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Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Pseudomyxoma Peritonei and Appendix Tumours

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Abstract

Pseudomyxoma peritonei (PMP) is the intra-peritoneal accumulation of mucus due to mucinous neoplasia, most often from a ruptured mucinous appendiceal neoplasm. A similar syndrome is caused by appendix cancer and other gastrointestinal malignancies. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) provides long-term survival in selected patients with these conditions. The management of the appendiceal neoplasm prior to development of peritoneal involvement is initially discussed. This is followed by an overview of the management of peritoneal disease caused by appendiceal neoplasms. The principles and basic techniques of CRS and intraperitoneal chemotherapy (both intraoperative and post operative) are then discussed. Survival outcomes from several large studies are summarised. Prognostic factors are also discussed. We report our basic outcome data for the 345 patients with PMP or appendix cancer treated at our institution. Finally, the promising upcoming treatment of mucolytic therapy is discussed. We conclude that appendiceal neoplasms, although rare can cause significant morbidity and mortality. With optimal management long-term survival is possible in the majority of patients. The key to treatment is complete cytoreduction and use of hyperthermic intraperitoneal chemotherapy.

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... Meta-analysis of eleven clinical trials 15,17,24,25,28,29,32,[35][36][37]39 including 1043 participants found that HIPEC and CRS. ...
... Mortality at 60-month: risk mortality was evaluated in eleven studies 15,17,24,25,29,30,32,[35][36][37]39 with 1043 patients. The risk was 28.8% (95% CI 25.9 to 32; I 2 = 92.1%). ...
... Meta-analysis of twelve studies, 15,17,24,25,29,30,32,33,35,36,37,39 assessing 1073 participants, evaluated HIPEC and CRS for the outcome: Mortality at 36-month was evaluated in five studies 17,31,32,35,36 including 357 participants. The risk of mortality was 48.5% (95% CI 43% to 54.1%, ...
Article
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The objective of this systematic review is to provide efficacy and safety data in the application of Intra-Abdominal Hyperthermia Chemotherapy (HIPEC) and Cytoreductive Surgery (CRS) in patients with Peritoneal Pseudomyxoma (PMP) of origin in the cecal appendix. The databases Medline and Central Cochrane were consulted. Patients with PMP of origin in the cecal appendix, classified as low grade, high or indeterminate, submitted to HIPEC and CRS. The results were meta-analyzed using the Comprehensive Metanalysis software. Twenty-six studies were selected to support this review. For low-grade PMP outcome, 60-month risk of mortality, Disease-Free Survival (DFS), and adverse events was 28.8% (95% CI 25.9 to 32), 43% (95% CI 36.4 and 49.8), and 46.7% (95% CI 40.7 to 52.8); for high-grade PMP, 60-month risk of mortality, Disease-Free Survival (DFS) and adverse events was 55.9% (95% CI 51.9 to 59.6), 20.1% (95% CI 15.5 to 25.7) and 30% (95% CI 25.2 to 35.3); PMP indeterminate degree, 60-month risk of mortality, Disease-Free Survival (DFS) and adverse events was 32.6% (95% CI 30.5 to 34.7), 61.8% (95% CI 58.8 to 64.7) and 32.9% (95% CI 30.5 to 35.4). The authors conclude that the HIPEC technique and cytoreductive surgery can be applied to selected cases of patients with PMP of peritoneal origin with satisfactory results.
... 5 CT of the chest, abdomen, and pelvis allows evaluation of the primary tumor and assessment of metastatic disease. 5 The diagnosis is often unknown prior to operative intervention for presumed appendicitis. Malignant neoplasia is identified in 2.3-12.0% of patients having appendectomy for appendicitis. ...
... This may require a partial cecectomy if the tumor involves the base of the appendix. 2,5 The specimen should be placed in a retrieval bag when done by the laparoscopic approach to decrease the risk for mucin spillage. When the risk for mucin spillage is considered high, an open approach should be considered. ...
... They are clinically more aggressive than neuroendocrine tumors and treatment is the same as for appendiceal adenocarcinomas. 2 Pseudomyxoma Peritonei PMP is characterized by appendiceal neoplasm perforation with intraperitoneal accumulation of mucin resulting in gelatinous mucinous ascites. 5,9 PMP occurs in 20% of patients with mucinous appendiceal neoplasms and more commonly in females (ratio 4:1) between the ages of 60-70. 9 In 2010, the American Joint Committee on Cancer (AJCC) and World Health Organization (WHO) classified PMP into 2 groups: low-grade PMP and high-grade PMP. ...
Preprint
Appendiceal cancers may be difficult to diagnose even after comprehensive investigation. This report of locally advanced perforated appendiceal adenocarcinoma attached to the terminal ileum, cecum, and rectosigmoid illustrates the management challenges that require comprehensive knowledge of pathologic variations and range from simple appendectomy to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.
... (13) PMP can develop for months or even years without causing any symptoms. (14) It is frequently asymptomatic in the early stages, diagnosed accidentally, and remains stable for many years, presenting with vague abdominal symptoms when the disease load is significant. Patients frequently do not recall any acute abdominal pain caused by the tumor rupture. ...
... The cytotoxic drugs for HIPEC include 5FU, mitomycin C, doxorubicin, irinotecan, and cisplatin. (14) At the end of the procedure, a completeness of cytoreduction (CC) score is assigned. CC0 implies complete cytoreduction and no apparent peritoneal illness. ...
Article
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Introduction and importance Pseudomyxoma peritonei (PMP) is characterized by the accumulation of mucinous fluid in the abdominal cavity, typically originating from mucin-producing tumors, most commonly arising in the appendix. Case presentation A 63-year-old male patient presented to the hospital with complaints of abdominal pain, significant weight loss, a palpable mass in the right iliac fossa, and evidence of ascites. A diagnosis of PMP was proposed based on findings from a computed tomography (CT) scan, which was subsequently confirmed through histopathological examination of a biopsy. The patient underwent successful treatment with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (CRS-HIPEC). Clinical discussion Diagnosing PMP presents challenges due to its rarity and the potential for extensive spread throughout the peritoneal cavity, necessitating a multidisciplinary approach for successful treatment. Conclusion Pseudomyxoma peritonei is a rare yet medically significant condition. Documenting a case of this ailment in Palestine has the potential to advance medical understanding, raise awareness, and improve patient care standards within the local healthcare system. By documenting this uncommon condition, healthcare practitioners in Palestine can gain valuable insights into its manifestations, diagnostic processes, and treatment modalities. This contribution not only enriches the global medical literature but also promotes collaboration in addressing the challenges associated with rare diseases.
... The combination of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has been regarded as standard treatment for PMP [3]. CRS aims to remove all visible tumors and includes peritonectomy and resection of adjacent organs [4], which has an affirmed effect [5,6]. However, the efficacy of HIPEC after CRS in the treatment of incomplete cytoreduction for appendiceal PMP is less reported. ...
... Inclusion criteria were: (1) diagnosis of appendiceal PMP on histology and histopathologic subtype confirmed by two experienced pathologists; and (2) CRS with or without HIPEC. Exclusion criteria were: (1) complete cytoreduction for appendiceal PMP (completeness of cytoreduction (CCR) = 0/1); (2) PMP derived from other organs or diseases (e.g., ovary, colon, and pancreas); (4) loss to follow-up; (5) incomplete medical records. A total of 526 patients were included in the final analysis. ...
Article
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Background To explore the application value of hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with incomplete cytoreduction for appendiceal pseudomyxoma peritonei (PMP). Methods We retrospectively analyzed the clinical data of 526 patients with incomplete cytoreduction for appendiceal PMP to discover its prognostic factors, and the therapeutic value of HIPEC. Results The 5-year and 10-year overall survival rates of patients after cytoreductive surgery (CRS) treated with HIPEC were significantly higher than those without HIPEC (5y-OS: 58% vs. 48%, 10y-OS: 37% vs. 16%, P = 0.032). The median progression-free survival (PFS) following CRS was 20 months, with a 20% 3-year PFS. The median PFS following CRS + HIPEC was 33 months, with a 60% 3-year PFS (P = 0.000). Univariate analysis indicated that HIPEC, gender, completeness of cytoreduction (CCR) and pathological grade had statistical difference. Multivariate analysis showed that CRS without HIPEC and high pathological grade were independent risk factors for poor prognosis and rapid tumor progression. Conclusions HIPEC may prolong the survival in patients with incomplete cytoreduction for low-grade appendiceal PMP. High pathological grade indicates poor survival and rapid tumor progression.
... However, studies have found enhanced survival benefit with lower PCI cut-offs of 10-16. For AAdenoCa (regardless of LM) a PCI of 39 may still be associated with long-term survival (3)(4)(5)(6). ...
... In the literature, CRAdenoCa patients have poorer survival than low-and high-grade AAdenoCa following CRS and HIPEC with 5-year survival times of 27-54% and 81% and 49%, respectively (4,10). There is also a paucity of evidence investigating comparative differences in OS between CRAdenoCa and AAdenoCa patients without sLM. ...
Article
Background/aim: Colorectal adenocarcinoma (CRAdenoCa) and appendiceal adenocarcinoma (AAdenoCa) are diseases of the same histopathological type that metastasise to the liver and peritoneum. In selected subgroups, peritonectomy and heated intraperitoneal chemotherapy (HIPEC) may be indicated as part of the multimodal treatment plan. However, literature comparing the survival outcomes and preoperative tumour activity and burden of CRAdenoCa and AAdenoCa peritonectomy patients without synchronous liver metastases (sLM) is scarce. Little is also known about the comparative incidence of sLM and metachronous LM (mLM) between CRAdenoCa and AAdenoCa peritonectomy patients. This study aimed to clarify the above. Patients and methods: A retrospective cohort study of 684 CRAdenoCa and AAdenoCa primary peritonectomy patients between 2001-2021 was conducted at St George Hospital in Sydney, Australia. Results: Median overall survival (years) was equivocal between CRAdenoCa and AAdenoCa peritonectomy patients (1.7 vs. 1.9, p=0.35). Peritoneal cancer index and preoperative carcinoembryonic antigen (CEA) were significantly elevated (25 vs. 9, p<0.0001 and 7.9 vs. 5, p=0.0080) in AAdenoCa versus CRAdenoCa peritonectomy patients without sLM. The incidence of sLM and mLM was increased in CRAdenoCa peritonectomy patients (24% vs. 3.1%, p<0.0001 and 26% vs. 10%, p=0.0001). Conclusion: This study demonstrates similar survival outcomes between CRAdenoCa and AAdenoCa peritonectomy patients. Despite elevated preoperative tumour burden and biological activity in AAdenoCa patients, CRAdenoCa patients had higher rates of sLM and mLM. Further studies are warranted to validate and identify cellular and molecular targets that increase CRAdenoCa's ability to metastasise to the liver.
... 4 Normal levels of CA-125 and CA 19-9 are associated with improved survival and decreased rates of recurrence. 5 CT of the chest, abdomen, and pelvis allows evaluation of the primary tumor and assessment of metastatic disease. 5 The diagnosis is often unknown prior to operative intervention for presumed appendicitis. ...
... 5 CT of the chest, abdomen, and pelvis allows evaluation of the primary tumor and assessment of metastatic disease. 5 The diagnosis is often unknown prior to operative intervention for presumed appendicitis. Malignant neoplasia is identified in 2.3%-12.0% of patients having appendectomy for appendicitis. ...
Article
Full-text available
Appendiceal cancers may be difficult to diagnose even after comprehensive investigation. This report of locally advanced perforated appendiceal adenocarcinoma attached to the terminal ileum, cecum, and rectosigmoid illustrates the management challenges that require comprehensive knowledge of pathologic variations and range from simple appendectomy to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. This report of a patient with locally advanced perforated appendiceal adenocarcinoma at surgery and normal appendiceal orifice at preoperative colonoscopy reveals the diagnostic challenges, pathologic variations, and treatment options that range from simple appendectomy to cytoreductive surgery and HIPEC. Histopathologic confirmation may not be possible prior to operative intervention.
