Mesothelial cell inclusions are a rare, but well-described, type of nonneoplastic, ectopic, epithelial tissue that are most commonly found in the sinuses of mediastinal and abdominal lymph nodes, often associated with effusions.1–22 Mesothelial cell inclusions in cervical lymph nodes, however, are an exceedingly rare finding, with only a handful of cases previously described.2–7 These inclusions can present morphologically as single cells, small clusters, or diffuse discohesive aggregates of cells (mimicking mesothelioma and sinus histiocytosis) or, less commonly, in pseudoglandular formations (mimicking metastatic adenocarcinoma). As such, their presence can lead to an erroneous diagnosis of malignancy that can ultimately affect clinical staging and treatment strategies.1,23 Herein, we present a case of predominantly pseudoglandular mesothelial cell inclusions in multiple cervical lymph nodes in a patient with multiple known malignancies.
The patient was a 27-year-old woman who initially presented to an outside hospital with left parotid enlargement and pain. The patient has a history of chronic myelogenous leukemia, diagnosed at age 5 years, for which she had undergone a matched unrelated bone marrow transplant with total body irradiation, etoposide, and antithymocyte globulin conditioning and has subsequently been in complete remission. The patient underwent a left parotidectomy. Intraoperative findings were remarkable for a left inferior parotid tumor with involvement of the left facial nerve. Gross pathologic examination at the outside facility showed a 5-g, 2.0 × 1.8 × 1.8-cm focally disrupted and hemorrhagic ovoid soft tissue fragment that was sectioned to reveal a well-circumscribed, firm, pale tan, and focally trabeculated mass on cut surface. Histological and immunohistochemical assessments were consistent with an alveolar soft part sarcoma with lymphovascular invasion and focal microscopic positivity at the resection margin.
The patient was referred for further management of the unexpected malignancy. A positron emission tomography–computed tomography (PET/CT) showed mild, subcentimeter, focal uptake in multiple bilateral level IB and level II cervical lymph nodes and no residual uptake in the left parotid gland. The PET/CT additionally showed a trace left pleural effusion, improved from previous chest x-rays obtained at the outside hospital. A magnetic resonance imaging scan revealed a prominent left level II lymph node with contrast enhancement, measuring 0.6 × 1.4 cm. With multidisciplinary input from tumor board, the patient underwent a left neck dissection. Despite likely microscopic residual disease based on focal microscopic positive margins, a revision left parotidectomy was not pursued. A total of 36 lymph nodes from levels IB, II, III, IV, and V were identified. Histological assessment showed no involvement by sarcoma in all 36 lymph nodes. However, 6 of 14 level IV/V lymph nodes contained clusters of bland, round to polygonal cells with pseudoglandular formation (Figs. 1A, B). These cells were positive for calretinin (Fig. 2B), CK7 (Fig. 2C), WT1, D2-40 (Fig. 2D), and pancytokeratin, consistent with mesothelial origin. Additionally, these cells were negative for MOC31, p63, TTF1, PAX8, thyroglobulin, mammaglobin, BRST2, MART1, and SOX10. No mitotic activity was identified. Overall, the histomorphology and immunoprofile were consistent with benign mesothelial cell inclusions.
Following the neck dissection, the patient has undergone genetic testing for a possible syndromic predisposition; however, initial screening, particularly for Li-Fraumeni syndrome, has thus far been negative. She has been monitored for approximately 18 months posttreatment, and her most recent surveillance magnetic resonance imaging showed no evidence of recurrent disease.
The finding of exogenous cells within lymph nodes is generally indicative of a metastatic neoplasm. An exception to this comes in the form of benign inclusions, which were first described by Ries24 in 1897. Benign lymph node inclusions can be broadly separated into glandular and nonglandular. The most common glandular lymph node inclusions are of müllerian origin and less infrequently include ectopic thyroid, salivary gland, breast, pancreas, renal tubules, urothelium, and colon inclusions.15,25 These inclusions are typically associated with the lymph nodes in proximity to the glandular organ of origin and are found in an intracapsular or intraseptal position in the involved lymph nodes.1,24 Nonglandular inclusions are significantly rarer and include nevus cells, decidua, leiomyomatosis, and mesothelial cells. Unlike glandular inclusions, nonglandular inclusions have been observed to occupy the sinuses of lymph nodes.
