Carcinoma Ex-goblet Cell Carcinoid of the Appendix

Definition

• Biphasic appendiceal neoplasm exhibiting both areas of typical GCC and areas of infiltrating adenocarcinoma

Alternate/Historical Names

• Adenocarcinoid
• Crypt cell carcinoma
• Mucinous carcinoid

Diagnostic Criteria

• Classification is based on the appearance of the primary tumor, not on the metastases
  • Metastases often appear more poorly differentiated or undifferentiated
• Typical goblet cell carcinoid is at least focally present
  • Typical cohesive nests of bland goblet cells may be only very focally preserved
  • Rare to scattered neuroendocrine cells always present
    • Seen on synaptophysin or chromogranin stains
    • Present in typical goblet cell carcinoid areas
    • Less reliably seen in carcinomatous components
• Carcinoma is present with the following features (criteria proposed by Tang 2008)
  • Signet ring cell type
    • Infiltrating signet ring cell carcinoma is present with at least one of the following features
      • Goblet cells / signet ring cells in irregular large clusters
    • Confluent sheets of cells indicates poorly differentiated carcinoma type, see below
    • Discohesive single file or single cell infiltration
      • Desmoplastic response
    • Significant cytologic atypia
      • Irregular hyperchromatic nuclei
  • Poorly differentiated type exhibits at least one of the following features
    • Confluent sheets of atypical cells
      • May or may not be signet cells
    • >1 low power field or >1 mm2 of conventional type adenocarcinoma, usually poorly differentiated or undifferentiated
      • May form glands
  • Features that may be shared by both types, but are not seen in pure goblet cell carcinoid
    • Cytologically atypical signet ring cells
    • Discohesive single file or single cell infiltration
    • Desmoplastic response
    • Significant cytologic atypia
      • Irregular hyperchromatic nuclei
• Regional lymph node involvement frequent
  • 73% in signet ring cell type
  • 100% in poorly differentiated type
• Extra-appendiceal spread to right colon, peritoneal surfaces and ovary is frequent
  • 88% in signet ring cell type
  • 100% in poorly differentiated type
• Hematogenous metastases rare

Robert V Rouse MD
Teri A Longacre MD
Department of Pathology
Stanford University School of Medicine
Stanford CA 94305-5342

Original posting : 7/12/10

Supplemental studies

Immunohistology

Differential Diagnosis

• Goblet cell carcinoid
• Appendiceal adenocarcinoma
• Usual carcinoid

Goblet Cell Carcinoid, Pure	Carcinoma ex GCC, Signet Ring Cell Type	Carcinoma ex GCC, Poorly Differentiated Carcinoma Type
Bland cytology	Atypical cytology	Atypical cytology
Cohesive clusters and cords	Discohesive cells with single cell infiltration	May have discohesive cells
No desmoplasia	Desmoplastic response to invasion	Desmoplastic response to invasion
Small clusters and cords, no poorly differentiated or undifferentiated carcinoma	Irregular large clusters, no poorly differentiated or undifferentiated carcinoma	May have confluent sheets of cells OR >1 low power field or >1 mm2 of conventional type adenocarcinoma, usually poorly differentiated or undifferentiated

Based on histopathologic findings in primary tumor
All must have at least focal typical goblet cell carcinoid
Based on Tang 2008

Appendiceal Adenocarcinoma	Carcinoma Ex-goblet Cell Carcinoid
No typical goblet cell carcinoid	At least focal typical goblet cell carcinoid
Usually low grade	Usually high grade

Based on histopathologic findings in primary tumor

Appendiceal Carcinoid / Well Differentiated Neuroendocrine Cell Neoplasm	Goblet Cell Carcinoid and/or Carcinoma ex-GCC
Chromogranin or synaptophysin positive	Chromogranin and synaptophysin stain rare to scattered cells only
No intracytoplasmic mucin (lumenal mucin may be present in tubular carcinoid)	Intracytoplasmic mucin in goblets
CK7 negative, CK20 variable	CK7 variable, CK20 100%
Rare mitotic figures at most	Mitotic figures may be numerous in carcinoma ex-GCC
Cohesive nests and cords	Single cell infiltration or sheet like growth in carcinoma ex-GCC
No desmoplasia	Desmoplasia may be present in carcinoma ex-GCC

Clinical

• Spread is primarily to the right colon, over the peritoneal surface and to ovaries
  • Regional nodes frequently positive
• Right hemicolectomy, debulking surgery and possible oophorectomy are recommended
• Adjuvant chemotherapy is generally given
• 5 year disease specific survival for stage IV patients
  • 38% for signet ring type
  • 0% for poorly differentiated type

Grading/Staging/Report

• Pure goblet cell carcinoid (GCC) is by definition low grade
• Tang 2008 has proposed separating the following based on the histopathologic findings in the primary tumor (see Diagnostic Criteria at left):
• Goblet cell carcinoid, typical / pure
• Carcinoma ex GCC, signet ring type
• Carcinoma ex GCC, poorly differentiated type
• TNM 7th edition staging should follow that of non-carcinoid appendiceal adenocarcinomas
• Findings relevant to extent of disease should be included in the report
  • Involvement of mesoappendix
  • Involvement of surgical margin
  • Involvement of lymph nodes
  • Involvement of other organs or tissues
    