... The combined treatment modality including CRS and hyperthermic intraperitoneal chemotherapy has led to a 5-year survival ranging from 5% to 100% in lowgrade disease, and a survival ranging from 0 to 65% for high-grade disease. 2,4,[12][13][14][15][16][17] Surgical treatment of LAMN, with peritoneal mucin shedding, is controversial. The published literature shows that there is a significant prognostic difference between acellular and cellular mucin. ...
... There are reported cases whose local recurrence was detected on CT performed within 1 year, who underwent complementary surgery. [15][16][17] The average follow-up period in our series was 31.25 months. Increased tumor marker levels in literature were associated with recurrence and associated colorectal cancer. ...
Article
Full-text available
Background: Appendix tumors are rare tumors found in the gastrointestinal tract, observed at a rate of about 0.2%-0.3%. Our aim in this study was to present the clinicopathological classification, treatment and long-term prognosis of patients with low grade appendiceal mucinous neoplasm (LAMN). Methods: Patients who underwent surgery in the Erciyes University Department of (Kayseri, Turkey), Department of General Surgery between December 2010 and December 2018, and who had LAMN as a result of pathology were included in our study. Demographic data, clinical and pathological features of the disease, their treatment and follow-up results after treatment were reviewed retrospectively. Results: We included 24 patients in the study. Of these patients, 10 (41.6%) were male. The mean age distribution was 56.4 ± 20.3 (21-91) years. Appendectomy was performed in 14 patients, and additional organ resections were performed in 8 patients. The most common symptom at the time of presentation was abdominal pain (79.1%; 95% CI, 58.3-91.7). The most common preliminary diagnosis in the preoperative period was acute appendicitis (50%; 95% CI, 29.2-70.8). Mean postoperative hospitalization time was 7.4 ± 7.96 (2-31) days. On pathological examination, appendectomy resection margins were positive in two patients. The mean (median) postoperative follow-up was 31.25 ± 23.9 (27) (1-90) months. One-year survival was 91.6%, and 5-year survival was 83.3%. Recurrence was detected in three patients during the follow-up period. Conclusion: If appendix mucinous neoplasia (AMN) is suspected in patients undergoing surgery with an initial diagnosis of acute or plastron appendicitis, care should be taken to remove the lesion without perforation. Pseudomyxomaperitonei, which may develop as a result of perforation, is associated with recurrence and decreased survival.
... Acceptable treatments include appendectomy, right hemicolectomy, partial colectomy combined with tumour reduction or palliative resection combined with chemotherapy (7). Combined postoperative hyperthermic intraperitoneal perfusion chemotherapy (HIPEC) may prolong the survival of patients with these diseases (8). The 5-year survival rate for patients with low-grade appendiceal mucinous tumours is statistically 62.5%-100% when patients are treated with a combination of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) (5). ...
Article
Full-text available
Low-grade appendiceal mucinous neoplasms (LAMNs) are rare and heterogeneous diseases that, despite their increased incidence, are well differentiated, tend to be painless, and histologically lack distinctive invasive features without infiltrative growth, destructive infiltration, or associated pro-fibroproliferative responses. However, the biological behaviour of these tumours is difficult to determine preoperatively or intraoperatively, and the possibility of rupture puts patients at risk for peritoneal pseudomucinous neoplasms (PMPs).Patients with low-grade appendiceal mucinous tumours and peritoneal pseudomucinous tumours experience slow disease progression and are incurable and have a high risk of recurrence, morbidity, and ultimately death, despite the reported 5- and 10-year survival rates of 50–86% and 45–68%, respectively. In this article, we report the case of a 80-year-old male with a giant low-grade appendiceal mucinous tumour associated with a peritoneal pseudomucinous tumour, and discuss the diagnostic and management strategies for giant low-grade appendiceal mucinous tumours in the context of a literature review.
... To date, HIPEC regimen-related studies have been mostly single-or multicenter large-sample analyses [17,19,[34][35][36][37][38][39][40][41][42][43][44][45][46][47][48]. In 2018, Levine et al. published the first multicenter randomized controlled trial on appendixderived PMP. ...
Article
Full-text available
Background Pseudomyxoma peritonei (PMP) is a clinical malignant syndrome mainly originating from the appendix, with an incidence of 2–4 per million people. As a rare disease, an early and accurate diagnosis of PMP is difficult. It was not until the 1980s that the systematic study of this disease was started. Main body As a result of clinical and basic research progress over the last 4 decades, a comprehensive strategy based on cytoreductive surgery (CRS) + hyperthermic intraperitoneal chemotherapy (HIPEC) has been established and proved to be an effective treatment for PMP. Currently, CRS + HIPEC was recommended as the standard treatment for PMP worldwide. There are several consensuses on PMP management, playing an important role in the standardization of CRS + HIPEC. However, controversies exist among consensuses published worldwide. A systematic evaluation of PMP consensuses helps not only to standardize PMP treatment but also to identify existing controversies and point to possible solutions in the future. The controversy underlying the consensus and vice versa promotes the continuous refinement and updating of consensuses and continue to improve PMP management through a gradual and continuous process. In this traditional narrative review, we systemically evaluated the consensuses published by major national and international academic organizations, aiming to get a timely update on the treatment strategies of CRS + HIPEC on PMP. Conclusion Currently, consensuses have been reached on the following aspects: pathological classification, terminology, preoperative evaluation, eligibility for surgical treatment, maximal tumor debulking, CRS technical details, and severe adverse event classification system. However, controversies still exist regarding the HIPEC regimen, systemic chemotherapy, and early postoperative intraperitoneal chemotherapy.
... Appendiceal mucocele is an uncommon affection accounting for 0.15 to 0.6% of appendectomies [4,5]. It affects preferably adults with an average age between 50 and 60 years [6,7], but can also affect children. It is a cystic dilatation of the appendix caused by the accumulation of mucus secretion intraluminally; this process is slow and progressive, without any sign of infection inside the organ. ...
... • těžké postižení (separace a četné stenózy) tenkého střeva, při jehož resekci by hrozil vznik syndromu krátkého střeva, obstrukce žlučových cest a hydronefróza [14][15][16][17][18][19][20][21]. ...
Article
Background: Pseudomyxoma peritonei is a rare tumorous disease with various grades of malignancy and is characterized by production of mucinous and gelatinous masses. Development of pseudomyxoma peritonei is usually associated with rupture of appendiceal mucinous tumors and other mucinous tumors of the gastrointestinal tract or ovaries. Pseudomyxoma peritonei is usually divided into three types: low-grade, high-grade, and high-grade with signet ring cells. Staging of the disease is determined by the peritoneal cancer index. Clinical findings are highly variable depending on disease staging. The typical finding of “jelly belly” syndrome worsens with disease progression. The diagnosis is based on the pre-operative cure by imaging methods, especially computed tomography. Methods: The Sugarbaker method involves maximal removal of tumorous masses, so-called cytoreductive surgery, and perioperative intraabdominal application of hot cytostatics (hyperthermic intraperitoneal chemotherapy) with the aim of achieving maximal liquidation of tumorous processes. Results: Our results are comparable with previous published data and confirm high effectivness of this method. The results show statistically very significant extention of overall survival, disease free interval with acceptable lethality 0-12 % and morbidity 27-56%. These results promote this method as the gold standard of treatment of pseudomyxoma peritonei in selected patients.
... Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) has been shown to be a promising treatment for the locoregional management of selected patients with US presenting with peritoneal dissemination [11,[13][14][15][16]. In the past, CRS/ HIPEC has been successfully used in patients with peritoneal mesothelioma [17] and peritoneal carcinomatosis from both gastrointestinal [18][19][20][21][22] and gynecological [23][24][25][26] origins; however, its use in US is still controversial [27,28]. We examined our experience with patients presenting with PS from US treated with CRS/HIPEC. 1 with CRS/HIPEC between May 2001 and November 2014 were identified. ...
Article
Full-text available
Key Clinical Message Peritoneal sarcomatosis from uterine sarcoma is a rare disease with no effective treatment and poor prognosis. Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) has successful results in peritoneal carcinomatosis from gastrointestinal/gynecological origins. We show that CRS/HIPEC is safe, feasible, and may benefit selected patients with peritoneal sarcomatosis from uterine sarcoma.
... If there is a need to also perform a total gastrectomy more than 1.5 m of the small bowel should be preserved. 28 As soon as the CRS ends, but before performing anastomosis, HIPEC is delivered. One of the advantages of this method is to keep systemic levels of the chemotherapy drugs low while regional levels remain high. ...
Article
Full-text available
Background Appendix tumors represent about 1% of all gastrointestinal neoplasia, in other words they are quite rare. However, there is a specific type of appendiceal neoplasms (mucinous adenocarcinoma) that spreads to the peritoneum and in almost 20% of the cases, resulting in a disease called pseudomyxoma peritonei. Although, it is a very rare condition, it is nonetheless a very severe one and therefore it is crucial to know how to correctly diagnose and treat it. Objective This study provides updated data on how to diagnose, classify and treat pseudomyxoma peritonei that originates from appendix tumors. Methods A bibliographic research was performed on PubMed database, including articles published since 2000, as well as, cross-referencing with the initial research. Discussion In the past, patients diagnosed with pseudomyxoma peritonei would only undergo palliative measures, so their overall survival rate was greatly reduced. Over the years pseudomyxoma peritonei treatment has evolved and patients are now undergoing treatment which is a combination of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. This new therapy has allowed an increase of survival chances of up to 5 years in those patients with values between 53% and 88%, depending on the type of tumor. Conclusion Despite the great progress we have witnessed in recent years, which have led to a large increase in survival rates, more research needs to be done, on what to do when the disease is in an unresectable stage. Finding a less aggressive therapy than cytoreductive surgery + hyperthermic intraperitoneal chemotherapy will be an important step forward.
... Surgical resection s the only potentially curative approach. Accepted management includes appendectomy, right hemicolectomy, partial colectomy with debulking or palliative resection combined with additional chemotherapy [11]. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) provides long-term urvival in selected patients with these conditions [12]. ...
Article
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A 43-year-old female presented at the accident and emergency department of Princess Marina Hospital, Gaborone, Botswana. She reported a deep dull aching pain of two years duration in the right iliac fossa that has been progressively becoming worse. Ultrasound revealed a large sausage like cystic mass extending from the pelvis up to the medial aspect of the ascending colon. CT scan showed a large sausage like cystic mass extending from the pelvis up to the hepatic flexure of the colon with the cecum displaced. No metastatic features were seen. We made an impression of appendiceal mucocele. A semi-elective laparotomy was scheduled. Intraoperative findings: a giant intact cystic distended appendix with involved base, displacing the cecum cranially. A right hemicolectomy was performed. The histopathological results revealed a low-grade appendicular mucinous neoplasm with no lymph node involvement. The surgical margins were free. The patient recovered uneventfully.
Article
Background Cytoreductive surgery (CRS) with hyperthermic intraperitoneal early chemotherapy has gained acceptance as the standard of care for peritoneal surface malignancy over the past decade. This study reports the results of the first 6 years of activity of the Western Australian Peritonectomy Service to compare outcomes of a low‐volume centre with world standards. Methods An audit of all patients who received CRS ± hyperthermic intraperitoneal early chemotherapy treatment at the Western Australian Peritonectomy Service in its first 6 years of operation was performed and results were compared to the recent world literature. Results A total of 130 patients were treated with 150 CRS procedures, including 50 pseudomyxoma peritonei (PMP), 53 colorectal cancers (CRCs), 27 appendix adenocarcinomas (AAs) and 20 other cancers. The median operating time was 12 h with median length of hospital stay of 15 days. Perioperative mortality was 0.67% and Clavien‐Dindo III/IV morbidity was 20%. The mean packed red cell transfusion requirement was 0.34 units/case. Post‐discharge readmission rate was 25% and the return to theatre rate was 13%. The 4‐year overall survival rates for PMP, CRC and AA were 97%, 49% and 81%, respectively. The 3‐year disease‐free survival rates for PMP, CRC and AA were 74%, 26% and 36%, respectively. Conclusion A CRS centre averaging 25 cases per year can achieve strong outcomes in line with high‐volume world centres.
