Appendiceal Mucinous Neoplasms
Facts and Fiction
Rhonda K. Yantiss, M.D.
Professor of Pathology and Laboratory Medicine
Department of Pathology and Laboratory Medicine
Weill Cornell Medicine, New York, NY
Introduction
Pseudomyxoma Peritonei
•Complex disease with unique biologic behavior
•Mucinous ascites and peritoneal implants
•Slow, relentless intra-abdominal growth without
distant metastases
• Redistribution phenomenon
•Usually derived from appendiceal mucinous
neoplasms
• Rarely associated with mucinous tumors of ovary (origin in mature
teratoma, not ”borderline” tumors), colon, urachus, pancreas
Appendiceal mucinous neoplasm Pseudomyxoma peritonei
Appendiceal mucinous neoplasm Pseudomyxoma peritonei
Natural History of
Pseudomyxoma Peritonei
Low-grade epithelium in
peritoneum
High-grade epithelium in peritoneum
Bradley, et al. Am J Surg Pathol 2006; 30(5): 551-559.
Not typical invasive pattern of cancer
Can see this in the appendix….
…but still see this in the peritoneum
Not terribly bad cytology Obviously malignant
Appendix Peritoneum
Problematic Issues
•A peritoneal tumor that looks benign, but it
isn’t
•An appendiceal tumor that doesn’t seem
invasive, but it is
•Not necessarily a correlation between
cytologic features of tumor in appendix and
those of cells in the peritoneum
Mucinous Tumors of Appendix
and Peritoneum
• Appendiceal tumor • Peritoneal disease
– Adenoma – Disseminated peritoneal
– Mucinous tumor of adenomucinosis
uncertain malignant – Low-grade appendiceal
potential mucinous neoplasm
– Low-grade appendiceal – Ruptured mucocele
mucinous neoplasm – Mucinous
– Mucinous adenocarcinoma adenocarcinoma
– Invasive mucinous – Disseminated mucinous
adenocarcinoma carcinomatosis
Overview
•Pseudomyxoma peritonei
•Definitions and grading
•Mucinous tumors confined to appendix
•Adenoma, low-grade appendiceal mucinous neoplasm
(LAMN), high-grade appendiceal mucinous neoplasm
(HAMN), and carcinoma
•Mucin limited to the right lower quadrant
•Mimics of mucinous neoplasia
Case 1
•44-year-old male with right lower
quadrant pain and suspected
appendicitis
•Imaging revealed thickened appendix
and fluid in right colic gutter
•Laparoscopic appendectomy and
biopsies of peritoneum
Peritoneum
Mucin and low-grade epithelium
Scant strips, cytologically bland
Appendix
Rupture with mucin on serosa
Appendix
Cytologically low-grade mucinous epithelium
Terminology Options
•Mucin and neoplastic epithelium in
peritoneum and appendix
•Pseudomyxoma peritonei
•Ruptured adenoma or cystadenoma of the appendix
•Low-grade appendiceal mucinous neoplasm (LAMN)
•Disseminated peritoneal adenomucinosis
•Low-grade mucinous carcinoma peritonei
Pseudomyxoma Peritonei is a Clinical
Diagnosis, Not a Histologic One
“Intraperitoneal accumulation of mucus
due to mucinous neoplasia characterized
by the redistribution phenomenon. It
can include mucinous ascites, peritoneal
implants, omental cake, and ovarian
involvement. It most commonly arises
from appendiceal neoplasia.”
Carr, et al. Am J Surg Pathol 2016; 40(1): 14-26.
Mucinous Tumors of Peritoneum
X
• Peritoneal disease
– Disseminated peritoneal
adenomucinosis
– Low-grade appendiceal Malignant behavior
mucinous neoplasm justifies carcinoma
– Ruptured mucocele terminology
– Mucinous
adenocarcinoma
– Disseminated mucinous
carcinomatosis
Cytologic Grade of Peritoneal
Disease is Important
Low-grade epithelium in
peritoneum
High-grade epithelium in peritoneum
Bradley, et al. Am J Surg Pathol 2006; 30(5): 551-559.
