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An Update on the Diagnosis, Grading, and Staging of Appendiceal Mucinous NeoplasmsReet Pai, MD University of Pittsburgh Medical Center

Session OutlineTopic 1: Classification and Staging of Low-Grade

Appendiceal Mucinous Neoplasm (LAMN)• Peritoneal Surface Oncology Group International

(PSOGI) Classification Proposal• AJCC 8th Edition Staging Update

Topic 2: Classification and Grading of Mucinous Adenocarcinoma• PSOGI and AJCC 8th Edition Terminology and

Grading Schemes• Challenges in Classifying Peritoneal Disease

Disclosure of Relevant Financial Relationships

USCAP requires that all planners (Education Committee) in a position to 

influence or control the content of CME disclose any relevant financial 

relationship WITH COMMERCIAL INTERESTS which they or their 

spouse/partner have, or have had, within the past 12 months, which relates to 

the content of this educational activity and creates a conflict of interest. 

Disclosure of Relevant Financial Relationships

USCAP requires that all faculty in a position to

influence or control the content of CME disclose any relevant financial

relationship WITH COMMERCIAL INTERESTS which they or their

spouse/partner have, or have had, within the past 12 months, which relates to

the content of this educational activity and creates a conflict of interest.

Dr. Pai declares he has no conflict of interest to disclose.

The Problem of Terminology• Peritoneal Surface Oncology Group International (PSOGI;

“peritoneal group”) recognized a persistent lack of uniformdiagnostic terminology in appendiceal mucinous neoplasia.

• An international working group of 71 participants (surgicalpathology, surgical oncology, medical oncology) onappendiceal mucinous neoplasia led by Dr. Norman Carr ofNorth Hampshire Hospital and University HospitalSouthampton in the UK.

• Adopted a consensus on diagnostic terminology published inthe American Journal of Surgical Pathology in 2016.

No. of Responses

Confined to mucosa

Dissecting Mucin

Pushing invasion Infiltrative Invasive Signet Ring Cells

11 ? Low‐grade mucinous neoplasm (LAMN)

Mucinous adenocarcinoma

5 Adenoma Low‐grade mucinous neoplasm (LAMN)

Mucinous adenocarcinoma

8 ? ? Low‐grade mucinous adenocarcinoma

High‐grade mucinous adenocarcinoma

High‐grade mucinous adenocarcinoma with 

signet ring cells

6 ? ? Low‐grade mucinous adenocarcinoma

High‐grade mucinous adenocarcinoma

2 Adenoma Adenocarcinoma

Classifications used by participants prior to PSOGI consensus proposal.

The Problem of Terminology

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Neoplasms without infiltrative invasion– Low‐grade appendiceal mucinous neoplasm 

(LAMN)

–High‐grade appendiceal mucinous neoplasm (HAMN) (new diagnostic category; rare)

– Serrated polyp with or without dysplasia–Conventional adenoma, resembling colorectal type (rare)

Carr N et al. Am J Surg Pathol 2016;40:14.

PSOGI Diagnostic Terminology for Primary Appendiceal Neoplasms

Neoplasms with infiltrative invasion– Mucinous adenocarcinoma 

– Mucinous adenocarcinoma with signet ring cells  (≤50% signet ring cells)

– Mucinous signet ring cell carcinoma (>50% signet ring cells)

– Non‐mucinous adenocarcinomaCarr N et al. Am J Surg Pathol 2016;40:14.

PSOGI Diagnostic Terminology for Primary Appendiceal Neoplasms

Definition of LAMN (PSOGI)• Mucinous neoplasm with low-grade cytology and

any of the following:• Loss of lamina propria and muscularis mucosae• Fibrosis of submucosa• Undulating, flattened, or villous epithelial growth• “Pushing invasion” (expansile or diverticulum like growth)• Dissection of acellular mucin in the wall• Mucin and/or neoplastic cells outside of the appendix

• Use of the term “mucinous adenoma” was not supported by the majority of the group.

LAMN: Loss of lamina propria and muscularis mucosae with submucosal fibrosis

Flattened Epithelium Undulating growth

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LAMN: Diverticulum-like growth LAMN: Acellular Mucin on Visceral Peritoneal Surface

High-Grade Appendiceal Mucinous Neoplasm (HAMN, New diagnostic category)

• Mucinous neoplasm with high-grade cytologic features but without infiltrative invasion.

• This includes cases where the high-grade cytology is focal.

• Very rare neoplasm – must entirely submit the appendix to evaluate for invasion and for cellular deposits on the appendiceal serosa.