Article
Background Cytoreductive surgery (CRS) with or without hyperthermic intraperitoneal chemotherapy (HIPEC) is indicated for patients with peritoneal dissemination of appendiceal cancer. The role of neoadjuvant chemotherapy (NAC) before CRS‐HIPEC remains controversial. Methods A retrospective review of adult patients who underwent CRS ± HIPEC for metastatic appendiceal cancer between 2000‐2017 was performed. Patients who received NAC followed by surgery were compared with those who underwent surgery first (SF) with and without 1:1 propensity score matching (PSM). Results Among 803 patients with appendiceal cancer who underwent CRS ± HIPEC, 225 (28%) received NAC, and 578 (72%) underwent SF. After PSM (n = 186), median overall survival (OS) did not differ (NAC: 40 vs SF: 56 months; P = .210) but recurrence‐free survival (RFS) was worse among patients who received NAC (14 vs 22 months; P = .007). NAC was independently associated with worse OS (hazards ratio [HR], 1.81; 95% confidence interval [CI], 1.03‐3.18) and RFS (HR, 1.93; 95% CI, 1.25‐2.99). Conclusion In this multi‐institutional retrospective analysis of patients with peritoneal dissemination from appendiceal cancer, the use of NAC before CRS‐HIPEC was associated with worse OS and RFS even after PSM and multivariable regression. Immediate surgery should be considered for patients with disease amenable to complete cytoreduction.
Article
Background: The role of systemic chemotherapy (SC) before cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) in appendiceal high-grade mucinous carcinoma peritonei (HGMCP) is controversial. We analyzed the effect of SC prior to CRS/HIPEC in HGMCP. Methods: A prospective database of CRS/HIPEC procedures for HGMCP without signet ring cells and with signet ring cells (HGMCP-S) from 1998 to 2017 was reviewed. Exclusion criteria was prior surgery >5 regions or >2 regimens of prior SC. Perioperative variables were analyzed. Results: There were 140 HGMCP/HGMCP-S identified: 64 with prior SC (preSC) and 76 without (noSC). Groups were balanced for lymph node status, complete cytoreduction rate, disease burden, complications, and postoperative SC. PreSC had more HGMCP-S, moderately/poorly differentiated histology, and longer time-to-surgery (median: 6 vs 2 months, p < 0.001). Median overall survival (mOS) was 40 vs 86 and median progression-free survival (mPFS) was 19 vs 43 months for preSC vs noSC, respectively (p = 0.006 and p = 0.007). In HGMCP-S subanalysis, mOS was 25 vs 39 and mPFS 16 vs 29 months for preSC vs noSC, respectively (p = 0.188 and p = 0.063). In moderately/poorly differentiated histology subanalysis, mOS was 38 vs 56 and mPFS 18 vs 29 months in preSC vs noSC, respectively (p = 0.199 and 0.082). Prior SC was not linked to improved OS or PFS in non-signet ring HGMCP or well-differentiated histology subanalysis. Conclusion: Prior SC was not associated with less disease burden, better cytoreduction rates, or improved clinical outcomes in HGMCP, regardless of histopathologic subtype. Traditional SC agents may not be effective in HGMCP in the neoadjuvant setting.
Article
Background Appendiceal epithelial neoplasms are rare cancers. Management of peritoneal disease from appendiceal neoplasms has historically been with debulking surgery. In recent decades, the advent of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has become the standard of care. Here, we report our single institution 10‐year experience with CRS and HIPEC for appendiceal neoplasms. Methods This is a retrospective review from 1 January 2008 to 1 June 2017 of all patients undergoing CRS and HIPEC for appendiceal neoplasms. Institutional ethics approval was granted for this project. Results One hundred and seventy‐two patients underwent 208 CRSs during this time. Overall, 83.72% of patients had one CRS and HIPEC procedure. Pseudomyxoma peritonei from a perforated appendiceal mucinous neoplasm accounted for 67.9% of cases. The median peritoneal carcinomatosis index (PCI) was 14, with complete cytoreduction achieved in 74.2% of patients. Fifty‐four percent of patients had at least one complication, with one (0.5%) peri‐operative mortality in our cohort. For the entire cohort, the median overall survival was 104 months and a 5‐year survival of 75%. In those having a complete cytoreduction, 5‐year survival was 90%, with a median disease free interval of 63 months. PCI and completeness of cytoreduction were independent predictors of overall survival. Conclusion Our results demonstrate that CRS and HIPEC for appendiceal neoplasms are safe and effective. Despite carrying some morbidity, it offers patients an excellent disease free and overall survival.
Chapter
Appendiceal tumours and pseudomyxoma peritonei (PMP) are both rare diseases that pose several diagnostic and therapeutic challenges. Appendiceal tumours are the source of PMP in most cases, and even those with benign histopathological features have a propensity for peritoneal spread. PMP has a varied biological behaviour. Over the past three decades, numerous classifications have been used to stratify these tumours according to their prognosis.
Chapter
Uterine sarcomas (US) are a group of rare heterogeneous mesenchymal malignancies arising from uterine stromal musculature or connective tissue [1]. US represent only 1% of all female genital malignancies and 3–9% of uterine tumors [2]. Over the past decade, the incidence of tumors from the uterine corpus has been rising, making up 60,050 (20%) of new cases of all female genital tract tumors reported in the United States in 2016 [3]. Risk factors are difficult to estimate, due to the rarity of the disease. However, it is generally accepted that race (African descent) [4, 5], chronic tamoxifen usage (>5 years) [6, 7], and inherited syndromes and conditions (hereditary leiomyomatosis, renal cell carcinoma, and retinoblastoma) increase the risk of developing US [8, 9].
Article
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Background: Treatment of peritoneal metastases (PM) and liver metastases (LM) from colon cancer remains controversial. LM has been viewed as exclusion criterion for cytoreductive surgery (CRS) on the basis that such spread represents systemic disease. CRS and intra-peritoneal chemotherapy (IPC) has gained increasing recognition as a treatment modality for selected patients with colon cancer and PM. This study analyses results of CRS and IPC for colon cancer and synchronous resection for treatment of LM and PM.
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Complete cytoreduction with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) has been shown to improve survival in patients with low-grade mucinous adenocarcinoma (LGMA). However, incomplete cytoreduction exposes patients to significant morbidity without a similar survival benefit. Preoperative assessment of the ability to achieve CRS is therefore a critical step in selecting patients for CRS/HIPEC. The aim of this study was to develop and validate a preoperative scoring system to accurately predict the ability to achieve complete cytoreduction in patients with LGMA of the appendix. A simplified preoperative assessment for appendix tumor (SPAAT) score was developed based on computed tomography scan findings thought to predict incomplete cytoreduction. We applied the SPAAT score to patients with LGMA to determine the ability of the score to predict complete cytoreduction. This scoring system was then applied to a separate cohort of patients from a different institution. Sensitivity and specificity were determined for the SPAAT score. Survival was calculated and correlated with the SPAAT score and the completeness of cytoreduction score. A SPAAT score of <3 is a significant predictor of complete cytoreduction in the derivation cohort. In the validation cohort, 40 of 42 patients with a SPAAT score <3 achieved a complete cytoreduction, for a positive predictive value of 95.2 % and a negative predictive value of 100 %. Additionally, the SPAAT score was a significant predictor of disease-free survival. The SPAAT score is a useful tool in the preoperative assessment of patients with LGMA who are under consideration for cytoreductive surgery. Prospective analysis of this scoring system is warranted to appropriately select patients who will benefit from CRS/HIPEC.
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Compared to current treatment for pseudomyxoma peritonei (PMP), the extraction of solubilised mucin through peritoneal catheter can be minimally invasive. However, mucin has variable appearance that may influence mucolysis. Hence, we investigated the mucolysis of 36 mucin samples with a novel agent. Using visual inspection and hardness index, PMP mucin was classified into three grades. The mucin pathological category was identified from patient record. Subsequently, the dissolution of the samples was tested. For in vitro, 1 g of mucin was treated to the mucolytic agent in 10 ml TRIS buffer at 37 deg. Celsius for 3 hours, with weighing of residual mucin. Control treatment was similar but received TRIS buffer. For in vivo, 2 g of implanted intra-peritoneal mucin in nude rats was treated to mucolytic (2 X 500 ul/24 hr, over 48 hours, plus another treatment before sacrifice at 56 hours, with weighing of residual mucin. Controls were treated but only with TRIS buffer. Six animals were used for each mucin grade (3 mucolytic treated & and 3 controls). Grades of mucin were soft mucin (62%), semi hard (20%) and hard mucin (18%). Diffuse peritoneal adenomucinosis had 50% of soft mucin and peritoneal mucinous carcinoma had 11% (P = 0.0382). In vitro and in vivo absolute disintegration was 100% for soft, 57.38% and 48.67% for semi hard, 50% and 28.67% for hard mucin. Majority of mucin were soft with complete disintegration, the rest showed variable disintegration, suggesting that the mucolytic has potential for treating PMP.
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The nomenclature and classification of pseudomyxoma peritonei (PMP) is confusing and controversial. Numerous classification systems have been proposed, none of which are easily reproducible or a useful guide for treatment. Patients with PMP of appendiceal origin were identified from our institution's database. Kaplan-Meier analyses were performed based on a proposed new PMP classification, a three-tiered grading system designated PMP1, PMP2, and PMP3. These results were compared with the established schemes by Ronnett and Bradley et al. There were 211 patients included in the analysis with a mean age of 51 ± 12 years at diagnosis. For PMP1, 86 patients (40.8%) included cases with abundant extracellular mucin and columnar nonstratified epithelium without dysplasia or atypia. For PMP3, 50 patients (23.7%) consisted of PMP with any percentage of signet ring cells (SRCs), For PMP2, 75 patients (35.5%) included all other patients. The mean age (± standard deviation) for PMP 1, 2, and 3 were 51 ± 12, 51 ± 12, and 51 ± 10 years, respectively (P = 0.90). The three groups had similar sex distribution (P = 0.24) and resection status (P = 0.47). Kaplan-Meier analyses showed median survivals of 120, 88, and 40 months and 5-year survival rates of 85.7, 63.05, and 32.2 per cent (P < 0.0001) for PMP 1, 2, and 3, respectively. Three distinct categories, PMP1, 2, and 3, were identified, which provide better stratification in terms of overall survival and represent differences in tumor biology that may impact treatment recommendations.
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Pseudomyxoma peritonei (PMP) is characteristically divided into two histopathological subtypes; disseminated peritoneal adenomucinosis (DPAM) and peritoneal mucinous carcinomatosis (PMCA). The latter is associated with a worse prognosis. However, even within the DPAM group, there is a considerable variation in outcome. In this study we investigate the role of baseline serum tumor markers CA 19-9, CEA and CA-125 in further stratifying survival. Over 16 years, 218 patients with PMP were treated with cytoreductive surgery (CRS) and perioperative intraperitoneal chemotherapy (PIC) at our institution. A CA-125 level of >35 U/L, CA 19-9 of >40 U/mL and CEA of >3 ng/mL were considered positive or elevated outside the laboratory reference range. The impact of clinicopathologic and treatment-related variables on overall survival (OS) was analyzed with the Kaplan Meier method. Survival curves were compared using the log-rank test. Variables deemed significant by univariate analyses were entered into multivariate analysis using the Cox proportional hazards model. Within the DPAM group, the 5-year survival of patients who were CA 19-9 positive versus those with normal values were 58% and 90% respectively (P<0.001). Other variables found to negatively impact on OS in univariate analyses were completeness of cytoreduction (CC) score 2/3 (P<0.001), peritoneal cancer index (PCI) >25 (P<0.001) and male gender (P=0.017). In the Cox regression model, only CA 19-9 positivity was found to be an independent prognostic factor for OS (P=0.034). In addition to marker positivity, the absolute level of CA 19-9 was also prognostically significant. In patients with CA 19-9>1,000 U/mL, the 5-year survival was 23%, in contrast to 90% in patients with CA 19-9<100 U/mL (P<0.001). In the PMCA cohort, only CC-score was found to be associated with OS (P<0.001). Our study provides relevant prognostic information for the DPAM subtype in staging and prioritizing surgery; as even in apparently indolent disease, some patients have poorer survival. CA 19-9 elevation may also be useful in identifying patients who would potentially benefit from adjuvant therapy and/or closer post-operative surveillance. The potential role of CA 19-9 in mediating tumor cell adhesion and disease progression in PMP should be further investigated to deepen our understanding of the disease's inherent biological behavior. If a true relationship exists, CA 19-9 may be a conceivable target for immunotherapy.
