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Histological Subtype Remains a Significant Prognostic Factor for Survival Outcomes in Patients With Appendiceal Mucinous Neoplasm With Peritoneal Dissemination
Abstract
Background:
It has been increasingly recognized that appendiceal mucinous neoplasm with peritoneal dissemination is not a homogenous disease.
Objective:
This study aimed to examine the impact of different histological subtypes on survival of a large cohort of patients with appendiceal mucinous neoplasms uniformly treated by cytoreductive surgery and intraperitoneal chemotherapy.
Design:
This was a retrospective study of prospectively collected data of patients with peritoneal dissemination of appendiceal neoplasm who underwent cytoreductive surgery and intraperitoneal chemotherapy.
Setting:
The study was conducted by 1 surgical team at St. George Hospital.
Patients:
A total of 444 patients formed the cohort of this study.
Main outcome measures:
Histological diagnoses were categorized based on Carr criteria to include acellular mucin, disseminated peritoneal adenomucinosis, peritoneal mucinous neoplasms without signet ring cells, and peritoneal mucinous carcinomatosis with signet cells.
Results:
Patients with low-grade appendiceal mucinous neoplasms with neoplastic epithelium absent tended to have lower CEA, CA19-9, and CA125 levels preoperatively (p = 0.109, 0.008, and 0.034). Factor analysis showed that histological diagnosis was an independent prognostic factor for survival outcomes (HR = 3.13 (95% CI, 2.34-4.39); p < 0.001), adjusted for peritoneal cancer index >20, completeness of cytoreductive score ≥2, use of early postoperative intraperitoneal chemotherapy, transfusion units, CEA >7.0 mg/L, CA19-9 >24.0 U/mL, and CA125 >24 U/mL.
Limitations:
This study was limited by its retrospective nature, lack of uniform classifications of appendiceal mucinous neoplasms in early years, and the heterogeneity of this study cohort given the long study period.
Conclusions:
Histological subtype remains a significant prognostic factor for survival outcomes in patients with appendiceal mucinous neoplasms. It should be taken into account when selecting patients for cytoreductive surgery, tailoring appropriate adjuvant therapies and follow-up surveillance plan.
... Other factors that were found to be associated with prognosis by isolated study groups were severe postoperative complications [87,91] preoperative SCT [79], elevated Ca19-9 [92], and intraoperative transfusion [92]. Table 1. ...
... Other factors that were found to be associated with prognosis by isolated study groups were severe postoperative complications [87,91] preoperative SCT [79], elevated Ca19-9 [92], and intraoperative transfusion [92]. Table 1. ...
... There are two study groups that have recently evaluated the prognostic impact of the four-tiered PSOGI classification [77]. In 2017, Huang et al. [92] observed significant differences in OS across the four subgroups with a HR of 3.13, p < 0.001. The median OS in patients with AM and LGMCP was not reached; in patients with HGMCP, it was 58.2 months and 31.1 months in those with HGMCP-SRCs. ...
Appendiceal mucinous neoplasms have been classified differently over time causing confusion when comparing results between working groups in this field and establishing a prognosis of the disease. A historical perspective of the different classification systems of these tumors is essential for the understanding of the evolution of concepts and histopathological definitions that have led up to the present moment. We carried out a systematic review of the pathological classifications of appendiceal mucinous tumors and how they have included the new criteria resulting from clinical and pathological research. The latest classifications by PSOGI and AJCC 8th edition Cancer Staging have made a great effort to incorporate the new pathological descriptions and develop prognostic groups. The introduction of these new classification systems has posed the challenge of verifying how they adapt to our casuistry and which one defines best the prognosis of our patients. We reclassified our series of patients treated for mucinous appendiceal tumors with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy following the PSOGI and the AJCC 8th edition criteria and concluded that both classifications correspond well with the OS and DFS of these patients, with some advantage relative to the PSOGI classification due to a better histopathological description of the different groups.
... Reported results reported have been inconsistent. In 2017, Huang et al. [10] observed that the four-tiered PSOGI classification significantly correlated with survival whereas Baratti et al. [8] were unable to reproduce these results. In order to generate effective treatment and follow-up regimes, both a universal language and adequate patient stratification are needed. ...
... All patients with AM peritoneal deposits were alive at 5-years, decreasing to 93.6 % in LGMCP cases, 53.6 % in HGMCP and to 66.7 % in HGMCP-SRC. These survival outcomes are in agreement with results obtained by previous study groups [8,10,20,21] (see Table 3). Huang et al. [10] observed 5-year OS rates of 95.2 % in AM, 83 % in disseminated peritoneal adenomucinosis (DPAM), 47 % in peritoneal mucinous carcinomatosis (PMCA) and 12.6 % in PMCA-SRC. ...
... These survival outcomes are in agreement with results obtained by previous study groups [8,10,20,21] (see Table 3). Huang et al. [10] observed 5-year OS rates of 95.2 % in AM, 83 % in disseminated peritoneal adenomucinosis (DPAM), 47 % in peritoneal mucinous carcinomatosis (PMCA) and 12.6 % in PMCA-SRC. The nomenclature used in this study is outdated even though the pathologic subgroups correlate to those proposed by PSOGI. ...
Objectives
The Peritoneal Surface Oncology Group International (PSOGI) consensus subdivided pseudomyxoma peritonei (PMP) into four groups according to histopathological features. The aim of this paper is to report survival outcomes after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) from a national referral centre and to correlate the PSOGI classification with survival.
Methods
A retrospective study of a prospectively maintained database was performed. Consecutive patients treated with CRS + HIPEC for PMP of appendiceal origin were included (September-2013 to December-2021). Pathological features of the peritoneal disease were used to classify patients into the four groups proposed by PSOGI. Survival analysis was performed to evaluate the correlation of pathology on overall survival (OS) and disease-free survival (DFS).
Results
Overall, 104 patients were identified; 29.6 % were reclassified as acellular mucin (AM), 43.9 % as low-grade mucinous carcinoma peritonei (LGMCP), 22.4 % as high-grade MCP (HGMCP) and 4.1 % as HGMCP with signet ring cells (HGMCP-SRC). Median PCI and rate of optimal cytoreduction were 19 and 82.7 %, respectively. Median OS and DFS were not reached, 5-year OS and DFS were 88.6(SD 0.04) % and 61.6(SD 0.06) %, respectively. Log-Rank test revealed significant differences in terms of OS and DFS across the different histological subgroups (p<0.001 in both cases). However, histology did not retain its significance in the multivariate analysis for OS or DFS (p=0.932 and p=0.872, respectively).
Conclusions
Survival outcomes after CRS + HIPEC for PMP are excellent. The PSOGI pathological classification correlates with OS and DFS, but differences were not significant at multivariate analysis when adjusted for other prognostic factors.
... Treatment and prognosis of PMP for AMN has changed significantly since improved survival has been found with HIPEC and CRS compared to previously employed therapies, including chemotherapy, repeated peritoneal draining and surgical debulking in some retrospective series [10,11,24]. Since this shift in practice patterns, multiple factors have been examined with regard to their effect on outcomes following HIPEC and CRS, including: age, performance status, histopathologic subtype, completeness of cytoreduction, lymph node status, pre-operative chemotherapy, tumor markers, and PCI [13,15,[25][26][27]. Interestingly, common perioperative clinical factors affecting outcome, including postoperative surgical complications and extent of CRS, have not been shown to consistently affect survival for patients undergoing HIPEC and CRS for cancers of appendiceal origin [12,14,16,28]. ...
... It is well-established that pseudomyxoma peritonei from AMN is a heterogenous disease including multiple different histopathologic subtypes [1,10,14,26]. Furthermore, these subtypes have been shown to significantly affect survival in patients with AMN [13,14,26]. ...
... It is well-established that pseudomyxoma peritonei from AMN is a heterogenous disease including multiple different histopathologic subtypes [1,10,14,26]. Furthermore, these subtypes have been shown to significantly affect survival in patients with AMN [13,14,26]. Interestingly, multiple different systems exist for classifying this diverse group of tumors, with most basing their groupings on differences in survival. ...
Background
We hypothesize that women undergoing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal carcinomatosis from appendiceal cancer will have a survival advantage compared to men.
Methods
The National Cancer Database (NCDB) public user file (2004–2014) was used to select patients with PC undergoing CRS and HIPEC from appendiceal cancer. Univariate and multivariable analyses were performed.
Results
1,190 patients with PC from appendiceal cancer underwent HIPEC and CRS. OS was significantly longer for women than for men, with mean and median OS being 73.8 months and 98.2 months for women vs 58.7 months and 82.5 months for men, respectively (p = 0.0032). On multivariable analysis, male sex (HR: 1.444, 95% CI: 1.141–1.827, p = 0.0022) and increasing age (HR: 1.017, 95% CI: 1.006–1.027, p = 0.0017) were both found to be independent risk factors for worse OS.
Conclusion
Women undergoing CRS and HIPEC for PC from appendiceal origin live longer than men undergoing the same treatment. Increasing age was also found to be independent risk factors for worse survival
... A recent consensus statement supports CRS with perioperative loco-regional chemotherapy as the primary mode of treatment for PMP. 15 This is the second largest series reporting on outcomes following CRS and HIPEC for PMP in Australia and New Zealand. 31 Despite being a young peritoneal center, our survival data is comparable to other series demonstrating 5-year survival rates of 43 to 83%, [16][17][18][19][20][21][22] with 5-year DFS rates of 43 to 56%. 18,32 Our recurrence rate of 18.6% following CRS and HIPEC was lower than most other studies that have reported recurrence rates of 26.4 to 46%. ...
... This is not unexpected, with other series also reporting histological grade influencing survival. 9,31,[35][36][37][38] It is notable that neither completeness of cytoreduction nor the use of HIPEC influenced survival on multivariate analysis. This is possibly due to a number of reasons. ...
... Research focusing on patients presenting with HG histology is an area of need, as HG histology is associated with poorer overall and disease-free survival. 31 Current research into biomarkers, such as the loss of expression of carbonic anhydrase II as a predictor of HG histology in PMP, 42 may help in better patient selection for treatment and help identify early recurrence. Personalized therapy utilizing patientderived organoid models, with drug testing and individualized therapy, along with use of mucolytic agents in unresectable PMP, are areas of ongoing research in this disease. ...
Background
Pseudomyxoma peritonei (PMP) is a rare clinical presentation, with considerable morbidity and mortality if left untreated. In recent decades, there is growing acceptance for the use of cytoreductive surgery (CRS) with heated intraperitoneal chemotherapy (HIPEC). The aim of this study was to report on our 10-year single-center experience on outcomes following CRS and HIPEC for PMP of appendiceal origin.
Methods
A retrospective analysis of a prospectively maintained database of all patients undergoing CRS and HIPEC for PMP of appendiceal origin over a 10-year period at a statewide referral center was conducted.
