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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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 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
Plasmacytoma, metastatic adenocarcinoma, metastatic melanoma, lymphoma, metastatic neuroendocrine
Primary Rectal Signet Ring Neuroendocrine Carcinoma ("Signet Ring Carcinoid") with Bone Metastases
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
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
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
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|
|Squamous cell carcinoma ||Keratin|
|Malignant mesothelioma ||Hyaluronic acid|
|Renal collecting duct carcinoma ||Edema|
|Oncocytic parotid tumor ||N/A|
|Pituitary adenoma ||Cytokeratin|
|smooth muscle utierine tumors ||Glycogen|
|Gastric shwannoma ||Mucopolysaccharides|
|granulocytic sarcoma ||N/A|
|Ovarian stromal tumor ||Hydropic changes; lipid|
|Ovarian sclerosing stromal tumor ||Lipid|
|Ovarian cystadenofibroma ||N/A|
Awareness of rectal SNRT should prompt appropriate histochemical and immunohistochemical evaluation
whenever a signet ring tumor is encountered in this location.
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- 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
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- 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.
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