1. Misdraji J, et al. Am J Surg Pathol 2003; 27:1103.2. Pai RK, et al. Am J Surg Pathol 2009;33: 1425.

• Two-thirds of patients with high-grade cytology without invasion in the primary appendix developed recurrent adenocarcinoma in the peritoneum (including all of the cases reported in the literature, none of the cases had the entire appendix submitted).

High-Grade Appendiceal Mucinous Neoplasm (HAMN)Low-power features of LAMN

HAMN: High-Grade Cytologic Features Mimics of Appendiceal Mucinous Neoplasms

• Appendiceal serrated polyps

• Ruptured Appendiceal Diverticula

• Endometriosis with intestinal metaplasia

• Acute appendicitis with mucosal hyperplasia

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Serrated Polyp without Dysplasia Serrated Polyp w/ Low-Grade Dysplasia (Resembling a Traditional Serrated Adenoma)

LAMN:  Should it be staged?• PSOGI Participants:

39 of 60 (65%) respondents within the group responded “Yes”.

• When staging LAMN, do you stage neoplastic epithelium, mucin, or both?

• The AJCC 8th edition provides some clarification.

LAMN: AJCC 8th Edition• Tis (LAMN): LAMN confined to the

muscularis propria. Mucin or mucinous epithelium may extend into the muscularis propria.

• T1 and T2 categories are not applicable to LAMN.

pTis (LAMN): Pushing into muscularis propria

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AJCC 8th Edition: pTis (LAMN)• Requires that the entire appendix be

submitted for histologic examination.

• Literature evidence indicates that patients with pTis(LAMN) do not develop tumor recurrence and are essentially cured by appendectomy.

• However, this requires correlation with intraoperative findings.

LAMN: AJCC 8th EditionT Category Description

T3 Tumor* extends through the muscularis propria into the subserosa or mesoappendix.

*For T3 category, “tumor” is not explicitly defined, but elsewhere in the chapter, acellular mucin in subserosa / mesoappendix is also designated as T3.

T4a Tumor penetrates the visceral peritoneum, includingacellular mucin or mucinous epithelium involving the serosa of the appendix or mesoappendix.

T4b Tumor directly involves adjacent organs or structures, including acellular mucin or mucinous epithelium (does not include luminal or mural spread into adjacent cecum).

Acellular mucin in subserosa (pT3) pT4a LAMN Due to Acellular Mucin

pT4a LAMN Due to Acellular Mucin• Low risk of peritoneal recurrence:

Of the cases reported in the literature, ~3% (2 of 58 patients) have developed peritoneal recurrence.

• Potential for over-staging: acellular mucin may be seen on the serosal surface due to “carry-over” related to specimen handling.

1. Yantiss RK, et al. Am J Surg Pathol 2009; 33:248.2. Pai RK, et al. Am J Surg Pathol 2009;33: 1425.

Mucin on visceral peritoneal surface due to “carry-over” from sectioning

Potential for over‐staging LAMN, as sectioning can “carry‐over” mucin onto the serosa.

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Mucin on visceral peritoneal surface with inflammatory reaction and neovascularization pT4a LAMN Due to Cellular Mucin

pT4a LAMN Due to Cellular Mucin

• High risk for peritoneal recurrence:

Of the cases reported in the literature, ~36% (5 of 14 patients) have developed peritoneal recurrence.

1. Yantiss RK, et al. Am J Surg Pathol 2009; 33:248.2. Pai RK, et al. Am J Surg Pathol 2009;33: 1425.

LAMN: AJCC 8th EditionM Category Description

M1a Intraperitoneal acellular mucin without identifiable tumor cells.

M1bIntraperitoneal metastasis only, including peritoneal cellular mucinous deposits.

M1c Metastasis to sites other than the peritoneum.

Acellular Intraperitoneal Mucinous Disease (M1a)

1. Young RH et al. Am J Surg Pathol 1991;15:4152. Pai RK et al. Am J Surg Pathol 2009;33:1425 3. Davison J et al. Mod Pathol 2014;40:14.

Young et al. 1991: 5 patients with 1 patient developing recurrence 18 years after presentation.

Pai et al. 2009: 2 patients with no patients developing recurrent disease (follow-up 163 and 206 months).

Davison et al. 2014: 5 patients with no patients developing recurrent disease (median follow-up 32 months).

• Suggests that patients with acellular mucinous peritoneal disease have a decreased risk of recurrence compared with patients with cellular disease.