Results
One hundred and seventy-five cytoreductive procedures were undertaken in 140 patients. The mean patient age was 57.4 years, with a female preponderance (56%). The median PCI was 16, with 73.1% of cases having a complete cytoreduction. Grade III/IV complications occurred in 36 (20.6%) cases, with no mortalities. The median overall and disease-free survival was 100 months and 40 months, respectively, with a 71% 5-year survival. High-grade histology was the main factor identified as an independent predictor of worse overall survival.
Conclusion
CRS and HIPEC are safe with acceptable rates of morbidity. It can provide very favorable survival in patients with PMP. High-grade histology is a key prognostic factor associated with a worse overall survival.
... PMP is classified histopathologically as acellular mucin, disseminated peritoneal adenomucinosis (DPAM) or peritoneal mucinous carcinomatosis (PMCA) 16 . Acellular mucin has been associated with the best prognosis 17 . The aim of this study was to obtain more insight into the clinical course and management of PMP originating from appendiceal neoplasms in patients treated with CRS-HIPEC. ...
... Almost half of the patients with PMP remained disease-free after treatment with CRS-HIPEC. The prevalence of histological subtypes for PMP is comparable with that in the literature 16,17,23 . Acellular mucin is associated with the best prognosis, with a 5-year survival rate of 93 per cent, compared with 69⋅8 per cent for DPAM and 55 per cent for PMCA. ...
... Acellular mucin is associated with the best prognosis, with a 5-year survival rate of 93 per cent, compared with 69⋅8 per cent for DPAM and 55 per cent for PMCA. Similar survival rates have been described elsewhere 17,24 . Several other studies 11,25 -27 focused on repeat CRS-HIPEC procedures and concluded that this was feasible, with a large group of patients remaining disease-free afterwards. ...
Background
Pseudomyxoma peritonei (PMP) is a rare disease, most commonly of appendiceal origin. Treatment consists of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS–HIPEC). The aim of this study was to identify prognostic factors for recurrence and survival.
Methods
This was an observational study using a prospectively designed database containing consecutive patients with PMP originating from the appendix, undergoing CRS–HIPEC at a tertiary referral centre between 1996 and 2015. Histopathological slides were reassessed. Cox regression was used for multivariable analyses.
Results
Of 225 patients identified, 36 (16·0 per cent) were diagnosed with acellular mucin, 149 (66·2 per cent) had disseminated peritoneal adenomucinosis (DPAM) and 40 (17·8 per cent) had peritoneal mucinous carcinomatosis (PMCA). The 5‐year overall survival (OS) rates were 93, 69·8 and 55 per cent respectively. Recurrence was observed in 120 patients (53·3 per cent), 39 of whom (17·3 per cent) were treated with a second CRS–HIPEC procedure. Factors independently associated with poor disease‐free survival were six or seven affected regions (hazard ratio (HR) 6·01, 95 per cent c.i. 2·04 to 17·73), incomplete cytoreduction (R2a resection: HR 1·67, 1·05 to 2·65; R2b resection: HR 2·00, 1·07 to 3·73), and more than threefold raised carcinoembryonic antigen (CEA) and/or carbohydrate antigen (CA) 19‐9 level (HR 2·31, 1·30 to 4·11). Factors independently associated with poorer OS were male sex (HR 1·74, 1·09 to 2·77), incomplete cytoreduction (R2a resection: HR 1·87, 1·14 to 3·08; R2b resection: HR 2·28, 1·19 to 4·34), and more than threefold raised CEA and/or CA19‐9 level (HR 2·89, 1·36 to 6·16).
Conclusion
CEA and CA19‐9 levels raised more than threefold above the upper limit identify patients with PMP of appendiceal origin and poorer survival.
... The histological grade (G) of PMP is an independent predictor of prognosis [11]. There are three grades of PMP in the World Health Organization (WHO) classification: G1 is low grade, G2 is high grade, and G3 is high grade with signet ring cells [12,13]. ...
... The associations between the various clinical features and survival in our results were generally as expected in the light of previous studies [11,35,36]. The CC score influenced survival more than any other factor in our data, and the appendiceal neoplasms showed better overall survival in the LAMN (G1) subgroup compared with the HAMN/MAC/SRC (G2/G3) subgroup. ...
Background and Aim
Pseudomyxoma peritonei (PMP) is an unusual condition with unique behaviour caused by a mucinous neoplasm, usually arising from the appendix. The aim of this study was to evaluate the prevalence of genomic alterations in clinical specimens of PMP using a targeted assay and correlate the findings with clinical, pathological and outcome data. Sequencing data from 223 patients were analysed.
Results
The median follow‐up interval was 48 months. The primary neoplasm was appendiceal in 216 patients, ovarian in 4, urachal in 2 and renal in one. We confirmed common mutations in GNAS and KRAS (42% each) with significant co‐occurrence of variants in these genes. TP53 mutations were found in 8%. Other mutations were rare but included novel mutations in BAP1 and ERBB4. Of 17 patients with acellular peritoneal mucin, 6 (35%) were positive for DNA mutations. The non‐appendiceal cases generally showed a similar mutational landscape to the appendiceal lesions with GNAS and KRAS commonly mutated, although one urachal lesion showed multi‐hit TP53 mutation without variants in either GNAS or KRAS. Survival was significantly associated with the grade of the primary neoplasm, the grade of the peritoneal disease, the completeness of cytoreduction score and with mutation in either GNAS, KRAS or both. The hazard ratio (HR) associated with mutation in GNAS and/or KRAS was 1.87 (p = 0.004).
Conclusions
Survival outcome was more closely associated with the grade of the peritoneal disease than with the grade of the primary neoplasm. Our findings support the developing concept that mutational analysis may provide prognostic information in patients with PMP.
... 11 Prognosis is heavily dependent on the histological grading of PMP. [12][13][14] Pre-operative evaluation and appropriate treatment of PMP is recommended because untreated disease has a 5 year survival rate of 55%-65%. Despite the increased in knowledge and insight of disease no strict guidelines is available for management of PMP. ...
... At present it is said that all kind of PMP should be considered for CRS+HIPEC. [12][13][14] In literatures, various quantitative prognostic systems have been described which can be assessed by preoperative imaging such as peritoneal cancer index (PCI), peritoneal surface disease severity score (PSDSS), simplified preoperative assessment for appendix tumour (SPAAT) score. These scoring systems are being used for selection of optimal candidates for CRS/HIPEC. ...
Appendiceal mucocele is a rare pathology of the appendix that can present with non-specific symptoms. Therefore, imaging evaluation is essential for accurate diagnosis and proper management. To document importance of pre-operative imaging, we reviewed the scans, reports, and clinical data of nine patients with appendiceal mucocele who were treated at our institute. We also studied the literature on CT findings, histopathology, surgical management, prognosis, and recent guidelines for appendiceal mucocele. We suggest that pre-operative imaging can aid surgeons in selecting the most appropriate treatment plan for each patient, resulting in better outcomes. Certain critical imaging features, such as mural nodularity, irregular wall thickening, lymphadenopathy, cecal involvement, presence of free mucus, or pseudomyxoma peritonei, can alert surgeons to prepare for frozen section and an appropriate surgical approach. In conclusion, we recommend pre-operative imaging as a crucial tool for the diagnosis and management of appendiceal mucocele. Its use in identifying critical imaging features can help surgeons decide on the best surgical approach for each patient and ultimately lead to better outcomes.
... In cases where a non-perforated HAMN is found after appendectomy, a right-sided hemicolectomy should be considered. 17. In cases where a perforated HAMN and/or peritoneal disease are found after appendectomy, a right-sided hemicolectomy associated with CRS and HIPEC should be considered. ...
... A preoperative work-up including serum markers (CEA, Ca19.9, and CA125), a CT scan, and a colonoscopy was rated as fully appropriate by the majority of the panelists (80%); in some studies, preoperative elevation of tumor markers was reported to be linked to the probability of complete cytoreduction [13] and strictly linked to outcome [14][15][16][17][18][19][20]. A CT scan should be the preferred diagnostic imaging technique [21,22]; MRI could be considered in selected cases [23][24][25]. ...
Simple Summary
Pseudomyxoma peritonei (PMP) is an uncommon pathology, and its rarity causes a lack of scientific evidence, precluding the design of a prospective trial. A diagnostic and therapeutic algorithm (DTA) is necessary in order to standardize disease treatment while balancing optimal patient management and the correct use of resources. The Consensus of the Italian Society of Surgical Oncology (SICO) Oncoteam aims at defining a diagnostic and therapeutic pathway for PMP and appendiceal primary tumors applicable in Italian healthcare.
Abstract
Aim: Pseudomyxoma peritonei (PMP) is an uncommon pathology, and its rarity causes a lack of scientific evidence, precluding the design of a prospective trial. A diagnostic and therapeutic algorithm (DTA) is necessary in order to standardize the disease treatment while balancing optimal patient management and the correct use of resources. The Consensus of the Italian Society of Surgical Oncology (SICO) Oncoteam aims at defining a diagnostic and therapeutic pathway for PMP and appendiceal primary tumors applicable in Italian healthcare. Method: The consensus panel included 10 delegated representatives of oncological referral centers for Peritoneal Surface Malignancies (PSM) affiliated to the SICO PSM Oncoteam. A list of statements regarding the DTA of patients with PMP was prepared according to recommendations based on the review of the literature and expert opinion. Results: A consensus was obtained on 33 of the 34 statements linked to the DTA; two flowcharts regarding the management of primary appendiceal cancer and peritoneal disease were approved. Conclusion: Currently, consensus has been reached on pathological classification, preoperative evaluation, cytoreductive surgery technical detail, and systemic treatment; some controversies still exist regarding the exclusion criteria for HIPEC treatment. A shared Italian model of DTA is an essential tool to ensure the appropriateness and equity of treatment for these patients.
... Stage IVb grouped together cellular peritoneal implants with high-grade atypia (M1bG2) with any SRC component (M1bG3). Huang et al, 10 found the four-tiered PSOGI classification to be associated with overall survival (OS) (HR 3.13, 2.34-4.39), whereas Baratti et al, 11 were unable to reproduce this association (HR 1.22, 0.93-1.59). ...
... Several study groups have made efforts to evaluate the prognostic significance of the four-tiered classification. Huang et al 10 supported the four-tiers as histological subtype was associated to OS in the multivariate analysis. The 5-year OS observed were 95.2% in AM, 83% in LGMCP, 47% in HGMCP and 12.6% in HGMCP-SRC. ...
Aims
Several classification systems are used for pseudomyxoma peritonei. The four-tiered classification system proposed by Peritoneal Surface Oncology Group International (PSOGI) and the two-tiered proposed by the eighth edition of the American Joint Committee on Cancer (AJCC) result from evolution in terminology and pathological insight. The aim is to evaluate the impact of PSOGI and eighth edition of the AJCC classifications on survival.
