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Chapter 6 Frozen Section Evaluation of the Appendix Abstract Appendiceal tumors are rarely diagnosed preopera- tively, and their classification is both challenging and controversial owing to their tendency to disseminate in the peritoneal cavity despite their frequent low-grade appearance. Frozen section analy- sis may be requested to assess the status of the appendiceal margin, determine whether extra-appendiceal epithelium is present, and to classify extra-appendiceal disease as low- or high-grade. Other types of appendiceal epithelial tumors, such as serrated neo- plasms, should be distinguished from mucinous tumors, since they tend to precede overtly malignant peritoneal disease (peri- toneal carcinomatosis). Goblet cell carcinoid tumors often spread to non-contiguous structures and, thus, may prompt intraoperative consultation. Keywords Appendicitis · Mucinous neoplasm · Extra-appendiceal mucin · Endocrine · Goblet cell carcinoid Introduction Primary appendiceal tumors are found in less than 2% of sur- gically removed appendices and typically bear a resemblance to their colonic counterparts. Most epithelial tumors are mucinous or contain villous projections, and those with serrated architecture 85 N.C. Panarelli, R.K. Yantiss, Frozen Section Library: Appendix, Colon, and Anus, Frozen Section Library 4, DOI 10.1007/978-1-4419-6584-4_6, C Springer Science+Business Media, LLC 2010

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Page 1: Chapter 6 Frozen Section Evaluation of the Appendixsinai918.com/uploadfile/20120611102925182.pdf · 86 6 Frozen Section Evaluation of the Appendix are increasingly recognized. Appendiceal

Chapter 6Frozen Section Evaluationof the Appendix

Abstract Appendiceal tumors are rarely diagnosed preopera-tively, and their classification is both challenging and controversialowing to their tendency to disseminate in the peritoneal cavitydespite their frequent low-grade appearance. Frozen section analy-sis may be requested to assess the status of the appendiceal margin,determine whether extra-appendiceal epithelium is present, and toclassify extra-appendiceal disease as low- or high-grade. Othertypes of appendiceal epithelial tumors, such as serrated neo-plasms, should be distinguished from mucinous tumors, sincethey tend to precede overtly malignant peritoneal disease (peri-toneal carcinomatosis). Goblet cell carcinoid tumors often spreadto non-contiguous structures and, thus, may prompt intraoperativeconsultation.

Keywords Appendicitis · Mucinous neoplasm · Extra-appendicealmucin · Endocrine · Goblet cell carcinoid

Introduction

Primary appendiceal tumors are found in less than 2% of sur-gically removed appendices and typically bear a resemblance totheir colonic counterparts. Most epithelial tumors are mucinous orcontain villous projections, and those with serrated architecture

85N.C. Panarelli, R.K. Yantiss, Frozen Section Library: Appendix,Colon, and Anus, Frozen Section Library 4, DOI 10.1007/978-1-4419-6584-4_6,C© Springer Science+Business Media, LLC 2010

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86 6 Frozen Section Evaluation of the Appendix

are increasingly recognized. Appendiceal endocrine neoplasmsare relatively common, incidentally discovered lesions that gen-erally do not require intraoperative consultation, although gobletcell “carcinoid” tumors may pose challenges to both surgeonsand pathologists [1]. Unfortunately, the diagnosis of appendicealneoplasia is rarely made preoperatively, since many patients haveclinical symptoms of appendicitis [2, 3]. As a result, intraopera-tive frozen section evaluation is commonly performed to determinethe surgical management of patients with these tumors. Mostimportant issues revolve around the diagnosis and classification ofmucinous neoplasms, as discussed below.

Appendicitis

The acutely inflamed appendix displays serosal hyperemia withor without fibrinopurulent exudates and inflammation (Fig. 6.1).Mucosal necrosis is accompanied by purulent luminal debris andneutrophilic inflammation within the muscularis propria, which

Fig. 6.1 An acutely inflamed appendix displays fibrinous adhesions onthe erythematous serosa. Inflammation in the mesoappendiceal fat reflectsperforation and a periappendiceal abscess

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Appendiceal Mucinous Neoplasms 87

may be associated with mesoappendiceal abscesses. A prolongedinterval between the onset of symptoms and surgical resectionmay result in intense eosinophil-rich inflammation in combinationwith granulomas, a foreign body giant cell-rich response to lumi-nal material, and organizing serositis (Fig. 6.2). Sheets of tissuemacrophages laden with ceroid pigment in combination with mult-inucleated giant cells and fat necrosis may prompt a diagnosis of“xanthogranulomatous appendicitis”.

