|Year : 2015 | Volume
| Issue : 3 | Page : 658
Signet ring cell neuroendocrine tumor liver with mesenteric metastasis: Description of a rare phenomenon, with literature review
Sheefa Haq1, Vineeta V Batra1, Kaushik Majumdar1, Amit Javed2, Anil K Agarwal2, Puja Sakhuja1
1 Department of Pathology, G.B. Pant Hospital, New Delhi, India
2 Department of Gastrointestinal Surgery, G.B. Pant Hospital, New Delhi, India
|Date of Web Publication||9-Oct-2015|
Vineeta V Batra
Department of Pathology, Academic Block, G B Pant Hospital, Jawaharlal Nehru Marg, New Delhi - 110 002
Source of Support: None, Conflict of Interest: None
Primary hepatic signet ring cell neuroendocrine tumor (NET) is extremely rare, and may show both neuroendocrine and glandular differentiation. Unlike the usual signet ring cells of adenocarcinoma, these cells are characterized by mucin negative, cytokeratin and chromogranin positive intracytoplasmic vacuoles resembling signet ring cells. These tumors are usually well demarcated surgically resectable lesions. To the best of our knowledge, we report the fifth case of primary hepatic signet ring cell NET, with the present case bearing multiple hepatic space occupying lesions and mesenteric metastasis. Due to very few isolated reports, prognosis of NET with signet ring cell morphology is largely unknown. Documentation of this case with review of related literature may enrich the existing knowledge regarding the outcome and management of this rare tumor.
Keywords: Liver, mesentery, metastasis, neuroendocrine, signet ring
|How to cite this article:|
Haq S, Batra VV, Majumdar K, Javed A, Agarwal AK, Sakhuja P. Signet ring cell neuroendocrine tumor liver with mesenteric metastasis: Description of a rare phenomenon, with literature review. J Can Res Ther 2015;11:658
|How to cite this URL:|
Haq S, Batra VV, Majumdar K, Javed A, Agarwal AK, Sakhuja P. Signet ring cell neuroendocrine tumor liver with mesenteric metastasis: Description of a rare phenomenon, with literature review. J Can Res Ther [serial online] 2015 [cited 2019 Nov 12];11:658. Available from: http://www.cancerjournal.net/text.asp?2015/11/3/658/139604
| > Introduction|| |
Primary hepatic neuroendocrine tumor (NET) with signet ring cell morphology is extremely uncommon, with only four cases reported to the best of our literature search. ,, These tumors are characterized by the presence of intracytoplasmic vacuoles resembling signet ring cells as seen in the traditional mucin secreting adenocarcinomas. However, these vacuoles are mucin negative, while positive for cytokeratin (CK) and neuroendocrine markers, thereby posing a diagnostic challenge.
| > Case report|| |
A 43-year-old female patient presented with low grade fever, weight loss and intermittent epigastric and right hypochondriac pain for 2 years. The pain was localized, dull aching with no relation to food intake, and was not associated with vomiting. Ultrasonography revealed massively enlarged liver with multiple varying sized heterogeneous complex focal lesions with mixed echogenicity (predominantly cystic) in both lobes, with peripheral vascularity. The largest lesion occupying the right lobe in segment VI measured 10.5 × 8 cm. Contrast-enhanced computed tomography abdomen also showed multiple hypodense nonenhancing cystic lesions with mural hyperdensities, largest measuring 11 × 10.5 × 10.4 cm in the right lobe of liver [Figure 1]a and b. Other complex cystic masses in segments III, IV, and VII showed heterogeneous enhancement in the arterial phase and hypodensity in redistribution phase.
|Figure 1: (a and b) CECT abdomen (dual phase liver) showing massive hepatomegaly and multiple hypodense nonenhancing cystic lesions, with heterogeneous enhancement in arterial phase and hypodense in redistribution phase; (b) loss of fat planes between the lesion in the left lobe and upper pole of spleen, along with a homogeneously enhancing mesenteric mass in left of midline surrounded by bowel (arrow)|
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Follow-up computed tomography scan after 6 months revealed a homogeneously enhancing mesenteric mass lesion measuring 4.5 × 4 × 3 cm. Serum alpha-fetoprotein and carcinoembryonic antigen were within the normal limits, while chromogranin (CG) was elevated (538.64 ng/ml). Upper and lower gastrointestinal endoscopy yielded a normal study.