Methods
Pathological slides were reviewed from a prospectively maintained database including patients treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for an appendiceal mucinous neoplasm with peritoneal dissemination between January 2009 and December 2019. Patients were reclassified according to PSOGI and AJCC eighth edition criteria. Survival analysis evaluated the impact of each classification system on overall survival (OS) and disease-free survival (DFS) while the concordance-index evaluated their predictive power.
Results
95 patients were identified; 21.1% were reclassified as acellular mucin, 55.8% as low-grade mucinous carcinoma peritonei, 8.4% as high-grade MCP (HGMCP) and 14 as HGMCP with signet ring cells. Median OS was not reached, 5-year OS and DFS were 86.1% and 51.5%, respectively. Multivariate analysis revealed significant associations with OS (PSOGI: HR 10.2, p=0.039; AJCC: HR 7.7, p=0.002) and DFS (PSOGI: HR 12.7, p=0.001; AJCC: HR 3.7, p<0.001). The predictive capacity of both classification systems was unacceptable for OS and DFS (concordance-index values <0.7).
Conclusions
Both classification systems behaved similarly when stratifying our series into prognostic groups. The PSOGI classification provides better histopathological description, but histology alone is insufficient for adequate patient prognostication.
... 1 PMP has been classified as a rare disease (ORPHA26790) 2 because its incidence is 1-2 per million per year, 3 and the proportion of PMP cases presenting acellular mucin varies among different studies, ranging from 9.8 to 16.8%. [4][5][6][7][8] Although there are mucinous tumors with different origins which can resemble the clinical characteristics of PMP, such as those found in the ovary, colon, pancreas and urachus, currently this disorder is defined by its appendicular origin. 9 PMP does not follow the typical patterns of a malignant disease, it rarely invades the lymph nodes or metastasizes outside ...
... Plasma, tissues and mucin were collected from mice at the end of the experiment and the analyses performed in these samples are also detailed in the scheme. CEA, carcinoembryonic antigen; ddPCR, droplet digital polymerase chain reaction; FFPE, formalin-fixed, paraffin-embeded.4 journals.sagepub.com/home/tam ...
Background
Acellular pseudomyxoma peritonei ( aPMP) is a rare peritoneal malignancy characterized by the accumulation of large amounts of mucin (lacking tumor cells) in the peritoneum. Many cases account for several kilograms of mucin to be screened by the pathologist. This is a comprehensive study of three patients with aPMP, whose tumors showed KRAS mutation, allowing for the tracking of this marker by liquid biopsy.
Methods
Pre and post-surgery plasma, and mucin removed during cytoreductive surgery were collected from the patients. KRAS mutations were analyzed using droplet digital polymerase chain reaction (ddPCR). Mucin was injected in mice. KRAS and cytokine levels were measured in plasma of the mice using ddPCR and a magnetic bead-based assay. Mucin microbiome was analyzed by 16S rRNA sequencing.
Results
KRAS mutations were detected in mucin cell-free DNA (cfDNA) from the three patients but not in the pre or post-surgery plasma. Electron microscopy detected microparticles (diameter <0.4 µm) in mucin. Mucin from one patient grew up inside the peritoneal cavity of mice and human KRAS was identified in mucin cfDNA, but not in plasma. All mucins showed the same bacterial profile. Cytokine levels were slightly altered in mice.
Conclusions
The three aPMP patients included in this study shared some common aspects: the absence of tumor cells in mucin, the presence of KRAS mutated cfDNA in mucin, and the absence of this tumor-derived mutation in the bloodstream, providing additional information to the routine pathological examinations and suggesting that mucin cfDNA could potentially play a role in aPMP recurrence and prognosis.
... Prognostic factors of ATs vary depending on the histological type and clinical presentation of the disease [54]. Higher-grade tumors often indicate a more aggressive disease and may have a worse prognosis. ...
Simple Summary
The 5th edition of the World Health Organization (WHO) classification system for digestive system tumors identifies four types of appendiceal tumors (ATs): serrated lesions and polyps, mucinous neoplasms, adenocarcinomas, and neuroendocrine neoplasms (NENs). Diagnosing ATs poses significant challenges in the medical field due to their uncommon nature and the scarcity of data from large-scale, randomized controlled studies. These tumors are often discovered in tissue samples from appendectomies performed for acute appendicitis. Despite advancements in the treatment of abdominal cancers over recent years, managing and treating ATs effectively remains difficult. This review aims to cover the diagnostic approaches, molecular diagnostics, staging, treatment differences, and prognostic indicators related to ATs.
Abstract
The 5th edition of the World Health Organization (WHO) classification of tumors of the digestive system distinguishes four categories of appendiceal tumors (ATs): serrated lesions and polyps, mucinous neoplasms, adenocarcinomas, and neuroendocrine neoplasms (NENs). The differential diagnosis of ATs can be challenging in medical practice, due to their rarity and lack of data from randomized controlled trials on a large, diverse group of patients. ATs are usually noted in specimens obtained during appendectomies due to clinical acute appendicitis. In the European population, most ATs (65%) occur over the age of 50 and among women (56.8%). According to histological type, 54.6% are neuroendocrine tumors (NETs); 26.8% cystic, mucinous, and serous neoplasms; and 18.6% adenocarcinoma not otherwise specified (NOS). On pathologic analysis, most AT findings are benign lesions or small NENs that do not require further therapeutic measures. The presence of appendiceal mucinous neoplasm (AMN) can lead to pseudomyxoma peritonei (PMP). While the multimodal treatment for abdominal malignancies has evolved over the past several decades, the clinical workup and treatment of ATs remain a challenge. Therefore, this review aims to describe the diagnostic possibilities, molecular-based diagnosis, staging, differences in the treatment process, and prognostic factors associated with ATs.
... Peritoneal malignancy (PM) is usually due to metastatic spread from an intra-abdominal primary cancer [11]. PM comes in different forms, such as colorectal peritoneal metastasis (CPM), Pseudomyxoma Peritonei (PMP) which is an unusual condition that usually arises from a mucinous tumor of the appendix, and peritoneal mesothelioma which can be associated with asbestos exposure [11][12][13][14][15][16]. Without treatment, the prognosis of PM is generally poor and usually fatal [17]. ...
Purpose
To assess Fear of Cancer Recurrence (FCR)—its prevalence, trajectory, and relationship to several demographic and clinical characteristics, and quality of life—in a sample of peritoneal malignancy survivors, up to 5 years post-surgery.
Methods
The Fear of Cancer Recurrence Inventory—Short Form (FCRI-SF) and 36-Item Short-Form Health Survey (SF-36) were used to collect cross-sectional data from peritoneal malignancy survivors to assess their Fear of Cancer Recurrence and quality of life respectively as well as other demographic and clinical data.
Results
The results show that more than two-thirds of the participants (N = 301) experience severe/clinical FCR. FCR is relatively stable over time. Younger patients who are struggling with anxiety or depression or receiving professional mental health support at the time of the surgery are at a higher risk of FCR. FCR is associated with a worse quality of life.
Conclusions
Peritoneal malignancy survivors are at a high risk of FCR, and it compromises their psychological, mental, and social well-being (quality of life).
Implications for cancer survivors.
Raise awareness about the high risk of FCR in this population and the demographic and clinical factors that are associated with it. Encourage peritoneal malignancy services and health professionals to address FCR in this population by normalizing it and providing support for those struggling with it.
... Previous studies showed higher rates of ovarian invasion in patients with grade 2-3 PMP (25); specifically, 62% of ovaries were invaded in patients with grade-1 PMP, and 87.5% of ovaries were invaded in patients with grade 2-3 PMP (26). Other studies confirm these findings (27)(28)(29)(30). Interestingly, in our study, neither PCI nor the use of HIPEC were independent predictors of prognosis. ...
Objective
To determine prognosis for young female patients with peritoneal pseudomyxoma (PMP) of appendiceal origin and unilateral or bilateral ovaries preserved during cytoreductive surgery (CRS).
Methods
Clinical data of female patients treated with CRS with or without hyperthermic intraperitoneal chemotherapy (HIPEC) at the Aerospace Center Hospital, Beijing between January, 2009 and December, 2019 were retrospectively reviewed. Patients had no changes in the bilateral ovaries on gross pathological observations or biopsy during CRS, and normal ovarian function. The demographic and clinical characteristics and prognosis of women with ovaries preserved (ovarian preservation group) or resected (ovarian resection group) during CRS were compared. Independent prognostic factors for survival were identified using univariate and multivariate analysis.
Results
40 patients were included in the final analysis. 19 patients chose ovarian preservation while 21 patients underwent ovarian resection. Completeness of cytoreduction (CCR) scores were CCR-0/1. There were significant differences in age (<40 vs. ≥40), symptoms, intraoperative HIPEC (Y vs. N), and histopathologic subtype of PMP (low-grade vs. high-grade) ( p < 0.001) between patients in the ovarian preservation and ovarian resection groups. In the ovarian preservation group, median overall survival (OS) was 59 months (range, 53–65 months), and the 5-year survival rate was 37.9%. Median disease-free survival (DFS) was 13 months (range, 9–17 months), and the 5-year recurrence rate was 87.4%. In the ovarian resection group, the 5-year survival rate was 87.7%, and the 5-year recurrence rate was 18.3%. Median OS and median DFS were not reached. In patients with low-grade PMP, median DFS was significantly longer in patients with ovarian resection compared to ovarian preservation ( p < 0.001). Univariate analysis showed histopathologic subtype of PMP (low-grade vs. high-grade, p < 0.001) was significantly associated with OS and DFS. On multivariate analysis, high-grade histopathologic subtype of PMP was an independent predictor of poor prognosis (OS and DFS).
Conclusion
Histopathologic subtype of PMP represents an independent predictor of prognosis in female patients with PMP of appendiceal origin and unilateral or bilateral ovaries preserved during CRS. These findings imply that ovarian preservation is a more suitable option for young females with low-grade PMP compared to high-grade PMP. Further prospective studies should be done investigating the role of resection of uninvolved ovaries in PMP.
... Consequently, there is no consensus regarding the PMP terminology because survival and recurrence are influenced by pathologic and clinical factors that affect patient outcomes. [1][2][3] Two recently published guidelines have recommended classifying PMP as acellular, low grade, high grade, or high grade with signet ring cells, based on its infiltration type and cellularity within the mucin, which is in accordance with the most recent classification provided by the World Health Organization (WHO). [4][5][6][7] However, most previous studies used different nomenclatures and classifications, and several questions regarding PMP management have remained unanswered. ...
Introduction
The pathologic classification of pseudomyxoma peritonei is controversial. This study aimed to standardize the histopathological evaluation of pseudomyxoma peritonei and identify the clinicopathological factors associated with survival.
Methods
A pathologic review was performed to systematize the pathology report and verify the relationship between clinical features and survival. Terminology was based on the World Health Organization and Peritoneal Surface Oncology Group International definitions. Preoperative serum levels of carcinoembryonic antigen, CA19-9, and CA-125 were evaluated to determine their association with overall survival (OS) and ability to predict CC0–1 cytoreduction.
