Hyperplastic Mesothelial Cells in Mediastinal Lymph Node Sinuses With Extranodal Lymphatic Involvement

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1 Hyperplastic Mesothelial Cells in Mediastinal Lymph Node Sinuses With Extranodal Lymphatic Involvement Phillip A. Isotalo, MD; John P. Veinot, MD, FRCPC; Maha Jabi, MD, FRCPC We describe a patient with hyperplastic mesothelial cells localized to mediastinal lymph node sinuses. These mesothelial cells were originally misdiagnosed as metastatic carcinoma, and the patient received radiotherapy. Histologic review, immunohistochemistry, and ultrastructural studies confirmed mesothelial cell origin. These nodal mesothelial cells were associated with pericardial and pleural effusions. Extranodal lymphatics also contained hyperplastic mesothelial cells, confirming their mode of lymphatic transport to node sinuses. This finding supports the theory that hyperplastic mesothelial cells derive from reactive serosal mesothelium and are dislodged into draining lymphatics. This is the first report, to our knowledge, that demonstrates the pathogenetic significance of this lymphatic transport mechanism. Awareness of intralymphatic and nodal benign hyperplastic mesothelial cells and their mimicry of invasive malignant neoplasms is important for accurate diagnoses and appropriate therapy. (Arch Pathol Lab Med. 2000;124: ) Hyperplastic mesothelial cells (HMCs) that involve lymph nodes were originally thought to be a rare occurrence. 1 4 Recent studies have demonstrated that HMCs are commonly associated with reactive mesothelium and serosal effusions. 5,6 With the high incidence of pleural, pericardial, and peritoneal effusions in the general population, nodal HMCs are probably not rare but are likely underrecognized. Mesothelial cells in lymph node sinuses may be confused with dendritic cells, histiocytes, metastatic carcinoma, melanoma, and metastatic mesothelioma. 1,3,5 The case presented herein illustrates this diagnostic dilemma and demonstrates the origin of sinus HMCs and spread via lymphatic transport of mesothelial cells. REPORT OF A CASE A 47-year-old woman was admitted to the hospital with a 3- week history of progressive neck pain and swelling and a 1-day history of edema and paresthesia of the left arm. Medical history Accepted for publication August 3, From the Department of Pathology and Laboratory Medicine, University of Ottawa (Drs Isotalo, Veinot, and Jabi), Division of Anatomical Pathology, Department of Laboratory Medicine, Ottawa Hospital Civic Campus, and The University of Ottawa Heart Institute (Dr Veinot), and Division of Anatomical Pathology, Department of Laboratory Medicine, Ottawa Hospital General Campus (Dr Jabi), Ottawa, Ontario. Reprints: John P. Veinot, MD, Anatomical Pathology, Ottawa Hospital Civic Campus, 1053 Carling Ave, Ottawa, Ontario, Canada K1Y 4E9 ( jpveinot@civich.ottawa.on.ca). included left scapular malignant melanoma surgically excised 19 years previously, hypothyroidism, diverticulitis that required segmental colectomy, and a cholecystectomy. She had no other significant medical history and no history of autoimmune disease, thrombosis, or bleeding disorders. Physical examination revealed diffuse neck and left arm edema. The left arm was diffusely mottled and tender to palpation. All peripheral pulses were palpable, and the results of the remainder of the physical examination were unremarkable. Duplex Doppler ultrasound revealed occlusive thrombosis of the left axillary, left subclavian, and left internal and external jugular veins. Chest x-ray revealed an enlarged upper mediastinum, and computed tomography of the thorax with contrast revealed an illdefined, 5-cm-diameter left anterior mediastinal soft tissue mass, approximating the aortic arch. Medium-sized pericardial and small left pleural effusions were identified. The constellation of imaging findings was suggestive of a neoplastic process. The patient underwent a left anterior mediastinotomy and biopsy of the mediastinal mass. This mass was predominantly composed of adipose tissue with anthracotic lymph nodes. Microscopic examination of the mass revealed mature adipose tissue and small areas of thymic tissue with foci of dystrophic calcification. The lymph nodes had a normal follicular pattern, but the subcapsular, radial, and medullary sinuses were expanded by clusters of round, polygonal epithelioid cells with eosinophilic cytoplasm and no pleomorphism. No mitotic figures or necrosis was identified. Focal papillary projections were present. Of specific note was the identification of these epithelioid cells within extranodal lymphatics. Immunohistochemical stains revealed only intense positive staining for cytokeratins AE1/AE3 (Boehringer Mannheim, Laval, Quebec). The patient was diagnosed as having metastatic carcinoma of unknown primary origin. Abdominal, pelvic, and