms of melanoma, lymphoma, and squamous cell carcinoma (11,18). MCC can be definitively identified with hematoxylin-eosin and immunohistochemical staining, electron microscopy, or both (20,23).
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Imaging and Management
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Because of the rarity of MCC and the resulting insufficient awareness of this neoplasm, imaging findings have been reported only in case reports and a few series (24,25). There is no universally accepted staging and imaging algorithm for MCC. Tentative classification relies essentially on clinical manifestation: stage 1, cutaneous involvement; stage 2, regional nodal invasion; and stage 3, systemic metastasis (26). Even though the diagnosis of MCC is exclusively pathologic, imaging is useful for staging, surgical guidance, therapeutic management, and follow-up (15,24,25,27).
Stage 1 and 2 MCC
Differentiation between stage 1 and 2 MCC may be difficult: Up to two-thirds of patients in whom stage 1 disease has been diagnosed have regional nodal spread at initial presentation, and only 7%–31% of those with stage 2 neoplasms present with enlarged, palpable nodes (13,26,28).
Because MCC behaves like malignant melanoma, with a pattern of orderly progression of nodal metastasis, lymphoscintigraphy may be used to localize sentinel nodes, which have the potential for harboring micrometastasis (15). As in melanoma, the presence of sentinel nodes appears to be a strong indicator of regional MCC disease (29–32). The sentinel node is the first node to drain technetium-99m–filtered sulfur colloid, 0.25–0.50 mCi (9.25–18.5 MBq) of which is injected intradermally around the MCC site (Fig 3). After a sentinel node has been demonstrated, usually within 2 hours after radiotracer injection, it is marked preoperatively with semipermanent ink and is identified intraoperatively with a vital blue dye and handheld gamma probe. Lymphoscintigraphy in combination with intraoperative lymphatic mapping allows accurate and selective sampling of sentinel nodes. Sentinel node localization is crucial in the head, neck, and trunk because of the complex lymphatic network in these anatomic regions: Unexpected nodal drainage is seen in 37%–84% of cases and is often missed without lymphoscintigraphic guidance (Fig 4) (33). Instances of false-negative findings at lymphadenectomy leading to inadequate staging of MCC and aggressive but unnecessary complete nodal dissection in patients with true stage 1 disease are thereby reduced (15).
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Figure 3. Lymphoscintigram of a nasal MCC shows a sentinel node in the left parotid region (solid arrow) and a non-sentinel node in the posterior triangle of the left side of the neck (open arrow). Lymphoscintigraphy was performed with injection of 0.25 mCi (9.25 MBq) of Tc-99m-filtered sulfur colloid around the MCC site (arrowhead). The profile outline was drawn with a radioactive cobalt pen and represents the contours of the patient’s face in the left lateral projection. SCM = sternocleidomastoid muscle.
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Figure 4a. (a) Lymphoscintigram of an MCC of the anterior chest wall near the midline shows bilateral axillary nodal drainage (arrows). Lymphoscintigraphy was performed with injection of 0.50 mCi (18.5 MBq) of Tc-99m-filtered sulfur colloid around the MCC site (arrowhead). The left axillary sentinel node (curved arrow) tested positive for micrometastasis. (b) Photomicrograph (original magnification, x200; immunoalkaline phosphatase with vector red stain) of the sentinel node shows micrometastasis in the red field of the slide.
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Figure 4b. (a) Lymphoscintigram of an MCC of the anterior chest wall near the midline shows bilateral axillary nodal drainage (arrows). Lymphoscintigraphy was performed with injection of 0.50 mCi (18.5 MBq) of Tc-99m-filtered sulfur colloid around the MCC site (arrowhead). The left axillary sentinel node (curved arrow) tested positive for micrometastasis. (b) Photomicrograph (original magnification, x200; immunoalkaline phosphatase with vector red stain) of the sentinel node shows micrometastasis in the red field of the slide.
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If the sentinel node is negative for disease, treatment of stage 1 MCC consists of wide-margin (2-cm) excision or Mohs micrographic surgical resection of the primary tumor in combination with sentinel node biopsy (19,32,34). Radiation therapy of the primary site is also recommended because of the aggressive behavior of MCC. If stage 2 disease is proved, management includes complete lymphadenectomy and postoperative irradiation of the primary tumor and regional nodal sites (15). Increased time to recurrence and decreased rate of locoregional recurrence after locoregional radiation therapy and elective and selective lymphadenectomy have been demonstrated (35–37).
Stage 3 MCC
Distant metastases are present in approximately one-third of patients at initial presentation (18,26). These lesions may be found incidentally at routine radiographic work-up or imaging evaluation for unrelated causes. Frequently, the detection of adenopathy and symptoms related to skeletal, visceral, or solid organ invasion prompts comprehensive cross-sectional imaging. The pattern of metastasis is not specific for MCC and mimics multifocal invasion by other small cell carcinomas.