Results
Among 109 patients with carcinomas resulting from primary appendiceal neoplasms, 72 had pseudomyxoma peritonei of appendiceal origin and underwent debulking surgery. CC0–1 cytoreduction and CC2–3 cytoreduction were achieved in 61% and 39% of patients, respectively. Patients in the CC0–1 and CC2–3 groups had an OS of 122.80 and 32.92 mo, respectively. The histologic grade was associated with CC0–1 cytoreduction; however, it did not influence OS. Patients with CC0–1 cytoreduction, acellular mucin, and low-grade lesions had better disease-free survival. Higher preoperative CA19-9 levels were associated with poor OS. Normal carcinoembryonic antigen values were associated with 100% sensitivity for predicting CC0–1. CA19-9 levels of 625 U/mL were associated with a low possibility of predicting CC0–1.
Conclusions
Histologic grades are associated with disease-free survival when CC0–1 cytoreduction is achieved. Normal preoperative CA19-9 levels were associated with a better OS. CC0–1 cytoreduction is the main determinant of longer survival.
... Scores range from 0 to 39. Cytoreductive surgery and HIPEC is most effective when the PCI is low, tumors are low grade, and complete or near complete cytoreduction is accomplished [41,45]. Various studies have shown that survival is improved with low-grade PMP compared to highgrade PMP [46,47]. Unresectable cases include PMP from adenocarcinoma with a PCI > 18 and PMP with simultaneous systemic metastases [8]. ...
Appendicectomy is one of the most performed surgical procedures. Neoplasms of the appendix are identified in approximately 1% of appendiceal specimens, and the incidence seems to be rising. The aim of this review was to summarize the current data on these neoplasms, focusing on the recent classification, clinical manifestations, management, and follow-up of such patients, which remain under debate. A literature search was performed using the database PubMed. The keywords used were related to appendiceal neoplasms, mucocele, pseudomyxoma peritonei and treatment. Records without abstracts, case reports, opinion articles and experimental studies were excluded. The appendix tumors can be classified between epithelial or nonepithelial. The epithelial variant is composed by mucinous neoplasms, nonmucinous adenocarcinoma, and signet ring cell tumors; instead, neuroendocrine tumors, lymphoma, and sarcoma are included in nonepithelial neoplasia. Goblet cell carcinoids share characteristics of both epithelial and nonepithelial tumors. The clinical presentation can be variable and the algorithm for evaluation and treatment is complex. Treatment is based on stage and histology. Our intention is to clarify some questions and help the surgeon in operative decisions, treatment strategies, and patient counseling.
Doi: 10.28991/SciMedJ-2021-0303-9
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... The prognostic impact of the four-tiered PSOGI classification 42 has been evaluated by two groups recently. In 2017, Huang et al. 29 observed that median OS was not reached in acellular mucin and LG-PMP groups; it was 58.2 months in groups with HG-PMP and 31.1 months in HG-PMP with SRCs (HR 3.13; P < 0.001). However, in 2018, Baratti and colleagues 31 found that the two-tiered WHO classification 40 (HR 1.48; P ¼ 0.028) correlated better with OS than the PSOGI classification 42 (HR 1.22; P ¼ 0.149). ...
Background
Mucinous appendiceal neoplasms with peritoneal dissemination (PD) show a wide spectrum of clinical behaviour. Histological grade has been correlated with prognosis, but no universally accepted histological grading has been established. The aim of this systematic review was to provide historical insight to understand current grading classifications, basic histopathological features of each category, and to define which classification correlates best with prognosis.
Methods
MEDLINE and the Cochrane Library were searched for studies that reported survival across different pathological grades in patients with mucinous neoplasm of the appendix with PD treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. PRISMA guidelines were followed.
Results
Thirty-eight studies were included. Ronnett’s classification was the most common (9 studies). Classifications proposed by the Peritoneal Surface Oncology Group International (PSOGI) (6 studies) and the seventh or eighth edition of the AJCC (7 studies) are gaining in popularity. Nine studies supported a two-tier, 12 a three-tier, and two a four-tier classification system. Three studies demonstrated that acellular mucin had a better prognosis than low-grade pseudomyxoma peritonei in the PSOGI classification or M1bG1 in the eighth edition of the AJCC classification. Four studies demonstrated that the presence of signet ring cells was associated with a worse outcome than high-grade pseudomyxoma peritonei in the PSOGI classification and M1bG2 in the eighth edition of the AJCC.
Conclusion
There is a great need for a common language in describing mucinous neoplasms of the appendix with PD. Evolution in terminology as a result of pathological insight turns the four-tiered PSOGI classification system into a coherent classification option.
... Such cases are said to exhibit discordant histology (62,64). (VII) T h e c l a s s i f i c a t i o n s h o w n i n Ta b l e 2 i s prognostically significant (82). Of particular note, if no neoplastic epithelial cells are found histologically despite reasonable sampling, the risk of progressive disease is low (Figure 8) (81,(83)(84)(85). ...
Pathology is central to the management of peritoneal surface malignancy. This article highlights some recent advances that have had an impact on patient management or could do so in the near future. Malignant peritoneal mesothelioma, particularly the epithelioid subtype, is amenable to radical therapy in selected cases, and factors such as ki67 proliferation index, expression of BAP1 and mutation in CDKN2A show promise as prognostic indicators. Our understanding of multicystic mesothelioma has improved in recent years; it is a true neoplasm for which surgery may be indicated. Serous carcinomas involving the peritoneum are now known to originate from tubal epithelium. They are of two distinct types, high grade and low grade, which are now recognized as different neoplasms with distinctive features, oncogenesis and behavior. Pseudomyxoma peritonei (PMP) is an unusual condition that usually arises from an appendiceal mucinous neoplasm. Recent consensus in the classification and nomenclature of these lesions is discussed, including the distinction between low grade and high grade appendiceal mucinous neoplasms (HAMN), and the diagnostic criteria for appendiceal adenocarcinoma. PMP is divided into four prognostic groups: acellular mucin, low grade mucinous carcinoma peritonei, high grade mucinous carcinoma peritonei, and high grade mucinous carcinoma peritonei with signet ring cells. The pseudomyxoma microbiome is a promising area for clinical intervention but has been the subject of little research activity. Goblet cell adenocarcinoma (previously known as 'goblet cell carcinoid') is a distinctive type of appendiceal adenocarcinoma. Its behavior correlates with histologic features, but no general consensus for classification has been reached.
... The presence of signet ring cells within the mucin is a further poor prognostic factor, with a 5 year survival rate of 12.6%. 5 This distinction can be explained by the lack of dysplasia seen in the LAMN/DPAM compared with PMCA, and thus the association with a more benign course. 6 In the case of our patient, initial pathology was consistent with moderately differentiated invasive mucinous adenocarcinoma most likely arising from a serrated adenoma of the appendix. ...
We report on a case of a healthy male patient who was referred to Urology for recurrent persistent urinary tract infections. Investigation revealed a large intraabdominal inflammatory collection abutting the cecum and bladder suspicious for ruptured appendicitis and colovesical fistula. He was taken to the operating room for exploratory laparotomy with General Surgery and Urology and found to have a ruptured appendix secondary to mucinous appendiceal neoplasm with invasion into the cecum and the bladder wall. He then underwent systemic chemotherapy followed by hyperthermic intraperitoneal chemotherapy. He is well with stable right lower quadrant inflammatory collection and without evidence of metastatic disease 22 months following initial surgery. This case presents a rare presentation of a rare disease process that is easy to misdiagnose or be delayed in diagnosis because of its vague and often varied presentation.
... [11] It has poor prognosis with a 5-year survival rate of 28%. [10,15] Mucinous signet ring cell carcinoma is a mucinous adenocarcinoma with 50% or more of the tumor containing signet ring cells. Tumors with signet ring morphology <50% are referred to mucinous adenocarcinoma with signet ring cells. ...
Background: The appendix is a vestigial tube-like organ. Its exact physiological function is unknown. Appendectomies are done usually following a clinical diagnosis of acute appendicitis. Neoplasms can arise from this organ as well. Carcinoids are the most common neoplasms arising commonly at the tips. This retrospective review of neoplasms of the appendix was aimed at identifying the incidence and describing the histological variants of neoplasms of the appendix in our environment. Materials and Methods: This study was a 10-year retrospective review of all appendectomy specimens submitted to the Department of Pathology, University College Hospital, Ibadan, Nigeria, from January 1, 2009, to December 31, 2018. Microscopy was done examining the longitudinal sections from the tip to the base of the appendix. The histological diagnosis was extracted from the records in the department and classified using the WHO classification of tumors of the appendix (2019). Patients' biodata such as age and sex were also extracted. The data were analyzed for frequency distribution using SPSS 23. Results: The incidence of neoplasms in the appendix was 0.84% of the 1071 appendectomies received in our department over the study period. Low-grade appendiceal mucinous neoplasm (LAMN) was the most common histological variant accounting for 55.5% of neoplasms, followed by metastatic carcinoma at 22.2% and carcinoids at 11.1%. There was a female preponderance of 77.8%. Conclusion: Neoplasms of the appendix are rare in our environment, and LAMN was the most common neoplasm of the appendix in our institution. There is a female preponderance among patients with appendiceal neoplasms.
... 7,8,11,25 More recent studies utilize PCI rather than quadrant division to evaluate dissemination. 17,19,24,26 PCI is a validated method to easily and accurately estimate tumor burden according to 13 established anatomical regions but does not account for PMD type. 18 To our knowledge, only one study assessed the impact of mucin composition and distribution on survival. ...
BACKGROUND Low-grade appendiceal mucinous neoplasms (LAMN) are tumors that frequently present with peritoneal spread of either acellular mucin (AM) or cellular mucin (CM). We aim to determine how mucin types and distribution affect survival.
PATIENTS METHODS A retrospective cohort study was conducted using a prospective database. Newly diagnosed LAMN patients with AM versus CM treated with cytoreductive surgery/hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) were compared. Postoperative pathology reports were reviewed to assess each involved abdominal zone. Survival was analyzed using the Kaplan–Meier method.
RESULTS Of 121 identified patients, 50 (41%) had peritoneal lesions with AM and 71 (59%) with CM. Peritoneal cancer index was lower in AM versus CM (mean: 19 ± 13 vs 28 ± 10, p = 0.004), but complete cytoreduction (CC) rates were similar (98% vs 96%, p = 0.642). The 5-year progression-free survival (PFS) was higher in AM versus CM (96% vs 69.8%, p = 0.002). CM patients had zones with both types of lesions: with and without cells. The CM subgroup analysis showed significant differences in 5-year progression-free survival (PFS) among patients with 1–3, 4–7, and 8–10 zones with cells (95.2%, 68.4%, and 35.7%, respectively, p < 0.001), but PFS was not affected by the number of zones with any lesion type. There was no difference in overall survival (OS) between groups.
CONCLUSION Despite comparable CC rates after CRS/HIPEC, CM patients have shorter PFS than AM patients. In CM patients, more zones with cells, but not the total number of involved zones, negatively impact PFS. Mucin type does not impact OS. It is important to assess and report mucin cellularity in LAMN specimens.