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Pseudomyxoma peritonei (PMP) originating from an appendiceal mucinous neoplasm remains a biologically heterogeneous disease. The purpose of our study was to evaluate outcome and long-term survival after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) consolidated through an international registry study. A retrospective multi-institutional registry was established through collaborative efforts of participating units affiliated with the Peritoneal Surface Oncology Group International. Two thousand two hundred ninety-eight patients from 16 specialized units underwent CRS for PMP. Treatment-related mortality was 2% and major operative complications occurred in 24% of patients. The median survival rate was 196 months (16.3 years) and the median progression-free survival rate was 98 months (8.2 years), with 10- and 15-year survival rates of 63% and 59%, respectively. Multivariate analysis identified prior chemotherapy treatment (P < .001), peritoneal mucinous carcinomatosis (PMCA) histopathologic subtype (P < .001), major postoperative complications (P = .008), high peritoneal cancer index (P = .013), debulking surgery (completeness of cytoreduction [CCR], 2 or 3; P < .001), and not using HIPEC (P = .030) as independent predictors for a poorer progression-free survival. Older age (P = .006), major postoperative complications (P < .001), debulking surgery (CCR 2 or 3; P < .001), prior chemotherapy treatment (P = .001), and PMCA histopathologic subtype (P < .001) were independent predictors of a poorer overall survival. The combined modality strategy for PMP may be performed safely with acceptable morbidity and mortality in a specialized unit setting with 63% of patients surviving beyond 10 years. Minimizing nondefinitive operative and systemic chemotherapy treatments before definitive cytoreduction may facilitate the feasibility and improve the outcome of this therapy to achieve long-term survival. Optimal cytoreduction achieves the best outcomes.
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Cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (HIPEC) is associated with significantly longer survival in patients with peritoneal carcinomatosis (PC). So far, no morphological imaging method has proven to accurately assess the intra-abdominal tumor spread. This study was designed to predict tumor load in patients with PC using dual-modality (18)FDG-PET/CT and to compare the results with those of PET and CT alone by correlating imaging findings with intraoperative staging. Twenty-two patients with PC from gastrointestinal (n = 13), ovarian cancer (n = 8), and mesothelioma (n = 1) underwent contrast-enhanced (18)FDG-PET/CT before surgery and HIPEC. In a retrospective analysis PET, CT, and fused PET/CT were separately and blindly reviewed for the extent of peritoneal involvement using the Peritoneal Cancer Index (PCI). Imaging results were correlated with the intraoperative PCI using Pearson's correlation coefficient and linear regression analysis. There was a strong correlation between the PCI obtained with PET/CT and the surgical PCI with respect to the total score (r = 0.951) as well as in the regional analysis (small bowel, r = 0.838; other, r = 0.703). The correlation was slightly lower for CT alone (total score, r = 0.919; small bowel, r = 0.754; other, r = 0.666) and significantly lower (p = 0.002) for PET alone (total score, r = 0.793; small bowel, r = 0.553, other, 0.507). Contrast-enhanced CT is superior compared with PET alone to predict the extent of PC. In our patient group, the combination of both modalities (contrast enhanced PET/CT) yielded the best results and proved to be a useful tool for selecting candidates for peritonectomy and HIPEC.
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The combination of complete cytoreductive surgery and perioperative intraperitoneal chemotherapy provides the only chance for long-term survival for selected patients diagnosed with a variety of peritoneal neoplasms, either primary or secondary to digestive or gynecologic malignancy. Hyperthermic intraperitoneal chemotherapy (HIPEC) delivered in the operating room once the cytoreductive surgical procedure is finalized, constitutes the most common form of administration of perioperative intraperitoneal chemotherapy. This may be complemented in some instances with early postoperative intraperitoneal chemotherapy (EPIC). HIPEC combines the pharmacokinetic advantage inherent to the intracavitary delivery of certain cytotoxic drugs, which results in regional dose intensification, with the direct cytotoxic effect of hyperthermia. Hyperthermia exhibits a selective cell-killing effect in malignant cells by itself, potentiates the cytotoxic effect of certain chemotherapy agents and enhances the tissue penetration of the administered drug. The chemotherapeutic agents employed in HIPEC need to have a cell cycle nonspecific mechanism of action and should ideally show a heat-synergistic cytotoxic effect. Delivery of HIPEC requires an apparatus that heats and circulates the chemotherapeutic solution so that a stable temperature is maintained in the peritoneal cavity during the procedure. An open abdomen (Coliseum) or closed abdomen technique may be used, with no significant differences in efficacy proven to date. Specific technical training and a solid knowledge of regional chemotherapy management are required. Concerns about safety of the procedure for operating room personnel are expected but are manageable if universal precautions and standard chemotherapy handling procedures are used. Different HIPEC drug regimens and dosages are currently in use. A tendency for concurrent intravenous chemotherapy administration (bidirectional chemotherapy, so-called "HIPEC plus") has been observed in recent years, with the aim to further enhance the cytotoxic potential of HIPEC. Future trials to ascertain the ideal HIPEC regimen in different diseases and to evaluate the efficacy of new drugs or drug combinations in this context are warranted.
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To report a large number of patients with peritoneal carcinomatosis (PC) treated with complete cytoreductive (CCR-0) plus intraperitoneal chemotherapy, and to compare the results according to the origin of the primary: colon, rectum, small bowel, and appendix (excluding peritoneal pseudomyxoma). Among 615 patients treated for PC originating from these 4 types of primaries in 23 French centers, 440 were retrospectively selected as having undergone complete cytoreductive surgery and with complete data retrieval. Primary sites were: colon (n=341), rectum (n=27), appendix (n=41), and small bowel (n=31). Postoperative mortality and morbidity (3.9% and 31%, respectively) did not differ according to the origin of the primary tumor. The mean follow-up was 60 months. The 5-year overall survival rates were not statistically different for the colon (29.7%), rectum (37.9%), nor the small bowel (33.8%), but was higher (P=0.01) for appendix adenocarcinoma (63.2%). The multivariate analysis of prognostic factors singled out the extent of peritoneal seeding (P<0.0001), positive lymph nodes (P=0.001), and adjuvant systemic chemotherapy (P=0.002), whereas the origin of the tumor was borderline (P=0.06) in favor of appendix tumors. Cytoreductive surgery plus intraperitoneal chemotherapy yields satisfying and similar survival results in the treatment of PC from colon, rectum, and small bowel adenocarcinomas. Results were better for appendix adenocarcinoma. When feasible, this combined approach should become the gold standard treatment of PC.
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The pineapple plant (Ananas comosus) was shown to contain at least four distinct cysteine proteinases, which were purified by a procedure involving active-site-directed affinity chromatography. The major proteinase present in extracts of plant stem was stem bromelain, whilst fruit bromelain was the major proteinase in the fruit. Two additional cysteine proteinases were detected only in the stem: these were ananain and a previously undescribed enzyme that we have called comosain. Stem bromelain, fruit bromelain and ananain were shown to be immunologically distinct. Enzymic characterization revealed differences in both substrate-specificities and inhibition profiles. A study of the cysteine proteinase derived from the related bromeliad Bromelia pinguin (pinguinain) indicated that in many respects it was similar to fruit bromelain, although it was found to be immunologically distinct.
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e14158 Background: This aim of this case-control study was to assess the prognostic impact of the presence of liver metastases (LM) in patients operated on colorectal peritoneal carcinomatosis (PC) who underwent complete cytoreductive surgery (CRS) and LM resection followed by intraperitoneal chemotherapy. Methods: From a prospectively maintained database, all patients with colorectal PC and synchronous LM who underwent CRS followed by intraperitoneal chemotherapy, were manually matched to all identical patients with isolated PC, operated on over the same period, on the following matching criteria: age, peritoneal cancer index (PCI), site of the primary colorectal cancer (colon or rectum), lymph node involvement on the primary colorectal cancer specimen (pN), and postoperative chemotherapy. Results: From 1993 to 2009, 37 patients with PC and LM were matched to 61 patients with isolated PC. After a mean follow-up of 36 months, 3-year overall (OS) and disease free survival rates were significantly lower in patients with PC and LM, respectively 40% and 66% (p=0.04) and 6% and 27% (p=0.001). In Cox regression analysis, a PCI ≥ 12 (Odds-ratio (OR): 4.6), a pN+ status (OR: 3.3), no adjuvant chemotherapy (OR: 3.0) and presence of LM (OR: 2.0) were identified as independent factors of poor OS. Thus, 3 groups could be identified: 1) patients with a low PCI (<12) and no LM, with an associated a median OS of 76 months; 2) patients with a low PCI (<12) and 1 or 2 LM, with an associated OS of 40 months; and 3) patients with a high PCI (≥12) or patients with ≥ 3 LM, with an associated OS of 27 months. Conclusions: This first case-control study confirms that prolonged survival can be achieved in highly selected patients operated on limited carcinomatosis and liver metastases less than 3. When the peritoneal and the liver involvement are greater, the complete surgical treatment followed by intraperitoneal chemotherapy should be discussed according to criteria of aggressiveness of the tumor disease.
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Mucinous ascites and pools of mucin within the peritoneal cavity associated with neoplastic, mucinous epithelium are the characteristic features of pseudomyxoma peritonei (PMP). Clinically, PMP presents with abdominal distension and gelatinous ascites. In female patients, pelvic masses can be seen. Radiologic findings on computed tomography include scalloping of the hepatic and splenic margins and dense ascites. Surgically, PMP is encountered as grossly visible mucin in the peritoneal cavity. The presence of mucin outside of the appendix, in the right lower quadrant, and beyond is an important diagnostic finding. The appendix may be distended or ruptured. In women, there is often bilateral surface involvement of the ovaries, raising the differential diagnosis of primary ovarian neoplasms; however, these are extremely rare causes of PMP. Because of the association between appendiceal lesions and metastatic mucinous neoplasms of the ovary, appendectomy in the setting of any mucinous peritoneal or ovarian process may be prudent, even if the appendix is grossly normal. The gastrointestinal tract, especially the hepatopancreato biliary system, also needs to be assessed by the surgeon. Pathologically, PMP arises almost exclusively from low- or high-grade mucinous neoplasms of the appendix. These neoplasms must be distinguished both from rare benign causes of mucinous ascites and from nonappendiceal primary tumors. PMP has a protracted clinical course with progressive fibrous adhesions and obstructive disease; aggressive surgical and cytoreductive therapy with hyperthermic intraperitoneal chemotherapy has been reported to improve clinical outcomes.
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Considering the suspected link between mucinous neoplasm (MN) and pseudomyxoma peritonei (PMP), one option could be to propose prophylactic hyperthermic intraperitoneal chemotherapy (HIPEC) to selected patients in order to prevent the occurrence of PMP. The aim of this study was to identify risk factors for developing PMP after curative surgery for a MN of the appendix. All consecutive patients referred to our single tertiary care cancer center between September 1992 and March 2014 for MN of the appendix, initially without PMP, were retrospectively studied. Patients who had received prophylactic intraperitoneal treatment were excluded from the analysis. Twenty-five patients with a median age of 51 (range=25-74) years were identified. At the initial appendectomy, 19 (76%) patients had a perforated MN. Nine of these patients (40%) exhibited disseminated-free acellular intraperitoneal mucin without PMP. Six (24%) patients had an unperforated MN without free intraperitoneal mucin. After a median follow-up of 50 months, 12 (52%) patients had developed PMP after a median time of 61 (range=13-121) months. Complete cytoreductive surgery plus HIPEC was possible in only seven (64%) out of these 12 patients. No factor reached statistical significance in predicting the occurrence of PMP but a trend was found in the case of perforated MN (p=0.068), associated with a 65% recurrence rate, compared to 17% without perforation. An appendicular MN cannot be considered a benign occurrence because PMP is common after resection and can occur up to 10 years after the initial appendectomy. Patients should be systematically followed up to detect PMP as early as possible. Patients with a perforated MN could be at higher risk of developing PMP. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.