Fig. 6.2 Prolonged acute appendicitis produces a fibroinflammatory appen-diceal mass that simulates a neoplasm. One may observe a mixed inflammatorycell infiltrate with sheets of macrophages associated with fat necrosis andfibrosis

Appendiceal Mucinous Neoplasms

Epithelial neoplasms of the appendix are generally classifiedas mucinous neoplasms and non-mucinous tumors. Appendicealmucinous neoplasms characteristically cause cystic dilatation ofthe appendix, but they may rupture, resulting in accumulationof mucin around the appendix (Fig. 6.3). Mucinous appendicealneoplasms may also disseminate through the peritoneum in the

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88 6 Frozen Section Evaluation of the Appendix

Fig

.6.3

Muc

inou

sne

opla

sms

prod

uce

copi

ous

muc

in,r

esul

ting

inst

riki

ngap

pend

icea

ldi

sten

tion

(a).

Rup

ture

dne

opla

sms

may

beas

soci

ated

with

peri

appe

ndic

ealm

ucin

depo

sits

,whi

chsh

ould

beex

haus

tivel

ysa

mpl

edto

excl

ude

the

poss

ibili

tyof

extr

a-ap

pend

icea

lep

ithel

ium

(b)

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Appendiceal Mucinous Neoplasms 89

form of mucin deposits, or pseudomyxoma peritonei (Fig. 6.4).They frequently metastasize to the ovary, which may be large andcystic, simulating the appearance of a primary ovarian neoplasm(Figs. 6.5 and 6.6). Pathologists will be called upon to classifyperitoneal tumor deposits in many institutions because immediatetreatment depends upon the degree of atypia present in extra-appendiceal epithelium. Patients with low-grade peritoneal diseasemay be treated with surgical debulking and peritoneal strippingwith the aim of complete cytoreduction either with, or without,intraoperative intraperitoneal chemotherapy. Moderate-to-poorlydifferentiated mucinous carcinomas may also produce gelatinousascites, but they do not respond to cytoreductive surgery, so thesepatients may be offered systemic chemotherapy. Therefore, pathol-ogists should clearly communicate the histologic findings andbiologic implications of their observations at the time of the frozensection.

Mucinous lesions typically display a circumferential growthpattern in the appendiceal mucosa and contain tall columnar muci-nous cells arranged in a single layer, or papillae with low-gradenuclei [4] (Fig. 6.7). When present, extra-appendiceal disease con-sists of pools of mucin containing strips or clusters of neoplasticepithelial cells that usually show bland cytologic features, similarto those of the appendiceal component [5] (Fig. 6.8).

Several groups have proposed a variety of classificationschemes that employ varied, and often confusing, terminology todescribe appendiceal mucinous tumors [6–10] (Table 6.1). Moststudies have shown that mucinous neoplasia confined to the appen-diceal mucosa is essentially cured by excision, regardless of thedegree of dysplasia, whereas peritoneal disease is associated withdisease recurrence and death in nearly half of patients. Emergingdata also suggest that acellular mucin pools limited to the appen-diceal wall and periappendix are associated with an excellentprognosis, provided the entire appendix is submitted for histo-logic evaluation to exclude the possibility of extra-appendicealepithelium. However, any amount of extra-appendiceal epitheliummay be associated with progressive mucinous ascites and death insome cases, even if one identifies only rare clusters of neoplasticepithelial cells surrounding the appendix [5] (Fig. 6.9). Extension

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90 6 Frozen Section Evaluation of the Appendix

Fig

.6.