... If there is spillage of mucin, additional cytoreductive surgery and hyperthermic intraperitoneal chemotherapy should be taken into account to improve outcome and long-term survival for appendiceal pseudomyxoma peritonei. [12][13][14] Hence, given the potential malignant progression, sensitive detection and adequate diagnosis of LAMNs confined to the appendix will improve the efficacy of the treatment, and allow for better prediction of the prognosis and outcome after therapy. However, prospective clinical diagnosis is often difficult because the presentations of Table 3 The CT values of cystic wall on an unenhanced, arterial phase and parenchymal phase images of LAMNs LAMNs are quite variable, vague and non-specific. ...
The clinical findings and CT images are investigate d in order to fulfill an early preoperative diagnosis and increase awareness of low-grade appendiceal mucinous neoplasm (LAMN) confined to the appendix. 17 cases with histologically proven LAMNs confined to the appendix were included in this study. All patients had received multiphase CT examinations before the surgery. The imaging criteria included shape, size, margin, attenuation, secondary degeneration and internal mass enhancement pattern. In CT images, all cases appeared as oval or tubular cystic masses (average attenuation 20.4±3.6 Hounsfield units), with the longest dimensions ranging from approximately 38 to 106 mm (mean 66.3 mm), and the ratio of length against width was 1.83 in average. The cystic wall was unevenly thickened, with a mean maximal wall thickness of 5.7 mm (>10 mm in 3 cases). The inner capsule wall was rough, and calcification was observed in 3 cases. A few amounts of periappendiceal fat stranding were noted in 2 cases. Mild ring mural enhancement of the cystic wall was seen during the arterial phase, with progressive enhancement during the portal venous phase. In addition, mini enhancing mural nodules was observed in 5 cases. Although preoperative diagnosis of LAMNs confined to the appendix remains challenging, it should be considered when a focal well-defined cystic mass with slightly higher than water attenuation, thickened cystic wall with ring mural enhancement and a characteristic progressive contrast enhancement in CT imaging, especially in older females with non-specific symptoms similar to appendicitis.
Rationale
Low-grade appendiceal mucinous neoplasm (LAMN) is a rare subtype of appendiceal pathology characterized by epithelial hyperplasia, cellular atypia, and mucinous accumulation within the appendiceal lumen, leading to obstructive expansion of the organ. Representing a mere 0.2% to 0.3% of all appendectomies and approximately 0.5% of gastrointestinal tumors, LAMN poses diagnostic challenges in surgical practice.
Patient concerns
We conducted a retrospective analysis of a patient with the appendiceal neoplasm. A 39-year-old female presented to Jiaozhou Hospital, East Hospital Affiliated to Tongji University on July 9, 2022, complaining of a nine-day history of right lower abdominal pain, distension, and nausea. Physical examination revealed a palpable measuring 15 × 6 cm in the right lower quadrant, accompanied by tenderness, rebound tenderness, and muscular guarding.
Diagnoses
Histopathological examination confirmed the diagnosis of a LAMN without evidence of lymphovascular invasion, serosal, or mesenteric infiltration.
Interventions
After antiinflammatory therapy and comprehensive assessment, the neoplasm was excised through three-dimensional laparoscopic surgery.
Outcomes
No recurrence was observed during an 32-month postoperative follow-up period.
Lessons
Despite its rarity, LAMN warrants clinical attention due to its nonspecific symptoms. Computed tomography scans significantly improve preoperative diagnostic accuracy, with pathological diagnosis serving as the gold standard. Surgical intervention is the preferred treatment option, albeit controversies persist regarding surgical extent and the utilization of preoperative and postoperative chemotherapy.
Background:
Appendiceal tumors comprise a heterogeneous group of tumors which frequently disseminate to the peritoneum. Management of appendiceal tumors is lacking high quality data, given its rarity and heterogeneity. In general, appendiceal tumor treatment is extrapolated in part from colorectal cancer or pooled studies, without definitive evidence of disease-specific benefit. Many practices are controversial and vary widely between institutions. A national consensus update of best management practices for appendiceal malignancies was performed to better standardize care. Herein we present recommendations for management of appendiceal tumors with peritoneal involvement.
Methods
As previously described, modified Delphi consensus was performed to update the previous 2018 Chicago consensus guideline. Recommendations were supported using rapid systematic reviews of key issues in surgical and systemic therapy. Key pathology concepts and recommendations were synthesized in collaboration with content experts.
Results
A consensus-based pathway was generated for any type of non-neuroendocrine appendiceal tumor with peritoneal involvement. The first round of Delphi consensus included 138 participants and 133 (96%) participated in the second round, with over 90% consensus achieved for all pathway blocks. Key items include recommending evaluation for cytoreduction to most patients with low-grade peritoneal disease who are surgical candidates, and to many patients with high-grade disease, as well as timing of systemic chemotherapy and surveillance protocols. Common pitfalls in pathologic classification and their clinical implications are also presented.
Conclusion
These consensus recommendations provide guidance regarding the management of appendiceal tumors with peritoneal involvement, including a review of current evidence in management of recurrent and unresectable disease.
Aim:
Peritoneal dissemination of infiltrative appendiceal tumors is a rare and poorly understood phenomenon. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is a well-recognized treatment option for selected patients. Neoadjuvant systemic chemotherapy (NAC) has been shown to be associated with improved overall survival (OS) in colorectal peritoneal metastases but little is known of the impact of this from an appendiceal adenocarcinoma perspective.
Method:
A prospective database of 294 patients with advanced appendiceal primary tumors undergoing CRS ± HIPEC between June 2009 and December 2020 was reviewed. Baseline characteristics and long-term outcomes were compared between patients with adenocarcinoma who received neoadjuvant chemotherapy or upfront surgery.
Results:
Eighty-six (29%) patients were histologically diagnosed with an appendiceal cancer. These included intestinal-type adenocarcinoma (11.6%), mucinous adenocarcinoma (43%), and goblet cell adenocarcinoma (GCA) or signet ring cell adenocarcinoma (SRCA) (45.4%). Twenty-five (29%) of these underwent NAC, of which eight (32%) exhibited some degree of radiological response. There was no statistical difference in OS at 3 years between the NAC and upfront surgery groups (47.3% vs. 75.8%, p = 0.372). Appendiceal histology subtypes, particularly GCA and SRCA (p = 0.039) and peritoneal carcinomatosis index >10 (p = 0.009), were factors independently associated with worse OS.
Conclusion:
Administration of NAC did not appear to prolong OS in the operative management of disseminated appendiceal adenocarcinomas. GCA and SRCA subtypes display a more aggressive biological phenotype.
Background:
Survival of patients affected by mucinous appendiceal neoplasms with peritoneal dissemination (PD) is mainly related to histopathological features. However, prognostic stratification is still a concern, as the clinical course of the disease is often unpredictable. The aim of this study is to construct and externally validate a nomogram predicting disease-free survival (DFS) in mucinous appendiceal neoplasms with PD treated by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC).
Patients and methods:
Patients treated in two referral centers were included: Hospital General Universitario Gregorio Marañón, Madrid, Spain (derivation cohort) and Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy (validation cohort). Cox regression analysis identified factors associated with shorter DFS in the derivation cohort. The nomogram performance was externally evaluated in the validation cohort using concordance index and calibration plots. Histology was classified according to the Peritoneal Surface Oncology Group International (PSOGI).
Results:
The derivation cohort included 95 patients, and the validation cohort 348. Five-year DFS rates were 51.5 and 62%, respectively. Cox regression analysis (derivation cohort) identified PSOGI histology of the peritoneal components, number of preoperative elevated tumor marker, and peritoneal disease extent, as assessed by peritoneal carcinomatosis index, to be predictors of DFS. The model's predictive capacity was higher than that of PSOGI classification alone, with respective concordance indexes of 0.702 ± 0.023 and 0.610 ± 0.018 (validation cohort). The nomogram approximated the perfect model in the calibration plots at 3- and 5-year DFS.
Conclusions:
An easy-to-use model that provides better prognostic stratification than histopathological features has been constructed. This nomogram may help clinicians in individualized survival predictions and informed clinical decision-making.
Introduction
Fear of cancer recurrence (FCR) is correlated with higher depression levels, worse quality of life and increased utilisation of healthcare services. There is no research on FCR in peritoneal malignancy (PM) patients—a rare type of abdominal cancer. This study aims to explore the prevalence, trajectory, demographic and clinical characteristics that are associated with FCR and its relationship with quality of life in PM patients.
Methods and analysis
This is a cross-sectional study. Validated measures will be used to collect data on the levels of FCR (Fear of Cancer Recurrence Inventory-Short Form) and quality of life (36-Item Short-Form Health Survey) of PM patients who have had surgery in the last 5 years at the Peritoneal Malignancy Institute in Basingstoke Hospital (minimum N=260). Descriptive statistics, Pearson χ ² tests and correlational tests will be used to analyse the data.
Ethics and dissemination
Ethical approval was obtained from the HRA and Health and Care Research Wales (HCRW). The results of this study will be shared with the participants of this study, presented at conferences and PM patients’ days in the form of presentations or posters, and published in a scientific journal.
Discussion
The results of this exploratory study will be used to inform a multicentre observational study to explore the effect of FCR on PM patients’ mental health (depression and anxiety), quality of life and healthcare utilisation which will inform a multicentre randomised controlled trial to assess the effectiveness of using evidenced-based interventions to lower FCR in PM patients.
Background
The WHO classification of mucinous appendix neoplasms and pseudomyxoma peritonei (PMP) describes low- and high-grade histology and is of prognostic importance. The metastatic peritoneal disease grade can occasionally be different from the primary appendix tumor. This analysis aimed to report outcomes from a high-volume center in patients with pathological discordance.Methods
This was a retrospective analysis of prospective data of patients treated by cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for PMP at a single institution between January 2016 and December 2020. Reporting was by pathologists with a special interest in peritoneal malignancy. Discordant pathology was classified as a low-grade primary appendix tumor with high-grade peritoneal disease, or a high-grade primary appendix tumor with low-grade peritoneal disease. Outcomes analyzed were overall and recurrence-free survival, and Kaplan–Meier survival curves and the log-rank test were used to analyze the outcomes.ResultsBetween 2016 and 2020, 830 patients underwent CRS and HIPEC for PMP, of whom 37 (4.4%) had discordant pathology. The primary appendix tumors were low-grade in 23 patients and high-grade in 14 patients. The median Peritoneal Cancer Index (PCI) was significantly higher in patients with a low-grade primary tumor (31 vs. 16; p = 0.001), while complete cytoreduction (CC0/1) was achieved in 31/37 (83.8%) patients. The median follow-up was 19 months. Overall survival was worse in those with high-grade peritoneal disease (p = 0.029), whereas recurrence-free survival was similar in both groups (p = 0.075).Conclusion
In PMP with pathological discordance, the peritoneal disease grade influences prognosis and survival.
