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Goblet Cell Carcinoid of the Appendix

Definition

  • Cytologically bland appendiceal neoplasm consisting of cohesive clusters composed of cells exhibiting intracytoplasmic mucin and scattered cells witih neuroendocrine differentiation

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 may appear poorly differentiated or undifferentiated
  • Cytologically bland
    • Mitotic figures infrequent
  • Many cells resemble goblet cells or signet ring cells
    • Mucin positive cytoplasm
    • Nucleus displaced by mucin
  • Rare to scattered neuroendocrine cells always present
    • <25% of cells
    • Seen on synaptophysin or chromogranin stains
  • Cohesive clusters and cords of cells
    • Discohesive, single cells rare
    • Cohesive cord or linear pattern usually seen within invaded muscularis propria
  • Well formed gland lumens not seen
  • Frequently little architectural distortion of appendix
    • Invasion of appendix wall shows scant desmoplasia
    • Invasion frequently circumferential and lateral
    • May not form a well defined tumor mass
  • Perineural invasion common
  • Pools of extracellular mucin may be seen
    • Clusters of bland goblet cells may be in and around the pools
  • Regional lymph node involvement is frequent (19%)
  • Extra-appendiceal spread is frequent (33%)
    • Usually to right colon, peritoneal surfaces and ovary
    • Hematogenous metastases rare
  • The presence of any of the following features suggests a diagnosis of carcinoma ex-goblet cell carcinoid
    • Irregular large clusters or sheets of cells
    • Discohesive cells
    • Significant cytologic atypia
    • Desmoplastic response to invasion
    • Presence of poorly differentiated or undifferentiated carcinoma
  • One small series of combined GCC and classical carcinoid reported (Chetty 2010)
    • This may represent a collision tumor as incidental classical carcinoids are not rare
  • Goblet cell carcinoid essentially arises only in the appendix
    • There are rare reports of GCC that claim an origin elsewhere in the gastrointestinal tract

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

Original posting/updates : 7/12/10, 8/21/10

Supplemental studies

Immunohistology

Marker Pure GCC Areas Signet Ring Type of Ca ex-GCC Poorly Differentiated Type of Ca ex-GCC
Synaptophysin 100% of cases, rare to 25% of cells Same as GCC Same as GCC
Chromogranin 100% of cases, rare to 25% of cells Same as GCC Same as GCC
CDX2 no data no data no data
CK7 Variable no data no data
CK20 100% no data no data
p53 Negative Positive Positive
MUC1 Negative Positive Positive
MUC2 Positive Negative Negative
Other neuroendocrine markers have been reported positive also
Neuroendocrine cells are positive with both argentaffin and argyrophil stains

Differential Diagnosis

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

Goblet Cell Carcinoid

GI Tract Adenocarcinoma

Bland cytologic features Atypical cytology
Chromogranin or synaptophysin positive (scattered) Chromogranin and synaptophysin negative
No desmoplastic response Desmoplastic response frequent
Rare mitotic figures Mitotic figures frequently numerous
Cohesive nests and cords Frequent single cell infiltration
No surface adenoma or in situ lesion May have surface adenoma or in situ component
p53-, MUC1-, MUC2+ p53+, MUC1+, MUC2 only 5% positive

Goblet Cell Carcinoid

Tubular Carcinoid (variant of classical carcinoid)

Solid nests and cords, no open lumens Tubules with open lumens
Abundant cytoplasmic mucin May have mucin in lumen but not in cytoplasm
Signet ring / goblet cell morphology Usual carcinoid morphology
<25% of cells mark as neuroendocrine Majority of cells mark as neuroendocrine

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
    • 33% present at stage IV
  • If no carcinoma component is present, the prognosis appears to be very good, even with distant spread or positive nodes (96% overall disease specific survival)
  • Right hemicolectomy recommended, especially for the following:
    • Tumor recognized intraoperatively
    • Appendiceal margin positive
    • Involvement beyond muscularis propria
    • Perforation
    • Presence of carcinoma component (see carcinoma ex-goblet cell carcinoid LINK)
  • It has been suggested that tumors confined to the appendiceal wall with a clear surgical margin can be treated by appendectomy alone
    • Must not have a carcinoma component

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):
  • 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

Appendiceal Epithelial Neoplasms and Proliferations

Clinical / Descriptive Terms

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.
  • Pai RK, Longacre TA. Appendiceal mucinous tumors and pseudomyxoma peritonei: histologic features, diagnostic problems, and proposed classification. Adv Anat Pathol. 2005 Nov;12(6):291-311.
  • Kende AI, Carr NJ, Sobin LH. Expression of cytokeratins 7 and 20 in carcinomas of the gastrointestinal tract. Histopathology. 2003 Feb;42(2):137-40.
  • Alsaad KO, Serra S, Schmitt A, Perren A, Chetty R. Cytokeratins 7 and 20 immunoexpression profile in goblet cell and classical carcinoids of appendix. Endocr Pathol. 2007 Spring;18(1):16-22.
  • Chetty R, Klimstra DS, Henson DE, Albores-Saavedra J. Combined classical carcinoid and goblet cell carcinoid tumor: a new morphologic variant of carcinoid tumor of the appendix. Am J Surg Pathol. 2010 Aug;34(8):1163-7
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