Pseudomyxoma Peritonei (PMP)

Presented by: Dr Happy Kagathara

16th February, 2013

Dept. of GI surgery and Liver Transplant

Sir Ganga Ram Hospital

• Introduction

• Historical background

• Epidemiology

• Pathology– Origin

– Pathogenesis

– Histology

• Clinical presentation

• Laboratory Tests and Immunohistochemical Markers

• Tumor Assessment– USG

– CT scan

– Peritoneal Cancer Index (PCI)

• Treatment– Traditional surgical management

– Combined modality management

– HIPEC

• Summary

Introduction

• Enigmatic condition

• First described - primary peritoneal disease looking like a myxoma

• Not a real myxoma nor primary peritoneal disease

• Disseminated disease from a primary lesion of one of intra-peritoneal organs

• Sound definition is not available and ongoing discussion around PMP

• Theory 1 (theory of “secretion”)– Consider any condition with gelatinous material (mucinous

ascites) in abdomen and pelvis

– Intra-peritoneal extravasations of mucus secretion of whatever cause

Limber GK, King RE, Silverberg SG. Ann Surg 1973;178:587-93

• Theory 2 (theory of “collection”)– Consider as a clinical syndrome

– Intra-peritoneal collection of gelatinous material and mucinous tumor cells

– Abdominal distension

Historical Background

• First reported by a gynecologist, R. Werth, in 1884– Unusual reaction of the peritoneum to a jelly-like substance

in relation to an ovarian neoplasm.Werth R. Arch Gynaecol Obstet 1884;24:100-18.

• The discussion regarding the etiology emerged in the first quarter of the 20th century

– Naeslund suggested

• Reaction of the peritoneal surface to mucoid material leads to metaplastic changes.

Cheng KK. J Pathol Bacteriol 1949;61:217-25, 4 pl

• Simultaneous occurrence of an appendiceal mucocele and cystadenoma of the ovary with PMP

• At the end of the century new treatment strategy emerged– Combination of extensive surgery with intra-peritoneal

chemotherapySugarbaker PH et al. Dis Colon Rectum 1993;36:323-9

Epidemiology

• Incidence – 1-2/million/year

• Predominance of women - 2 to 3 times

• Found in 2/10,000 laparotomies

• Approximately 10% epithelial appendiceal neoplasm develop PMP

• Increased to 20% in mucinous appendiceal neoplasms

Pathology

• Origin– Appendix, generally mucinous adenoma

– Colon, stomach, pancreas, ovary, and urachus

– The primary tumor consists

• mucinous cystadenoma

• cystadenocarcinoma with low malignant potential

– Debate about origin in concurrent mucinous tumor at appendiceal and ovarian sites

• Immunoreactivity tests

– PMP – +ve for CK18 and CK20 both, -ve for CK7

–Ovarian neoplasms - +ve forCK7

• Ovarian PMP deposits are secondary to a primary mucinous epithelial appendiceal tumor

– “Redistribution phenomenon”

• Gravity accumulates deposits in the pelvis

• Irregular surface of the ovaries and fimbriae act as a stepping stone for PMP tumor cells

Redistribution phenomenon

• Pathogenesis

Appendiceal mucinous neoplasm

Mucus production by tumor cells into the appendiceal lumen 

Obstruction of the appendiceal base by tumor or fecal material 

Intraluminal mucus accumulation

Appendiceal mucocele

Rising intraluminal pressure

Small perforation of the appendiceal wall or blow-out of the mucocele

Slow leak or sudden release of mucus

Free mucinous epithelial tumor cells into the peritoneal cavity 

Tumor cells continue to proliferate

Mucinous ascites production

• Free mucus at different abdominal sites, containing no or few epithelial tumor cells

• This stage is called PMP

• Histology– Previously, terminology applied to both benign and

malignant mucinous appendiceal neoplasms

• Variable and poor prognosis

– Ronnett et al proposed three subtypes

• Different pathological characteristics and prognoses

• Base on broad spectrum of aggressivenessRonnett BM et al. Am J Surg Pathol 1995;19:1390 –1408