Appendiceal neoplasms include a heterogeneous group of epithelial and nonepithelial tumors that exhibit varying malignant potential. This review article summarizes current diagnostic criteria, classification systems, and optimal therapeutic strategies for the five main histopathologic subtypes of appendiceal neoplasms. In particular, the management of epithelial appendiceal neoplasms has evolved. Although their treatment has historically been extrapolated from colon cancer, improved understanding of their unique histopathologic and molecular characteristics and a growing body of published clinical data support a more nuanced approach to their management.
Introduction
To determine the effect of signet ring cell (SRC) histopathology in appendix cancer with peritoneal dissemination on overall survival (OS) in patients undergoing cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC).
Materials and methods
Retrospective cohort study from a prospectively maintained database of patients that underwent CRS/HIPEC for appendix cancer from April 1999 to December 2019.
Results
255 patients were identified. 174 had high-grade disease with no SRC component, 35 with a low count of SRC and 46 with a high count of SRC. Median OS without SRC was 93.8 months vs 58.2 months for low count SRC and 23.7 months for high count SRC (P < 0.001). 5-year OS was 60% for patients with no SRC, 35.5% and 10% in those with low count and high count SRC respectively. On multivariate analysis, presence of SRC and complete cytoreduction score were identified as independent factors that affect OS.
Conclusion
The presence of SRC in appendix cancer with peritoneal dissemination is associated with worse OS when compared to an absence of SRC in patients undergoing CRS/HIPEC.
Introduction
Low grade appendiceal mucinous neoplasms (LAMN) are known to metastasise to the peritoneum resulting in pseudomyxoma peritonei (PMP). Literature suggests that the long-term outcome is dependent on the cellular grade of the peritoneal histology, less is known about the risk to patients with acellular mucinosis (AM) alone. This study aims to review long-term outcomes in patients with PMP treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (CRS/HIPEC), whose peritoneal histology was AM secondary to LAMN.
Methods
Pathological and treatment outcomes were collected from a prospectively maintained database between 2005 and 2019. Data was collected on patients with LAMN and AM diagnosed following CRS/HIPEC. A single institution performed the surgery and pathology reporting, samples reported by three different pathologists.
Results
Of the 2079 patients with any appendiceal neoplasm referred between 2005 and 2019, 809 underwent CRS/HIPEC, 67 (8%) of those had PMP with purely AM secondary to a LAMN. In the AM group the median age was 59, 37 (55%) were female, follow up was for a median 39 (2–145) months. Inpatient mortality occurred in 1 patient (1.5%), disease specific mortality in 2 (3%), recurrence in 2 (3%) and disease progression in 1 (1.5%).
Conclusion
This study has identified AM secondary to LAMN as a low risk group for recurrence following CRS/HIPEC compared with epithelial pathology. Given such a low rate of recurrence we would recommend low intensity surveillance post CRS/HIPEC. Agreed standardised pathological assessment is required to exclude cellular material in specimens and diagnose AM.
Neoplasms of the appendix are infrequent diseases that can be generally diagnosed with surgery or pathological examination. One of the most commonly fulfilled surgeries today is appendectomy. The neoplastic diagnoses that come out as a result of the examination of pathological specimens need to be well known. Even benign neoplastic diseases of the appendix may require extended follow-up periods and serious treatments if pseudomyxoma peritonei is involved. For example, serrated adenomas classified as benign may be dysplastic, and when they are diagnosed, the colonoscopic examination should be done to determine simultaneous colonic serrated polyps. Epithelial appendix neoplasm can be categorized as mucinous and non-mucinous. Their majority is mucinous neoplasm. Mucinous neoplasm causes pseudomyxoma peritonei without producing distant metastasis. Low-grade appendiceal mucinous neoplasms also hold the appendix wall, although in benign morphology, and may disseminate throughout the peritoneum. In benign pathologies, appendectomy may be sufficient provided that the disease is restricted to the appendix, no mucin or mucinous epithelium is detected outside the appendix serosa, and the resection border is clear. However, if these conditions are not provided or there is an appendix cancer, more painful surgical procedures are required. The peritoneal spread, lymphatic spread, and distant metastasis possibilities of appendix adenocarcinomas can be determined and treated according to the type of subdiagnosis (colonic-type, mucinous, or goblet cell). In this section, we tried to clarify the issue of appendix neoplasm.
Background:
The aim of this population-based study was to determine the prognostic value of the histologic subtypes mucinous (MAC), non-mucinous (AC) and signet ring cell (SRCC) adenocarcinoma among patients with appendiceal cancer.
Methods and materials:
Data from the Netherlands Cancer Registry (NCR) of patients with primary appendiceal adenocarcinomas with MAC, AC and SRCC histologic subtype, diagnosed between 2001 and 2015 were used (n = 675). To categorize patients according to the recent histopathological classification, the NCR was linked with the Dutch Pathology Registry (PALGA). Log-rank tests and Kaplan-Meier analyses were performed to estimate overall survival (OS), and the cox proportional hazards model was run to identify prognostic factors.
Results:
AC was the most frequently encountered histologic subtype (50.9%), followed by MAC (35.8%) and SRCC (13.3%). In locoregional disease, histologic subtype was not a prognostic factor for OS with 5-year survival rates for patients with AC, MAC and SRCC of 60.0%, 60.5% and 69.6% respectively (p = 0.68). Metastatic disease was more common in SRCC (53.8%) than in MAC (38.8%) and AC (23.4%) (p < 0.0001). Median OS for patients with metastatic disease was 12.6, 27.7 and 18.2 months in AC, MAC and SRCC respectively (p < 0.005). MAC was associated with higher survival compared to AC (HR 0.48, 95%CI 0.34-0.69). In subanalyses, MAC was only a positive prognostic factor compared to AC in patients with peritoneal metastases (HR 0.42, 95%CI 0.28-0.62).
Conclusion:
Histologic subtype had no prognostic relevance in locoregional or systemic metastatic disease in appendiceal adenocarcinoma. In peritoneal metastases, mucinous histologic subtype was a favorable prognostic factor, compared to non-mucinous and signet ring cell subtype.
Introduction:
Early recurrence (ER) is defined as development of loco-regional peritoneal disease within 12-month of the initial CRS/PIC. Our aims were to identify overall survival (OS), recurrence-free survival (RFS) and independent prognostic factors associated with ER in PM of appendiceal neoplasm.
Materials and methods:
A prospectively-maintained database for patients with appendiceal neoplasm undergoing cytoreductive surgery (CRS) and perioperative intraperitoneal chemotherapy (PIC) from year 1996-2018 was retrospectively analysed.
Results:
208 female and 185 male patients were identified. With a median follow-up of 40-month, 40.2% of the patients developed ER. The median OS for ER was 24 months compared to late (LR) at 64 months. Median OS was not reached in non-recurrence (NR). 5-year survival for ER was less favourable compared to LR and NR (19.3%vs54.6%vs94%). No patients in ER group survived beyond 10-year. Independent negative predictors associated with ER on multivariate analysis were male patient (p = 0.013), blood transfusion of >8 units (p = 0.013), elevated preoperative CEA levels (>5 ng/ml; p = 0.002) and hard intraoperative tumour consistency (p < 0.001). Protective factor was a combination of CC1, hard tumour consistency and use of EPIC (p = 0.039). Independent prognostic factors that predicted recurrence of appendiceal PM were PCI >20 (p = 0.049), non-use of EPIC (p = 0.012), hard tumour consistency (p = 0.004) and use of previous chemotherapy (p = 0.023).
Conclusion:
ER following CRS and PIC of appendiceal PM is associated with reduced survival outcomes. Our data alludes to the importance of optimising the risk factors in order to delay loco-regional recurrence and improve long-term survival of these patients.
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.
Background
Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) is effective in select patients with peritoneal carcinomatosis (PC). Signet ring cell (SRC) pathology is associated with poor prognosis. The role of CRS/HIPEC in this population is unclear.
Methods
Patients diagnosed with PC due to appendiceal (AC), colorectal (CRC), and gastric cancer (GC) undergoing CRS/HIPEC 2007‐2016 were included.
Results
A total of 268 patients were referred for CRS/HIPEC. Of the 204 patients who underwent complete CRS/HIPEC, 101 (49.5%) had AC, 85 (41.7%) CRC, and 18 (8.8%) GC. Patients with GC had higher rates of SRC pathology than AC and CRC: 12 (66.7%) vs 16 (15.8%) and 10 (11.7%). The 3‐year survival rate after CRS/HIPEC was 5.7% for the SRC group and 66.1% for the non‐SRC group (P < 0.001). This was true for both AC and CRC subgroups (P < 0.001 for both). Overall, patients with SRC were more likely to have a peritoneal carcinomatosis index (PCI) score > 15 (P = 0.046). Upon multivariate analysis of the SRC population, PCI > 20 (P = 0.007) and GC (P = 0.008) were found to be independent predictors of poor overall survival.
Conclusions
Performing CRS/HIPEC for PC from gastrointestinal malignancies presenting SRC features is recommended on patients with select diseases of appendiceal and colorectal origins.
Background:
This study examines the impact of intraoperative macroscopic tumour consistency on short-term and long-term outcomes after cytoreductive surgery (CRS) with intraperitoneal chemotherapy (IPC) for appendiceal adenocarcinoma with peritoneal metastases.
Methods:
Macroscopic intraoperative tumour consistency was classified in three groups as soft (jelly-like geltatinous tumours), hard (hard tumour nodules without gelatinous features) and intermediate (both soft and hard features). In-hospital mortality, major morbidity, intensive care unit (ICU), high dependency unit (HDU) and total hospital stay, disease-free survival (DFS) and overall survival (OS) were compared.
Results:
The three groups had similar perioperative short-term outcomes. Patients with soft, intermediate and hard tumours revealed differences in OS (p < 0.001) and DFS (p = 0.03). Multivariable analysis revealed a shorter OS for patients with hard versus soft tumours (HR for hard tumours = 4.43, 95%CI 2.19-9.00).
Conclusions:
Intraoperative macroscopic tumour consistency may be used as a prognostic marker for survival in patients with appendiceal adenocarcinoma with peritoneal metastases.
Until recently, many classifications existed for the terminology and histopathologic classification of appendiceal mucinous neoplasms, mucinous appendiceal adenocarcinomas, and pseudomyxoma peritonei (PMP). A major accomplishment was achieved by consensus-based histopathologic classifications on behalf of the Peritoneal Surface Oncology Group International regarding mucinous appendiceal tumours and PMP. As different classifications were used over the years and also owing to the rare nature of these tumors, many clinicians are not familiar with the terminology and the impact on patient management. Hence, an overview concerning mucinous appendiceal neoplasms, mucinous appendiceal adenocarcinomas, and PMP is provided to serve as an introduction into the basic morphology of these tumors with tentative recommendations for management.