head computed tomographic scans, bilateral mammograms, and a skeletal survey all failed to reveal a primary tumor. The patient was treated with external-beam mediastinal radiotherapy, although a primary tumor was never discovered. Continued clinical and radiologic evaluations failed to identify recurrent disease, and the patient remained well 6 years later. PATHOLOGIC FINDINGS At the clinician s request, the mediastinal biopsy specimens were reviewed, considering the patient s long disease-free period after mediastinal radiotherapy. Review of hematoxylin-eosin stained sections showed preserved follicular architecture of mediastinal lymph nodes, with the sinuses and extranodal lymphatics containing eosinophilic epithelioid cell clusters (Figure 1). Individual epithelioid cells had prominent homogeneous cytoplasm, irregular membrane borders, prominent nucleoli, and vesicular nuclei with little nuclear pleomorphism. Histologic review favored a HMC appearance. Immunohistochemistry was performed on 4- m-thick Arch Pathol Lab Med Vol 124, April 2000 Hyperplastic Mesothelial Cells Isotalo et al 609

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3 Figure 2. A, Extranodal lymphatic permeation by hyperplastic mesothelial cells. Subcapsular lymph node sinuses are involved, suggesting lymphatic transport of dislodged mesothelial cells as the mechanism for nodal hyperplastic mesothelial cells (hematoxylin-eosin, original magnification 100). B, Mesothelial cells strongly positive for AE1/AE3 cytokeratins (AE1/AE3 cytokeratins, original magnification 100). C, Mesothelial cells stain positive for HBME-1 (HBME-1, original magnification 200). D, Mesothelial cells stain positive for calretinin (calretinin, original magnification 200). deparaffinized tissue sections using an avidin-biotin horseradish peroxidase method. All prior immunohistochemical stains were repeated. Cytokeratins AE1/AE3 (Boehringer Mannheim) and vimentin (Dako Corporation, Carpinteria, Calif) intensely stained the epithelioid cell clusters in the node sinuses and extranodal lymphatics (Figure 2, A and B). The cells also demonstrated strong staining with HBME-1 (Dako) and calretinin (Zymed Laboratories Inc, San Francisco, Calif) antibodies (Figure 2, C and D). BER-EP4, carcinoembryonic antigen, epithelial membrane antigen, CD15, S100, thyroglobulin, factor VIII, and CD68 immunohistochemical stains were all negative (all Dako). Gross cystic disease fluid protein-15 immunostain (Signet Laboratories Inc, Dedham, Mass) was also negative. Electron microscopy performed on formalinfixed tissue revealed epithelioid cells with sparse organelles, prominent microvilli, perinuclear intermediate filaments, desmosomes, and tight junctions (Figure 3). No mucin granules were identified. These immunohistochemical and ultrastructural features confirmed the mesothelial origin of the epithelioid cells. The diagnosis was revised to benign HMCs localized to mediastinal nodal sinuses and extranodal lymphatics. COMMENT Benign sinus mesothelial cells that involve mediastinal lymph nodes were originally described by Brooks et al in They described mesothelial inclusions in 2 patients with pleuritis and pleural effusions. 1 Rutty and Lauder in 1994 described an additional case of mesothelial cells within mediastinal lymph node sinuses, associated with both a pleural and pericardial effusion. 2 In addition, HMCs have been reported in abdominal, pelvic, and cervical lymph node sinuses. 3 6 Most of these cases have occurred concurrently with serosal effusions. The most recent series of 6 cases of HMC clusters within lymph node Figure 1. A, Photomicrograph demonstrating subcapsular and trabecular sinus involvement by clusters of reactive hyperplastic mesothelial cells. This sinus expansion by mesothelial cells may mimic metastatic carcinoma (hematoxylin-eosin, original magnification 100). B, Higher-power view demonstrating nodal lymphatic involvement by hyperplastic mesothelial cells (vimentin, original magnification 200). Arch Pathol Lab Med Vol 124, April 2000 Hyperplastic Mesothelial Cells Isotalo et al 611

4 Figure 3. A, The mesothelial origin of sinus cells is supported by electron microscopy demonstrating characteristic slender microvilli, perinuclear intermediate filaments, and cell junctions (original magnification ). B, Electron micrograph illustrating the long microvilli characteristic of mesothelial cells (original magnification ). sinuses, acquired by Argani and Rosai, demonstrated an association with serosal effusions in 5 of 6 cases. 5 These cases of mesothelial cell involvement of lymph node sinuses do not represent classic lymph node mesothelial inclusions, since these are characterized by a capsular rather than sinus location. 5 Intracapsular mesothelial cell aggregates, representing classic lymph node inclusions, have been described in pelvic and periaortic lymph nodes. 