Radiographs show mostly thoracic and skeletal involvement: mediastinal adenopathy, pulmonary nodules or masses (Fig 5), and related chest wall invasion. Ultrasonographic (US) evaluation of soft tissue shows hypoechoic solid nodules arising from the dermis and extending into the subcutaneous fat, with variable degrees of posterior acoustic transmission (24). Contrast material–enhanced computed tomography (CT) demonstrates high-attenuation adenopathy and soft-tissue nodules (Figs 6, 7) (24,25). Adenopathy is frequently detected in the neck (especially the parotid region), axilla, mediastinum, retroperitoneum (Fig 8), and groin. Soft-tissue metastases may involve the chest wall or abdominal wall withmusculoskeletal invasion (Figs 9, 10). At CT, cutaneous fat stranding adjacent to the primary site of MCC may suggest the presence of engorgement and edema from lymphatic invasion (24). Any solid abdominal organ may be targeted by metastasis—especially the liver—which manifests as hypervascular lesions with ringlike enhancement (Fig 10). Hollow viscera such as the stomach (Fig 11) and urinary bladder may be involved hematogenously or by local spread (38, 39). Invasion of the central nervous system is rare but should not be overlooked: Any neurologic symptoms such as diplopia, hearing impairment, ataxia, and paraneoplastic manifestations should be taken into consideration. Work-up in such cases is best performed with magnetic resonance (MR) imaging (Figs 12, 13) (40–42).
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Figure 8. Contrast-enhanced abdominal CT scan shows retroperitoneal (white arrow) and peripancreatic (black solid arrow) adenopathy from MCC. Note the associated hepatic metastasis (open arrow).
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Figure 10. Contrast-enhanced abdominal CT scan shows MCC invasion of the lower left anterior chest wall and lower left rib. The chest wall mass (arrow) abuts and displaces the stomach medially (arrowhead). Note also the liver metastases with ringlike enhancement.
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Figure 11a. (a) Contrast-enhanced CT scan shows a soft-tissue MCC that abuts and invades the larger curvature of the stomach (arrow). (b) CT scan obtained with the patient in the right lateral decubitus position shows ulcerative MCC of the stomach (arrow).
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Figure 11b. (a) Contrast-enhanced CT scan shows a soft-tissue MCC that abuts and invades the larger curvature of the stomach (arrow). (b) CT scan obtained with the patient in the right lateral decubitus position shows ulcerative MCC of the stomach (arrow).
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Figure 12a. (a, b) Axial (a) and coronal (b) contrast-enhanced T1-weighted MR images obtained in a patient who presented with ataxia show leptomeningeal enhancement within the posterior fossa and around the brainstem (arrows), findings that are compatible with MCC leptomeningeal metastasis. (c) Photomicrograph (original magnification, x400; Papanicolaou stain) shows cerebrospinal fluid containing clusters of malignant cells, a finding that is consistent with MCC mixed with lymphocytes.
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Figure 12b. (a, b) Axial (a) and coronal (b) contrast-enhanced T1-weighted MR images obtained in a patient who presented with ataxia show leptomeningeal enhancement within the posterior fossa and around the brainstem (arrows), findings that are compatible with MCC leptomeningeal metastasis. (c) Photomicrograph (original magnification, x400; Papanicolaou stain) shows cerebrospinal fluid containing clusters of malignant cells, a finding that is consistent with MCC mixed with lymphocytes.
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Figure 12c. (a, b) Axial (a) and coronal (b) contrast-enhanced T1-weighted MR images obtained in a patient who presented with ataxia show leptomeningeal enhancement within the posterior fossa and around the brainstem (arrows), findings that are compatible with MCC leptomeningeal metastasis. (c) Photomicrograph (original magnification, x400; Papanicolaou stain) shows cerebrospinal fluid containing clusters of malignant cells, a finding that is consistent with MCC mixed with lymphocytes.
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Figure 13a. Axial T2-weighted (a) and coronal contrast-enhanced T1-weighted (b) MR images show lobulated metastasis from MCC in the brainstem (arrow). The cerebrospinal fluid tested positive for MCC cells.
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Figure 13b. Axial T2-weighted (a) and coronal contrast-enhanced T1-weighted (b) MR images show lobulated metastasis from MCC in the brainstem (arrow). The cerebrospinal fluid tested positive for MCC cells.
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Locoregional recurrence and distant metastasis may be evaluated with somatostatin receptor scintigraphy (SRS) based on the neuroendocrine characteristics of MCC (27). Octreotide, a somatostatin analogue tagged with indium-111, has been used successfully in the detection of occult neuroendocrine tumors and metastasis not readily detected with other imaging techniques (Fig 14). SRS is performed in both planar and single photon emission CT imaging mode at 4 hours and 24 hours after administration of 5–6 mCi (185–222 MBq) of octreotide. SRS is helpful in comprehensive pre- and posttherapeutic evaluation of MCC (Fig 15). Compared with CT and MR imaging, functional imaging with SRS and positron emission tomography (discussed later) is less affected by inflammation, edema, and granulation tissue at the surgical and irradiation site. However, SRS may be limited in assessing metastasis in organs with physiologic uptake of octreotide such as the liver, kidneys, and spleen.