Session OutlineTopic 1: Classification and Staging of Low-Grade

Appendiceal Mucinous Neoplasm• Peritoneal Surface Oncology Group International

(PSOGI) Classification Proposal• AJCC 8th Edition Staging Update

Topic 2: Classification and Grading of Mucinous Adenocarcinoma• PSOGI and AJCC 8th Edition Terminology and

Grading Schemes• Challenges in Classifying Peritoneal Disease

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Mucinous Adenocarcinoma• Defined by infiltrative destructive invasion

• High-grade cytologic features typically present and may show a mix of both low and high cytologic grade.

• PSOGI and the AJCC 8th edition advocate a three-tier grading of mucinous neoplasia based mostly on literature evaluating outcome in patients with stage IV peritoneal disease.

Asare EA et al. Cancer 2016;122:213.

National Cancer Database (NCDB): 5971 patients classified as having primary appendiceal neoplasms with mucinous histology. No pathology re-review performed and criteria for grading not explicitly discussed.

Well-differentiated

Moderately-differentiated

Poorly-differentiated

Three-Tiered Grading in Appendiceal Mucinous Neoplasia (Stage IV)

Three-Tiered Grading in Appendiceal Mucinous Neoplasia (Stage IV)

p<0.0001

1. Davison J et al. Mod Pathol 2014;40:14.2. Shetty S et al. Am Surg 2013;79:1171.

G1 / PMP1 = Low-grade peritoneal diseaseG2 / PMP2 = High-grade peritoneal disease without signet ring cellsG3 / PMP3 = High-grade peritoneal disease with signet ring cells

n=219 n=211

AJCC Grade for Primary and

Intraperitoneal Disease

PSOGI Grade for Intraperitoneal

Disease

Characteristics

G1, well differentiated Low-gradeLow cytologic grade & no infiltrative invasion

G2, moderately differentiated

High-gradeHigh cytologic grade

without signet ring cells

G3, poorly differentiatedHigh-grade with signet

ring cellsHigh cytologic grade with signet ring cells

AJCC 8th Edition and PSOGI Grading

AJCC grades G2 and G3 are considered high-grade.

Two-Tiers: Therapeutic Decision Making

Two-Tier versus Three-Tier Grading Schemes: Which is Better?

• Patients with high-grade (G2 and G3) peritoneal disease are often treated with systemic chemotherapy with the option of CRS-HIPEC at some institutions. The role of CRS-HIPEC is not entirely well-delineated although is used aggressively at many institutions with evidence of survival benefit.

• Patients with low-grade (G1) peritoneal disease benefit from cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) with no benefit from systemic chemotherapy.

Prognostic Groups (10-yr overall survival, Stage IV)G1 / PMP1 / Well-differentiated: ~50% G2 / PMP2 / Mod-differentiated: ~30%G3 / PMP3 / Poorly-differentiated: ~10-20%

Molecular Features G1 G2 G3 p- value

KRAS mutation 61% 72% 19% <0.001

BRAF mutation 0% 0% 0% NS

GNAS mutation 35% 37% 13% 0.2

Molecular Differences between Groups

1. Davison J et al. Mod Pathol 2014;40:14.2. Singhi A et al. Hum Pathol 2014;45:1737.

Two-Tier versus Three-Tier Grading Schemes: Which is Better?

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Moderately Differentiated (G2) Mucinous Adenocarcinoma Moderately Differentiated (G2) Mucinous Adenocarcinoma

Moderately Differentiated (G2) Mucinous Adenocarcinoma Moderately Differentiated (G2) Mucinous Adenocarcinoma

Poorly Differentiated (G3) Mucinous Signet Ring Cell Carcinoma

Poorly Differentiated (G3) Mucinous Signet Ring Cell Carcinoma

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Poorly Differentiated (G3) Mucinous Signet Ring Cell Carcinoma AJCC: The Problem of Terminology

• Throughout the AJCC 8th edition chapter the terms “well-differentiated mucinous adenocarcinoma” and “low-grade appendiceal mucinous neoplasm” are used interchangeably.

• In the section on histologic grading, the AJCC states “G1 mucinous tumors with peritoneal involvement may be categorized as LAMN with peritoneal involvement”.

PSOGI: The Problem of Terminology

• A principle endorsed by PSOGI is that the classification of the primary appendiceal tumor is different than the peritoneal disease.

• This approach necessitates using different names for the appendiceal primary and the peritoneal disease, which can result in some confusion.

PSOGI Terminology for Primary Neoplasm

PSOGI Terminology for Peritoneal Disease

AJCC Terminology for Primary & Peritoneal Disease

Low-grade appendiceal mucinous neoplasm

Low-grade mucinous carcinoma peritonei

Low-grade appendiceal mucinous neoplasm (G1)

• My approach: I use the term “low‐grade appendiceal mucinous neoplasm” for both the primary and peritoneal neoplasm.

