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Adenomatoid Tumor of the Skin: Differential Diagnosis of an Umbilical Erythematous Plaque

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Adenomatoid Tumor of the Skin: Differential Diagnosis of an Umbilical Erythematous Plaque Title: Adenomatoid tumor of the skin: differential diagnosis of an umbilical erythematous plaque Keywords: Adenomatoid tumor, skin, umbilicus Short title: Adenomatoid tumor of the skin Authors: Ingrid Ferreira1, Olivier De Lathouwer2, Hugues Fierens3, Anne Theunis1, Josette André1, Nicolas de Saint Aubain3 1Dermatopathology laboratory, Department of Dermatology, Saint-Pierre University Hospital, Université Libre de Bruxelles, Brussels, Belgium. 2Department of Plastic surgery, Centre Hospitalier Interrégional Edith Cavell, Waterloo, Belgium. 3Department of Dermatology, Saint-Jean Hospital, Brussels, Belgium. 4Department of Pathology, Jules Bordet Institute, Université Libre de Bruxelles, Brussels, Belgium. Acknowledgements: None Corresponding author: Ingrid Ferreira This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/cup.13872 This article is protected by copyright. All rights reserved. Abstract Adenomatoid tumors are benign tumors of mesothelial origin that are usually encountered in the genital tract. Although they have been observed in other organs, the skin appears to be a very rare location with only one case reported in the literature to our knowledge. We report a second case of an adenomatoid tumor, arising in the umbilicus of a 44-year-old woman. The patient presented with an 8 months old erythematous and firm plaque under the umbilicus. A skin biopsy showed numerous microcystic spaces dissecting a fibrous stroma and being lined by flattened to cuboidal cells with focal intraluminal papillary formation. This poorly known diagnosis constitutes a diagnostic pitfall for dermatopathologists and dermatologists, and could be misdiagnosed as other benign or malignant entities. Through this case report, a practical approach and diagnostic keys have been devised to avoid misdiagnosis and overtreatment. Keywords: Adenomatoid tumor, skin, umbilicus This article is protected by copyright. All rights reserved. Introduction The umbilicus is characterized by a complex conformation; it is the crossroads of important structures such as venous and lymphatic systems. In addition to primary tumors and embryonal remnants, it can also be affected by metastasis or direct extension of visceral tumors. The majority of tumors found at this location are benign (32% of endometriosis and 30% of primary benign tumors). Malignant tumors, and more precisely metastatic tumors, are diagnosed in 30% of cases, while primary malignant tumors represent 8%1. Case report A 44-year-old woman presented at a dermatology consultation for a lesion under the umbilicus. It was erythematous, scaly and firm to palpation (Figure 1). The lesion was first noticed 8 months ago during an episode of cellulitis, which was successfully treated with antibiotics. Subsequently, the patient described a cyclic evolution of the lesion. The patient was in good health, with no relevant past medical history. An ultra-sonography revealed fibrosis. A skin biopsy showed a dermal tumor characterized by numerous channels, which were lined by flattened to cuboidal cells with focal intraluminal papillary formation, dissecting a fibrous stroma (Figures 2A and 2B). In addition, epithelioid cells and signet-like ring cells were observed. There was This article is protected by copyright. All rights reserved. also a mild lymphocytic infiltrate. Tumors cells expressed calretinin (Figure 2C) and cytokeratin 5/6 (Figure 2D). Re-excision was performed two and three months later and the margins remained focally involved. No recurrence nor metastasis were observed after 10 years follow-up. Discussion Adenomatoid tumors are rare benign tumors of mesothelial origin. The mesothelium is a single layer epithelium derived from mesoderm. It covers walls of body cavities as well as internal organs. Depending on the anatomic site its name differs: pleura (lining the lungs and chest wall), peritoneum (lining the abdominal organs and wall), pericardium (lining the heart) and tunica vaginalis (lining the testes). Adenomatoid tumors usually occur in genital tract of both sexes and less frequently in heart2, mediastinum3-5, pancreas6, liver7-12, pleura13, mesocolon14, omentum14-16, lymph node17, peritoneum9,18, intestinal mesentery19, adrenal glands20-55 and skin56. Most tumors are discovered incidentally. The pathogenesis of adenomatoid tumor remains unknown. However, an increased incidence of this tumor is noticed in patients undergoing iatrogenic immunosuppression57-61 or with chronic viral infection28,47,62. Histopathologically, the lesion is unencapsulated with a