4A

ppen

dice

alm

ucin

ous

neop

lasm

sm

aydi

ssem

inat

ein

the

peri

tone

alca

vity

and

appe

aras

gela

tinou

sde

posi

tsw

ithin

peri

tone

alfa

t(a)

and

onth

ein

test

inal

sero

sals

urfa

ce(b

)

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Appendiceal Mucinous Neoplasms 91

Fig. 6.5 Metastatic appendiceal mucinous tumors result in massive ovarianenlargement with multiple loculated cysts filled with mucinous material

beyond the appendix should also be distinguished from herniationsof mucosa through the wall, or diverticula, since this finding has nobiologic implications (Fig. 6.10).

The proposed classification schemes for appendiceal mucinousneoplasia reflect differences of opinion regarding the fundamentalnature of peritoneal disease. At one extreme, some investigatorsfeel that peritoneal dissemination results from appendiceal rup-ture and spillage of both mucin and neoplastic, but non-invasive,epithelium into the peritoneal cavity. Proponents of this hypoth-esis classify tumors limited to the appendiceal mucosa as muci-nous cystadenomas. They consider gelatinous ascites containinglow-grade epithelium to represent disseminated peritoneal ade-nomucinosis but reserve the term “carcinoma” for tumors thatdisplay high-grade cytologic features (Figs. 6.11 and 6.12) [8,10]. Conversely, most authorities, including the World HealthOrganization, now consider pseudomyxoma peritonei to representcarcinoma and grade the cytologic features present in extra-appendiceal epithelium. Low-grade tumors corresponding to “dis-seminated peritoneal adenomucinosis” are classified as low-grade

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92 6 Frozen Section Evaluation of the Appendix

Fig

.6.6

App

endi

ceal

muc

inou

sne

opla

sms

that

met

asta

size

toth

eov

ary

prod

uce

larg

em

ucin

-fille

dcy

sts

(a)l

ined

bybl

and

epith

eliu

mth

atm

aysi

mul

ate

apr

imar

yov

aria

ntu

mor

(b)

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Appendiceal Mucinous Neoplasms 93

Fig

.6.7

Muc

inou

sne

opla

sms

circ

umfe

rent

ially

invo

lve

the

appe

ndic

ealm

ucos

a(a

)an

dco

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llous

,or

flat,

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-gra

dem

ucin

ous

epith

eliu

mw

ithsl

ight

lyen

larg

ed,b

asal

lylo

cate

dnu

clei

(b)

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94 6 Frozen Section Evaluation of the Appendix

Fig

.6.8

Peri

tone

alm

ucin

depo

sits

cont

ain

rare

clus

ters

ofep

ithel

ialc

ells

(a)

that

show

low

-gra

decy

tolo

gy(b

)

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Appendiceal Mucinous Neoplasms 95

Tabl

e6.

1Pr

opos

edcl

assi

ficat

ion

sche

mes

for

appe

ndic

ealm

ucin

ous

neop

lasm

s

Car

ran

dSo

bin

Mis

draj

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iand

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eR

onne

ttet

al.

Wor

ldH

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Org

aniz

atio

n

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nfine

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Lim

ited

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ucos

aL

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rade

cyto

logy

Ade

nom

aL

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muc

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deno

ma

Ade

nom

aA

deno

ma

Hig

h-gr

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Ade

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aN

on-i

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ive

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stad

enoc

arci

nom

aA

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ma

Ade

nom

aA

deno

ma

Posi

tive

surg

ical

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gin

Ade

nom

aL

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appe

ndic

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tain

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ig-

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ma

Cel

lula

rm

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all

Inva

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muc

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sad

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arci

nom

aL

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rade

appe

ndic

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muc

inou

sne

opla

smU

ncer

tain

mal

ig-

nant

pote

ntia

lIn

vasi

vem

ucin

ous

aden

ocar

cino

ma

Tum

orbe

yond

appe

ndix

Low

-gra

deep

ithel

ium

inpe

rito

neal

muc

in

Inva

sive

muc

inou

sad

enoc

arci

nom

aL

ow-g

rade

appe

ndic

eal

muc

inou

sne

opla

smL

ow-g

rade

with

high

risk

ofre

curr

ence

Dis

sem

inat

edpe

rito

neal

ade-

nom

ucin

osis

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-gra

dem

ucin

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aden

ocar

cino

ma

Hig

h-gr

ade

epith

eliu

min

peri

tone

alm

ucin

Inva

sive

muc

inou

sad

enoc

arci

nom

aIn

vasi

vem

ucin

ous

aden

ocar

cino

ma

Inva

sive

muc

inou

sad

enoc

arci

nom

aPe

rito

neal

muc

inou

sca

rcin

omat

osis

Hig

h-gr

ade

muc

inou

sad

enoc

arci

nom

a

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96 6 Frozen Section Evaluation of the Appendix

Fig

.6.

