New Classifications of Appendiceal Tumors and Understanding The Connection Between Appendix and Ovary: The Pathologist's View

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1 New Classifications of Appendiceal Tumors and Understanding The Connection Between Appendix and Ovary: The Pathologist's View Christopher Otis, MD Director, Surgical Pathology Baystate Medical Center Springfield, Massachusetts Leslie H. Sobin, MD Co-Chair, TNM Project International Union Against Cancer Geneva, Switzerland The American Cancer Society has provided financial support for the development and presentation of this webinar. The information provided does not necessarily represent the views of the American Cancer Society, Society staff or its Board of Directors. ACCREDITATION The American College of Surgeons is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. CME CREDIT The American College of Surgeons designates this educational activity for a maximum of 1 AMA PRA Category 1 Credits. Physicians should only claim credit commensurate with the extent of their participation in the activity. FACULTY DISCLOSURE The presenter of this activity has nothing to disclose. Overview Identify the new classification for appendix No longer a part of the colon chapter Includes carcinomas and carcinoid Understand the relationship between appendix and ovary Discuss the rationale for the changes Review prognostic factors

2 Appendix Carcinoma & Carcinoid Appendix WHO Classification Carcinomas (2010) Adenocarcinoma 8140/3 Mucinous adenocarcinoma 8480/3 Low-grade appendiceal mucinous neoplasm 8480/1* Signet ring cell carcinoma 8490/3 Undifferentiated carcinoma 8020/3 Appendix Mucinous Carcinomas Mucinous appendiceal carcinoma Has better prognosis than nonmucinous especially if well differentiated Mucinous carcinoma limited to the RLQ Has better prognosis than those spread beyond RLQ Surface spread is amenable to debulking surgery

3 Appendix 7th Edition Carcinoma (part of colon classification in TNM 6) Colon - Rectum T4 Tumor directly invades other organs or structures and/or perforates visceral peritoneum T4a perforates visceral peritoneum T4b directly invades other organs or structures M1 Distant metastasis M1a one organ M1b > one organ or peritoneum Appendix - Carcinoma: Separate mucinous from nonmucinous T4a Perforates visceral peritoneum / Mucinous peritoneal tumor within right lower quadrant T4b Other organs or structures M1a Intraperitoneal metastasis beyond RLQ M1b Non-peritoneal metastasis Differs from colon Appendix 7th Edition Carcinoid Carcinoma T1 < 2 cm: 1a <1cm; 1b >1-2cm T2 > 2 4 cm; cecum T3 > 4 cm; ileum T4 Perforates peritoneum; other organs, structures N1 Regional Stage I T1 N0 M0 Stage II T2, T3 N0 M0 Stage III T4 N0 M0 Any T N1 M0 Stage IV Any T Any N M1 Based mainly on size T1 Submucosa T2 Muscularis propria T3 Subserosa, mesentery T4a Perforates visceral peritoneum / Mucinous peritoneal tumor within right lower quadrant T4b Other organs or structures N1 < 3 regional N2 > 3 regional M1a Intraperitoneal metastasis beyond right lower quadrant M1b Non-peritoneal metastasis Like colon, based on depth; includes goblet cell carcinoid No subdivision of N1, N2 Different subdivision of M1 Appendix WHO Classification Neuroendocrine Neoplasms (2010) Neuroendocrine tumor (NET): Mixed NET G1 (carcinoid) 8240/3 adenoneuroendocrine NET G2 8249/3 carcinoma 8244/3 Neuroendocrine carcinoma EC cell, serotoninproducing NET 8241/3 (NEC) 8246/3 Large cell NEC 8013/3 Goblet cell carcinoid 8243/3 Small cell NEC 8041/3 L cell, Glucagon-like peptide/pp/pyy-producing NETs 8152/1* Tubular carcinoid 8245/1

4 Staging: Carcinoids and Neuroendocrine Tumors GI tract: Carcinoid : separate staging by site Small cell/large cell: stage as carcinoma Pancreas: stage as carcinoma Lung: stage as carcinoma Skin: separate classification for Merkel cell carcinoma Terminology Problems: Carcinoids and Neuroendocrine Tumors NET vs Carcinoid NET cannot easily stand alone Needs distinguishing between Classical carcinoid (WD, NET; NET G1) Atypical carcinoid (NET G2; well differentiated neuroendocrine carcinoma) Neuroendocrine carcinoma refers to both Small cell and Large cell neuroendocrine carcinoma (PD NEC) Carcinoids (NET) 7th Edition Gastrointestinal Appendix T1 < 2 cm T2 > 2 4 cm; cecum T3 > 4 cm; ileum T4 Perforates peritoneum; adjacent structures Stomach Tis < 0.5 mm confined to mucosa T1 Lam propria or submucosa & < 1cm T2 Muscularis propria or > 1 cm T3 Subserosa T4 Perforates serosa; adjacent structures Small Intestine T1 Lam propria/ submucosa and < 1 cm Large Intestine T2 Muscularis propria or > 1 cm T1 Lam propria or submucosa or < 2cm T3 Jejunal, ileal: subserosa T1a < 1 cm; T1b 1 to 2 cm Ampullary, duodenal: pancreas or T2 Muscularis propria or >2 cm retroperitoneum T3 Subserosa, or pericolorectal tissues T4 Perforates serosa; adjacent T4 Perforates serosa; adjacent structures structures