AJCC vs. PSOGI: Terminology for Low‐Grade Primary & Peritoneal Disease 

• Exception:  Discordant grades between the primary and peritoneal disease do exist and complicate classification.

Discordant Grades between Primary & Peritoneal Disease• Discordant grading between primary and peritoneal disease

does occur.• AJCC 8th edition not clear what overall grade to assign, but most PSOGI

participants agreed that the grade of the peritoneal disease more likely influences prognosis and should be used for staging purposes.

• Scenario #1:• Primary: Low-grade appendiceal mucinous neoplasm (G1)• Peritoneum: Mucinous adenocarcinoma, moderately differentiated (G2)• Overall grade should be assigned as G2.

• Scenario #2:• Primary: Focal high-grade cytology in o/w low-grade neoplasm• Peritoneum: Low-grade (G1)• Overall grade should be assigned as G1.

• PSOGI did not provide specific histologic criteria for distinguishing low-grade from high-grade cytology.

• “Grey zone” cases that straddle between grades.

Low (G1) High (G2)

Distinguishing Low- and High- Grade Cytology within Peritoneal Disease

Grey Zone High (G3)

Grey Zone

Cytoarchitectural atypia

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• Criteria for high-grade cytology that I use are the same as for the rest of the luminal GI tract:– Nuclear enlargement and rounding of the nuclei

– Nuclear hyperchromasia

– Irregular chromatin

– Macronucleoli

– Increased mitotic activity

– Loss of nuclear polarity

Distinguishing Low- and High- Grade Cytology within Peritoneal Disease

Low-Grade (G1) High-Grade (G2)High-Grade (G2)

Grade Heterogeneity

Grade Heterogeneity

Moderately Differentiated (G2) Mucinous Adenocarcinoma: Additional Features• High cellularity at low-power (2x objective)

magnification (seen in most of cases).

• Destructive, infiltrative stromal and/or organ invasion.– “Small cellular mucin pool” pattern of invasion is common.

• Lymph node metastases in ~20% of cases.

Low-grade (G1) Peritoneal Disease

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Moderately Differentiated (G2) Mucinous Adenocarcinoma “Small Cellular Mucin Pool” Pattern of Invasion

Moderately Differentiated (G2) Mucinous Adenocarcinoma 

Moderately Differentiated (G2) Mucinous Adenocarcinoma Infiltrating Glands

Moderately Differentiated (G2) Mucinous Adenocarcinoma Cribriform Growth

Isolated Glands in Stroma (Not infiltrative invasion)Best classified as Low-Grade (G1, well-differentiated)

Pushing, Not Infiltrative Invasion, Best Classified as Low‐Grade (G1, well‐differentiated)

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Challenges in Peritoneal Disease

• Predominantly low-grade (G1) disease but with a:

• Focal area of increased cytologic atypia.

• Focal area of questionable infiltrative invasion.

• Signet ring cells versus cellular degeneration imparting a signet ring-like morphology.

Predominantly low‐grade (G1) with area of increased atypiaMicroscopic area with increased cytologic atypia

Distinguishing Between Grade G2 and Grade G3 in Mucinous Neoplasia• In general, G3 tumors are defined by the presence of

signet ring cells.

• How many signet ring cells are required to classify a lesion as G3?

• Is there a difference between signet ring cells floating within mucin and infiltrating signet ring cells?

Floating Signet Ring Cells Infiltrating Signet Ring Cells

Degenerative changes imparting signet ring‐like morphology (we do not classify these as signet ring cells) Sirintrapun SJ et al. Hum Pathol 2014;45:1597.

• “Signet ring cells” with degenerative changes floating in mucin pools (in most cases these cells comprised less than 5% of the tumor burden).

• Patients with degenerative cells with signet ring‐like morphology had significantly  better overall survival compared to those with infiltrating signet ring cells.

• Degenerative changes imparting signet ring‐like morphology ≠ G3 grade.

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Conclusions• PSOGI provided diagnostic criteria for LAMN and the AJCC 8th

edition clarified staging of LAMN.

• Both the AJCC and PSOGI emphasize the importance of distinguishing between low-grade and high-grade disease and advocate for a three-tier grading scheme.

• Distinguishing between grades in peritoneal disease can be challenging. Discordant grading between primary and peritoneal disease exists. “Grey zone” cases likely affect reproducibility of grading peritoneal disease.

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No claims can be processed after that date!

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