9R

uptu

red

appe

ndic

eal

muc

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sne

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disp

lay

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ous

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muc

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posi

ts(a

),w

hich

may

cont

ain

rare

clus

ters

ofex

tra-

appe

ndic

ealt

umor

cells

(b)

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Appendiceal Mucinous Neoplasms 97

Fig

.6.

10D

iver

ticul

aar

eco

mm

only

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unte

red

inas

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atio

nw

ithap

pend

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lm

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ous

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san

dre

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ent

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iatio

nsof

muc

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thro

ugh

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ris

prop

ria

(a).

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icul

am

aybe

asso

ciat

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lar

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inte

rpre

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pres

enta

neop

lasm

(b)

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98 6 Frozen Section Evaluation of the Appendix

Fig

.6.

11M

ucin

ous

appe

ndic

eal

neop

lasm

sth

atsp

read

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assi

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base

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cyto

-lo

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iapr

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a-ap

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.L

ow-g

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cons

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s(a

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atco

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ant

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ters

ofm

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ithm

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).T

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ider

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sem

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muc

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sad

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arci

nom

aby

othe

rs

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Appendiceal Mucinous Neoplasms 99

Fig

.6.

12So

me

muc

inou

sne

opla

sms

cont

ain

mor

enu

mer

ous

cell

clus

ters

and

disp

lay

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ruct

ion

and

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sion

(a).

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vere

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gic

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ures

with

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und

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ei,

nucl

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and

mito

ticfig

ures

(b).

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emen

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sues

anag

gres

sive

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se,d

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notr

espo

ndw

ellt

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rgic

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and

shou

ldbe

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sifie

das

aden

ocar

cino

ma

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100 6 Frozen Section Evaluation of the Appendix

Fig

.6.

13C

lust

ered

and

sing

lein

filtr

atin

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llsw

ithde

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last

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sue

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ruct

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(a)

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mas

,de

spite

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ence

ofm

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uctio

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Non-mucinous Appendiceal Epithelial Neoplasms 101

mucinous adenocarcinomas (Figs. 6.8, 6.9, and 6.11). More cellu-lar lesions that display malignant cytology are considered to rep-resent high-grade mucinous adenocarcinomas [5, 11] (Fig. 6.12).Notably, carcinomas that infiltrate the peritoneal soft tissue assingle cells or cluster associated with desmoplasia are uniformlyclassified as high-grade adenocarcinomas, regardless of the pres-ence of mucin production. They seed the peritoneum in the formof solid tumor nodules, or carcinomatosis, which is not amenableto surgery (Fig. 6.13). The term “mucinous adenocarcinoma” isgenerally avoided when describing such cancers in order to avoidconfusion.

The primary goals of intraoperative examination are to (1)determine whether the mucinous neoplasm is limited to theappendix, (2) assess extra-appendiceal mucin for the presenceof neoplastic epithelium, and (3) grade the severity of cytologicatypia within extra-appendiceal epithelium. Tumors limited to theappendix are treated with appendectomy alone, whereas a rightcolectomy or cecectomy may be considered when the appendixis ruptured, or the neoplasm is present at the appendiceal resectionmargin.

Non-mucinous Appendiceal Epithelial Neoplasms

Non-mucinous adenomas and carcinomas are histologically simi-lar to their colonic counterparts and are commonly referred to as“colonic-type” lesions (Fig. 6.14). Colonic-type appendiceal ade-nomas are relatively uncommon and are generally observed inpatients with familial adenomatous polyposis or represent colonicadenomas that extend to involve the appendiceal mucosa from thececum [4]. More frequently, non-mucinous appendiceal neoplasmsdisplay serrated architecture. They may contain non-dysplastic ordysplastic epithelium and show molecular features similar to thoseof serrated colonic polyps [12] (Fig. 6.15).