Mesothelial cell inclusions were first described by Brooks et al1 in 1990 in the mediastinal lymph nodes of 2 patients with pleuritis and pleural effusions. They have since been described in a variety of anatomic sites, most commonly in mediastinal and abdominal lymph nodes and less so in pelvic, renal hilar, and periaortic lymph nodes.8–22 Mesothelial cell inclusions in superficial cervical lymph nodes are an exceedingly rare occurrence with, to date, only 6 reported cases.2–7 Histologically, these inclusions present as cuboidal cells with bland nuclei and low nuclear-to-cytoplasmic ratios and have well-defined cellular borders. Mitotic figures are typically absent. Most commonly, mesothelial inclusions appear as single cells, small clusters, or diffuse sheets of discohesive cells, almost exclusively involving the nodal sinuses. When clustered, they exhibit mesothelial “windows,” small intercellular spaces that have been described in reactive mesothelium, coinciding with the presence of fuzzy peripheral microvillous borders.26 Of the 6 reported cases of mesothelial cell inclusions within cervical lymph nodes, all have exhibited this morphological pattern.2–7 Less commonly, mesothelial cell inclusions are observed as partially or predominantly pseudoglandular, as shown in the case herein described. While pseudoglandular mesothelial inclusions have been observed in other anatomic sites,13,19 to the best of our knowledge, this morphology has not been described in cervical lymph nodes.
The pathophysiology of intranodal inclusions has not been completely elucidated; however, 3 mechanisms have been proposed. The majority of glandular inclusions are thought to originate from either the entrapment of remnant cells during embryonal development or from metaplastic proliferation of the embryonic coelomic epithelium.25,27 Brooks et al1 suggested that the developmental and metaplastic theories cannot be applied to mesothelial cell inclusions given their unique sinusoidal location. The authors instead postulated these inclusions were the consequence of inflammatory or neoplastic processes leading to mesothelial irritation and subsequent shedding of mesothelial cells into the pleural or peritoneal cavity. These cells are believed to migrate through preformed stomata located in the pleura or peritoneum which link to submesothelial lymphatics.1,28 Pleural and peritoneal inflammation and mesothelial reactions disrupt mesothelial stomata and distend the lymphatics, facilitating access of the mesothelial cells to the lymphatic system, ultimately depositing within the nodal sinuses.1,9,18,21 This proposed pathogenesis of mesothelial cell inclusions is supported by the finding that the vast majority of mesothelial cell inclusions occur in patients with serosal effusions of either the pleural, pericardial, or peritoneal cavities, or a combination thereof.6 Additionally, Argani and Rosai2 have suggested that unlike neoplastic cells, which are capable of proliferating, mesothelial cells typically undergo a degeneration process after they migrate to lymph nodes, contributing to the rarity of their finding.
When found in lymph nodes, mesothelial cell inclusions can present a diagnostic dilemma for even experienced pathologists, as they can mimic metastases of carcinoma, melanoma, or mesothelioma, as well as sinus histiocytosis.1,2,15,16 In particular, pseudoglandular formations on routine hematoxylin-eosin (H&E) stains, as seen in the case presented here, can strongly mimic metastatic adenocarcinoma and pseudoglandular formation observed in malignant mesothelioma. These inclusions can typically be distinguished from metastatic carcinoma, melanoma, and sinus histiocytosis based on their immunoprofile demonstrating positivity for CK7, pancytokeratin, calretinin, WT1, and D2-40 and negativity for p63, TTF1, PAX8, MART1, and SOX10, which establishes their mesothelial origin. The distinction between benign mesothelial cell inclusions and metastatic mesothelioma is substantially more difficult given their considerable clinical and pathological overlap. This distinction is particularly important, as well as lymph node metastasis can be the initial manifestation of malignant mesothelioma.29 Additionally, malignant mesotheliomas can be associated with inflammatory serosal effusions and may follow a very indolent course.30 Histologically, high nuclear atypia; microtubular, tubulopapillary, and alveolar patterns; and destructive stromal infiltrates favor a malignant diagnosis.9 However, the degree of cytological atypia and mitotic activity can be minimal in mesothelioma, further complicating their distinction from benign inclusions. Unfortunately, immunohistochemistry cannot distinguish between benign and malignant mesothelial cells, and ultimately, the pathological distinction between these 2 entities may not always be possible.2 However, the vast majority of malignant mesotheliomas present with a definite primary lesion, that is, an obvious mass or multiple discrete, irregular nodules, and therefore clinical and radiological correlations are required in difficult cases. In the case presented here, thorough clinical evaluation for malignancy, including multiple negative surveillance PET/CT scans, supports a benign diagnosis.
In summary, we present a rare case of predominantly pseudoglandular mesothelial cell inclusions within multiple cervical lymph nodes. Mesothelial cell inclusions can present a challenge to even experienced pathologists as they can closely mimic metastatic adenocarcinoma or metastatic mesothelioma on routine H&E staining. These inclusions can typically be distinguished from metastatic carcinoma based on their immunoprofile, but can still be difficult to distinguish from metastatic mesothelioma, often requiring thorough clinical and radiological evaluation for malignancy. Recognition of this rare benign finding is essential to avoid the misdiagnosis of malignancy that could affect clinical staging and therapeutic management in these patients.
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