Low-grade mucinous carcinoma peritonei
Paucicellular
Low-grade mucinous carcinoma peritonei
Polarized cells with abundant mucin
Low-grade mucinous carcinoma peritonei
Nucleus located at cell base and confined to bottom one-third of cell
Beware of a lot of epithelium; take more sections
More cellular lesions are more likely to contain high-grade mucinous carcinoma peritonei
High-grade mucinous carcinoma peritonei
Irregular pools at invasive front
Architecturally complex
High-grade mucinous carcinoma peritonei
Clusters in mucin
Prominent nucleoli
Large nuclei, mitotic figures
High-grade mucinous carcinoma peritonei
Complex glands, tissue destruction
Infiltrating glands with desmoplasia (if present, not low-grade)
High-grade mucinous carcinoma peritonei
Infiltrating signet ring cells usually only a focal finding
High-grade mucinous carcinoma peritonei
Signet ring cells in mucin pools; not a feature of low-grade disease
Importance of Signet Ring Cells
Angiolymphatic Perineural Lymph Node 5-Year
Invasion Invasion Metastases Survival
Grade 1 disease (low-grade cytology) 0% 0% 0% 91%
Grade 2 disease (high-grade cytology) 17% 5% 17% 61%
Grade 3 disease (high-grade cytology 70% 70% 72% 23%
with signet ring cells)
If signet ring cells are present, then classify as high-grade and mention it
Davison, et al. Mod Pathol 2014; 27: 1521-1539
Goblet cell neoplasms can make mucin when they show high-grade features
Pools tend to be smaller with floating and infiltrating single cells
This is NOT mucinous carcinoma peritonei
Nests of mucinous cells; think goblet cell neoplasia, not mucinous neoplasia
Importance of Signet Ring Cells
Angiolymphatic Perineural Lymph Node 5-Year
Invasion Invasion Metastases Survival
Grade 1 disease (low-grade cytology) 0% 0% 0% 91%
Grade 2 disease (high-grade cytology) 17% 5% 17% 61%
Grade 3 disease (high-grade cytology 70% 70% 72% 23%
with signet ring cells)
63% of cases had >95% signet ring cells
30% of cases had 50-95% signet ring cells
11/12 appendices with signet ring cells in peritoneum were not derived
from mucinous tumors in appendix
Pseudomyxoma Peritonei
Appendix Organ Lymph Node 5-Year
Epithelium
Primary Metastases Metastases Survival
Low-grade disease/disseminated
peritoneal adenomucinosis (DPAM) Scant 43% 12% 3% 84%
Intermediate-grade Mixed 79% 79% 21% 38%
*40% of cases derived from colonic primary
High-grade disease/peritoneal
mucinous carcinomatosis (PMCA) Abundant 40% 97% 50% 7%
Ronnett, et al. Am J Surg Pathol 1995; 19(12): 1390-1408.
Signet ring cells and mucin in peritoneum of a patient with colon cancer
This is NOT mucinous carcinoma peritonei, just call it high-grade mucinous adenocarcinoma
Any adenocarcinoma can make a lot of mucin...
This is NOT mucinous carcinoma peritonei, just call it high-grade adenocarcinoma
Peritoneal Mucinous Neoplasia
A Quick Summary So Far
•Pseudomyxoma peritonei is a clinical term describing a
malignancy with copious mucin
•Eliminate equivocal terminology, as behavior is not benign or
unpredictable
•Behavior dependent on cytologic grade
• Low-grade mucinous carcinoma peritonei: 60% 10-year survival
• High-grade mucinous carcinoma peritonei: 10% 10-year survival
•Mucin-producing tumors with malignant cytology, desmoplasia,
small mucin pools, infiltrating signet ring cells usually derived
from other sites or other types of appendiceal cancers
Mucinous Lesions Limited to the
Appendix and Peri-Appendix
Case 2
•54-year-old female with incidental
appendectomy during gynecologic
surgery
•Ovary contained a serous cystadenoma
•Appendix was grossly normal
Mucinous neoplasm with villiform architecture
Mostly low-grade Some complex areas with more atypia
What is the Best Diagnosis?
