case report Wien Klin Wochenschr DOI 10.1007/s00508-014-0660-z
Merkel cell carcinoma of the lower leg with retroperitoneal GIST: a very rare association Uwe Wollina · Gesina Hansel · Felicitas Zimmermann · Jacqueline Schönlebe · Andreas Nowak
Received: 12 August 2014 / Accepted: 19 October 2014 © Springer-Verlag Wien 2014
Summary Merkel cell carcinoma (MCC) is a rare neuroendocrine tumor of the skin. Although its association with other malignancies is well known, an association with gastrointestinal stromal tumor (GIST) has yet not been described. We report about a 65-year-old female patient who presented with a hypervascularized subcutaneous tumor mass of her left calf. Resection of the primary tumor and histopathological investigations confirmed the diagnosis of MCC. The patient was treated by delayed Mohs surgery, and tumor-free margins were obtained. Sentinel lymph node biopsy was negative for metastatic spread. Primary tumor and lymph node basin were treated by adjuvant radiotherapy. During staging of the patient, a second malignancy—a GIST—was detected. Neoad-
U. Wollina, MD () · G. Hansel, MD Department of Dermatology and Allergology, Academic Teaching Hospital Dresden-Friedrichstadt, Friedrichstrasse 41, 01067 Dresden, Germany e-mail:
[email protected] F. Zimmermann, MD Department of Vascular Surgery, Academic Teaching Hospital Dresden-Friedrichstadt, Friedrichstrasse 41, 01067 Dresden, Germany J. Schönlebe, MD Institute of Pathology “Georg Schmorl”, Academic Teaching Hospital Dresden-Friedrichstadt, Friedrichstrasse 41, 01067 Dresden, Germany A. Nowak, MD Department of Anesthesiology and Intensive Care Medicine, Emergency Medicine and Pain Management, Academic Teaching Hospital Dresden-Friedrichstadt, Friedrichstrasse 41, 01067 Dresden, Germany
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juvant treatment with multikinase inhibitor imatinib induced a partial response of GIST that was eventually removed by surgery. However, 8 months later, the patient developed subcutaneous regional metastases of MCC, which were surgically removed. Adjuvant therapy was planned by oncologists. To the best of our knowledge, the occurrence of MCC and GIST in the same patient has yet not been reported. In contrast to GIST, MCC did not respond to imatinib, although c-kit mutations are common in MCC. Keywords Merkel cell carcinoma · Gastrointestinal stromal tumor · Multikinase inhibitor · Sentinel lymph node biopsy · Second malignancy
Merkelzellkarzinom des Unterschenkels und retroperitenaler GIST – eine sehr seltene Assoziation Zusammenfassung Das Merkelzellkarzinom (MCC) ist ein seltener neuroendokriner Tumor der Haut. Obwohl bekannt ist, dass es mit anderen Malignomen gemeinsam vorkommen kann, wurde die Assoziation zum gastrointestinalen Stromatumor (GIST) bislang noch nicht beschrieben. Wir berichten über eine 65-jährige Patientin, die sich mit einem hypervaskularisierten Tumor der rechten Wade vorstellte. Die Resektion des Tumors erfolgte, und die histologische Aufarbeitung ergab die Diagnose eines MCC. Es wurde die Komplettresektion des Tumors mittels verzögerter Mohs-Chirurgie eingeleitet, und tumorfreie Schnittränder wurden erzielt. Die Sentinellymphonodektomie zeigte keine Hinweise auf metastatische Absiedlungen. Das Gebiet des Primärtumors und die regionalen Lymphknoten wurden adjuvant bestrahlt. Im Rahmen des Tumorstagings wurde ein Zweittumor – hier ein GIST – entdeckt. Die neoadjuvante Behandlung mit
Merkel cell carcinoma of the lower leg with retroperitoneal GIST: a very rare association
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case report
dem Multikinaseinhibitor Imatinib induzierte eine partielle Response des GIST, eine chirurgische Entfernung schloss sich an. Acht Monate später mussten subkutane regionale Metastasen des MCC operativ entfernt werden. Eine adjuvante onkologische Therapie ist geplant. Das gemeinsame Auftreten von MCC und GIST ist unseres Wissens noch nicht beschrieben worden. Imatinib konnte in unserem Fall den GIST verkleinern, hatte jedoch auf das MCC keinen therapeutischen Einfluss gezeigt. Schlüsselwörter Merkelzellkarzinom · Gastrointestinaler Stromatumor · Multikinaseinhibitor · Sentinellymphknotenbiopsie · Zweittumor
Introduction Merkel cell carcinoma (MCC) is a rare neuroendocrine tumor of the skin [1]. The majority of MCCs occur in the head and neck region. MCC is a tumor occurring in at a higher age [2, 3]. There are three major subtypes, the intermediate variant (most common), the trabecular variant, and the small cell variant [1]. MCC is cytokeratin 20 (CK20) positive and expresses survivin, c-KIT, and somatostatin receptor type 2 among others [2, 4, 5]. MCC polyoma virus was found to be integrated in up to 80 % of tumors in North America and Germany but in only 24 % in tumors of Australian origin [2, 6]. Other known risk factors for MCC are chronic ultraviolet exposure and immunosuppression [2]. Five-year survival rates are between 36 and 62 % [2, 7, 8]. Patients with a positive sentinel lymph node (SLN) biopsy bear a higher risk for the development of distant metastases and poorer outcome [9]. We report an extremely rare association of MCC with gastrointestinal stromal tumor (GIST) [10].
