Goblet cell carcinoid
“The Dr. Jekyll and Mr. Hyde Tumour”
Dr. Tze Sheng Khor
PathWest Laboratory Medicine WA
Goblet cell carcinoid
• Distinctive and unique chimeric neoplasm with
amphicrine lineage and demonstrating features
of mucinous / glandular and neuroendocrine
differentiation
History
Author
Year
Oberndorfer
1907 “Karzinoide Tumoren”
Gagne
Tumors of the appendix associating
histologic features of carcinoid and
1969
adenocarcinoma. (“Intermediate” type
carcinoid)
Subbuswamy 1974 Goblet cell carcinoid
Klein
Wolff
Warkel
Isaacson
1974
1976
1978
1981
Mucinous carcinoid tumour
"Microglandular" carcinoma
Adenocarcinoid
Crypt cell carcinoma
Controversy
• Classification and nature of tumour
– Carcinoid vs adenocarcinoma
• Histogenesis
– Unitary hypothesis: single pluripotent
neoplastic stem cell with divergent
neuroendocrine and mucinous differentiation
– Simultaneous, integrated, neoplastic
proliferation of several histogenetically
different cell elements
Clinical features
• Age-adjusted incidence of appendiceal malilgnancies: 0.12 per
million
• GCC 5% or less of appendiceal neoplasms
• Almost exclusively found in appendix
• Mean age 5th decade
• Gender distribution variable; female predominance, equal gender
distribution
• Presentation:
– Abdominal pain suggestive of acute appendicitis
– Chronic intermittent / recurrent abdominal pain +/- palpable
mass
– Incidental / asymptomatic
• Pre-operative diagnosis seldom made
Gross Pathology
•
•
•
•
Induration of the wall, stenosed lumen, exudate
Bulbous or fusiform swelling
Firm / hard – suspicious for neoplasm
A discrete lesion seldom appreciated
Microscopic Pathology
• Intact non-neoplastic mucosal surface
• Diffuse circumferential thickening without
stromal reaction or architectural disruption
• Associated acute appendicitis common
Pathology (Microscopic)
• Cells often concentrated around base of crypts and
submucosa and extending transmurally
• Small clumps, nests or rosettes with indistinct lumen
• Uniformity of nuclei, no / rare mitoses
• Principal cell with goblet-like morphology; variable
non-mucinous cells cytoplasmic granules, Paneth
cells
• Linear arrays between muscle; extracellular mucin
• LVI and PNI frequent
Ultrastructure
• Electron microscopy:
– Goblet cells with mucin
– Neuroendocrine cells (electron dense
granules)
– Amphicrine cells: mucin and electron dense
granules within the same cell
Immunohistochemistry
CEA
+
CK7
+/-
CK20
+
CK19
+
CD99
+
S100
-
CDX2
+
Synaptophysin, chromogranin,
CD56, NSE, PGP9.5
+/-
Serotonin
+/-
Substance P
+/-
Somatostatin
+/-
Enteroglucagon
+/-
Pancreatic polypeptide
+/-
Up to 70% may be positive with 5-50%
cells staining
May be variable and focal and may be
absent
Molecular Studies
• Allelic loss 11q, 16q, 18q (similar to ileal
carcinoids)
• No KRAS, Beta-catenin, DPC4 mutations
• No EGFR or BRAF mutations
• No MSI
• P53 mutations up to 25%
Differential diagnosis
• G1 WDNET
– Clear cell
– Tubular
• Signet ring cell
carcinoma
• Adenocarcinoma
• Metastatic
adenocarcinoma
(e.g. breast, prostate,
pancreatobiliary)
Clinical course and Prognosis
• Spectrum of behaviour is appreciated
– G1 WDNET ↔ Adenocarcinoma
• 5 year survival: 60% - 84%
• At diagnosis >50% invaded through serosa or
into mesoappendix
• 15-30% metastasized lymph nodes or distant
Predicting behaviour
• Early investigators: cytologic atypia, mitotic
activity (>2/10HPF), extension beyond appendix
associated with more aggressive behaviour
• Size not helpful, often difficult to determine
accurately
• Perineural invasion and lymphatic/vascular