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Peritoneal carcinomatosis (PC) results from the secondary spread of many intraabdominal tumour types, such as colorectal malignancy (colorectal cancer, CRC), disseminated peritoneal adenomucinosis (DPAM), appendiceal cancer, ovarian carcinoma, sarcoma or from the occurrence of primary peritoneal disease such as peritoneal mesothelioma. The combination of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has seen improvements in survival in selected cases of these cancers. Between 1996 and 2014, a prospective database of 675 patients was created for the peritonectomy unit at our hospital. In total, 827 peritonectomy procedures (including redo CRS) were performed for the major subgroups of PC: DPAM 220; appendiceal cancer (peritoneal mucinous adenocarcinoma (PMCA)) 191; CRC 234; diffuse malignant peritoneal mesothelioma (DMPM) 73 and others 109. There were 152 redo-peritonectomy procedures within the total mentioned earlier (CRC 26; DPAM 58; DMPM 18; appendix 40; other 10). The 5-year survivals for DPAM and PMCA were 80% and 42% respectively. The 5-year survivals for appendiceal cancer with peritoneal cancer index (PCI) <10, 10-20 and >20 were 60, 57 and 37% respectively (P = 0.09). The 2- and 5-year survivals for CRC were 56 and 24% respectively. The 5-year survivals for PCI 0-5, 6-10, 11-15 and >15 were 59, 15, 7 and 0% respectively (P = 0.000). The 5-year survival for DMPM with PCI < 10, 10-20 and >20 were 100, 55 and 39% respectively (P = 0.01). CRS in combination with HIPEC provides a chance of long-term survival in selected cases of PC when compared with systemic therapy alone. © 2015 Royal Australasian College of Surgeons.
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Treatment of peritoneal metastases (PM) and liver metastases (LM) from colon cancer remains controversial. LM has been viewed as exclusion criterion for cytoreductive surgery (CRS) on the basis that such spread represents systemic disease. CRS and intraperitoneal chemotherapy (IPC) has gained increasing recognition as a treatment modality for selected patients with colon cancer and PM. This study analyses results of CRS and IPC for colon cancer and synchronous resection for treatment of LM and PM. Seventy-eight patients with PM/LM colon cancer were analysed. Forty-two patients with PM were treated for disease limited to the peritoneum (A), and 36 patients received treatment for both PM and LM (B). Overall survival (OS), disease-free survival (DFS), morbidity, mortality and recurrence were compared. Median OS and DFS was 32.8 and 13.5 months. The median OS for A and B were 45.5 and 24.4 months respectively. Within B patients, 18 had a peritoneal carcinomatosis index (PCI) >7 and >3 LM and median survival of 21.8 months compared with 18 patients with PCI ≤7 and LM ≤3 with median survival of 38.4 months. Median DFS for A and B were 17.7 and 8.5 months respectively. Twenty-seven in total experienced major complications following surgery. Sixty-one patients recurred. Of A, 71.4% recurred compared with B at 86.1%. While our study is limited, it has demonstrated encouraging evidence that long-term survival outcomes can be achieved in this small but significant number of patients treated by CRS/IPC and additional synchronous liver resection with no significant increase in morbidity when compared with CRS/IPC alone. © 2015 Royal Australasian College of Surgeons.
Article
Objective: Although quality assessment is gaining increasing attention, there is still no consensus on how to define and grade postoperative complications. This shortcoming hampers comparison of outcome data among different centers and therapies and over time. Patients and methods: A classification of complications published by one of the authors in 1992 was critically re-evaluated and modified to increase its accuracy and its acceptability in the surgical community. Modifications mainly focused on the manner of reporting life-threatening and permanently disabling complications. The new grading system still mostly relies on the therapy used to treat the complication. The classification was tested in a cohort of 6336 patients who underwent elective general surgery at our institution. The reproducibility and personal judgment of the classification were evaluated through an international survey with 2 questionnaires sent to 10 surgical centers worldwide. Results: The new ranking system significantly correlated with complexity of surgery (P < 0.0001) as well as with the length of the hospital stay (P < 0.0001). A total of 144 surgeons from 10 different centers around the world and at different levels of training returned the survey. Ninety percent of the case presentations were correctly graded. The classification was considered to be simple (92% of the respondents), reproducible (91%), logical (92%), useful (90%), and comprehensive (89%). The answers of both questionnaires were not dependent on the origin of the reply and the level of training of the surgeons. Conclusions: The new complication classification appears reliable and may represent a compelling tool for quality assessment in surgery in all parts of the world.
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Twenty cases of ovarian metastases derived from appendiceal adenocarcinomas were analyzed. The most common presentation was a pelvic mass. The appendiceal and ovarian tumors were diagnosed concurrently in 15 cases; in the remaining five, the ovarian tumors were diagnosed before the appendiceal tumor. The appendiceal adenocarcinomas demonstrated four morphologic patterns: 1) signet ring cell type, with or without glandular or goblet cell differentiation (14 cases); 2) mixed signet ring cell and intestinal type (two cases); 3) intestinal type (two cases); and 4) typical colorectal type (two cases). The ovarian tumors were bilateral in 16 cases and were histologically similar to the associated appendiceal tumor in each case. Ovarian metastases that demonstrate signet ring cell, glandular, and goblet cell differentiation mimic metastases from gastric adenocarcinoma. Those that are derived from well-differentiated mucinous appendiceal adenocarcinomas mimic primary ovarian mucinous tumors and metastases from the pancreas and biliary tract. Metastases of appendiceal adenocarcinomas of colorectal type simulate both metastatic colorectal carcinoma and primary ovarian endometrioid carcinomas. The appendiceal and ovarian tumors were immunophenotypically identical in each case. Approximately 50% of the appendiceal and ovarian tumors were positive for cytokeratin 7 (CK 7), and all were positive for cytokeratin 20 (CK 20). CK 20 positivity of the ovarian tumors is consistent with gastrointestinal origin; CK 7 positivity does not confirm ovarian origin, because appendiceal carcinomas are positive in 50% of cases. Metastatic appendiceal adenocarcinoma should be considered in the differential diagnosis of mucinous ovarian tumors with signet ring cell, goblet cell, or intestinal type differentiation, especially when these tumors are associated with extraovarian disease and are bilateral.
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Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) is a treatment commonly applied to peritoneal surface disease from low-grade mucinous tumors of the appendix. Some centers have extended this therapy to carcinomatosis from more aggressive malignancies. Therefore, we reviewed our experience with CRS/HIPEC for patients with goblet cell carcinomatosis. Patients with carcinomatosis from appendiceal primaries with goblet cell features were identified in a prospectively maintained database of 1198 CRS/HIPEC procedures performed between 1991 and 2014. Patient demographics, disease characteristics, morbidity, mortality, and survival were reviewed. A total of 31 patients with carcinomatosis originating from appendiceal goblet cell tumors underwent CRS/HIPEC during the study period. Patients were generally young (mean age, 53 y) and otherwise healthy (84% without comorbidities) with good performance status (94% Eastern Cooperative Oncology Group 0 or 1). The mean number of visceral resections was 3.5, and complete cytoreduction of macroscopic disease was accomplished in 36%. Major 90-d morbidity and mortality rates were 38.7% and 9.7%, respectively. Median overall survival (OS) for all patients was 18.4 mo. Patients with negative nodes had better survival than those with positive nodes (median OS, 29.2 versus 10.2 mo), respectively (P = 0.002). Although complete cytoreduction was associated with longer median OS after CRS/HIPEC (R0/R1 28.6 versus R2 17.2 mo, P = 0.47), the observed difference did not reach statistical significance. CRS/HIPEC may improve survival in patients with node negative goblet cell carcinomatosis when a complete cytoreduction is achieved. Patients with disease not amenable to complete cytoreduction should not be offered CRS/HIPEC. Copyright © 2015 Elsevier Inc. All rights reserved.
Article
The classification of appendiceal mucinous neoplasms has been controversial, largely focused on a particular subset of low-grade mucinous tumors that, despite their innocuous appearance, can disseminate to the peritoneal cavity as pseudomyxoma peritonei (PMP). Recent WHO classification of these tumors as low-grade appendiceal mucinous neoplasms acknowledges their unique morphologic appearance and biologic behavior. Still, debate about the use of this term and its parameters continues to impede the adoption of consensus classification for appendiceal mucinous neoplasms. The classification of PMP has also been the subject of debate, with international authorities advocating for the use of malignant terminology to describe all grades of PMP, even though some authorities consider low-grade PMP to be dissemination of adenomatous epithelium in the peritoneum. Recent data also emphasize the importance of histologic grade of the peritoneal tumors in defining prognosis of these patients.
Article
Background Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemoperfusion (HIPEC) is routinely used to treat certain peritoneal carcinomatoses (PC), but it can be associated with relatively high complication rates, prolonged hospital length of stay, and potential mortality. Our objective was to determine the learning curve (LC) of CRS/HIPEC in our high-volume institution. Methods A total of 370 patients with PC from mucinous appendiceal neoplasms (MAN = 282), malignant peritoneal mesothelioma (MPM = 60), and gastric cancer (GC = 24) were studied. Outcomes analyzed included incomplete cytoreduction (IC), severe morbidity (SM), 60-day mortality, progression-free survival (PFS), and overall survival (OS). Risk-adjusted sequential probability ratio test (RA-SPRT) was employed to assess the LC of CRS/HIPEC for IC and SM using prespecified odds ratio (OR) boundaries derived from previously published data. Risk adjusted-cumulative average probability (RA-CAP) was used to analyze 1-year PFS and 2-year OS. Results Complete cytoreduction, severe morbidity, and 60-day mortality were 84.2, 30, and 1.9 % respectively. Higher simplified peritoneal cancer index was the major independent risk factor for IC, whereas high-grade histology, IC, and diagnosis of MPM and GC (compared with MAN) were predictors of SM after CRS/HIPEC (p
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Purpose: To compare the accuracy of MRI and CT for predicting the Peritoneal Cancer Index (PCI) preoperatively compared with the PCI tabulated at surgery. Methods: Twenty-two patients underwent preoperative MRI and CT scanning followed by cytoreductive surgery for appendiceal (n = 17) and ovarian (n = 5) cancer. MR and CT examinations were retrospectively reviewed to determine the PCI. The results of these scores were compared with PCI tabulated at surgery. Patients were categorized as small volume tumor (PCI 0-9), moderate volume (PCI 10-20), and large volume (PCI > 20). Respective anatomic site scores for MRI and CT were compared with surgical findings. Results: Compared with surgical PCI, MRI correctly categorized tumor volume in 20 (0.91) of 22 patients, including 3 of 4 patients with small volume tumor, 2 of 2 patients with moderate volume tumor, and 15 of 16 patients with large volume tumor. CT correctly categorized tumor volume in 11 of 22 (0.50) patients, including 2 of 4 patients with small-volume tumor, 2 of 2 patients with moderate volume tumor, and 7 of 16 patients with large-volume tumor. In 19 of 22 patients, CT underestimated the volume of tumor found at surgery. For all patients, the median PCI score at surgery was 33 compared with 36 for MRI and 15 for CT. Surgery confirmed 222 sites of tumor. MRI demonstrated per site sensitivity of 0.95, specificity 0.70, and accuracy 0.88. CT showed a corresponding per site sensitivity 0.55, specificity 0.86, and accuracy 0.63. Conclusions: MRI more accurately predicts PCI preoperatively in patients undergoing evaluation for cytoreductive surgery.
