Case 4 -

Primary Rectal Signet Ring Neuroendocrine Carcinoma ("Signet Ring Carcinoid") with Bone Metastases Noam Harpaz, The Mount Sinai Medical Center, New York, NY

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Clinical History The patient was a 50-year-old male who presented with pain of the left upper extremity. He had been diagnosed with a rectal tumor 5 years earlier at another facility and treated with chemotherapy and local radiation. Radiological examination now revealed a large lytic tumor in the left humerus and further work-up revaled hepatic, pulmonary and intracranial lesions. A biopsy of the humeral tumor was performed and a slide of the original rectal biopsy was retrieved for comparison. Case 4 - Figure 1 Dyscohesive tumors cells with peripherally displaced nuclei. Inset: Biopsy tissue from lytic tumor of humerus Case 4 - Figure 2 Signet ring features, nuclear atypia and paranuclear zone at higher magnification Case 4 - Figure 3 Negative stains for DPAS, HMB45, CD45 and lambda light chain Case 4 - Figure 4 Cytoplasmic staining for AE1/AE3. The cytoplasmic staining is heterogeneous and occasionally globular Case 4 - Figure 5 Positive staining for synaptophysin Case 4 - Figure 6 Positive membranous staining for CD56 Case 4 - Figure 7 Ki-67 proliferation index = 10% Case 4 - Figure 8 Electron microscopy reveals small neuroendocrine granules and paranuclear aggregates of 10nm filaments Case 4 - Figure 9 Case 4 - Figure 10 Earlier rectal biopsy demonstrates invasive tumor arranged in irregular cords and single cells. Case 4 - Figure 11 Despite some crush artifact, similarity of the rectal tumor cells to those of the bone tumor is evident at high magnification. Case 4 - Figure 12 Second case of rectal signet ring neuroendocrine carcinoma. The tumor presented endoscopically as a 7cm rectal mass. Case 4 - Figure 13 Rectal biopsy shows the mucosa infiltrated by dyscohesive signet ring cells Case 4 - Figure 14 Negative stains for mucicarmine and BRST2 and positive stains for CAM5.2 and synaptophysin. Pathological/Microscopic Findings and any Immunohistochemical or Other Studies: The tumor consists of dyscohesive cells containing hyperchromatic, pleomorphic nuclei, many of which are crescentic and peripherally displaced, and an indistinct pale paranuclear zone. There is no mitotic activity or tumor necrosis. Negative results were obtained with mucin stains (DPAS, mucicarmine, Alcian blue) and the following panel of immunohistochemical stains: CD45, CD20, CD30, CD138, kappa, lambda, CD68, CD1a, HMB45, S100 protein, melan-A, E-cadherin and CDX2. No abnormal lymphocyte phenotype was detected by flow cytometry. The tumor cells were positive for neuroendocrine differentiation markers (synaptophysin +, CD56 +, chromogranin -), cytokeratin (AE1/AE3 +, CAM5.2 +, CK19 +, CK7 -, CK20 -, keratin 903 -), and occasionally vimentin (~5% of cells). The cytokeratin immunostains hinted at the presence of globular intracytoplasmic condensations. The Ki-67 proliferation index was 10%. Electron microscopy revealed cytoplasmic dense core granules and paranuclear aggregates of 10nm filaments. Comparison of the histology with a slide of the patient's rectal biopsy performed 5 years earlier and reported as a malignant neuroendocrine tumor, confirmed the tumor as being of primary rectal origin. Differential Diagnoses: Plasmacytoma, metastatic adenocarcinoma, metastatic melanoma, lymphoma, metastatic neuroendocrine carcinoma Final Diagnosis: Primary Rectal Signet Ring Neuroendocrine Carcinoma ("Signet Ring Carcinoid") with Bone Metastases Case Discussion: Signet-ring cell tumors are so designated based on the appearance of cells with crescentic nuclei displaced to the periphery by cytoplasmic contents of varied composition. The most familiar of these are the diffuse-type adenocarcinomas seen in the stomach and less commonly the large intestine, and a subset of appendiceal goblet cell carcinoids. Tumors with mucin-negative signet ring features are uncommon and only a few have involved the GI tract (Table 1). As a result, the occurrence of mucin-negative signet ring tumors in biopsies of the GI tract can present diagnostic pitfalls. In the signet ring tumor illustrated in Figs. 1-11, the initial diagnostic considerations based on its morphology and the clinical scenario of a middle-aged patient presenting with a lytic bone tumor included metastatic adenocarcinoma, multiple myeloma, metastatic melanoma and lymphoma, however, all were excluded by mucin stains and a panel of corresponding immunohistochemical stains. Positive immunohistochemical stains for neuroendocrine differentiation markers and for cytokeratin, the latter hinting at the presence of intracytoplasmic inclusions, led to a diagnosis of metastatic signet ring neuroendocrine tumor (SRNT). The diagnosis was supported by electron microscopic demonstration of dense core granules and aggregates of intermediate filaments. Comparison of the bone tumor with the rectal biopsy performed 5 years at another hospital earlier identified it as metastatic from a primary rectal SRNT, which had originally been diagnosed as a malignant tumor with neuroendocrine features. Following the original biopsy, the patient