Peritoneal carcinomatosis is among the poor prognostic factors in different types of malignancies. Cytoreductive surgery and intraperitoneal chemotherapy improved the prognosis of these cases. Mechanisms of peritoneal carcinomatosis are being evaluated. The most favored of these mechanisms is the spillage to the tumoral cells to the peritoneal cavity, either by visceral peritoneal invasion by carcinoma or by traumatic mechanisms, leading to tumor formation at different sites as examples of soil and seeding. The mesenchymal transition of the mesothelial cells seems to be an important contributing factor in this process. However, lymphatic route has also been proposed for early gastric carcinoma cases with peritoneal dissemination. The classification and mechanisms of peritoneal carcinomatosis are presented in this chapter. The possibility of the importance of mechanisms leading to tumor deposit formation elsewhere is discussed in connection with peritoneal carcinomatosis. Different types of morphological variants of tumor deposits are presented.
Background:
Mucinous appendiceal tumors (MAT) are rare neoplasms that can metastasize to the peritoneum and often are treated with cytoreductive surgery (CRS) and HIPEC. Pathologic classification and outcomes vary, but standardized histologic definitions are emerging. We sought to evaluate outcomes in this disease after CRS/HIPEC using standardized pathologic criteria.
Method:
Outcomes of MAT with peritoneal metastases (PM) after CRS/HIPEC from 2007 to 2015 were reviewed at our institution. Standardized histologic categories per WHO and consensus definitions were used: low-grade appendiceal mucinous neoplasm (LAMN), low-grade adenocarcinoma (LGAC), or high-grade adenocarcinoma (HGAC) primary tumors; and acellular mucin (AM), low-grade mucinous carcinoma peritonei (LGMCP), or high-grade mucinous carcinoma peritonei (HGMCP) peritoneal metastases. Cox proportional hazards model was used identify predictors of progression-free survival (PFS) by univariate and multivariate analyses.
Results:
A total of 183 patients undergoing 197 CRS/HIPECs were included. Among 75 patients with primary histology review, there were 33 (44.0%) LAMNs, 28 (37.3%) LGACs, and 14 (18.7%) HGACs. Peritoneal histology was benign in 6 (3.0%), AM in 33 (16.8%), LGMCP in 114 (57.9%), and HGMCP in 44 (22.3%). PFS was not reached for AM, 34.3 months for LGMCP, and 16.8 months for HGMCP (p < 0.001). Peritoneal histology predicted PFS on multivariate analysis (hazard ratio 9.82 and 24.60 for LGMCP and HGMCP, respectively, vs. AM, p < 0.001). Among the LGMCP group, CEA and completeness of cytoreduction (CC score) predicted PFS on multivariate analysis.
Conclusions:
Standardized peritoneal histology in patients with PM from MAT predicts PFS and patients with low-grade histology can be further discriminated by CEA and CC score.
Background:
Controversies still persist regarding the terminology and pathologic classification of appendiceal mucinous neoplasms and associated pseudomyxoma peritonei (PMP). We assessed reproducibility and prognostic significance of the classification recently proposed by the Peritoneal Surface Oncology Group International (PSOGI).
Methods:
A prospective database of 265 PMP patients uniformly treated by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) from 1995 to 2017 was reviewed. According to the PSOGI, peritoneal disease was retrospectively classified into three categories: low-grade (LG-PMP), high-grade (HG-PMP), and signet-ring cells (SRC-PMP). Acellular mucin (AC) was classified separately. The extent of peritoneal involvement was quantified by the peritoneal cancer index (PCI).
Results:
Twenty-six patients were diagnosed with AC (9.8%), 197 with LG-PMP (74.4%), 38 with HG-PMP (14.3%), and 4 with SRC-PMP (1.5%). In the overall series, median follow-up was 65.5 months (95% confidence interval 53.7-78.8) and 10-year overall survival was 62.9% (median 148.7 months). Operative death occurred in 10 patients (3.8%) and major complications occurred in 89 patients (33.6%). Ten-year survival was 89.6% for AC, 63.2% for LG-PMP, 40.1% for HG-PMP, and 0 for SRC-PMP. In a multivariate model, the World Health Organization (WHO) pathological classification independently correlated with survival (p = 0.028). In a separate model, the PSOGI classification did not reach statistical significance (p = 0.149). Completeness of cytoreduction and PCI > 22 correlated with prognosis in both models.
Conclusions:
AC and SRC-PMP pathological categories of the PSOGI classification identified two subsets of patients with favorable and exceedingly dismal prognosis, respectively. It remains unclear whether the PSOGI classification might provide better prognostic stratification than the current WHO classification. Further studies in larger prospective series are needed.
Pseudomyxoma peritonei (PMP) is a complex disease with unique biological behavior that usually arises from appendiceal mucinous neoplasia. The classification of PMP and its primary appendiceal neoplasia is contentious, and an international modified Delphi consensus process was instigated to address terminology and definitions. A classification of mucinous appendiceal neoplasia was developed, and it was agreed that "mucinous adenocarcinoma" should be reserved for lesions with infiltrative invasion. The term "low-grade appendiceal mucinous neoplasm" was supported and it was agreed that "cystadenoma" should no longer be recommended. A new term of "high-grade appendiceal mucinous neoplasm" was proposed for lesions without infiltrative invasion but with high-grade cytologic atypia. Serrated polyp with or without dysplasia was preferred for tumors with serrated features confined to the mucosa with an intact muscularis mucosae. Consensus was achieved on the pathologic classification of PMP, defined as the intraperitoneal accumulation of mucus due to mucinous neoplasia characterized by the redistribution phenomenon. Three categories of PMP were agreed-low grade, high grade, and high grade with signet ring cells. Acellular mucin should be classified separately. It was agreed that low-grade and high-grade mucinous carcinoma peritonei should be considered synonymous with disseminated peritoneal adenomucinosis and peritoneal mucinous carcinomatosis, respectively. A checklist for the pathologic reporting of PMP and appendiceal mucinous neoplasms was also developed. By adopting the classifications and definitions that were agreed, different centers will be able to use uniform terminology that will allow meaningful comparison of their results.
Background
Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) has survival benefit in the treatment of selected patients with peritoneal carcinomatosis (PC) from appendiceal cancer (AC). We evaluated factors affecting the survival of patients with PC from AC after CRS/HIPEC.
Methods
A retrospective analysis of 387 CRS/HIPEC procedures performed between February 1998 and February 2013 identified 202 patients with PC from AC. Tumor histopathology, complete cytoreduction (CC 0–1), Peritoneal Cancer Index (PCI), and lymph node (LN) status were related to overall survival (OS) and progression-free survival (PFS) using the Kaplan–Meier method.
Results
Overall, 129 women (64 %) and 73 men (36 %), mean age 54 years (range 25–81), with a mean follow-up of 36 months were included in the study. Seventy-seven low-grade tumors (disseminated peritoneal adenomucinosis [DPAM]; 38 %) and 125 high-grade tumors (peritoneal mucinous carcinomatosis [PMCA]; 62 %) were identified. Five- and 10-year OS was 56 % and 47 %, respectively, with PFS of 44 % at 5 and 10 years. Five-year OS in DPAM patients was 83 %, with a 5-year OS significant difference related to CC 0–1 versus CC 2–3 (incomplete cytoreduction) [p = 0.021]. Five-year OS in PMCA patients was 41 %, with a 5-year OS significant difference related to CC 0–1 versus CC 2–3 (p
Previous studies have demonstrated that the prognosis of disseminated mucinous appendiceal neoplasms is highly dependent upon tumor grade. Reflecting this, the 7th edition of the American Joint Committee on Cancer (AJCC) staging system now incorporates a three-tier grading system for prognostic staging of mucinous appendiceal tumors. However, the grading criteria are not well described. In order to address this issue, we evaluated clinicopathologic and molecular features of 219 cases from 151 patients with widely disseminated appendiceal mucinous neoplasia treated at our institution between 2004 and 2012. We identified histologic features that were associated with worse overall survival on univariate analysis: destructive invasion, high cytologic grade, high tumor cellularity, angiolymphatic invasion, perineural invasion, and signet ring cell component (all with P<0.0001). We used these morphologic characteristics to classify neoplasms into three grades: AJCC grade G1 lacked all adverse histologic features; AJCC grade G2 had at least one adverse histologic feature (except a signet ring cell component); and AJCC grade G3 were defined by the presence of a signet ring cell component. Patients with AJCC grade G2 and grade G3 adenocarcinomas had a significantly worse prognosis compared with AJCC grade G1 (P<0.0001 for each). A trend toward worse overall survival was identified for patients with AJCC grade G3 adenocarcinomas compared with AJCC grade G2 adenocarcinomas (P=0.07). Our multivariate analysis found that this three-tier grading system was a significant predictor of outcome (P=0.008), independent of other prognostic variables. After controlling for other prognostic variables, AJCC grade G2 was associated with a 2.7-fold increased risk of death (95% confidence interval (CI), 1.2-6.2) and AJCC grade G3 was associated with a 5.1-fold increased risk of death (95% CI, 1.7-14) relative to grade G1 tumors. Our results indicate that evaluation of a limited set of adverse histologic features allows for the separation of disseminated mucinous neoplasms of appendiceal origin into three morphologically defined and prognostically relevant grades as advocated by the AJCC.Modern Pathology advance online publication, 14 March 2014; doi:10.1038/modpathol.2014.37.
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.
Poorly differentiated and signet ring cell adenocarcinomas of the appendix represent a subset with aggressive tumor biology and poor outcomes with few studies evaluating the impact of systemic chemotherapy and cytoreductive surgery (CRS).
A retrospective chart review of patients with either poorly differentiated and signet ring cell appendiceal adenocarcinomas was completed from 1992 to 2010.
One hundred forty-two patients were identified. Seventy-eight patients with metastatic disease received chemotherapy. Radiographic response was 44%, median progression-free survival (PFS) was 6.9 months, and median overall survival (OS) was 1.7 years. In multivariate analysis, response to chemotherapy [hazard ratio (HR) 0.5; P = 0.02] predicted improved PFS, and complete CRS (HR 0.3; P = 0.004) predicted improved OS. Patients who underwent complete CRS (n = 26) had a median relapse-free survival (RFS) of 1.2 years and a median OS of 4.2 years. In multivariate analysis for this subset, complete cytoreduction score of 0 was significantly correlated with improved RFS (HR 0.07; P = 0.01) and OS (HR 0.02; P = 0.01).
Systemic chemotherapy appears to be a viable treatment option for patients with metastatic poorly differentiated and signet ring cell appendiceal adenocarcinomas. Complete CRS is associated with improved RFS and OS, though part of this benefit likely reflects the selection of good tumor biology.
Background:
Tumors that show a signet ring or adenocarcinoid histomorphology have been associated with a poor prognosis. This study aimed to analyze the clinicopathologic and prognostic features in patients with peritoneal metastasis from mucinous adenocarcinoma (PMCA), adenocarcinoma with signet ring cell (PMCA-S), or adenocarcinoid (PMCA-A) of the appendix treated with cytoreductive surgery and perioperative intraperitoneal chemotherapy.