Article
Background Left upper quadrant involvement by peritoneal surface disease (PSD) may require distal pancreatectomy (DP) to obtain complete cytoreduction. Herein, we study the impact of DP on outcomes of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). Methods Analysis of a prospective database of 1,019 procedures was performed. Malignancy type, performance status, resection status, comorbidities, Clavien-graded morbidity, mortality, and overall survival were reviewed. Results DP was a component of 63 CRS/HIPEC procedures, of which 63.3 % had an appendiceal primary. While 30-day mortality between patients with and without DP was no different (2.6 vs. 3.2 %; p = 0.790), 30-day major morbidity was worse in patients receiving a DP (30.2 vs. 18.8 %; p = 0.031). Pancreatic leak rate was 20.6 %. Intensive care unit days and length of stay were longer in DP versus non-DP patients (4.6 vs. 3.5 days, p = 0.007; and 22 vs. 14 days, p
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Background Cytoreductive surgery (CRS) plus perioperative intraperitoneal chemotherapy is a highly invasive treatment of peritoneal metastasis and requires many surgical procedures before mastering. The aim of this study was to estimate how many procedures are needed before stabilization can be seen in surgical outcome (R1 surgery, adverse events and bleeding) in patients with pseudomyxoma peritonei (PMP). Patients and methods All 128 patients with PMP who were treated with CRS alone or CRS plus perioperative intraperitoneal chemotherapy between 2003 and 2008 at the Uppsala University Hospital, Uppsala, Sweden, were included. The learning curve was calculated using the partial least square (PLS) and cumulative sum control chart (CUSUM) graph. Two groups were formed based on the results of the learning curve. The learning curve plateau was considered the same as the stabilization in the CUSUM graph. Group I consisted of patients included during the learning period (n = 73) and Group II of patients treated after the learning period ended (n = 55). Comparisons between the groups were made on surgical outcome, survival and adverse events. Results Stabilization was seen after 220 ± 10 procedures. A higher occurrence of R1 surgery was seen in Group II (80%) compared to Group I (48%; P = 0.0002). Overall survival increased at four years after surgery in Group II compared to Group I (80% vs. 63%; P = 0.02). Conclusion CRS plus perioperative intraperitoneal chemotherapy is a highly demanding procedure that requires more than 200 procedures before optimisation in surgical outcome is seen.
Article
The decision to perform optimal surgery when peritoneal metastases (PM) are associated with liver metastases (LM) is extremely complex. No guidelines exist. The purpose of this study was to present a simple and useful statistical tool that generates a graphical calculator (nomogram) to help the clinician rapidly estimate individualized patient-specific survival before undergoing optimal surgery. An analysis of 287 patients with liver metastasis (LM), 119 patients with peritoneal metastasis (PM), and 37 patients with LM + PM, who underwent optimal surgery plus chemotherapy between 1995 and 2010 was performed. A minimal number of parameters were taken into account to obtain a nomogram that would be very simple to use. With the overall tumor load as the main prognostic factor, we included the number of lesions for LM and the peritoneal carcinomatosis score (PCI) for PM. The Cox model was used to generate the nomogram. The 5-year overall survival was, respectively, 38.5, 36.5, and 26.4 % in the LM group, the PM group, and the LM + PM group. The summation of 3 parameters (the number of LM, the PCI, and the type of surgery [liver resection, HIPEC, or both]), makes it easy to calculate a score that graphically corresponds to an estimation of survival after optimal surgery (nomogram). It can be used for LM alone, PM alone, or both. A graphic nomogram that is simple to calculate and easy to use enables us to rapidly appreciate the prognosis of patients according to the number of LM, the PCI, or both. This nomogram must be validated in prospective studies in other tertiary centers.
Article
The discovery of unexpected peritoneal carcinomatosis (PC) at the time of hepatectomy for colorectal liver metastases (CLM) is usually considered a contraindication for continuing resection. The first aim of this study was to assess the long-term outcome of patients operated for CLM, and who presented unexpected PC during laparotomy. The second aim was to identify preoperative predictors of PC. All patients at a single center between 1985 and 2010 who had unexpected PC, discovered during planed resection of CLM, and negative preoperative imaging for PC were selected. Clinicopathological data were retrospectively analyzed to assess survival outcomes and to identify predictors of unexpected PC. Out of the 1340 operated patients for CLM, 42 (3%) had unexpected PC. Only patients (n = 30; 71%) who had PC limited to two abdominal regions (Median peritoneal cancer index (PCI): 2 (1-6)) were resected. Twelve patients were not resected due to the extent of peritoneal disease. The overall survival of the 30 patients resected for CLM who had limited PC was 18% at 5 years (median: 42 months). On multivariate analysis, a previous history of PC, a pT4 stage and bilobar CLM were independent predictors of unexpected PC. Unexpected PC should not be a contraindication for resection provided that the PCI is low and complete resection of all peritoneal and hepatic lesions can be achieved. Previous history of PC, a pT4 primary tumor and bilobar CLM are associated with increased risk of unexpected PC.
Article
Although, numerous clinical attempts have been made to disintegrate mucin secreted by pseudomyxoema peritonei (PMP), none are in clinically recommended. Through examination of the pharmacologic characteristics of two novel agent, we titrated an optimized combination of Bromelain and N-Acetyl Cysteine that demonstrates in-vitro and in-vivo efficacy in the dissolution of mucinous ascites from PMP. In the in-vitro experiments, one gram of mucin was incubated in varying concentration of bromelain (0 - 400 ug/ml) and NAC (0-5%) individually followed by a combination before arriving at a therapeutic combination dose of 300 ug/ml bromelain + 4% NAC. This established an effective dose of Bromelain 300 ug/ml + 4% NAC at pH 7.0. When tested in a rat model implanted with 3g of mucin intraperitoneally (ip). IP administration of the drug in a rat model of PMP was shown to result in mucin disintegration within 72 hours with no toxicity observed. SIGNIFICANCE - An effective pharmacologic combination of two novel agents - bromelain and n-acetyl cysteine has been shown to have mucolytic properties in the dissolution of mucinous ascites from pseudomyxoma peritonei. This finding may allow further therapeutic development of this combination agent to provide a medical based approach to managing this complex disease. © 2013 Wiley Periodicals, Inc.
Article
Mucinous ascites and pools of mucin within the peritoneal cavity associated with neoplastic, mucinous epithelium are the characteristic features of pseudomyxoma peritonei (PMP). Clinically, PMP presents with abdominal distension and gelatinous ascites. In female patients, pelvic masses can be seen. Radiologic findings on computed tomography include scalloping of the hepatic and splenic margins and dense ascites. Surgically, PMP is encountered as grossly visible mucin in the peritoneal cavity. The presence of mucin outside of the appendix, in the right lower quadrant, and beyond is an important diagnostic finding. The appendix may be distended or ruptured. In women, there is often bilateral surface involvement of the ovaries, raising the differential diagnosis of primary ovarian neoplasms; however, these are extremely rare causes of PMP. Because of the association between appendiceal lesions and metastatic mucinous neoplasms of the ovary, appendectomy in the setting of any mucinous peritoneal or ovarian process may be prudent, even if the appendix is grossly normal. The gastrointestinal tract, especially the hepatopancreato biliary system, also needs to be assessed by the surgeon. Pathologically, PMP arises almost exclusively from low- or high-grade mucinous neoplasms of the appendix. These neoplasms must be distinguished both from rare benign causes of mucinous ascites and from nonappendiceal primary tumors. PMP has a protracted clinical course with progressive fibrous adhesions and obstructive disease; aggressive surgical and cytoreductive therapy with hyperthermic intraperitoneal chemotherapy has been reported to improve clinical outcomes.
Article
Background: The surgical management of mucinous adenocarcinoma of the appendix (MA) is controversial, given its infrequent nodal metastases and its propensity for peritoneal dissemination compared to nonmucinous adenocarcinoma. We sought to identify the appropriateness of a right hemicolectomy (RH) for MA in staging and treatment of these tumors. Methods: We queried all patients with MA captured in the Surveillance, Epidemiology, and End Results (SEER) database from 1973 to 2007. Demographics, and tumor and therapy characteristics were extracted. Overall and disease-specific survival was compared by Cox regression analyses. Results: Of 2,101 patients with MA, the median age was 59 (range 49-72) years; 55 % were women (n = 1,151). Tumor, node, metastasis staging revealed that tumors were frequently T3 (33 %) or T4 (46 %), N0 (80 %), and M1 (46 %). Fifty-one percent (n = 666) of patients underwent an appendectomy. In patients with complete staging information who underwent RH, nodal metastases were less frequent than the nonmucinous adenocarcinoma group (odds ratio 0.63, p = 0.003). Well-differentiated tumors had a low likelihood of nodal metastases (6 % T1, 0 % T2, 7 % T3, 22 % T4). Adjusted survival for patients undergoing appendectomy was similar to those undergoing a RH (hazard ratio 0.93, p = 0.52). Median survival for both groups was similar with positive nodes (28 [appendectomy] vs. 26 months [RH], p = 0.26) or metastatic disease (52 [appendectomy] vs. 43 months [RH], p = 0.28). Conclusions: There does not appear to be a therapeutic benefit to a RH in the setting of known node-positive or metastatic disease. Benefits of a staging operation can be individualized on the basis of the probability of nodal metastases, which is lower than nonmucinous tumors.
Article
Objective: Assess the overall outcome in colorectal cancer (CRC) patients that present with a combination of peritoneal metastases (PM) and liver metastases (CRLM) after curative resection and hyperthermic intraperitoneal chemotherapy (HIPEC) in the current literature. Methods: A systematic literature search according to the PRISMA guidelines was conducted using the PubMed database of the U.S. National library of Medicine using the keywords: colorectal cancer, liver metastasis, extra-hepatic, peritoneal metastases, peritoneal carcinomatosis, cytoreductive surgery (CRS), HIPEC and combinations hereof. Papers focussing on CRS and HIPEC for PM combined with curative treatment of CRLM were included, provided sufficient information on survival outcomes could be extracted. Duplicate publications were excluded. Meta-analysis was performed using the method described by Tierney et al. Results: After screening and full-text assessment of 39 papers, six articles were included containing data on combined PM and CRLM in patients treated with curative resection of both sites and HIPEC or early postoperative intraperitoneal chemotherapy (EPIC). Three articles provided enough statistical information for meta-analysis. Pooled hazard ratio (HR) was extracted from survival curves and was 1.24 (CI 0.96-1.60). A comparison was made with patients presenting with isolated PM undergoing CRS and HIPEC and with patients with disseminated disease undergoing (modern) systemic chemotherapy. Conclusions: In the absence of randomized controlled studies, we found in this systematic review and meta-analysis of patients with a combination of colorectal metastases in the liver as well as in the peritoneum show a trend towards a lower overall survival after curative resection and HIPEC, when compared to patients with isolated peritoneal metastases after CRS and HIPEC (pooled HR1.24, CI 0.96-1.60). However, patients with metastatic CRC show a tendency towards increased median overall survival after CRS and HIPEC combined with resection of liver metastases when compared to treatment with modern systemic chemotherapy.
Article
Objective: This study aimed to assess the prognostic impact of liver metastases (LM) in patients with colorectal peritoneal carcinomatosis (PC) who underwent complete cytoreductive surgery and resection of LM, followed by intraperitoneal chemotherapy. Background: Synchronous surgical treatment of PC and LM with curative intent remains controversial. Methods: From a prospective database, all patients with PC and synchronous LM who had undergone cytoreductive surgery and LM resection followed by intraperitoneal chemotherapy were matched with patients with PC alone according to the following criteria: age, peritoneal cancer index (PCI), site and lymph node involvement (pN) of primary cancer, and postoperative chemotherapy. Results: From 1993 to 2009, 37 patients with PC and LM were matched with 61 patients with PC alone. After a mean follow-up of 36 months, 3-year overall survival (OS) and disease-free survival rates were significantly lower in patients with PC and LM, respectively, 40% and 66% (P = 0.04) and 6% and 27% (P = 0.001). A PCI of 12 or more [odds ratio (OR): 4.6], a pN+ status (OR: 3.3), no adjuvant chemotherapy (OR: 3.0), and presence of LM (OR: 2.0) were identified as independent factors for poor OS. Three groups were singled out: (1) patients with a low PCI (<12) and no LM (median OS: 76 months); (2) patients with a low PCI (<12) and 1 or 2 LM (median OS: 40 months); and (3) patients with a high PCI (≥12) or patients with 3 LMs or more (median OS: 27 months). Conclusions: This case-control study seems to confirm that prolonged survival can be achieved in highly selected patients operated on for limited PC and fewer than 3 LM.