– Disseminated peritoneal adenomucinosis (DPAM)

• Low-grade lesion

• Abundant extracellular mucin

• Lack of cytological atypia or mitotic activity

• Usually from mucinous neoplasms of the appendix

• Good prognosis

– Peritoneal mucinous adenocarcinoma (PMCA)

• High-grade metastatic adenocarcinoma

• Abundant mucinous epithelium with architectural and cytologic features of carcinoma

• Derived from the appendix and colon

– Intermediate type PMP (PMCA-I)

• Predominant features of DPAM

• Also focal areas of PMCA

• Prognosis between that of DPAM and PCMA

– Misdraji et al classifies into;

• Low-grade appendiceal mucinous neoplasm (LAMN)

– Papillary or flat mucinous tumors

– Low-grade cytologic atypia

–Analogous to low-grade dysplasia in other parts of the gastrointestinal tract

• High-grade mucinous adenocarcinoma (MACA)

–Destructive invasion of the appendiceal wall

–High-grade cytologic atypia

–Complex epithelial proliferation

–Aggressive clinical course than LAMNMisdraji J et al. Am J Surg Pathol 2003;27:1089 –1103

Clinical PresentationSugarbaker PH et al. Adv Surg 1996;30:233-80

Esquivel J, Sugarbaker PH. Br J Surg 2000;87:1414-8

• 30 to 50% pts - “Jelly belly” (Abdominal distension)

• Intestinal obstruction associated with compressing tumor and ascites

• 50 to 80% pts - local symptoms, reflecting the location of the primary or metastatic tumor– Appendicitis-like symptoms

• 20 to 30% of female pts– Detection of ovarian mass

– Evaluation for lower abdominal pain, a pelvic mass, menstruation problems or infertility

• 1 to 20% pts - coincidently detected on USG or CT scan for whatever reason, at laparotomy, or during hernia repair when mucus is found in the hernia sac

• < 1% pts - presenting with a suspected bladder tumor or right femoral neuropathy

• Interval between the discovery of the primary (appendiceal) tumor and the clinical diagnosis of PMP– Vary significantly

– Approximately 2 yrs

– Up to 20 yrs intervalSmeenk RM et al. Eur J Surg Oncol 2008; 34:196-201

Darnis E et al. J Gynecol Obstet Biol Reprod (Paris) 16:343-53, 1987

Laboratory Tests and Immunohistochemical Markers

• CA-125– Gynecological marker to exclude an ovarian neoplasm

– Not widely used as a tumor marker

– Elevated in benign or inflammatory diseases

– Sensitivity – 60%

• Cytokeratin (CK) 20, CEA, and CDX-2 - +ve in primary tumors of colorectal or appendiceal origin

• CK7 +ve in primary tumors of ovarian origin

• IL-9 +ve in 96% pts

• CEA elevation - 56 to 75% of pts

• CA 19-9 elevation - 58% to 67% of pts

Tumor Assessment

• USG abdomen:– Useful appendiceal mucocele or PMP

– Usually in combination with CT

– Advantages

• Low costs

• Accessibility

• Possibility of immediate FNA Biopsy

–Disappointing

– Inconclusive

• Sparse cellular density of both low and high grade lesions

• CT scan with oral, rectal, and IV contrast– Gold standard diagnostic

– Mucinous ascites

• higher density (5 to 20 HU) compared to normal ascites

– Low attenuation of soft tissue masses

– Rim like calcifications

– Septae

– In earliest stage

• Mucus around the appendix and appendiceal primary neoplasm or mucocele

– Visceral and mesenteric sparing - favorable post-surgery prognosis

– In end-stage disease

• Entanglement of the gastric antrum, lesser omentum, left sub-phrenic region, spleen and rectosigmoid

• Impression of the liver surface – “scalloping of the hepatic margin”

• Displacement/compression of the intestines by the excessive amount of mucus

– Criterias of non-resectibility

• Segmental obstruction of small bowel

• Tumor nodule >5cm diameter on small bowel surface or adjacent to small bowel messentery