    
  Goblet Cell Carcinoid, Pure vs. Carcinoma Ex-GCC Incidence by Stage at Presentation with Survival

  Type	Stage I	Stage IIA	Stage IIIB	Stage IV
  GCC, pure	1%* 5 yr DSS 100%	60% 5 yr DSS 100%	3%* 5 yr DSS 100%	33% 5 yr DSS 100%
  Ca ex-GCC, signet ring cell type	0%	4%* 5 yr DSS 100%	8%* 5 yr DSS 100%	88% 5 yr DSS 38%
  Ca ex-GCC, poorly diff.	0%	0%	0%	100% 5 yr DSS 0%

  DSS = Disease Specific Survival
  Entries marked with * represent only 1 or 2 cases
  Stage IIA represents invasion of muscularis propria without node involvement
  Stage IIIB represents node involvement without metastasis
  Based on Tang 2008

Classification/Lists

Gastrointestinal Endocrine Cell Proliferations and Neoplasms

• Well differentiated processes including carcinoids
  • Esophagus
    • Very rare
  • Stomach
    • Gastric neuroendocrine cell hyperplasia and dysplasia
    • Carcinoid
  • Duodenum and proximal jejunum
    • Predominantly ampullary
      • Somatostatinoma
      • Gangliocytic paraganglioma
    • Duodenum NOS and proximal jejunum
      • Gastrin cell neoplasm see also Zollinger Ellison syndrome
  • Ileum and distal jejunum and cecum
    • Carcinoid, predominantly enterochromaffin cell, serotonin producing
  • Appendix
    • Carcinoid, predominantly enterochromaffin cell, serotonin producing
    • Goblet cell carcinoid
      • Goblet cell carcinoid (GCC), pure
      • Carcinoma ex GCC, signet ring cell type
      • Carcinoma ex GCC, poorly differentiated type
  • Large intestine
    • Cecum (see Ileum)
      • Carcinoid, predominantly enterochromaffin cell, serotonin producing
    • Rectum and distal colon
      • Carcinoid, predominantly L cell, glucagon-like peptide and pancreatic peptide (PP) producing
  • Anus
    • Very rare
• Poorly differentiated neuroendocrine carcinoma, all sites
  • Small cell
  • Large cell

Appendiceal Epithelial Neoplasms and Proliferations

• Adenocarcinoma
• Carcinoid / well differentiated neuroendocrine neoplasm
• Carcinoma ex-goblet cell carcinoid
• Goblet cell carcinoid
• Hyperplastic polyp / mucosal hyperplasia
• Mucinous adenoma / cystadenoma
• Mucinous neoplasm with high risk of recurrence
• Mucinous neoplasm with low risk of recurrrence
• Sessile serrated polyp / adenoma
• Traditional serrated adenoma

Clinical / Descriptive Terms

• Mucocele
• Pseudomyxoma peritonei

Bibliography

• Riddell RH, Petras RE, Williams GT, Sobin LH. Tumors of the Intestines, Atlas of Tumor Pathology, AFIP Third Series, Fascicle 32, 2003.
• Hamilton SR, Aaltonen LA eds. Pathology and genetics of tumours of the digestive system. World Health Organization classification of tumours, Vol. 2. Lyon: IARC Press 2000.
• Isaacson P. Crypt cell carcinoma of the appendix (so-called adenocarcinoid tumor). Am J Surg Pathol. 1981 Apr;5(3):213-24.
• Burke AP, Sobin LH, Federspiel BH, Shekitka KM, Helwig EB. Goblet cell carcinoids and related tumors of the vermiform appendix. Am J Clin Pathol. 1990 Jul;94(1):27-35.
• Varisco B, McAlvin B, Dias J, Franga D. Adenocarcinoid of the appendix: is right hemicolectomy necessary? A meta-analysis of retrospective chart reviews. Am Surg. 2004 Jul;70(7):593-9.
• Tang LH, Shia J, Soslow RA, Dhall D, Wong WD, O'Reilly E, Qin J,Paty P, Weiser MR, Guillem J, Temple L, Sobin LH, Klimstra DS. Pathologic classification and clinical behavior of the spectrum of goblet cell carcinoid tumors of the appendix. Am J Surg Pathol. 2008 Oct;32(10):1429-43.
• Plöckinger U, Couvelard A, Falconi M, Sundin A, Salazar R, Christ E, de Herder WW, Gross D, Knapp WH, Knigge UP, Kulke MH, Pape UF; Frascati Consensus Conference participants. Consensus guidelines for the management of patients with digestive neuroendocrine tumours: well-differentiated tumour/carcinoma of the appendix and goblet cell carcinoma. Neuroendocrinology. 2008;87(1):20-30.