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Krukenberg Tumors & Pseudomyxoma Peritonei

Seoul National University Hospital

Soon Beom Kang, MD, PhD Yun Hwan Kim, MD, PhD International APOCP Congress / Bridging Continents for Cancer Control in Istanbul"

Case I

· · · · 45y/o, female Slightly distended abdomen History: LAR for rectal cancer Work-up · Labs.

Carcinoembryonic antigen[CEA] 23ng/mL: elevated Other tumor markers (CA125, CA19-9, CA72-4, AFP): within normal limits

Case I

· Pelvis CT: a tumor in right ovary

(12x7cm in size)

· Treatments

· TAH with BSO · Ascites cytology

negative for malignancy

Case I

· Solid mass showing signet ring cells within a hypercellular ovarian stroma (a), Adjacent with hypocellular edematous regions (b).

Case I

· Further evaluation after operation

· GFS: a 3 x 2 cm-sized ulcero-fungated lesion in the lower body of the stomach. · Biopsy: signet ring cell carcinoma · Colonoscopy: WNL

· Further treatments

· Total gastrectomy with regional lymph node dissection

diagnosis: AGC, signet ring cell type, stage IV.

· Methotrexate(MTX)/5-fluorouracil(5-FU)

Krukenberg tumors - definition

Metastatic signet ring cell adenocarcinoma of the ovary Primary sites

· Stomach (70%) · Colon, appendix, breast (mainly invasive lobular carcinoma) · Others (gallbladder, biliary tract, pancreas, small intestine, ampulla of Vater, cervix, urinary bladder)

Krukenberg tumors ­ incidence

· Uncommon

· 5% of ovarian cancer · 30-40% of metastatic cancers to the ovaries · Varies with the incidence of gastric carcinoma

Japan (high prevalence of gastric carcinoma)-17.8% of all ovarian cancers

· Women with an average age of 45 years.

· Young age of distribution ­ related to the increased frequency of gastric signet ring cell carcinomas in young women.

Krukenberg tumors symptoms

· · · · · Abdominal pain and distension Nonspecific gastrointestinal symptoms Vaginal bleeding or change in menstrual habits Asymptomatic Virilization (hormone production by ovarian stroma) · Ascites (about 50% of the cases)

Krukenberg tumors -pathogenesis

· Stomach-ovarian axis

· Route of metastasis

: retrograde lymphatic spread, or hematogenous most likely

· Evidences

Peritoneal involvement : usually absent Tumor cells are found within the ovary and not growing inwards Spread of early gastric cancers confined only to the mucosa and submucosa (a rich lymphatic plexus) Risk of ovarian metastasis in gastric cancer when the number of metastatic lymph nodes (+)

Primary tumors -diagnosis

· Diagnosis of the primary carcinoma

· Preoperatively · During the operation for the ovarian metastasis · Within a few months postoperatively Often, the primary tumor is too small to be detected. Careful radiographic (abdominopelvic sonography and CT scans) and endoscopic exploration of the digestive system warranted!

Krukenberg tumors-Image findings

· Bilateral in about 80% · Solid mass occasionally contains thin walled cysts · Round or reniform

Krukenberg tumor- pathologic features

· Gross features

· Usually solid with occasionally cystic · Capsular surface: typically smooth and free of adhesions or peritoneal deposits · Yellow or white sectioned surfaces

Krukenberg tumor- pathologic features

· Microscopic features (2 components)

· Epithelial: mucin-laden signet ring cells with eccentric hyperchromatic nuclei · Stroma: plump and spindle-shaped cells with minimal cytologic atypia (ovarian stromal origin)

Krukenberg tumor- pathologic features

· Immunohistochemical evaluation

­ Immunohistochemisty could help to discriminate the origin of carcinoma. · Primary ovarian carcinomas: CK7+(90-100%)/CK20· Metastatic gastric carcinoma: CK7+ (55%)/CK20+ (70%) · Colorectal adenocarcinomas:CK7-/CK20+

· CK7+/CK20- favors a primary ovarian carcinoma · CK7-/CK20+ or CK7+/CK20+ favors a metastatic gastrointestinal carcinoma

Ronnett BM, et al. Am J Surg Pathol. 1997;21:1144-55.