Serrated appendiceal lesions are relatively common, but havebeen poorly characterized. They are usually incidentally discov-ered in colectomy specimens obtained for medical indications but

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102 6 Frozen Section Evaluation of the Appendix

Fig. 6.14 Colonic-type appendiceal adenomas protrude into the lumen andcontain cells with enlarged pseudostratified nuclei and faintly eosinophiliccytoplasm, reminiscent of tubular or villous adenomas of the colon

may occur in patients with concomitant proximal colon cancers.Importantly, serrated appendiceal lesions occasionally precedeinvasive adenocarcinomas that show overtly malignant featuresand a destructive growth pattern characteristic of colonic cancers(Fig. 6.16a). Although these cancers may contain abundant extra-cellular mucin, peritoneal disease is in the form of solid tumornodules, and pursues a uniformly malignant course (Fig. 6.16b).Therefore, this type of tumor should not be considered within thespectrum of pseudomyxoma peritonei but is simply graded andstaged as invasive adenocarcinoma [12].

Endocrine Neoplasms of the Appendix

The most common appendiceal tumors are well-differentiatedendocrine neoplasms. These tumors have been historically clas-sified as “carcinoid” tumors because they are invasive similar to

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Endocrine Neoplasms of the Appendix 103

Fig

.6.

15Se

rrat

edad

enom

asci

rcum

fere

ntia

llyin

volv

eth

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pend

icea

lm

ucos

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like

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inou

stu

mor

s,th

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ngo

blet

and

non-

gobl

etep

ithel

ial

cells

with

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dant

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ilic

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plas

m(a

).T

hese

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ypts

are

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ithba

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,sim

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ose

ofco

lore

ctal

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ated

aden

omas

(b)

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104 6 Frozen Section Evaluation of the Appendix

Fig

.6.1

6C

arci

nom

asde

rive

dfr

omse

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edne

opla

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may

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lay

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entio

nal,

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ous

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orce

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ated

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opla

stic

stro

ma

(b)

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Endocrine Neoplasms of the Appendix 105

carcinomas, but generally pursue an indolent course, even whenmetastases are present. Recently, the World Health Organizationrecommended that such tumors be classified as endocrine, or neu-roendocrine, neoplasms, and abandoned the carcinoid terminology,since the biologic behavior of endocrine tumors varies dependingon anatomic location and other factors.

Appendiceal endocrine neoplasms display a variety of mor-phologic features and vary with respect to their biologic poten-tial. Most are comprised of enterochromaffin cells that expressserotonin in addition to synaptophysin and chromogranin. Theselesions are usually incidentally discovered firm, yellow nodulesthat occur in the distal tip of the appendix (Fig. 6.17). Theycontain nests of bland polygonal cells with abundant faintlyeosinophilic cytoplasm enmeshed within paucicellular collagenousstroma (Fig. 6.18a). The nuclei are monotonous, smooth, andround, without perceptible atypia, and mitotic figures are lacking(Fig. 6.18b). Endocrine neoplasms derived from L-cells are muchless common and express glucagon and peptide YY in addition

Fig. 6.17 Appendiceal endocrine neoplasms form solid tan-yellow nodules inthe distal tip of the appendix

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Endocrine Neoplasms of the Appendix 107

to chromogranin and synaptophysin. They also show a predilec-tion for the distal appendix. L-cell endocrine neoplasms containtrabeculae, cords, and, rarely, tubules, of bland endocrine cellswith ovoid nuclei and no mitotic activity. Both enterochromaffinand L-cell endocrine neoplasms are generally benign or pursue anindolent clinical course when metastases are present. Tumors thatspan less than 1 cm are adequately treated by appendectomy, andthe risk of metastases from tumors smaller than 2 cm is proba-bly less than 1%. Extensive resection and regional lymph nodedissection is reserved for larger tumors, or those associated withmetastases, increased mitotic activity, and angioinvasion [1].