Pseudomyxoma peritonei throughout the subdiaphragmatic regions

Peritoneal cavity with mucinous tumor in the pelvis

Small bowel (Red arrow) centralization by compressive effect in disseminated peritoneal adenomucinosis (Green arrow)

• Sugarbaker Peritoneal Cancer Index– Used in decision making process as abdomen is explored

– Size of intra-peritoneal nodules must be assessed

– Lesion Size score (LS) is used

• LS 0 – No visualization of malignant deposits in particular abdomino-pelvic

region

• LS 1 - Nodules <0.5cm

• LS 2 - Nodules 0.5 – 5 cm• LS 3 - Nodules > 5 cm

• Maximum score – 39 (13X3)

– Number of nodules is not scored

– Only size of largest nodule is scored

– Regions – 13

• Abdomino-pelvic regions – 9

• Small bowel regions – 4

• Score <12 – Favorable prognosisBerthet B et al. Eur j Cancer 1999; 35:413-9

– Pitfalls

• Non-invasive malignancy

– Large mass of non-invasive tumor can be completely cytoreduced

– Pseudomyxoma peritonei, grade I sarcoma, minimal invasive peritoneal mesothelioma

– E.g. PCI of 39 for these tumors can be converted to 0 by cytoreduction

• Invasive tumor at crucial anatomic sites

– E.g. Invasive tumor not resectable from CBD cause poor prognosis even with low PCI

–Act as systemic disease in assessing prognosis with invasive cancer.

• Completeness of Cytoreduction (CC) scoring system– Scores

• CC 0 - En bloc resection of tumor mass with clear margins

• CC 1 - Residual implants of < 2.5 mm

• CC 2 - Residual implants of 2.5 to 25 mm

• CC 3 – Residual as implants > 25 mm

– Predictibility

• Morbidity

• Disease-free survival

• Overall survival

Treatment

• Traditional Surgical Treatment– Consists of

• Cytoreductive surgery

• Removal of all mucinous ascites

• ± Additional modalities

– Long-term survival could be achieved by surgery alone

– MSKCC- NY

• Aim – Symptom management

• 97 pts

• Mean of 2.2 de-bulking operations

• Complete cyto-reduction – 54%

• Survival was independently associated with;

– Low-grade pathologic subtype

–Ability to achieve complete cytoreductionMiner TJ et al. Ann Surg 2005; 241:300-8

• Combined Modality Treatment– Introduced in the 1990s by Sugarbaker

– Aims at achieving cure or at least long-term remission

– Aggressive cytoreductive surgery

• Parietal peritonectomy

–Greater omentectomy

– Splenectomy

– Stripping of the left diaphragm and the right diaphragm

–Cholecystectomy

– Lesser omentectomy

–Antrectomy

– Pelvic peritonectomy

–Resection of recto-sigmoid and internal gynecological organs

• Hyperthermic intraperitoneal chemotherapy (HIPEC)

– Mucinous tumor on parietal peritoneum

• Resection by high-power electrocautery with a ball-tipped handpiece on high voltage pure cut

• Possible due to noninvasive behavior of PMP

• Dissected with finger and gauze if involving residual visceral peritoneum on stomach, colon, or small bowel

– Concentration of disease in ileo-cecal region

• Ileo-cecum resection or a right hemicolectomy

• Ileum might be anastomosed or brought out as a ileostomy

– Greater omentectomy

• Ligation of the gastric branches in the (right) gastric arcade

• Contribute blood supply to stomach and left gastric artery not be able to sustain adequate gastric blood flow.

• Results in gastric paresis and postoperative ileus

• Therefore, gastrostomy and a high jejunostomy for gastric emptying and nutrition.

• Hyperthermic intraperitoneal chemotherapy (HIPEC)– Direct delivery into the peritoneal cavity

– Permits high concentrations of drugs directly toward the tumor deposits

– Without important systemic side effects

– Hyperthermia enhance the penetration of cytostatic drugs and synergism with various cytostatic drugs

– Effective only in minimal residual macroscopic disease because of the limited penetration depth of drugs

– Should be performed intra-operatively before anastomoses, to maximize uniform drug distribution and tumor exposure

Los G et al. Cancer Res 1992;52:1252-8

– In h/o prior surgery, adhesiolysis should be performed to prevent nonuniform drug distribution

• All microscopic tumor residue is not eliminated

• Lead to recurrent disease

– Mitomycin as an intraperitoneal drug, either as single drug or in combination

van Ruth S et al. Surg Oncol Clin N Am 2003;12:771-80.