had been diagnosed with liver metastases. Despite chemotherapy he experienced further progression with pulmonary, intraabdominal, pelvic and bone metastases and expired 5-1/2 years later. A second case of the same entity is presented in Figs. 12-14. The patient was a 60-year-old woman who presented with a 2-month history of abdominal pain and intermittent hematochezia. Digital and endoscopic examinations revealed a firm, 7-cm rectal mass. A biopsy showed diffuse invasion of the rectal mucosa by a tumor composed of dyscohesive cells with signet ring features. The main diagnostic considerations were primary and metastatic adenocarcinoma, lymphoma and melanoma, but they were excluded on the basis of negative staining for mucin and corresponding immunohistochemical differentiation markers. Positive staining for cytokeratin and neuroendocrine markers led to a diagnosis of rectal SRNT. CT examination disclosed metastases in the liver and retroperitoneum. The patient refused surgery and was treated with octreotide but succumbed approximately 8 months after the diagnosis. SRNT is a rare entity that has been described hitherto in the liver [1, 2, 3, 4] and pancreas [5, 6, 7, 8]. Histologically, it is characterized by crescentic nuclei displaced to the cell periphery by pale or eosinophilic intracytoplasmic vacuoles variously described by the terms "signet ring", "paranuclear clear zone" or "rhabdoid." Ultrastructurally, these inclusions consist of aggregates of intermediate filaments with a skeinoid or whorling appearance variably admixed with Golgi membranes, mitochondria, dense core granules or, rarely, myelin bodies. They are thought to be a by-product of abnormal subcellular metabolism and organization of intermediate filaments consisting at least partially of cytokeratin. They have been likened to the so-called fibrous bodies of pituitary adenomas, which are also regarded as a degenerative phenomenon. The clinical significance of the unique signet ring phenotype of neuroendocrine tumors is uncertain. Based on limited experience, it appears that pancreatic lesions are relatively aggressive, with nodal or hepatic metastases and/or fatal outcomes reported in ~30% of published cases despite tumor diameters less than 4cm and low mitotic and Ki67 indices. Pancreatic tumors with eosinophilic ("rhabdoid") rather than pale inclusions, which have similar utrastructural characteristics, have been implicated as an unfavorable subgroup based on anecdotal evidence. By contrast, the 4 primary hepatic tumors described thus far in the literature have had favorable clinical courses (5-49m follow-up) despite 3 of them having diameters of 10cm or more, paralleling the experience with histologically conventional primary hepatic carcinoid tumors. Both cases of rectal SRNT presented herein were aggressive and diagnosed in their late stages. Clearly, much more experience with this entity will be needed to determine the similarities to and differences from conventional rectal neuroendocrine tumors with respect to their clinical and prognostic implications. Table 1. Non-mucinous tumors with reported signet ring variants Signet ring tumor Cytoplasmic contents B cell lymphoma Immunoglobulins, RER cisternae B and T-cell lymphomas Multivesicular bodies Plasmacytoma Immunoglobulins; amyloid Fibrils Basal cell carcinoma Cytokeratin Melanoma Vimentin Squamous cell carcinoma Keratin ovary Vimentin Chondrosarcoma Lipid Malignant mesothelioma Hyaluronic acid Renal collecting duct carcinoma Edema Oncocytic parotid tumor N/A Pituitary adenoma Cytokeratin smooth muscle utierine tumors Glycogen GIST Glycogen? Gastric shwannoma Mucopolysaccharides seminoma Glycogen? granulocytic sarcoma N/A Ovarian stromal tumor Hydropic changes; lipid Ovarian sclerosing stromal tumor Lipid Ovarian cystadenofibroma N/A Conclusion(s): Awareness of rectal SNRT should prompt appropriate histochemical and immunohistochemical evaluation whenever a signet ring tumor is encountered in this location. References: Sioutos N, et al. Primary hepatic carcinoid tumor. An electron microscopic and immunohistochemical study. Am J Clin Pathol. 1991;95:172-5 Aoki K, et al. Signet-ring cell carcinoid: a primary hepatic carcinoid tumor with cytoplasmic inclusions comprising of aggregates of keratin. Jpn J Clin Oncol. 1992;22:54-9 Oh YH, e al. Primary hepatic carcinoid tumor with a paranuclear clear zone: a case report. J Korean Med Sci 1998;13:317–20 Zhu H, et al. Primary hepatic signet ring cell neuroendocrine tumor: A case report with literature review. Semin Liver Dis. 2010;30:422-7 Stokes MB,et al. Pancreatic endocrine tumor with signet ring cell features: a case report with novel ultrastructural observations. Ultrastruct Pathol. 1998;22:147-52 Serra S, Asa SL, Chetty R. Intracytoplasmic inclusions (including the so-called "rhabdoid" phenotype) in pancreatic endocrine tumors. Endocr Pathol. 2006;17:75-81. Shia J, et al. Whorls of intermediate filaments with entrapped neurosecretory granules correspond to the "rhabdoid" inclusions seen in pancreatic endocrine neoplasms. Am J Surg Pathol. 2004;28:271-8 Perez-Montiel MD, et al. Neuroendocrine carcinomas of the pancreas with 'rhabdoid' features. Am J Surg Pathol 2003;27:642–649