Neoplasms that express endocrine markers and contain cyto-plasmic mucin have been termed “goblet cell carcinoid tumors”,although they are more aggressive than other appendicealendocrine neoplasms. They do not form nodular masses but, rather,display circumferential growth in the appendiceal submucosa andmuscularis propria (Fig. 6.19). Goblet cell carcinoid tumors con-tain nests and clusters of tumor cells with large mucin vacuoles that

Fig. 6.19 Goblet cell carcinoid tumors spare the mucosa but diffusely infil-trate the appendiceal wall and extend onto the serosal surface

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Endocrine Neoplasms of the Appendix 109

Fig. 6.21 Nests of goblet cell carcinoid tumor diffusely infiltrate peritonealfat and are associated with a fibroinflammatory tissue response

compress the nuclei (Fig. 6.20). Neoplasms with these features areoften of advanced pathologic stage at the time of diagnosis. Theypenetrate the serosa, occasionally metastasize to regional lymphnodes, and form tumor deposits in the peritoneal cavity and/orovary, which may prompt frozen section evaluation (Fig. 6.21).Perineural and lymphovascular invasion are frequently observed[13]. In addition, goblet cell carcinoid tumors may precede devel-opment of frank adenocarcinomas, which either form glands orresemble signet ring cell or diffuse-type carcinoma, leading someinvestigators to propose terms, such as “adenocarcinoma ex gobletcell carcinoid” and “mixed goblet cell carcinoid adenocarcinoma”(Fig. 6.22).

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References 111

References

1. Carr NJ, Sobin LH (2004) Neuroendocrine tumors of the appendix. SeminDiagn Pathol 21(2):108–119

2. Jordan FT, Mazzeo RJ, Hoshal VL (1983) Primary adenocarcinoma ofthe appendix. Can preoperative or intraoperative diagnosis be made? AmSurg 49(5):278–281

3. Younes M (2005) Frozen section of the gastrointestinal tract, appendix,and peritoneum. Arch Pathol Lab Med 129(12):1558–1564

4. Misdraji J, Young RH (2004) Primary epithelial neoplasms and otherepithelial lesions of the appendix (excluding carcinoid tumors). SeminDiagn Pathol 21:120–133

5. Yantiss RK, Shia J, Klimstra DS, Hahn HP, Odze RD, Misdraji J (2009)Prognostic significance of localized extra-appendiceal mucin depositionin appendiceal mucinous neoplasms. Am J Surg Pathol 33(2):248–255

6. Bradley RF, Stewart JH, Russell GB, Levine EA, Geisinger KR (2006)Pseudomyxoma peritonei of appendiceal origin: a clinicopathologic anal-ysis of 101 patients uniformly treated in a single institution, with literaturereview. Am J Surg Pathol 30(5):551–559

7. Carr NJ, McCarthy WF, Sobin LH (1995) Epithelial noncarcinoid tumorsand tumor-like lesions of the appendix: a clinicopathologic study of184 patients with a multivariate analysis of prognostic factors. Cancer75(3):757–768

8. Misdraji J, Yantiss RK, Graeme-Cooke FM, Balis UJ, Young RH (2003)Appendiceal mucinous neoplasms: a clinicopathologic analysis of 107cases. Am J Surg Pathol 27(8):1089–1103

9. Pai RK, Beck AH, Norton JA, Longacre TA (2009) Appendiceal muci-nous neoplasms: clinicopathologic study of 116 cases with analysis offactors predicting recurrence. Am J Surg Pathol 33(10):1425–1439

10. Ronnett BM, Zahn CM, Kurman RJ, Kass ME, Sugarbaker PH,Shmookler BM (1995) Disseminated peritoneal adenomucinosis and peri-toneal mucinous carcinomatosis: a clinicopathologic analysis of 109cases with emphasis on distinguishing pathologic features, site of ori-gin, and relationship to “pseudomyxoma peritonei”. Am J Surg Pathol19(12):1390–1408

11. Hamilton SR, Aaltonen LA (1999) Tumours of the appendix. WHOclassification of tumours: tumours of the digestive system. WHO Press,Geneva

12. Yantiss RK, Panczykowski A, Misdraji J, Odze RD, Rennert H, Chen Y(2007) A comprehensive study of non-dysplastic and dysplastic serratedpolyps of the vermiform appendix. Am J Surg Pathol 31(12):1742–1753

13. Tang LH, Shia J, Soslow RA, et al (2008) Pathologic classification andclinical behavior of the spectrum of goblet cell carcinoid tumors of theappendix. Am J Surg Pathol 32(10):1429–1443