5 Appendix: Carcinoid, Chromogranin Unlike carcinomas, small appendiceal carcinoids can be deeply invasive in the wall without lymph node metastasis Carcinoids (NET) 7th Edition Stage Groups Carcinoid: Appendix Stage I T1 N0 M0 Stage II T2, T3 N0 M0 Stage III T4 N0 M0 Any T N1 M0 Stage IV Any T Any N M1 Carcinoid: other GI sites Stage I T1 N0 M0 Stage IIA T2 N0 M0 IIB T3 N0 M0 Stage IIIA T4 N0 M0 IIIB Any T N1 M0 Stage IV Any T Any N M1 Very similar Appendix Carcinoids / Neuroendocrine Tumors ENETS T1 <1 cm; invasion of muscularis propria T2 <2 cm and <3mm invasion of subserosa/mesoappendix AJCC/UICC TNM T1 < 2 cm T1a <1 cm T1b >1-2 cm T2 >2-4 cm or extension to cecum T3 >2 cm or > 3mm invasion of subserosa/mesoappendix T3 >4 cm or extension to ileum T4 perforates peritoneum or invades other adjacent organs T4 perforates peritoneum or invades other adjacent organs

6 Appendix Carcinoids / Neuroendocrine Tumors - ENETS T1 <1 cm; invasion of muscularis propria T2 <2 cm and <3mm invasion of subserosa/mesoappendix T3 >2 cm or >3mm invasion of subserosa/mesoappendix T4 perforates peritoneum or invades other adjacent organs Critique Tumor size appears more important than depth of invasion for appendiceal carcinoids Mesoappendiceal invasion is of questionable significance; it would require precise measurement Appendix Carcinoids / Neuroendocrine Tumors Appendiceal (and pancreatic) NETs in AJCC/UICC TNM 7, have site specific classifications that differ with those proposed by the European Neuroendocrine Society. The European and the AJCC/UICC TNM GI neuroendocrine classifications represent consensus proposals rather than being strictly evidence-based. It is recommended that they be tested and compared for applicability (precision) and clinical relevance (accuracy). Rindi G, Kloppel G, Couvelard A, et al. TNM staging of mid and hindgut (neuro)endocrine tumors: A consensus proposal including a grading system. Virchows Arch 2007;451: Appendix Carcinoids / Neuroendocrine Tumors - Prognostic Factors Carcinoid syndrome Typically associated with liver metastasis Elevated serum chromogranin A Considered poor prognostic sign Neural invasion Common in appendiceal carcinoids But doesn t seem to be a critical prognostic factor Histological grading Not carried out for appendiceal carcinoids But 2-10 mitoses/10hpf or necrosis indicates an atypical carcinoid (WD NEC), rare here unlike the lung

7 Appendix Carcinoids / Neuroendocrine Tumors - Prognostic Factors/SSFs Site-Specific Factors (SSFs) Recorded in the medical record by physicians Collected by cancer registrars Serum Chromogranin A Appendix Carcinomas Prognostic Factors/SSFs Site-Specific Factors (SSFs) Recorded in the medical record by physicians Collected by cancer registrars Carcinoembryonic antigen (CEA) CA 19-9 Tumor deposits (TD) Microsatellite instability (MSI) 18q Loss of Heterozygosity (LOH) Appendix: Mucinous Cystadenoma More common than colonic type adenomas

8 Appendix: Mucinous Adenocarcinoma Common in appendix. Often well differentiated, slow growing. Appendix: Carcinoma Ex Adenoma Not as common as the mucinous type Appendix: Goblet Cell Carcinoid A hybrid between carcinoid and carcinoma. Stage as carcinoma.

9 Appendix: Goblet Cell Carcinoid Arises in mucosa from crypt cells Appendix: Goblet Cell Carcinoid Concentric growth makes size difficult to assess for T status Appendix: Goblet Cell Carcinoid Concentric growth makes poorly defined tumor difficult to measure and to identify grossly

10 Appendix: Carcinoid Size is the main criterion for T status of early appendiceal carcinoids CAP Protocols Protocol for the Examination of Specimens from Patients with Carcinoma of the Appendix Protocol applies to all carcinomas including goblet cell carcinoid tumors Protocol for the Examination of Specimens from Patients with Neuroendocrine Tumors (Carcinoid Tumors) of the Appendix Relationship between Appendix & Ovary

11 Ovary and Appendix Low Grade Mucinous Neoplasm of the Appendix Synonyms: Mucinous cystadenoma of LMP, UMP Ovary and Appendix Low Grade Mucinous Neoplasm of the Appendix Synonyms: Mucinous cystadenoma of LMP, UMP Ovary and Appendix Metastatic Low Grade Mucinous Neoplasm of the Appendix Ovarian metastasis Ovarian surface mucin Pseudomyxoma ovarii