Needle biopsy from the liver showed a tumor composed of cells arranged in sheets and nests, separated by fibrocollagenous tissue. The cells were large, polygonal with monomorphic round to oval nuclei and stippled chromatin. Many of these cells displayed an eccentric nucleus with a moderate amount of pale eosinophilic to vacuolated cytoplasm, resembling the classical signet ring cell morphology [Figure 2]a. The cytoplasmic globules were negative for periodic acid Schiff with alcian blue stain [Figure 2]b, and positive for both CK and CG [Figure 2]c and d. A diagnosis of primary multifocal (cystic) NET liver with signet ring cell morphology was thus suggested.
|Figure 2: (a) Needle biopsy from the liver showing sheets of large polygonal cells with eccentric nuclei and moderate pale eosinophilic to vacuolated cytoplasm, resembling classical signet ring cell morphology (H and E, ×200); (b) Cytoplasmic globules negative for Periodic acid Schiff with alcian blue (PAS-AB) stain (PAS-AB, ×200); (c and d) Cytoplasmic globules in signet ring cells positive for both cytokeratin and chromogranin respectively, confirming their neuroendocrine nature (×200)|
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Liver lesions were too large and multiple to be operated upon. However to relieve the epigastric pain, the isolated mesenteric mass was resected laparoscopically. Cut surface of this lesion was greyish white, firm to hard with areas of hemorrhage. Microscopic examination revealed similar morphology and immunophenotype, but signet ring cells were not as widespread as seen in the liver biopsy [Figure 3]. The MIB 1 (Ki-67) labeling index was 8% [Figure 4]a. Postoperative positron emission tomography scan [Figure 4]b was consistent with previous CT findings and did not reveal any other metabolically active mass lesion.
|Figure 3: (a) Photomicrograph from the mesenteric mass showing an encapsulated tumor composed of polygonal to columnar cells in glands and trabeculae (H and E, ×100); (b) Cells with round to oval nuclei, stippled chromatin, moderate eosinophilic cytoplasm, and focal signet ring cell morphology (arrow) (H and E, ×400); (c and d) Tumor cells expressing cytoplasmic positivity for both cytokeratin and chromogranin, respectively (×400)|
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|Figure 4: (a) Immunohistochemistry for Ki-67 showing labeling index of 8% (×200); (b) Postoperative positron emission tomography scan showing multiple solid cystic lesions with increased uptake, consistent with previous computed tomography findings|
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The patient was treated by slow release subcutaneous depot preparations of octreotide along with three cycles of chemotherapy comprising of dacarbazine, etoposide, ifosfamide, and carboplatin. The patient is on regular follow-up for 18 months and is fairly well-preserved.
| > Discussion|| |
Primary hepatic NET represents 0.3% of all NETs, and is derived from argentaffin or Kulchitsky cells of the intrahepatic biliary tree. , Since the majority of the liver NETs are metastatic, careful systemic examination is required to rule out metastasis from other sites.  Primary hepatic NET with signet ring cell morphology is extremely rare, , and is characterized by pale to eosinophilic intracytoplasmic vacuoles that push the nucleus to one side giving the traditional signet ring cell appearance. These intracytoplasmic inclusions are thought to be caused by abnormal metabolism and organization of intermediate filaments like CK.  Hence, these intracytoplasmic vacuoles are characteristically mucin negative and CK positive. Ultrastructurally, these vacuoles demonstrate collections of intermediate filaments or accumulation of myelin figures. ,,, In contrast, the signet ring cells in adenocarcinomas show intracytoplasmic vacuoles, which are mucin positive and CK negative. However, these cells take up membranous CK positivity. Another morphological differential diagnosis includes goblet cell carcinoid, seen in the appendix and characterized by well-formed goblet cells in clusters with minimal cytological atypia. Goblet cell carcinoids are positive for neuroendocrine markers; however, the intracytoplasmic vacuoles contain mucin and are negative for CKs.  Hence, tumors with signet cell morphology mandate careful clinicopathological correlation and performance of immunohistochemical panel to arrive at a correct diagnosis. 
Tumors that show evidence of both neuroendocrine and glandular differentiation are uncommon, and have been subdivided into 3 categories as follows: Composite, collision, and amphicrine tumors. , Composite tumors show distinct glandular and neuroendocrine elements that are present within the same tumor in separately identifiable components. In collision tumors both the two forms of tumor occur in close proximity, resulting in close admixture of glandular and neuroendocrine elements. Amphicrine tumors are characterized by both neuroendocrine and glandular differentiation occurring within the same cell. 