•Mucinous tumor of appendix confined to
mucosa with some high-grade areas
•Mucinous adenoma/cystadenoma
•Mucinous cystadenocarcinoma
•Low-grade appendiceal mucinous neoplasm
(LAMN)
•High-grade appendiceal mucinous neoplasm
(HAMN)?
WHO (2010): Adenoma
•Neoplasm limited to mucosa
• Supported by lamina propria
•Often dilated due to mucin
accumulation (cystadenoma)
•Epithelium with low- or high-grade
cytologic atypia
•No mucin outside appendix
•Designation implies lesion is benign
and cured by excision
A Few Points Regarding Adenomas
•Adenomas show variable atypia
throughout GI tract
•Low-grade dysplasia
•High-grade dysplasia
•No risk of recurrence or metastasis
•Lesions confined to appendiceal
mucosa are unassociated with
biologic risk
•“Mucinous cystadenocarcinoma”
should be avoided
Adenoma Issues Unique to Appendix
•Elsewhere in GI tract,
adenoma is confined to Lamina propria tissue
basement membrane
•May be difficult to be sure
lesion is confined to mucosa
•Lamina propria always
decreased in mucinous
adenomas and LAMNs
Proliferative epithelium associated with compressed lamina propria
Atrophy and fibrosis of lamina propria
Atrophy and fibrosis of lamina propria, no lymphoid tissue
Is this lamina propria?
Is this lesion still confined to the mucosa?
Obliteration of mucosal elements; lymphoid atrophy
WHO (2010) Recommendations
Adenoma vs. LAMN
•Consider adenoma only when muscularis
mucosae intact
•LAMN terminology recommended when there
is obliteration of muscularis mucosae
•Hint that all mucinous things are LAMNs or
worse
Carr, et al. in WHO Classification of Tumors of the Digestive System, 2010; 122-125.
World Health Organization (2010): Adenoma
Lamina propria
Muscularis mucosae
Obliterated muscularis mucosae and lamina propria within the realm of a LAMN
New Recommendations (WHO and Others)
Adenoma vs. LAMN
•Eliminate mucinous adenoma altogether
•Criteria for low-grade appendiceal
mucinous neoplasm (LAMN) expanded
•Any mucinous tumor classified as LAMN, or worse
•Adenoma restricted to conventional tubular
and villous adenomas of appendix
(uncommon)
Carr, et al. Histopathology 2017; 71(6): 847-858.
Practical implications: “Adenoma” limited to colonic-type lesions
Adenoma according to WHO now, LAMN according to later
Lamina propria
Muscularis mucosae
LAMN: If We Were in the Business of
Naming Things, We Could’ve Done Better
•This is a dumb term
•We chose not to call them adenomas because some
are not limited to mucosa
•Introduced LAMN because one could not predict
status of peritoneum based on appendix findings
•Term implies some uncertainty with respect to behavior
•We recognized that these tumors were essentially benign
when confined to appendix
Misdraji, JM, Yantiss, RK, Graeme-Cook, FM, Balis, UJ, and Young, RH. Am J Surg Pathol 2003; 27(8): 1089-1103.
Intestinal-type Neoplasm of the Colon?
Adenoma with high-grade dysplasia Carcinoma in an adenoma
Carcinoma in colonic wall Liver metastasis
The Truth About LAMN
•Not a single well-documented case of progressive
disease when completely confined to inner
appendices of patients without peritoneal disease
at the time of appendectomy
•Labeling tumors that are benign as potentially
malignant (i.e. LAMN) is overly aggressive
•Places patient in a risk category that is unwarranted,
provided peritoneum is clear of disease
•There is a need for a benign category
Staging Low-Grade Tumors
AJCC 8th Edition
•Skirts the issue of mucinous adenoma
•LAMN in situ does not extend beyond muscularis
propria (i.e. there is no T1 or T2 LAMN)
•If epithelium and/or mucin are confined to appendix
proper, not a risk factor for recurrence
•Subserosal tumor staged as T3
•Mucin or epithelium on serosa staged as T4a
Mucinous lesion confined to muscularis propria: LAMN in situ
Stop and think about that for a moment
And this in the ovary and peritoneum…
Diagnosis: LAMN in situ associated with low-grade mucinous carcinoma peritonei
I would call this a mucinous adenoma today and I will still do it next week
Lamina propria
Muscularis mucosae
Does Mucinous Epithelium at
Margin Matter?
