Ken's Notes

Appendiceal Adenocarcinoma

Epidemiology and Etiology:

Association with neoplasia elsewhere in the large intestine
Chronic UC maybe a risk factor

Common sites:

Pseudomyxoma peritonei often, if spread to the peritoneal cavity

Large volume disease often in greater omentum, beneath right hemidiaphragm, right retrohepatic space, ligament of Treitz, left abdominal gutter, and in the pelvis (relative sparing of peritoneal surfaces of the bowel)
LAMN usually does not spread beyond the peritoneum or give nodal metastases
High-grade mucinous adenocarcinoma is more likely to invade these structures

Ovary (if both ovary and appendiceal neoplasms are present, appendix is almost always the primary)

Gross features:

>1.5 cm diameter on imaging is suspicious

Histologic features:

Invasion beyond the muscularis mucosae (by definition)

May be pushing type of invasion

Mucinous:

>50 % extracellular mucin
Low-grade appendiceal mucinous neoplasm (LAMN)

Resting on fibrous tissue rather than lamina propria (in contrast to adenomas)

No desmoplasia
Note: an otherwise typical adenoma with the presence of mucin outside of the appendix (even acellular) should be called LAMN

May show widespread epithelial denudation
Atrophy of the underlying lymphoid tissue
Single layer of cells
Variable morphology:

Villous, serrated, undulating
Columnar, cuboidal, flattened

Nuclei small and regular
Low-grade dysplasia

May be deceptively bland

Mitoses rare

Mucinous Adenocarcinoma

Invasive pattern with desmoplastic stroma
High-grade dysplasia, at least focally
Residual luminal mucinous tumour resembling LAMN maybe
Mitoses more common and may be atypical
Intracellular mucin variable
Signet-ring cells maybe

Non-mucinous adenocarcinoma
Signet ring cell carcinoma (high-grade)

Signet-ring cells account for more than 50% of the neoplasm

Undifferentiated carcinoma
Goblet cell carcinoid (GCC)

Predominantly submucosal growth with mucosal sparing characteristically
Infiltrating appendiceal wall in a concentric manner typically

Minimal architectural distortion of the appendiceal wall

Ill-defined tumour mass
Small, rounded nests

Clusters or cohesive linear pattern
Gland lumina infrequently observed

Signet-ring-like cells resembling normal intestinal goblet cells

Minimal cytologic atypia
Low mitotic activity (rare; up to 4/10 HPF in high-grade metastatic lesions)
Ki67 proliferation index < 20 %

Minimal to no desmoplasia
Vascular and perineural invasion commonly
Periappendiceal fat infiltration commonly
Degenerative change with extracellular mucin is acceptable
Surrounding epithelium without evidence of adenomatous change

Fibrous obliteration of the lumen maybe

Paneth cells (Lysozyme-positive) maybe
Brunner gland-like foci maybe

Adenocarcinoma ex GCC, signet ring type (Tang et al. “group B”):

Goblet cells or signet ring cells

Significant cytologic atypia

Irregular large clusters, but not confluent sheets

Discohesive single file or single cell infiltration

Desmoplasia and associated destruction of the appendiceal wall

Adenocarcinoma ex GCC, poorly-differentiated carcinoma type:

At least focal evidence of goblet cell morphology
> 1 mm² or > 1 low power field of poorly differentiated adenocarcinoma, such as:

Gland-forming
Confluent sheets of signet ring cells
Undifferentiated carcinoma

Mixed adenoneuroendocrine carcinoma (MANEC)

Progression from a pre-existing goblet cell carcinoid

Lack of neoplastic change in the mucosal epithelium usually

Signet-ring cell type
Poorly differentiated carcinoma type

Immunophenotype:

Marker:	Sensitivity:	Specificity:
CK20	100% of GCC	Classical carcinoids also are positive often
CDX2	Goblet cell carcinoid generally strongly positive
CK7	“many”
MUC2	GCC “group A and B” are positive Loss of MUC2 in poorly-differentiated MANEC and GCC “group C”	Normally expressed by intestinal goblet cells
Ki67: < 20% in goblet cell carcinoid	Mean 11 % for GCC	Mean 16% for AdenoCA ex GCC, signet ring type Mean 80% for AdenoCA ex GCC, poorly-differentiated type
Lysozyme – if Paneth cells present in goblet cell carcinoid
Mucin (intensely positive within goblet cells and extracellular mucin pools)
Chromogranin A Synaptophysin CD56 (NCAM1) (endocrine-cell component of goblet cell carcinoid)	GCC: Inconsistent positivity for neuroendocrine markers; focal, patchy	Strong and diffuse in classic carcinoid
CEA (goblet cells)	GCC generally strongly positive
CK19 CK20
p53	Poorly-differentiated adenocarcinoma type of MANEC
MUC1	Poorly-differentiated adenocarcinoma type of MANEC “group C” GCC

Molecular features:

Microsatellite stable (only rare cases MSI)
Mutations:

BRAF
KRAS

Mostly codon 12
Few codon 13
Rarely found in carcinoids or goblet cell carcinoids

SMAD4/DPC4

Not in goblet cell carcinoids

NOT CTNNB1

LOH:

5q (APC)
18q21 and 18q22 (SMAD4/DPC4)

GCC:

Most studies indicate similarity between ileal carcinoids and GCC
Losses:

11q
16q
18q

TP53 mutation (25% in one study)
Not mutations in KRAS, DPC4 (Smad4) or B-catenin, in contrast to colonic ADC

Other features:

Non-mucinous histology is poorer prognosis
GCC prognosis:

Goblet-cell carcinoid is more aggressive than conventional carcinoid, but less than adenocarcinoma of the appendix

5-year OS 74% overall
Stage-matched 5-year DSS (Tang et al. 2008):

100% for typical GCC (group A)
38% for AdenoCA ex GCC, signet ring type (group B)
0% for AdenoCA ex GCC, poorly-differentiated type (group C)

Stage is most important (AJCC)
Histologic features are debateable but some have been associated with aggressive behavior:

High mitotic count (> 2 / 10 HPF)
High ki-67 index (> 3%)
Serosal or meso-appendiceal extension
Angioinvasion (not lymphatic or perineural invasion, which are common)
Nodal involvement
Increased number of Paneth cells
Increased mucin secretion
Pancreatic polypeptide production

References:

WHO 2010
Tang et al. Pathologic Classification and Clinical Behavior of the Spectrum of Goblet Cell Carcinoid Tumors of the Appendix. Am J Surg Pathol 2008;32(10):1429-1443.
Roy P, Chetty R. Goblet cell carcinoid tumors of the appendix: an overview. Worl J Gastrointest Oncol 2010;2(6):251-258.