Article
Background: We assessed the learning curve (LC) of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in treating peritoneal surface malignancies (PSM) in two centers and evaluated in which extent surgical tutoring could abbreviate the learning process. Methods: Six hundred and forty-one cases submitted to CRS using peritonectomy procedures and HIPEC were considered. After having overcome its own LC, the NCI of Milan has provided technical assistance to Bentivoglio's centre for the development of a new PSM program since 2003. The risk-adjusted sequential probability ratio test (RA-SPRT) was employed to assess the LC of the two centers. Outcomes were incomplete cytoreduction, G3-5 morbidity (NCI-CTCAE.v3) and procedure-related mortality (PRM). Results: Rates of incomplete cytoreduction, G3-5 morbidity, and PRM were 8.4%, 30.1%, and 3.9%, respectively, in the entire series. The breaking points of the LC concerning incomplete cytoreduction, G3-5 morbidity, and PRM were achieved at 141, 158, and 144 cases, in the Milan's experience, and at 126, 134, and 60 cases in the Bentivoglio's experience. Conclusions: Surgical tutoring could substantially shorten the steep LC associated with CRS and HIPEC. Our data should be confirmed by further studies on LC focusing oncological outcomes. Other factors that could influence the length of learning process should be identified.
Article
For 15 patients with refractory gastric cancer and peritoneal metastasis, intraperitoneal hyperthermic perfusion (IPHP) using mitomycin C combined with extensive surgery was prescribed. The antitumor effects were assessed cytohistologically in pre-IPHP and post-IPHP specimens of the abdominal effusion and peritoneal tissue. Gastric cancer cells in the abdominal effusion and/or lavage vanished from post-IPHP peritoneal exudate obtained from the pouch of Douglas. Peritoneal tissues from nine patients were harvested just after the IPHP treatment. All the nuclei of cancer cells were pyknotic in three of nine patients, and two of these three patients are alive with no local recurrence; one patient died of hepatic metastasis. In the remaining six patients, four with preoperative ascitic effusion and positive post-IPHP histologic findings died of peritoneal, intraabdominal, and pericardial metastases. The other two had some residual microscopic foci in the subperitoneal deep layer; one patient died of pleural recurrence, and the other is alive with no evidence of recurrence 42 months after the IPHP. Among the other six patients, whose post-IPHP peritoneal tissues were not available because of disappearance of disseminating foci as a result of the IPHP, two are living with no recurrence and, of the remaining four patients, three died of hepatic and intraabdominal metastases and the other one died of other causes. The histologic findings are suggestive of the following: (1) uniform heat and drug distribution in the abdominal cavity with IPHP treatment, except for an area adjacent to the inflow point of the perfusate; and (2) limited penetration of heat and drug through the subperitoneal layer. Thus, IPHP treatment results in complete destruction of cancer cells in the abdominal effusion and on and just beneath the peritoneum.
Article
Malignant neoplasms of the appendix have different behavior based on their histologic subtypes in anecdotal series. Current staging systems do not capture the diversity of histologic subtypes in predicting outcomes. We queried all patients with appendiceal malignancies captured in the Surveillance, Epidemiology, and End Results (SEER) database from 1973 to 2007. Tumors were classified as colonic type adenocarcinoma, mucinous adenocarcinoma, signet ring cell type, goblet cell carcinoid, and malignant carcinoid. We compared incidence, overall survival, and disease-specific survival for these tumors on the basis of patient, tumor, and therapy characteristics. Estimates from Cox proportional hazard modeling were used to predict hazard ratios for differing histologic subtypes with similar tumor, node, metastasis system (TNM) stages. Of the 5672 patients identified, we included 5655 (99%) in our analysis. The 5-year disease-specific survival rates were 93% for malignant carcinoid, 81% for goblet cell carcinoid, 55% for colonic type adenocarcinoma, 58% for mucinous adenocarcinoma, and 27% for signet ring cell type. Predicted estimates of adjusted hazard ratios revealed an 8-fold difference between histologic subtypes for similar TNM stages. Histologic subtype is an important predictor of disease-specific survival and overall survival in patients with appendiceal neoplasms. Addition of the histologic subtype to the TNM staging is simple and may improve prognostication.
Article
To evaluate the utility of CT of peritoneal carcinomatosis (PC) by comparing preoperative radiological and intraoperative peritoneal cancer index (PCI) scores. This study collected 76 patients of PC from different disease origins. The sensitivity, specificity and accuracy were calculated in each of the abdominopelvic region, and by tumor histologic type. An overall sensitivity of CT was 69%. The detection rate was highest in appendix and lowest in stomach group( 84% and 47%, respectively) by the origin of primary disease. There was a lower detection rate (59% vs 79%, p=0.001), and a higher underestimation rate (29% vs 21%, p<0.05) of small bowel lesion compared with overall abdomino-pelvic region. CT predicted an individual regional PCI score accurately in 65%, underestimated in 24%, and overestimated in 11%. CT detection rate in small tumor (<0.5 cm) was 29%, and increased to 97% with nodules size exceeding 5 cm. CT significantly underestimated the clinical PCI value in overall. The sensitivity of CT in detecting PC was influenced by histologic type, tumor location and size. CT underestimated the clinical PCI score in PC patient.
Article
For many years the clinical syndrome of PMP has been enigmatic. Based on recent studies reevaluating the condition, tumors previously designated PMP can now be viewed as two pathologically and prognostically distinct disease processes. Disseminated peritoneal adenomucinosis is characterized by copious mucinous ascites (the classical clinical syndrome of PMP) and histologically bland peritoneal mucinous tumors. The condition can be attributed to a ruptured appendiceal mucinous adenoma in the vast majority of cases. It has an indolent clinical course when surgically treated but may recur over months to years. Peritoneal mucinous carcinomatosis is characterized by abundant peritoneal mucinous tumor, similar to the clinical presentation of adenomucinosis. However, microscopically, the peritoneal tumors have the architectural and cytologic features of carcinoma, are derived from gastrointestinal mucinous adenocarcinomas, and are associated with a significantly worse prognosis than cases of adenomucinosis. A third group of tumors displays intermediate or discordant histologic features but manifests a clinical course very similar to cases of pure peritoneal carcinomatosis. Women often have concomitant ovarian mucinous tumors that suggest primary ovarian neoplasia. Morphologic, immunohistochemical, and molecular studies support the interpretation that the ovarian tumors are secondary and that adenomucinosis is of appendiceal origin in women as well as men. The recognition that the ovarian tumors in nearly all of the cases of DPAM and mucinous carcinomatosis are secondary seriously calls into question the existence of a borderline group of ovarian mucinous tumors. Therefore, primary ovarian mucinous tumors should be classified as either benign or malignant. Tumors exhibiting the features currently interpreted as borderline should be included in the benign group and designated atypical proliferative mucinous tumors.
Article
Pseudomyxoma peritonei syndrome is a clinical entity characterized by mucinous ascites usually originating from a perforated mucinous appendiceal tumor. Currently optimal therapy is considered complete macroscopic tumor removal (complete cytoreduction) combined with heated intraperitoneal chemotherapy. When complete cytoreduction is not achievable, major tumor debulking is undertaken. The long-term follow-up of patients undergoing surgery for perforated appendiceal tumors in a national pseudomyxoma center is reported. Between March 1994 and July 2009, 456 patients with pseudomyxoma peritonei syndrome from perforated appendiceal tumors underwent surgery. The treatment strategy involved a combination of cytoreductve surgery aiming for macroscopic tumor removal, combined with hyperthermic intraperitoneal chemotherapy with mitomycin C. Where complete tumor removal was not possible, maximal tumor debulking was performed. Perioperative outcomes and predicted 5- and 10-year survival are reported. Overall 15 of 456 (3%) tumors were not resectable at laparotomy. Of the 441 patients who had resection, 289 (66%) had complete cytoreduction and 152 (34%) had major tumor debulking. Postoperative in-hospital mortality was 1.6% and grade 3/4 morbidity was 7%. The Kaplan-Meier method predicted 5- and 10-year overall survival of 69% and 57%, respectively. Five- and 10-year predicted survival was 87% and 74% for the 289 patients who had complete cytoreduction compared with 34% and 23% for the 152 who had major tumor debulking. Complete tumor removal was achieved in 289 of 441 (66%) patients with peritoneal dissemination from perforated appendiceal tumors with good long-term survival and probable cure in more than two-thirds.
Article
In the past, cancer surgery for gastrointestinal malignancy focused on clearance (an R-0 resection) and containment (no surgically induced spillage of cancer cells). A new responsibility that cancer surgeons must accept is the knowledgeable prevention or treatment of cancer that disseminates to peritoneal surfaces. Carcinomatosis can be prevented and can be successfully treated using cytoreductive surgery and perioperative chemotherapy. J. Surg. Oncol. 2010;101:713-724. (C) 2010 Wiley-Liss, Inc.
Article
Cancer dissemination on peritoneal surfaces can be treated by cytoreductive surgery and perioperative intraperitoneal chemotherapy. To maximize benefits a complete cancer removal precedes the chemotherapy treatments. During cytoreductive surgical procedures a variable bridge of liver parenchyma that covers the round ligament of the liver was observed. This bridge of liver parenchyma is referred to as the pont hepatique (hepatic bridge). Failure to remove tumor nodules from beneath the pont hepatique will result in recurrent disease. If the pont hepatique is opened as part of a cytoreductive procedure for peritoneal dissemination of cancer, cancer nodules will often be found beneath. These nodules can be removed using electrosurgical dissection taking care to avoid damage to the left hepatic artery. Division of the pont hepatique and removal of cancer nodules around and on the round ligament will facilitate a complete cytoreduction.
Article
Primary signet-ring cell carcinoma (SRC) of colorectal and appendiceal origin is a rare entity with an aggressive biology and clinical behavior. The majority of patients develop peritoneal carcinomatosis (PC) early in the disease. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) may potentially improve survival. An observational study of 33 patients with SRC of colorectal or appendiceal origin was identified through a retrospective review of two peritoneal surface malignancy databases between January 1997 and December 2008. Survival analysis was performed using the Kaplan-Meier method. Thirty-three patients (18 women (55%); mean age at diagnosis of carcinomatosis, 49 (standard deviation = 12) years) were identified to have SRC, with 15 cases of colorectal and 18 of appendiceal origin. For patients with colonic SRC who underwent complete CRS and HIPEC versus systemic chemotherapy only, the median survival was 13 and 18 months (P = 0.75). For patients with appendiceal SRC who underwent complete CRS and HIPEC versus systemic chemotherapy only, the median survival was 27 and 15 months (P = 0.12). There seems to be less survival benefits after a complete CRS and HIPEC as a curative treatment for PC from colorectal SRC compared with that for non-SRC colorectal adenocarcinoma. However, in patients with appendiceal SRC, long-term survival is a reality after treatment.
Article
The lack of consensus on how to define and grade adverse postoperative events has greatly hampered the evaluation of surgical procedures. A new classification of complications, initiated in 1992, was updated 5 years ago. It is based on the type of therapy needed to correct the complication. The principle of the classification was to be simple, reproducible, flexible, and applicable irrespective of the cultural background. The aim of the current study was to critically evaluate this classification from the perspective of its use in the literature, by assessing interobserver variability in grading complex complication scenarios and to correlate the classification grades with patients', nurses', and doctors' perception. Reports from the literature using the classification system were systematically analyzed. Next, 11 scenarios illustrating difficult cases were prepared to develop a consensus on how to rank the various complications. Third, 7 centers from different continents, having routinely used the classification, independently assessed the 11 scenarios. An agreement analysis was performed to test the accuracy and reliability of the classification. Finally, the perception of the severity was tested in patients, nurses, and physicians by presenting 30 scenarios, each illustrating a specific grade of complication. We noted a dramatic increase in the use of the classification in many fields of surgery. About half of the studies used the contracted form, whereas the rest used the full range of grading. Two-thirds of the publications avoided subjective terms such as minor or major complications. The study of 11 difficult cases among various centers revealed a high degree of agreement in identifying and ranking complications (89% agreement), and enabled a better definition of unclear situations. Each grade of complications significantly correlated with the perception by patients, nurses, and physicians (P < 0.05, Kruskal-Wallis test). This 5-year evaluation provides strong evidence that the classification is valid and applicable worldwide in many fields of surgery. No modification in the general principle of classification is warranted in view of the use in ongoing publications and trials. Subjective, inaccurate, or confusing terms such as "minor or major" should be removed from the surgical literature.