•No data to suggest that mucinous neoplasia in
mucosa at the margin poses biologic risk
•No data to suggest that mural acellular (no
epithelium) mucin at the margin poses risk
•Although imaging for peritoneal disease may be
of value, right colectomy to obtain a negative
margin is not
Arnason, et al. Arch Pathol Lab Med 2015; 139(4): 518-521.
Mucinous Appendiceal Tumors
A Quick Summary So Far….
•Lesions limited to mucosa (intact lamina
propria and muscularis mucosae) are benign
•WHO allows for an adenoma but is ambiguous
• No need to classify as low-grade or high-grade adenoma
•Movement to label these as LAMN
•Mucosal disease at appendiceal margin
unassociated with recurrence risk
•No need for colectomy and lymph node staging
Other situations in which low-grade
mucinous neoplasm (LAMN) is the best term
Low-Grade Appendiceal Mucinous
Neoplasms (WHO Criteria)
•Pushing invasion (expansile or diverticulum-
like growth)
•Dissecting acellular mucin in wall
associated with neoplasm
•Mucin outside appendix
•Ruptured appendix
No muscularis propria
Mucinous neoplasia
Don’t call this adenoma
Is this still confined to the mucosa?
LAMN probably best option in this situation
Consider LAMN when lesion not clearly confined to mucosa
Not sure where this is in relation to layers of appendiceal wall
Don’t use adenoma when expansile, diverticulum-like growth is present
LAMN is probably best option in this situation
What about extra-appendiceal mucin in right lower quadrant?
No epithelium in mucin Epithelial cells in mucin
Extra-Appendiceal Mucin
•Any epithelium outside appendix
•Approximately 1/3 of patients develop peritoneal disease
•Call this LAMN or worse depending on amount of
epithelium and degree of atypia (I generally call this well-
differentiated mucinous carcinoma)
•No epithelium in extra-appendiceal mucin
•Essentially cured by appendectomy
•Submit all of peri-appendiceal mucin
•Probably best to consider this to be LAMN
Yantiss, et al. Am J Surg Pathol 2009; 33(2): 248-255.
Consider Using LAMN When…
•Cannot determine where lesion is in appendiceal wall
• Fibrosis, atrophy, dilatation, loss of mural elements
•Diverticulum-like protrusions lined by neoplastic
epithelium
•Mucinous neoplasm with mural mucin, or mucin in
mesoappendix
•Any neoplastic epithelium beyond the mucosa
•Generally a good idea to make a comment explaining
rationale for diagnosis
When Should I Use Mucinous
Adenocarcinoma in the Appendix?
Appendiceal Mucinous Neoplasms
Classification of High-Grade Lesions
•Some cases show high-grade
architectural and cytologic atypia
•Almost all high-grade luminal
lesions associated with carcinoma
•High-grade appendiceal mucinous
neoplasm (HAMN)
•Reserved for cases with mural
changes typical of LAMN, not just
cancer in an appendix
Well differentiated mucinous adenocarcinoma of the appendix
Infiltrative pattern, not “pushing” invasion
Mucinous adenocarcinoma of the appendix, well differentiated
Mucinous adenocarcinoma of the appendix (not HAMN)
Mucinous adenocarcinoma, moderately differentiated (not HAMN)
Mucinous adenocarcinoma, poorly differentiated (not HAMN)
Mimics of Mucinous Neoplasia
Case 3
•51-year-old woman with ulcerative colitis and
primary sclerosing cholangitis presented with
right lower quadrant pain
•Imaging revealed thickened appendiceal wall and
peri-appendiceal fluid suggesting appendicitis
•Symptoms resolved with antibiotic therapy
•Imaging one-year later revealed a 1 cm cyst
•Underwent appendectomy
Ruptured appendix with peri-appendiceal mucin
Villiform and undulating mucinous epithelium
Lamina propria with scattered crypts that contain Paneth cells
What is this and what does it
mean for the patient?