As mentioned earlier, only 4 cases of hepatic signet ring cell NETs have been documented.  Age of these patients ranged from 39 to 68 years. All four patients had well-demarcated surgically resectable lesions in the liver. The clinical course is usually indolent with an expected 5-year survival of 74% and recurrence rate of 18% after resection.  Neither the patient described here nor the previously reported four cases had hormone-related symptoms. However, this patient had high serum CG.
The World Health Organization classification of the gastroenteropancreatic neuroendocrine neoplasms designates well-differentiated tumors, regardless of whether indolent or metastatic, as NETs. NETs are graded as G1 (Ki-67 < 2%) or G2 (Ki-67 = 2-20%). All poorly differentiated neoplasms are termed neuroendocrine carcinomas and graded G3 (Ki-67 > 20%). These tumors are stratified to predict their prognosis and for deciding therapeutic guidelines.  This case belongs to the category of NET with intermediate growth (G2) and hematogenous metastasis (in the mesentery), with potential management being surgery and additional treatment in the form of chemotherapy.
Surgical resection is possible in majority of the hepatic NETs.  Survival of patients with primary hepatic carcinoids appears to be better than carcinoid tumors at other sites. Experience with non-surgical treatment is much limited, and the modalities that may be available are local ablation, somatostatin, and transarterial chemoembolization.  In this patient, surgical resection was not possible because of the large size and multicystic nature of the tumor. The mesenteric mass was however resected laparoscopically to relieve the symptoms, with subsequent postoperative chemotherapy. Due to limited number of reported cases, predicting the behavior of hepatic NETs with signet cell component requires further analysis.
| > Conclusion|| |
Signet ring cell NET of liver is extremely rare, with reported cases being well demarcated, solitary, surgically resectable lesions. To the best of our knowledge, we report the fifth case, with the present case bearing multiple hepatic cystic space occupying lesions and mesenteric metastasis. Diagnosis is established by histomorphology and unique mucin negative, CK and CG positive phenotype of the intracytoplasmic vacuoles. The prognostic significance is still largely unknown, indicating analysis of further documented cases.
| > References|| |
Sioutos N, Virta S, Kessimian N. Primary hepatic carcinoid tumor. An electron microscopic and immunohistochemical study. Am J Clin Pathol 1991;95:172-5.
Aoki K, Sakamoto M, Mukai K, Kosuge T, Takayama T, Hiroshashi S. 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.
Zhu H, Sun K, Ward SC, Schwartz M, Thung SN, Qin L. Primary hepatic signet ring cell neuroendocrine tumor: A case report with literature review. Semin Liver Dis 2010;30:422-8.
Iwao M, Nakamuta M, Enjoji M, Kubo H, Fukutomi T, Tanabe Y, et al
. Primary hepatic carcinoid tumor: Case report and review of 53 cases. Med Sci Monit 2001;7:746-50.
Oh YH, Kang GH, Kim OJ. Primary hepatic carcinoid tumor with a paranuclear clear zone: A case report. J Korean Med Sci 1998;13:317-20.
Shia J, Erlandson RA, Klimstra DS. Whorls of intermediate filaments with entrapped neurosecretory granules correspond to the "rhabdoid" inclusions seen in pancreatic endocrine neoplasms. Am J Surg Pathol 2004;28:271-3.
Tang LH, Shia J, Soslow RA, Dhall D, Wong WD, O'Reilly E, et al
. Pathologic classification and clinical behavior of the spectrum of goblet cell carcinoid tumors of the appendix. Am J Surg Pathol 2008;32:1429-43.
Lewin K. Carcinoid tumors and the mixed (composite) glandular-endocrine cell carcinomas. Am J Surg Pathol 1987;11 Suppl 1:71-86.
Ganesan K, Achmad E, Sirlin CB, Bouvet M, Datnow B, Weidner N, et al
. Amphicrine carcinoma of the liver. Ann Diagn Pathol 2011;15:355-7.
Klöppel G. Classification and pathology of gastroenteropancreatic neuroendocrine neoplasms. Endocr Relat Cancer 2011;18 Suppl 1:S1-16.
Soga J. Primary hepatic endocrinomas (carcinoids and variant neoplasms). A statistical evaluation of 126 reported cases. J Exp Clin Cancer Res 2002;21:457-68.
[Figure 1], [Figure 2], [Figure 3], [Figure 4]