Article
An aggressive therapy comprising of cytoreductive surgery (CRS) and perioperative intraperitoneal chemotherapy (PIC) and liver resection/ablation is generally not offered to patients with both colorectal peritoneal carcinomatosis (CRPC) and liver metastases (LM) as it no longer represents a loco-regional disease. We review the outcomes of patients who underwent an aggressive treatment with a curative intent for both CRPC and LM as a prelude towards determining the suitability of this treatment. Patients with CRPC were treated with cytoreductive surgery and perioperative intraperitoneal chemotherapy in our institution. Patients with LM underwent additional treatment of liver resection/ablation. The characteristics and survival of patients with isolated CRPC and those with both CRPC and LM were compared. Fifty-five patients underwent complete cytoreductive surgery for treatment of CRPC, amongst which 16 patients had LM. The overall median survival was 36 months. Fourteen of the 16 patients treated for CRPC and LM underwent synchronous treatment. When patients with CRPC alone or CRPC with LM were compared, patients with CRPC and LM had a lower PCI (p=0.03), received less HIPEC infusion (p<0.001), received less of both HIPEC and EPIC infusion (p=0.007), had a shorter procedural duration (p=0.001) and required less blood transfusion (p=0.02). There was no difference in survival between patients who had CRPC alone or CRPC with LM who underwent aggressive treatment (p=0.77). A curative procedure may be offered to selected patients with CRPC and LM, especially in those with a low peritoneal cancer index.
Article
Respiratory diseases such as asthma and COPD (chronic obstructive pulmonary disease) are characterized by increased numbers of goblet cells and excessive mucus production, which contribute to the underlying disease pathology. Mucins form a major component of the mucus contributing to its viscoelastic properties, and in the airways the mucins MUC5AC and MUC5B are found at increased levels in both asthmatic and COPD subjects. A diverse range of stimuli have been shown to regulate MUC5AC expression and cause increases in the number of mucus-producing goblet cells. Perhaps the best characterized of these mediators is the cytokine IL (interleukin)-13, which causes increases in MUC5AC-expressing goblet cells in the airways. Several transcription factors have been linked with goblet cell formation and mucus production and include STAT6 (signal transducer and activator of transcription 6), FOXA2 (forkhead box A2) and the SPDEF [SAM (sterile alpha motif) domain-containing prostate-derived Ets factor]. In mouse airways, goblet cells are normally rare or absent, but increase rapidly in number in response to certain stimuli. The origins of these goblet cells are not well understood, although Clara cells and ciliated cells have been implicated as goblet cell progenitors. An understanding of the origin and processes regulating goblet cell formation in human airway epithelial cells has important implications for the identification of therapeutic targets to treat respiratory diseases.
Article
The appendiceal malignancies usually arise within a mucocele. The tumor within this structure can be minimally aggressive or of an invasive character. If a low-grade appendiceal malignancy is removed intact, recurrence does not occur. If rupture of the wall of the mucocele occurs with either low-grade or high-grade disease, the epithelial cells within will disseminate to the peritoneal surfaces. Sometimes a second-look surgery must be performed to determine if intraperitoneal spread of mucus and cancer cells has occurred. If the diagnosis of peritoneal dissemination of an appendiceal malignancy has been established, a new treatment with curative intent is indicated. Cytoreductive surgery is combined with perioperative intraperitoneal chemotherapy as a comprehensive management plan. In approximately 900 patients treated at the Washington Cancer Institute, the quantitative prognostic indicators for appendiceal cancer with peritoneal dissemination have been determined. Patients with a complete cytoreduction and low-grade tumor have an 80% survival at 20 years; with high-grade tumors, the survival drops to approximately 45%. The extent of malignancy present within the abdomen by the peritoneal cancer index has a significant impact on survival for both high-grade and low-grade disease. The most important indicator is the completeness of cytoreduction; for both high-grade and low-grade disease, all patients with an incomplete cytoreduction have died by 10 years. The presence versus absence of lymph nodal metastases on survival have minimal significance (P = 0.0495). These results of treatment can be achieved with a 19% incidence of severe complications and a 2% mortality.
Article
Cytoreductive surgery (CS) and intraperitoneal hyperthermic chemotherapy (IPHC) can improve outcomes for selected patients with peritoneal carcinomatosis (PC) from colorectal cancer. The presence of parenchymal hepatic metastases (HM) is considered a relative contraindication for CS and IPHC. The purpose of the current study was to compare the overall survival of patients with HM to those without and to examine predictive factors. This was a retrospective study of patients undergoing CS and IPHC between 1991 and 2007. Clinicopathologic information was obtained from a prospectively collected database and electronic medical records. Univariate and multivariate analyses were performed to evaluate variables predictive for overall survival. There were 142 patients who underwent CS and IPHC for PC from colorectal cancer, with 14 (9.9%) patients noted to have concurrent HM. The median number and size of the liver lesions was 1 (range, 1-7 lesions) and 3.0 cm (range, 0.4 cm-12 cm), respectively. The median overall survival for patients with HM was 23.0 months. Two-year and 4-year survival rates were 43.3% and 14.4%, respectively. Patients without HM had 2-year and 4-year survival rates of 36.8% and 17.4%, respectively. Overall survival was not significantly different for patients with and without HM (log-rank P=.39). Patients with HM undergoing CS and IPHC for colorectal cancer were found to have no significant difference in overall survival compared with those without HM. Most patients had a single small lesion treated with a minor hepatic resection. Further study is indicated to define which patients with HM benefit most from this multimodality approach.
Article
: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has been offered in many institutions worldwide since the 1990s. Despite its existence of more than 10 years, this treatment has received heavy criticism for its morbidity and mortality rates. This consequentially resulted in a lack of randomized trials being conducted and translates into a lack of the most reliable form of scientific evidence in clinical research, hence limiting its general acceptance. : To report the morbidity and mortality outcomes of CRS and HIPEC from all institutions performing this treatment as a prelude toward establishing the safety of this treatment for peritoneal carcinomatosis. : A systematic review of relevant studies before August 2008 was performed. Each study was appraised using a predetermined protocol. The quality of studies was assessed. The morbidity and mortality of the treatment were synthesized through a narrative review with full tabulation of results of all included studies. : The morbidity and mortality outcomes of CRS and HIPEC are similar to a major gastrointestinal surgery, such as a Whipple's procedure. To derive the maximal benefit of this treatment, careful patient selection with an optimal level of postoperative care must be advocated to avoid undesirable complications of this treatment.
Article
Peritoneal Cancer Index (PCI) has been recognized as an independent prognostic indicator for long-term outcomes. It also influences the likelihood of complete cytoreduction, another principal determinant of long-term survival. The objective of this study was to evaluate the utility of preoperative CT in estimating PCI during the patient selection process. The efficacy of CT in demonstrating peritoneal disease was evaluated by comparing the radiological and intraoperative lesion size and PCI scores using the Wilcoxon signed-rank test. Tumor distribution was assessed in each abdominopelvic region as tumor present versus absent. The sensitivity, specificity, positive predictive value, and negative predictive value were calculated in each abdominopelvic region. Overall, where CT identifies the presence of disease, it portrayed lesion size accurately in 60%, underestimated in 33%, and overestimated in 7% of cases. Analysis of individual abdominopelvic regions demonstrated a statistically significant difference between radiologically and intraoperatively visualized lesion sizes (P < 0.05) except in the epigastrium, left upper, and left flank regions. The sensitivity of CT in detecting peritoneal implants was influenced by lesion size. Small nodules (<0.5 cm) were visualized on CT with only a sensitivity of 11%, which is in contrast to 94% with nodules exceeding 5 cm. Radiological PCI scores significantly underestimated intraoperative PCI (P < 0.001). This study demonstrated that the sensitivity of CT in detecting peritoneal implants was influenced by lesion size and CT PCI significantly underestimated clinical PCI. The role of CT in refining patient selection and improving prognosis remains to be closely evaluated.
Article
Pseudomyxoma peritonei is a rare clinical entity in which the peritoneal surfaces and omentum are involved with diffuse gelatinous mucinous implants. It originates from ruptured mucinous tumors of the appendix or ovary. The authors examined the experience with 34 patients with pseudomyxoma peritonei seen at Memorial Sloan-Kettering Cancer Center from 1952-1989. Of these, 17 cases were identified to be of appendiceal origin. All patients underwent celiotomy and cytoreduction. The median survival time from diagnosis was 75 months. It was found that long-term survival can be achieved by operation alone. When conditions do recur, chemotherapy may be valuable. Pseudomyxoma peritonei of appendiceal origin is a rare low-grade malignancy. Initial treatment consists of cytoreduction in an attempt to render the patient locally disease-free. Long-term survival can be obtained by operation alone, even if gross disease is present at the end of the procedure. Systemic chemotherapy should be reserved for patients with proven recurrence.
Article
Pseudomyxoma peritonei (PMP) is a poorly understood condition characterized by mucinous ascites and mucinous implants diffusely involving the peritoneal surfaces. There is considerable debate regarding the definition, pathology, site of origin, and prognosis of PMP. We analyzed the clinicopathologic features of 109 cases of multifocal peritoneal mucinous tumors to develop a pathologic definition of cases characterized by the clinical condition PMP. Cases were separated into two diagnostic categories: disseminated peritoneal adenomucinosis (DPAM) and peritoneal mucinous carcinomatosis (PMCA). Cases classified as DPAM were characterized by peritoneal lesions composed of abundant extracellular mucin containing scant simple to focally proliferative mucinous epithelium with little cytologic atypia or mitotic activity, with or without an associated appendiceal mucinous adenoma. Cases classified as PMCA were characterized by peritoneal lesions composed of more abundant mucinous epithelium with the architectural and cytologic features of carcinoma, with or without an associated primary mucinous adenocarcinoma. Sixty-five of the 109 cases (59.6%) were classified as DPAM consistent with origin from an appendiceal mucinous adenoma. Thirty-seven of the 65 cases (56.9%) had a documented appendiceal mucinous adenoma. Thirty cases (27.5%) were classified as PMCA consistent with origin from an appendiceal or intestinal mucinous adenocarcinoma. Fourteen cases (12.8%) were classified as PMCA with features intermediate between DPAM and PMCA or with discordant features based on the finding of at least focal areas of carcinoma in the peritoneal lesions, whether or not the primary site demonstrated carcinoma. The cases with intermediate features were derived from well-differentiated appendiceal or intestinal mucinous adenocarcinomas and had peritoneal lesions displaying features of DPAM as well as focal areas of mucinous carcinoma. The cases with discordant features were derived from atypical appendiceal adenomas with little or no histologic evidence of a transition from adenoma to carcinoma and had peritoneal lesions uniformly composed of mucinous carcinoma. There was a statistically significant difference in survival between cases classified as DPAM, those classified as PMCA with intermediate or discordant features, and those classified as PMCA (p < 0.0001). The age-adjusted 5-year survival rates were 84% for patients with DPAM, 37.6% for patients with PMCA with intermediate or discordant features, and 6.7% for patients with PMCA. The term DPAM should be used to diagnose the histologically benign peritoneal lesions associated with ruptured appendiceal mucinous adenomas and those that are pathologically identical but lack a demonstrable appendiceal adenoma. Cases with the pathologic features of adenocarcinoma should be designated PMCA because they have recognizably different pathologic features and a significantly worse prognosis.