Methods:
Retrospective analysis of a prospectively maintained database for all patients treated for appendiceal adenocarcinoma from 1989 to 2012 was performed.
Results:
The study cohort consisted of 494 patients including 361 patients with PMCA (73.1 %), 80 patients with PMCA-S (16.2 %), and 53 patients with PMCA-A (10.7 %). The patients comprised 273 men (55.3 %) and 221 women (44.7 %) with a mean age at presentation of 50.7 years for the PMCA-S patients, 47.3 years for the PMCA patients, and 47.5 years for the PMCA-A patients (p < 0.03). The 3- and 5-year survival rates were respectively 51 and 38 % for PMCA compared with 30 and 22 % for PMCA-S and 26 and 15 % for PMCA-A. The median survival time was 45.4 months for PMCA compared with 18.9 months for PMCA-S and 26.8 months for PMCA-A (p < 0.000). The groups did not differ significantly in the completeness of cytoreduction achieved, with 53.5 % of the PMCA patients having a CC0/1 compared with 46.2 % of the PMCA-S patients and 41.6 % of the PMCA-A patients (p < 0.20). In the multivariate analysis, the independent predictors of a reduced survival were incompleteness of cytoreduction, histomorphology of PMCA-S or PMCA-A, and distant metastasis.
Conclusion:
The findings showed that PMCA-S or PMCA-A histomorphology contributes to the poor prognosis associated with peritoneal metastasis from appendiceal adenocarcinoma. The independent predictors for a poor overall survival included incompleteness of cytoreduction, PMCA-S and PMCA-A histomorphology, and distant metastasis.
Background:
The importance of absent neoplastic epithelium in specimens from cytoreductive surgery (CRS) is unknown. This study aimed to investigate the prevalence and prognostic value of histopathology without neoplastic epithelium in patients treated with CRS and hyperthermic intraperitoneal chemotherapy (HIPEC).
Methods:
Data were extracted from medical records and histopathology reports for patients treated with initial CRS and HIPEC at Uppsala University Hospital, Sweden, between 2004 and 2012. Patients with inoperable disease and patients undergoing palliative non-CRS surgery were excluded from the study. Patients lacking neoplastic epithelium in surgical specimens from CRS, with or without mucin, were classified as "neoplastic epithelium absent" (NEA), and patients with neoplastic epithelium were classified as "neoplastic epithelium present" (NEP).
Results:
The study observed NEA in 78 of 353 patients (22 %). Mucin was found in 28 of the patients with NEA. For low-grade appendiceal mucinous neoplasms and adenomas, the 5-year overall survival rate was 100 % for NEA and 84 % for NEP, and the 5-year recurrence-free survival rate was 100 % for NEA and 59 % for NEP. For appendiceal/colorectal adenocarcinomas (including tumors of the small intestine), the 5-year overall survival rate was 61 % for NEA and 38 % for NEP, and the 5-year recurrence-free survival rate was 60 % for NEA and 14 % for NEP. Carcinoembryonic antigen level, peritoneal cancer index, and completeness of the cytoreduction score were lower in patients with NEA.
Conclusions:
A substantial proportion of patients undergoing CRS and HIPEC have NEA. These patients have a favorable prognosis and a decreased risk of recurrence. Differences in patient selection can affect the proportion of NEA and hence explain differences in survival rates between reported series.
Peritoneal carcinomatosis is a common evolution of gastrointestinal cancers. The prognosis of patients with such disease is dependent upon pre-operative and post-operative variables. CT scan of the abdomen and the pelvis represents the adequate standardized radiologic exam for pre-operative evaluation of tumor volume and location in the peritoneal cavity. It may provide informations regarding the selection of patients for complete cytoreductive surgery. Clinical factors like the extent of prior surgical procedures, the grade of the primary tumor, and the mucin content of peritoneal implants may also help to select patients for an adequate treatment approach. Several intra-operative factors including the cancer distribution into the peritoneal cavity and the completeness of surgery need to be prospectively recorded by the surgeon in order to assess quantitatively their impact on the prognosis of patients with peritoneal carcinomatosis. This review provides standardized methodologies in the assessment of these clinical variables.
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.
The following methodologies may be strictly applied to quantitatively evaluate patients with peritoneal carcinomatosis or sarcomatosis in regard to disease progression or regression: (1) Preoperative CT scan and the intraoperative assessment of cancer extent is analyzed region by region (AR-0-12) and an estimation of tumor volume (V0-V3) is evaluated according to the standardized scoring system previously described. At laparotomy, the volume of tumor nodules to adjacent organs, the viscosity (mucinous vs. solid) of tumor mass, and the pattern of distribution is assessed. (2) Radiologic abdominopelvic CT parameters that predict an incomplete cytoreduction are focal obstructions of bowel by CT assessment and tumor involvement of proximal ileum (AR-11). (3) The extent of prior surgical interventions (PS-1 through PS-3) must be recorded because aggressive deep dissections without perioperative chemotherapy severely jeopardize the possibility for complete cytoreduction. (4) Many tumor samples should be sent for histopathologic analysis. A proportion of mucin > 80% confirms a mucinous cancer. The malignant differentiation of cells, stroma morphology, the presence of signet ring cells, and evidence of invasion are used to grade cancers as mucinous tumor grade 0-3 (MTG-0 through MTG-3). (5) Once the cytoreductive procedure is accomplished, the surgeon estimates the residual volume of disease. (6) Objective response criteria from CT scan, tumor marker, and radiolabeled monoclonal antibody studies are necessary in a regular follow-up schedule.
Cancer of the appendix is an uncommon disease that is rarely suspected rarely before surgery. Although several case series of these tumors have been published, little research has been anchored in population-based data on cancer of the appendix.
This analysis included all actively followed cases of appendiceal neoplasms reported to the National Cancer Institute's Surveillance, Epidemiology and End-Results (SEER) program between 1973 and 1998. Tumors were classified as "colonic type" adenocarcinoma, mucinous adenocarcinoma, signet ring cell carcinoma, goblet cell carcinoid, and "malignant carcinoid" (SEER only collects data on carcinoids specifically classified as malignant). We compared incidence, overall survival and survival rates by extent of disease at diagnosis.
Between 1973 and 1998, 2117 appendiceal malignancies were reported to the SEER program, of which 1645 cases were included in the analysis. Age-adjusted incidence of cancer of the appendix was 0.12 cases per 1,000,000 people per year. Demographic characteristics of patients with goblet cell carcinoid tumors were midway between those of patients with malignant carcinoid and all types of adenocarcinomas. After controlling for age and extent of disease at diagnosis, the overall survival rate for patients diagnosed between 1983 and 1997 (n = 1061) was significantly worse for those with signet ring cell carcinoma than for those with any other tumor type (P < 0.01). In addition, overall survival rates were better for patients with malignant carcinoid (P = 0.01).
Demographic characteristics of patients with cancer of the appendix vary by histology. Except for signet ring cell carcinoma and malignant carcinoid, the extent of disease at time of diagnosis is a more important predictor of survival than histology.
The aim of this study was to analyze the survival of patients with peritoneal dissemination of appendiceal malignancy having incomplete cytoreductive surgery.
Cytoreductive surgery plus perioperative intraperitoneal chemotherapy has emerged as a new and potentially curative treatment option for patients with peritoneal dissemination of appendiceal mucinous tumors. The goal of surgery is to remove all visible disease. Nevertheless, in some patients, complete cytoreduction is not possible.
Over a 30-year period, 645 patients with epithelial peritoneal surface malignancy of appendiceal origin were treated with cytoreductive surgery and intraperitoneal chemotherapy by a single surgeon. One hundred seventy-four (27.1%) of these patients had an incomplete cytoreduction. A critical statistical analysis of the impact of selected clinical features on survival was performed from a prospective database.
Mortality and morbidity rates were 0% and 33.3%, respectively. Median survival of these 174 patients was 20.5 months and their 1-year, 3-year, and 5-year survival rates were 71%, 34%, and 15%, respectively. By multivariate analysis, the presence of signet ring cells and lymph node involvement were independent prognostic indicators of poor survival (P = 0.047 and P < 0.001, respectively). Patients who underwent more than 1 cytoreduction or repeat intraperitoneal chemohyperthermia showed significant improvement in survival (P = 0.018 and P < 0.001, respectively)
Incomplete cytoreduction plus perioperative intraperitoneal chemotherapy of peritoneal dissemination from appendiceal malignancy results in limited long-term survival. Patients with signet ring histology or lymph node involvement have an especially poor outcome. Repeat cytoreduction and intraperitoneal chemohyperthermia may improve outcome.
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.
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.
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.
The new complication classification appears reliable and may represent a compelling tool for quality assessment in surgery in all parts of the world.
Appendiceal mucinous neoplasms sometimes present with peritoneal dissemination, which was previously a lethal condition with a median survival of about 3 years. Traditionally, surgical treatment consisted of debulking that was repeated until no further benefit could be achieved; systemic chemotherapy was sometimes used as a palliative option. Now, visible disease tends to be removed through visceral resections and peritonectomy. To avoid entrapment of tumour cells at operative sites and to destroy small residual mucinous tumour nodules, cytoreductive surgery is combined with intraperitoneal chemotherapy with mitomycin at 42 degrees C. Fluorouracil is then given postoperatively for 5 days. If the mucinous neoplasm is minimally invasive and cytoreduction complete, these treatments result in a 20-year survival of 70%. In the absence of a phase III study, this new combined treatment should be regarded as the standard of care for epithelial appendiceal neoplasms and pseudomyxoma peritonei syndrome.
Decisions regarding the treatment of cancer depend on the anatomic location of the malignancy and the biologic aggressiveness of the disease. Some patients may have isolated intraabdominal seeding of malignancy of limited extent or of low biologic grade. In the past these clinical situations have been regarded as lethal. We have used the cytoreductive approach to achieve long-term disease-free survival in some patients with peritoneal carcinomatosis, peritoneal sarcomatosis, or mesothelioma. The cytoreductive approach may require six peritonectomy procedures to resect or strip cancer from all intraabdominal surfaces. These are (1) greater omentectomy-splenectomy, (2) left upper quadrant peritonectomy, (3) right upper quadrant peritonectomy, (4) lesser omentectomy-cholecystectomy with stripping of the omental bursa, (5) pelvic peritonectomy with sleeve resection of the sigmoid colon, and (6) antrectomy. These peritonectomy procedures and preparation of the abdomen for early postoperative intraperitoneal chemotherapy are described.
Clinical research methodologies in diagnosis and staging of patients with peritoneal carcinomatosis.
- Jacquet
Hyperthermic intraperitoneal chemotherapy + early postoperative intraperitoneal chemotherapy versus hyperthermic intraperitoneal chemotherapy alone: assessment of survival outcomes for colorectal and high-grade appendiceal peritoneal carcinomatosis.
- Lam