invasion is common, and do not correlate with
prognosis
Predicting Behaviour
Burke et al
• Carcinomatous component:
– Fused or cribriform glands
– Single file structures
– Diffusely infiltrating signet ring cells
– Sheets of solid cells
– Compressed goblet cell nests with small glands and signet ring
cells with little or no intervening stroma
– Extracellular mucin pools harboring glandular epithelium with
gland fusion and without lumina
• Classified into:
– GCC with <25% adenocarcinoma component
– GCC with >50% adenocarcinoma component (Mixed carcinoidadenocarcinoma)
Burke et al
• GCC
– 25 of 33 had follow-up
– No metastases or residual disease developed
mean follow-up 19 months
Burke et al
• Mixed carcinoid-adenocarcinoma
– 10 of 14 had follow-up, average 16 months
– 8 of 10 DOD
– 1 of 10 alive at 41 months (Bladder and lymph node
disease)
– 1 of 10 free of disease at 48 months
• Reclassified Warkel’s series (n=23)
– GCC (n=16) and MCA (n=7)
– All 7 MCA developed metastases and DOD
– All GCC alive at last follow up, mean 97 months
Tang et al
Taggart et al
• Definition of carcinomatous component
– Individual dyshesive cells, solid sheets of cells, infiltrative cords of
cells (not within muscularis propria or larger cords incompatible with
GCT)
– Complex glandular architecture (irregular, angulated glands,
cribriform glands, or tufting)
– Clusters of cells simulating GCT but with cytologic or architectural
atypia beyond typical goblet cell carcinoid nests (enlarged or
irregular nests/glands, cytologic atypia, increased mitotic activity)
– The presence of destructive invasion or desmoplasia also
considered areas of adenocarcinoma
• Divided into:
– Group 1: <25% carcinomatous component
– Group 2: 25-50% carcinomatous component
– Group 3: >50% carcinomatous component
Lee et al
Lee et al
Tang et al
Taggart et al
Morphology
• 8 different patterns, typically coexist, highly
variable from section to section, organ to organ
• No specific clinical association
• Distinctive; raises the possibility of appendiceal
primary and allows distinction from other
metastases when observed in metastatic sites
Reid et al
•
•
•
•
•
(I) Conventional goblet cell carcinoid/ crypt pattern
(II) Poorly cohesive goblet cell pattern
(III) Poorly cohesive non-mucinous cell pattern
(IV) Microglandular pattern without goblet cells
(V) Mixed component of other non-specific carcinoma
types
• (VI) Goblet cell carcinoid pattern with high-grade
cytomorphology
• (VII) Ordinary ‘carcinoid-like’ pattern
• (VIII) Solid sheet-like growth pattern, often punctuated by
goblet cells or microglandular units
Reid et al
77% had or developed peritoneal carcinomatosis
Pattern of spread
• Direct involvement of caecum or ileum
• Propensity to spread intra-abdominally /
intra-peritoneally
– Involves ovaries in females
– Up to 50% females have metastases at
presentation and >50% involvement of
ovaries
• Lymph nodes
• Haematogenous spread less common
• Late recurrences (>15 years) may occur
• Many participants felt “goblet cell carcinoid” is misleading and
inappropriate
• On the other hand, well-established and recognized (including
by tumour registries)
• 90% (55 / 61) agreed “GOBLET CELL TUMOR” be introduced
as synonym
• 79% (33/42) support classifying goblet cell lesions as
mucinous or nonmucinous the former having >50%
extracellular mucin
• Adenocarcinoma ex goblet cell carcinoid preferred to WHO
“mixed adenoneuroendocrine carcinoma” (MANEC)
• On the other hand, 58% (23 / 40) preferred not to include
subcategories of Tang et al on the reporting checklist
Thank you