Case report A 65-year-old woman presented with a rapidly growing tumor of her left calf 3.4 cm × 4.3 cm in size that developed within the past 2 months. The patients suffered from type II insulin-dependent diabetes mellitus and arterial hypertension. The reddish painless firm tumor (Fig. 1a) demonstrated hypervascularization in preoperative vascular magnetic resonance imaging (MRI) leading to a working diagnosis of a partially thrombotic hemangioma. After surgery, histologic investigations revealed a tumor composed of sheets of tumor cells with scant cytoplasm and broad interceptions of hyalinized connective tissue. The tumor cells showed small watery nuclei, mitotic activity, and numerous apoptotic bodies. By immunohistochemistry, tumor cells were positive for CK20, synaptophysin, and chromogranin A, but negative for LCA (leukocyte common antigen or CD45) and S-100 (Fig. 2). The diagnosis of an intermediate type MCC was made.
Fig. 1 a A 65-year-old woman with a hypervascularized subcutaneous tumor mass of her left calf. b Delayed Mohs surgery, with a 3-cm safety margin
Abdominal MRI for staging suggested a perigastric tumor and several suspicious iliacal lymph nodes. Gastroscopy and endosonography confirmed this. A fineneedle biopsy demonstrated a mesenchymal spindle cell tumor of low mitotic rate. Immunostaining was positive for CD117 (c-KIT) and DOG1 (discovered on GIST; Fig. 3). The presence of GIST was hereby confirmed. Further investigation excluded multiple endocrine neoplasia type I or type II. MCC was treated by delayed Mohs surgery, with a 3-cm safety margin (Fig. 1b). SLN biopsy was negative. The tumor was staged pT2pN0(sln)M0 R0—stage IIA. In the interdisciplinary tumor board, radiotherapy for the primary MCC localization and the regional nodal basin (left groin) were recommended (total dosage: 50 Gy for each site). This was combined with neoadjuvant imatinib for GIST, with a dosage of 400 mg/day. The retroperitoneal GIST tumor size decreased after 6 months of adjuvant imatinib therapy from 5 × 5.3 × 4.3 cm to 3 × 4.4 × 4 cm. Then, the tumor was removed laparoscopically, together with a second smaller lesion detected during surgery in the same region.
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Fig. 2 Merkel cell carcinoma histology. (a) hematoxylin-eosin × 10. Immunostaining showing positive cytokeratin 20 (b) and synaptophysin (c) (Immunoperoxidase, × 10)
Fig. 3 GIST histology. (a) Hematoxylin-eosin × 10. Immunostaining showing positive CD117 (b) and DOG1 (c) stains (Immmunoperoxidase, × 10) Fig. 4 Three in-transit metastases developed after 2 weeks
Eight months after primary MCC surgery, the patient presented with two cutaneous satellite metastases distally to the primary tumor 30 × 16 mm and 30 × 19 mm in size. Within 2 weeks, three in-transit metastases approximately 5 mm in diameter developed on both sides of her knee (Fig. 4). A complete surgical excision of metastases was performed with temporary vacuum-assisted closure. The patient was referred to the oncologist for adjuvant treatment.
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Discussion Patients with MCC have a significantly increased risk for other malignancies, whereas patients with primary prostate cancer, colorectal cancer, non-Hodgkin lymphoma, and lymphoid leukemia possess a higher risk for subsequent MCC [11]. An association of MCC with GIST is extremely rare [10].
Merkel cell carcinoma of the lower leg with retroperitoneal GIST: a very rare association
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GIST is the most common mesenchymal neoplasm of the gastrointestinal tract (GIT). GISTs arise from stromal stem cells. They account for less than 1 % of GIT malignancies. In 85–95 % of GISTs, activating c-KIT (CD117) mutations are detected [12]. Imatinib (Glivec) is a multikinase inhibitor with activity against c-KIT, PDGFRA, Abelson nonreceptor protein kinase (ABL), and breakpoint cluster region-ABL. The substance binds close to the ATP-binding site of these kinases inhibiting thereby protein phosphorylation and by that downstream signaling [13]. Clinical trials demonstrated antitumor activity of imatinib in metastatic or unresectable GISTs, in an adjuvant and neoadjuvant setting after primary surgery [14, 15]. MCCs often overexpress c-KIT. In the present case, MCC was not investigated for c-kit mutations. MCC responding to imatinib has been observed occasionally [16, 17]. In the present patient, however, the multikinase inhibitor was ineffective in preventing local metastases but decreased the size of the associated GIST. Short bullet points ●● Merkel cell carcinoma is a rare neuroendocrine tumor with a tendency toward second malignancies. ●● The association of Merkel cell carcinoma with gastrointestinal stromal tumor (GIST) is exceptionally rare. ●● Multikinase inhibitor imatinib produced a mixed response—partial response of GIST (neoadjuvant) but progress of Merkel cell carcinoma (adjuvant). Conflict of interest The authors declare that they have no conflict of interest.
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