– Also apply post-operative intra-peritoneal chemotherapeutic treatment

– Continuing and further increasing exposure of tumor residue

van Leeuwen BL et al. Ann Surg Oncol 2008; 15:745-53

– Two techniques

• Open

– Small bowel floats in drug solution

• Closed

–No loss of heat or drug

– Entire peritoneum is exposed

–Allow administration of drug under pressure

– Noninvasive, low grade disease eligible for complete cytoreduction

– non-DPAM / high-grade disease excluded if involving 6 to 7 abdominal regions and/or small bowel

– Study by Smeenk and colleagues

• Report on learning curve

• 130 procedures, (133), Time period – 10 yrs

• The rate of complete (R1) cytoreduction increased from 15.4% to 49%

• Overall morbidity and mortality decreased from 68% to 28%

• In-hospital stay decreased from 24 to 17 daysSmeenk RM, Verwaal VJ, Zoetmulder FA. Br J Surg 2007;94:1408-14

– Yan and colleagues analyzed

• 140 consecutive (134) pts

• Compared the initial 70 pts with the subsequent 70 pts.

• Morbidity was reduced from 30% to 10%

• Delayed morbidity was reduced from 29% to 10%

• Independent risk factors for severe adverse events

– Small bowel resection

–Greater than 4 peritonectomy proceduresYan TD et al. Ann Surg Oncol 2007;14:2270-80

– Chemotherapeutic agents • Doxorubicin (15mg/m2)• Melphalan • Mitomycin-C (12mg/m2)• Cisplatin (50mg/m2)• Gemcitabine • Mitoxantrone • Oxaliplatin • Etoposide • Irinotecan • Paclitaxel• Docetaxel • 5-Fuorouracil (500 mg/m2)• Carboplatin

– Carriers of chemotherapeutic agents

• Isotonic salt solutions and dextrose solutions

–Rapid absorption

– Inability to maintain a prolonged high intraperitoneal fluid volume

–Most commonly used

• Hypotonic solutions

–Cisplatin accumulates in tumor cells & enhances its cytotoxicity

–High incidence of unexplained postoperative peritoneal bleeding with oxaloplatin

• Hypertonic solutions

–High intra-peritoneal volume achieved for prolonged duration

–Dilution of intra-peritoneal drug

• Isotonic high molecular weight solutions

– Prolonged high intra-peritoneal volume

– Duration for perfusion

• 410C x 90 min

• 430C x 30–40 min

• 420C x 60 min

– Complications

• 30-45%

• Chemotherapy toxicity to kidneys, bone marrow, liver, lungs- 2-5%

• Organ damage secondary to hyperthermia

• Surgical complications – 25-30%

– Small bowel fistula

• Moratlity - 0-5%

• Other treatment modality– Laparoscopic approach

• allows thorough exploration of the abdomen

• irrigation and aspiration of the thick mucinous material, and the instillation of mucolytic agents, 5% dextrose solution.

Summary

• incidence is 2 per million per year with an unexplained female dominance

• Redistribution phenomenon predicts location

• It is thought to be peritoneal disseminated disease from a primary appendiceal mucinous epithelial neoplasm unless (very rarely) proven otherwise with a normal appendix and a primary tumor elsewhere

• It is suspected in case of intraperitoneal mucus with cellular content, found during laparotomy or at physical examination (abdominal girth)

• combination of (aggressive) surgical debulking with peritonectomy and hyperthermic intraperitoneal chemotherapy seems to improve the outcome.

• Patients with high-grade disease (peritoneal mucinous carcinomatosis), disease extent with more than 5 involved abdominal regions, and/or small bowel involvement should receive palliative treatment because they do not benefit from aggressive treatment approaches