•Ruptured mucinous neoplasm (LAMN)
•Risk for peritoneal dissemination
•Surveillance for a really long time
•Patient anxiety
•Something non-neoplastic
•No risk for peritoneal dissemination
•No need for surveillance
•Patient relief
Low-grade appendiceal mucinous neoplasm with extra-appendiceal mucin
Neoplasm in the lumen
Diverticulum-like protrusion of mucin
Low-grade appendiceal mucinous neoplasm
Copious cytoplasmic mucin, mostly not goblet cell configuration
Atrophy and fibrosis of lamina propria
Mimics of Mucinous Neoplasia
•Endometriosis
•Diverticulosis
•Post-inflammatory mucosal hyperplasia
Endometriosis mimics mucinous neoplasia
Courtesy Dr. Joseph Misdraji, Massachusetts General Hospital
Endometriosis with mucinous metaplasia
Courtesy Dr. Joseph Misdraji, Massachusetts General Hospital
Endometriosis mimics mucinous neoplasia
Cellular stroma
Courtesy Dr. Joseph Misdraji, Massachusetts General Hospital
Cellular stroma
Endometriotic glands become dilated and mucin-filled
Mucin accumulation associated with decidualized stroma
Mucin accumulation associated with decidualized stroma
Clue to non-neoplastic diagnosis: Appendix lacks mucinous neoplasia in lumen
Diverticulosis
•Extra-appendiceal mucin is scant,
localized
•Associated with apparent diverticula (also
lined by non-neoplastic epithelium)
•Lamina propria and crypts
Abundant lamina propria
Decreased lymphoid tissue
Diverticulosis Attenuated lamina propria
Appendiceal diverticula
Mucosal hyperplasia
Diverticulum
Clue: lamina propria and crypts in a diverticulum
Mucosal hyperplasia
Scattered crypts
Abundant lamina propria
Intact muscularis mucosae
Post-inflammatory Mucosal
Hyperplasia
•Delayed appendectomy increasingly
common
•Especially true among stable patients with
walled-off perforated appendicitis
•Surgery can occur weeks to years after
symptom onset
•Organizating inflammation accompanied
by mucosal regeneration and hyperplasia
Post-inflammatory mucosal hyperplasia
Goblet cells
Lots of lamina propria
Post-inflammatory mucosal hyperplasia
Mucosal hyperplasia with abundant mucin
Lots of crypts and lamina propria
Post-inflammatory mucosal hyperplasia
Endocrine cells, Paneth cells, goblet cells
Post-inflammatory mucosal hyperplasia
Mucinous neoplasm Mucosal hyperplasia
Mucinous neoplasm Mucosal hyperplasia
Mucinous neoplasm Mucosal hyperplasia
Back to case
Not really papillary or villous
Lots of well-formed goblet cells
Tangential sectioning of mucosal hyperplasia (no fibrovascular cores)
Lamina propria with scattered crypts that contain Paneth cells
Diagnosis: Post-inflammatory mucosal hyperplasia
Mimics of Mucinous Neoplasia
Quick Summary
•Mucinous epithelium is in the wall but
not the lumen
•Dealing with interval appendectomy
specimens
•Crypts supported by lamina propria are
present
•Muscularis mucosae is of normal
thickness
Appendiceal Mucinous Lesions
Take Home Points
•Strictly defined adenoma pursues benign course
•We can learn to recognize it again and we should
•Neoplastic epithelium beyond muscularis
mucosae has risk
•Cytology and architecture: LAMN, HAMN, or carcinoma
•Movement to classify all mucinous neoplasms as
potentially malignant (LAMN or HAMN)
•Avoid over-interpreting non-neoplastic lesions