Krukenberg tumor- Treatment

· No optimal treatment strategy

1. Radical operation? (removal of the ovaries and the colon or appendix if involved)

Pros (if metastasis is limited to the ovaries): Can get the patient free of residual disease and improve survival Cons (if the primary tumor metastasizes to other sites in addition to ovaries): Lower resectability and the overall dismal prognosis

Effect of metastasectomy

DFS

OS

· 34 patinets with Krukenberg tumor from stomach. · Metastasectomy may significantly improve the overall and progression free survival if it could render a complete gross resection.

Cheong JH, et al. J Surgical Oncology. 2004;87:39-45.

Krukenberg tumor- Treatment

2. Chemotherapy or radiotherapy?

No significant effect on prognosis If used before surgery, may shrink the tumor and facilitate its removal

3. Prophylactic oophorectomy?

· Prophylaxis has been considered (bilateral oophorectomy at the time of operation of the primary tumor) esp. in young patients with advanced stage · Need further study and evaluation

McGill FM, et al. Gynecol Obstet Invest. 1999;48:61-5.

Krukenberg tumor- prognosis

· Most patients die within 2 years

median survival 14 months, 5-10% 5-year survival rates

· Prognosis - depending on the timing when the primary

tumor is identified · Poor when the primary tumor is identified after the ovarian metastasis is discovered · Worse when the primary tumor remains covert

Summary ­ Krukenberg tm

· There is no established treatment for Krukenberg tumors. · Metastasectomy with no residual tumor may improve prognosis of patients with Krukenberg tumors. · Prophylatic treatment by oophorectomy at the time of operation of the primary tumor has been considered, but this requires further study and evaluation.

Pseudomyxoma peritonei (PMP)

Case II

· Present illness

· A 54-year-old postmenopausal woman · Chief complaint: abdominal distension (since last 3 months) · CT scan

Case II

· Workup

· CT-guided aspiration of pelvic fluid mucinous adenocarcinoma

· Operative course

· Appendiceal mass · Diffuse, mucinous material in whole abdomen · Cytoreductive surgery including appendectomy, omentectomy, and peritonectomy

Case II

· Pathology: well-differentiated invasive mucinous adenocarcinoma, mucin pools with calcifications

PMP - definition

· Diffuse, intraperitoneal collection of gelatinous fluid with mucinous tumor implants on peritoneal surfaces and omentum. · Mostly, etiology is mucinous tumor of the appendix · Ovarian, pancreatic cancer similar feature

PMP- etiology, epidemiology

· Mostly originating from ruptured low malignant potential mucinous tumors of the appendix. · Mucinous tumors of the ovary have also been implicated. · Rarely associated with mucinous carcinomas of bile ducts, stomach, pancreas, bladder, breast, and lung.

· Epidemiology

· 2-3 times more common in females than males. · Median ages at diagnosis: 51-61 years old. · Present in 2 of every 10,000 laparotomies.

Mann WJ et al. Cancer 1998;66:1636-40.

PMP ­ Classification

· Ronnett et al.

· DPAM (disseminated peritoneal adenomucinosis)

· Abundant extracellular mucin · Little cytologic atypia

· PMCA (peritoneal mucinous carcinomatosis)

· Carcinomatous cytologic feature

· PMCA -I (peritoneal mucinous carcinomatosis intermediate or discordant features)

· Focal area of mucinous carcinoma

Ronnett BM, et al.,Cancer 2001;92:85­91.

PMP - Pathophysiology

· Mucocele rupture

dissemination of mucinproducing tumor cells throughout peritoneal cavity

·

Characteristic and predictable pattern of tumor progression:

1) Gravity

collection of tumor on dependent site (pelvis, retrohepatic space, paracolic gutters, Treitz) accumulation of tumor cells to distinct sites:

Between liver and Rt hemidiaphragm Greater, lesser omentum

Sugarbaker, PA. Histopathology 2001; 39, 525-528.

2) Resorption of peritoneal fluid by lymphatics

PMP ­ clinical features

· Symptoms

· · · · Abdominal or pelvic pain, bloating, distension Digestive disorders Weight changes Infertility

·

Presented with

· Suspected appendicitis (27%) · Increasing abdominal distension (23%) · A new onset hernia (14%)

·

In women, most commonly diagnosed while being evaluated for ovarian mass (39%)

PMP - diagnosis

· CT: Central displacement of the small bowel and compression of retroperitoneal structures

CT scan when the peritoneal cavity is completely filled with PMP.