variable demarcation, depending on the location, and an infiltrative microscopic appearance which can lead to misdiagnosis as adenocarcinoma63-65. Multifocal and diffuse architecture are more often encountered in the context of iatrogenic immunosuppression61. The tumor is characterized by gland-like cystic/microcystic spaces lined by flattened cells or cords and tubules made of cuboidal cells with abundant eosinophilic cytoplasm. These structures dissect smooth muscle fascicles, desmoplastic or edematous stroma63-65. The cytology is bland with no mitotic figure63-65. Prominent cytoplasmic vacuoles can mimic signet ring cells63-65. Infarction is sometimes encountered63-65. Several histologic patterns have been reported including adenoid, angiomatoid, cystic and solid, which can be mixed in an unique tumor32. Mesothelial origin is supported by expression of mesothelial markers such as calretinin, podoplanin (D2-40), cytokeratin 5/6 and WT-1 (Wilm’s tumor 1)66. Tumor cells also express pancytokeratin and BAP1 (BRCA1-associated protein-1). CEA (carcinoembryonic antigen) and BerEp4 (Ep-CAM, epithelial cell This article is protected by copyright. All rights reserved. adhesion molecule) staining are negative63,65. Molecular studies reported clonality of the mesothelial cells and somatic TRAF7 mutation which causes aberrant NF-κB pathway activation67,68. Adenomatoid tumors of the skin are extremely rare; to our knowledge, only one case56 has been described. According to the literature and our case, it appears predominantly in women (2F/0M) with a median age of 39 years (range, 34-44 years). The clinical presentation is an infiltrated plaque with or without associated nodule. The umbilicus seems to be a preferential site as it is the only anatomic location where skin can be closely linked to mesothelial tissue due to the embryologic development. For both lesions, the diagnostic was made following local umbilical infection with a duration of evolution of 4 weeks to 8 months. Tumors of umbilicus are rare and include a range of benign to malignant neoplasms; the latter could be primary or secondary. In the following section, differential diagnoses are discussed and a practical panel of immunostains is summarized in Table 1. Sister Mary Joseph nodules consist of an umbilical metastatic lesion originating mostly from intra- abdominal or pelvic malignant tumours69. Adenocarcinomas are the most frequent umbilical metastases. Primary sites such as the gastrointestinal tract, especially the stomach, in men and the gynecological tract, particularly ovary and endometrium, in women are the most common69. Other primary sites include the colon, pancreas, small intestine, fallopian tubes, kidney, prostate, and bladder; the origin is unknown in 15% to 30% of cases69. Mesotheliomas have also been reported70; it can share similar morphological features with adenomatoid tumors, in particular in its bland-looking adenomatoid-like variant, and also biomarkers as they come from the same origin71. Cutaneous cribriform carcinomas also share some microscopic similarities with adenomatoid tumors such as thin tread-like intraluminal bridging strands and intraluminal papillary projections72,73. Those tumors occur more frequently on the limbs of women (19F/7M) at a median age of 47.8 years72. Finally, hemangioma and endometriosis are two benign entities which are often described in the umbilicus and have to be included in the differential diagnosis. This article is protected by copyright. All rights reserved. In conclusion, adenomatoid tumors of the skin are rare benign neoplasms of mesothelial origin, which appears to be preferentially located in the umbilicus, and must be distinguished from a variety of benign and malignant neoplasms. References 1. Barrow MV. Metastatic tumors of the umbilicus. J Chronic Dis. 1966;19(10):1113-1117. 2. Natarajan S, Luthringer DJ, Fishbein MC. Adenomatoid tumor of the heart: report of a case. Am J Surg Pathol. 1997;21(11):1378-1380. 3. Goto M, Uchiyama M, Kuwabara K. Adenomatoid tumor of the mediastinum. Gen Thorac Cardiovasc Surg. 2016;64(1):47-50. This article is protected by copyright. All rights reserved. 4. Parekh V, Winokur T, Cerfolio RJ, Stevens TM. Posterior Mediastinal Adenomatoid Tumor: A Case Report and Review of the Literature. Case Rep Pathol. 2016;2016:6898526. 5. Plaza JA, Dominguez F, Suster S. Cystic adenomatoid tumor of the mediastinum. Am J Surg Pathol. 2004;28(1):132-138. 6. Overstreet K, Wixom C, Shabaik A, Bouvet M, Herndier B. Adenomatoid tumor of the pancreas: a case report with comparison of histology and aspiration cytology. Mod Pathol. 2003;16(6):613-617. 7. Adachi S, Yanagawa T, Furumoto A, et al. Adenomatoid tumor of the liver. Pathol Int. 2012;62(2):153-154. 8. Nagata S, Aishima S, Fukuzawa
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