7 Lymphatic transport of dislodged mesothelial cells has been postulated to be the pathogenetic mechanism responsible for lymph node mesothelial cell clusters. 1,2,5 Mesothelial reactions are thought to disrupt mesothelial stomata, allowing dislodged mesothelial cells access to submesothelial lymphatics. 1,2,5 The presence of peritoneal and pleural stomata have been confirmed in animal studies. 8 This theory of pathogenesis is supported by the significant association of pleural, pericardial, and peritoneal effusions with HMCs in lymph node sinuses. 5,6 The present case of HMCs within mediastinal lymph nodes had concurrent pericardial and left pleural effusions secondary to venous thrombosis that involved the left axillary, subclavian, and left internal and external jugular veins. In addition to mesothelial cells in the lymph node sinuses, there were mesothelial cell clusters identi- 612 Arch Pathol Lab Med Vol 124, April 2000 Hyperplastic Mesothelial Cells Isotalo et al

5 fied within both nodal and extranodal lymphatics. The presence of extranodal lymphatic permeation by mesothelial cells is evidence confirming their lymphatic transport. This provides strong support for the mesothelial cell dislodgment theory of pathogenesis for mesothelial cell aggregates within lymph nodes. To the best of our knowledge, there has been only 1 previous report of extranodal lymphatic involvement by HMCs in the presence of lymph node sinus HMCs. 3 In that case, a 59-year-old woman had bilateral ovarian serous borderline tumors, extensive peritoneal mesothelial hyperplasia, and HMCs within both lymph node sinuses and extranodal lymphatics. 3 Often HMCs can present a diagnostic dilemma to the pathologist. 5 This case clearly illustrates that lymph node HMCs may be confused with metastatic carcinoma. It was only after review of the patient s original mediastinal lymph node biopsy specimens, due to her clinical course, that the correct diagnosis of benign HMCs in the node sinuses was established. Unfortunately, the patient had received radiotherapy. The patient s clinical and radiologic evaluations during a 6-year period failed to identify any malignant neoplasms, thus confirming the benign nature of these nodal HMCs. In addition to metastatic carcinoma, sinus mesothelial cells may also be confused with normal dendritic cells, sinus histiocytes, and metastatic melanoma and malignant mesothelioma. 1,3,5,9 The benign histologic appearance of HMCs and their immunohistochemical staining pattern are important features in identifying them. 1,3,5,10 Localized to lymph node sinuses, HMCs likely result from the displacement and subsequent lymphatic transport of mesothelial cells in the presence of serosal effusions. Although HMCs are benign, their identification may present a diagnostic dilemma. Awareness of these mesothelial cells, their location, and their possible mimicry of invasive malignant neoplasms is important in preventing both misdiagnosis and the inappropriate therapeutic management of patients. We thank the histotechnologists at the Ottawa Hospital, Civic and General sites, for technical assistance with this case. References 1. Brooks JSJ, Li Volsi VA, Pietra GG. Mesothelial cell inclusions in mediastinal lymph nodes mimicking metastatic carcinoma. Am J Clin Pathol. 1990;93: Rutty GN, Lauder I. Mesothelial cell inclusions within mediastinal lymph nodes. Histopathology. 1994;25: Clement PB, Young RH, Oliva E, Sumner HW, Scully RE. Hyperplastic mesothelial cells within abdominal lymph nodes: mimic of metastatic ovarian carcinoma and serous borderline tumor a report of two cases associated with ovarian neoplasms. Mod Pathol. 1996;9: Cohn DE, Folpe AL, Gown AM, Goff BA. Mesothelial pelvic lymph node inclusions mimicking metastatic thyroid carcinoma. Gynecol Oncol. 1998;68: Argani P, Rosai J. Hyperplastic mesothelial cells in lymph nodes: report of six cases of a benign process that can simulate metastatic involvement by mesothelioma or carcinoma. Hum Pathol. 1998;29: Parkash V, Vidans M, Carter D. Benign mesothelial cells in mediastinal lymph nodes [abstract]. Mod Pathol. 1997;10:169A. 7. Weeks DA, Beckwith JB, Mierau GW. Benign nodal lesions mimicking metastases from pediatric renal neoplasms: a report of the National Wilms Tumor Study Pathology Center. Hum Pathol. 1990;21: Wang N. The preformed stomas connecting the pleural cavity and the lymphatics in the parietal pleura. Am Rev Respir Dis. 1975;111: Sussman J, Rosai J. Lymph node metastasis as the initial manifestation of malignant mesothelioma: report of six cases. Am J Surg Pathol. 1990;14: Sheibani K, Shin SS, Kezirian J, Weiss LM. Ber-EP4 antibody as a discriminant in the differential diagnosis of malignant mesothelioma versus adenocarcinoma. Am J Surg Pathol. 1991;15: Arch Pathol Lab Med Vol 124, April 2000 Hyperplastic Mesothelial Cells Isotalo et al 613