PMP­ pathologic findings

· Histologically, malignant cells may be scanty. · When found, seen as strip, small group, often with abundant intracellular mucin. · Cytologic dysplasia: typically low grade

Mucinous ascites

PMP ­ treatment

· Variable

· From watchful waiting · To debulking and cytoreductive surgery with/without intra-peritoneal chemotherapy

· For now, cytoreductive surgery(CRS) and perioperative loco-regional chemotherapy(PLC) demonstrate best survival.

· Survival

Complete vs. incomplete cytoreduction (80% vs. 20%) Low-grade vs. high-grade (80% vs. 28%) 5-year (72%) and 10-year (55%)

Gonzalez-Moreno S et al. Br J Surg2004;91:304-11.

Rationale for Complete Cytoreductive Surgery (CRS)

1) 2) 3) 4) Low aggressiveness of tumor; rare LN or liver involvement Small bowel is largely spared (Redistribution phenomenon: due to motility?) Areas of spread are treatable by peritonectomy/omentectomy Regional chemotherapy can attack all surfaces exposed to tumor

Sugarbaker, PA. EJSO 2006; 27: 239-243

Perioperative loco-regional chemotherapy (PLC)

· HIPEC (hyperthermic

intra-peritoneal chemotherapy)

PMP ­ Treatment

· EPIC (early

postoperative intraperitoneal chemotherapy) · Commonly used agents Mitomycin(MMC), cisplatin, 5-FU Usually administered for 30-120 mins.

Brendan M et al. J Surg Oncol. 2008;98:277-82.

PMP ­ Treatment

Advantage of moderate HIPEC

General

Help reversal of systemic hypothermia from long surgery With minimal toxicity for normal tissue (<43 ) Stimulation of host immune system

Manual distribution

Decrease unexposed surface Make mechanical debridement of cancer cells

Enhance the efficacy of chemotherapy

Increased Cytotoxicity of the chemotherapy Increased drug penetration

Sugarbaker PH. Expert Opin Pharmacother. 2009 Aug;10(12):1965-77.

PMP ­ Treatment

Sugarbaker Protocol

· Radical debulking of tumor load:

­ appendix, peritoneum, omentum; ­ additional viscera as indicated ­ Curative therapy : remove all nodules > 2.5 mm

· Intraoperative heated mitomycin (44 °C) · Post-operative 5-FU chemotherapy for 5days

Sugarbaker, PA. Histopathology 2001; 39, 525-528

PMP ­ Treatment

Results

Sugarbaker, PA. EJSO 2001; 27: 239-243

· 385 patients : CRS+HIPEC · 10 yr survival - 80% · Morbidity 27%, mortality 2.7%

­ Pancreatitis, EC fistula

PMP ­ prognosis

· Histology histology DPAM PMCA-I/D PMCA · Survival rate

· Miner et al(2005). 21%(10-year) · Gough et al(1994). 32%(10-year) · Sugarbaker et al(2004). 72%(5-year) and 55%(10-year)

Brendan M et al. J Surg Oncol. 2008;98:277-82.

5-year survival rates (%) 75 50 14

10-year survival rates (%) 68 21 3

Pseudomyxoma peritonei ­ Korean data

Lee JK, Kang SB et al. Int J Gynecol Cancer 2008;18:916-20.

Pseudomyxoma peritonei ­ Korean data

· 35 patients from 11 institutes

­ 25 (71.4%) DPAM ­ 5 (14.3%) PMCA-I ­ 5 (14.3%) PMCA

· 34 (97%) : Cytoreduction + chemotherapy · 5yrSR: 87%

Lee JK, Kang SB et al. Int J Gynecol Cancer 2008;18:916-20.)

Summary ­ Pseudomyxoma peritonei

· Cytoreductive surgery with/without intraperitoneal chemotherapy may be the best treatment strategy for PMP. · Surgery should be performed to remain no or minimal residual tumor by specialized and experienced surgeon.

Thank you for your attention!!

Seoul National University Hospital

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