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Figures 14. Planar SRS image obtained 24 hours after injection of In-111 octreotide shows heterogeneous liver uptake from space-occupying metastases (straight arrow) and retroperitoneal adenopathy (curved arrow) from MCC.
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Figure 15a. (15a) Initial 24-hour In-111 octreotide planar SRS image shows right mandibular MCC with metastasis to the neck, right shoulder, and midanterior thorax (arrows). (15b) Twenty-four-hour scintigram obtained after the patient had undergone chemotherapy and radiation therapy shows improvement of the tumor, with resolution of the abnormal foci of uptake in the right mandible, neck, right shoulder, and midanterior thorax. (15c) Follow-up 24-hour scintigram obtained 5 months later shows recurrent locoregional and distant metastases from MCC.
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Figure 15b. (15a) Initial 24-hour In-111 octreotide planar SRS image shows right mandibular MCC with metastasis to the neck, right shoulder, and midanterior thorax (arrows). (15b) Twenty-four-hour scintigram obtained after the patient had undergone chemotherapy and radiation therapy shows improvement of the tumor, with resolution of the abnormal foci of uptake in the right mandible, neck, right shoulder, and midanterior thorax. (15c) Follow-up 24-hour scintigram obtained 5 months later shows recurrent locoregional and distant metastases from MCC.
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Figure 15c. (15a) Initial 24-hour In-111 octreotide planar SRS image shows right mandibular MCC with metastasis to the neck, right shoulder, and midanterior thorax (arrows). (15b) Twenty-four-hour scintigram obtained after the patient had undergone chemotherapy and radiation therapy shows improvement of the tumor, with resolution of the abnormal foci of uptake in the right mandible, neck, right shoulder, and midanterior thorax. (15c) Follow-up 24-hour scintigram obtained 5 months later shows recurrent locoregional and distant metastases from MCC.
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Positron emission tomography with the glucose analog 2-[fluorine-18] fluoro-2-deoxy-Dglucose (FDG) may also have an important role in assessing and monitoring MCC (43). FDG competes with glucose for phosphorylation by hexokinase and represents a reliable measure of intracellular glycolysis. After FDG is in the cell, it is unable to go through most of the glucose metabolic pathways and relies on a catalyst, glucose-6-phosphatase, to exit normal cells (44). Thus, with enhanced hexokinase activity and decreased dephosphorylation in aggressive tumors such as neuroendocrine tumors and MCC, the entrapped FDG allows differentiation between normal and malignant tissue.
The prognosis for patients with stage 3 MCC is poor, with an average interval of 8 months between diagnosis and death (15). Treatment consists of chemotherapy, palliative radiation therapy, and surgical therapy. Because of the rarity of MCC, there is no consensus about chemotherapeutic guidelines. Chemotherapy for MCC includes numerous regimens of cyclophosphamide, doxorubicin, vincristine, cisplatin, 5-fluorouracil, and etoposide (15). Therapeutic success with somatostatin has been reported anecdotally (45). Chemotherapy has only short-lived success in patients with MCC (15,19).
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Conclusions
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With an overall survival rate of 58%–79% (26,28), MCC is a highly malignant cutaneous tumor that requires timely diagnosis, adequate staging, and aggressive therapy. Even after treatment, MCC necessitates close surveillance because of its high recurrence rate: 30%–40% locally within 12 months, 50% regionally within 2 years, and 36%–49% for systemic metastasis (2,13,18,28). Among imaging modalities, nuclear medicine procedures appear to be especially valuable for evaluating MCC and helping make therapeutic choices at different stages: sentinel node lymphoscintigraphy for stage 1 and 2 differentiation and SRS and positron emission tomography for comprehensive "head-to-toe" pre- and posttherapeutic monitoring of metastasis and recurrence. Functional scintigraphy may be used to supplement judicious cross-sectional US, CT, or MR imaging evaluation of the anatomic area of interest (14,24,25,27). To date, clinical information is still insufficient to fully appreciate the role of imaging in MCC management. A better imaging algorithm is expected with increased awareness and improved clinical understanding of this uncommon skin neoplasm.
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Acknowledgments
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The authors gratefully thank Drs John D. Port, Scott D. Eggers, and Steven A. Vernino for their help.
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Footnotes
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** indicates multiple body systems. 
Abbreviations: FDG = [fluorine-18]fluoro-2-deoxy-D-glucose,
MCC = Merkel cell carcinoma,
SRS = somatostatin receptor scintigraphy
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Ann. Onc.,
October 1, 2006;
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M. F. Blacksin, D.-H. Ha, M. Hameed, and S. Aisner
Superficial Soft-Tissue Masses of the Extremities
RadioGraphics,
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S. E. Anderson, K. T. Beer, A. Banic, L. S. Steinbach, M. Martin, E. E. Friedrich, E. Stauffer, P. Vock, and R. H. Greiner
MRI of Merkel Cell Carcinoma: Histologic Correlation and Review of the Literature
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Abstract
Introduction