12 Ovary and Appendix Metastatic Low Grade Mucinous Neoplasm of the Appendix Ovarian metastasis Mimics primary mucinous ovarian LMP, intestinal type Tall mucinous epithelium Ovary and Appendix Metastatic Low Grade Mucinous Neoplasm of the Appendix Clues to Metastatic Mucinous Appendiceal Neoplasm to the Ovary History or clinical evidence of appendiceal tumor Ovarian bilaterality Gross tumor on surface of ovary Microscopic surface implants or mucin Colloid pattern of mucin Young, RH. From Krukenberg to Today: The ever present problems posed by metastatic tumors in the ovary. Adv Anat Pathol 2006;13: Pseudomyxoma Peritonei Nearly always indicative of extraovarian primary (most commonly appendiceal primary) Disseminated peritoneal adenomucinosis (DPAM) 84% 5 year survival Peritoneal mucinous carcinomatosis (PMCA) 6.7% 5 year survival Ronnett BM, Zahn CM, Kurman RJ, et al. Am J Surg Pathol. 1995;19:

13 Pseudomyxoma Peritonei Synchronous Appendiceal and Ovarian Mucinous Neoplasms Historically controversial Synchronous appendiceal and ovarian mucinous tumors probably do exist, particularly if the clinical, gross and microscopic features associated with metastasis from the appendix to the ovary are absent Loss of heterozygosity of co-existent appendiceal and ovarian mucinous tumors support the existence of synchronous tumors Chuaqui RF, Zhuang Z, Emmert-Buck MR, et al. Genetic analysis of synchronous mucinous tumors of the ovary and appendix. Hum Pathol. 1996;27: Synchronous Appendiceal and Ovarian Mucinous Neoplasms Appendix Ovary

14 Synchronous Appendiceal and Ovarian Mucinous Neoplasms Appendix Ovary Goblet Cell Carcinoid (of the Appendix) Conflicting literature concerning biologic behavior (likely a function of definition and low case numbers) Goblet cell carcinoid (GCC) tumors of the appendix have a mixed phenotype, with partial neuroendocrine differentiation and intestinal type goblet cell morphology Tang LH, Shia J, Soslow RA, et al. Pathologic classification and clinical behavior of the spectrum of goblet cell carcinoid tumors of the appendix. Am J Surg Pathol. 2008;32: Goblet Cell Carcinoid (of the Appendix) Spectrum of biologic behavior related to grade Classic GCC (100% 5 year survival) Adenocarcinoma ex GCC (signet ring cell carcinoma with neuroendocrine differentiation) Signet ring cell type (38% 5 year survival) Poorly differentiated (0% 5 year survival) adenocarcinoma type Tang LH, Shia J, Soslow RA, et al. Pathologic classification and clinical behavior of the spectrum of goblet cell carcinoid tumors of the appendix. Am J Surg Pathol. 2008;32:

15 Goblet Cell Carcinoid (of the Appendix) Adenocarcinoma ex GCC Goblet Cell Carcinoid (of the Appendix) Adenocarcinoma ex GCC Synaptophysin IHC Chromogranin IHC Goblet Cell Carcinoid (of the Appendix) Adenocarcinoma ex GCC Metastatic to the Ovary

16 Goblet Cell Carcinoid (of the Appendix) Adenocarcinoma ex GCC Metastatic to the Ovary Frozen section of ovary Goblet Cell Carcinoid (of the Appendix) Adenocarcinoma ex GCC Metastatic to the Ovary Resemblance to Sertoli Cell Tumor Goblet Cell Carcinoid (of the Appendix) Adenocarcinoma ex GCC Metastatic to the Ovary Ovarian stromal hyperplasia

17 Goblet Cell Carcinoid (of the Appendix) Adenocarcinoma ex GCC Metastatic to the Ovary Frozen section of the appendix Goblet Cell Carcinoid (of the Appendix) Adenocarcinoma ex GCC Metastatic to the Ovary Clinical presentation usually related to ovarian symptoms including effects of ovarian stromal proliferation Differential diagnosis for primary: Gastric, Intestines (colorectal), Breast, Biliary system, Appendix (perhaps underestimated due to occult nature/small size) Gross features: Bilateral, solid, lobulated, fleshy, rarely cystic (microcystic) Histologic features: Signet ring cells, small gland formation, tubule-like arrangement, stromal hyperplasia Look a-likes: Sertoli-Leydig Cell Tumor, Fibroma, Sclerosing Stromal Tumor, Clear Cell Carcinoma Young, RH. From Krukenberg to Today: The ever present problems posed by metastatic tumors in the ovary. Adv Anat Pathol 2006;13: Summary Separate classification for appendiceal carcinomas New classification for appendiceal carcinoids Addition of prognostic factors collected by cancer registrars

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