Appendiceal neoplasms and pseudomyxoma peritonei: A population based study

Background

Pseudomyxoma peritonei (PMP) is a rare disease with an estimated incidence of 1 per million per year, and is thought to originate usually from an appendiceal mucinous epithelial neoplasm. However it is not known exactly how often these neoplasms lead to PMP. The aim of this study is to investigate the incidence of both lesions and their relation.

Methods

The nationwide pathology database of the Netherlands (PALGA) was searched for the incidence of all appendectomies, the incidence of primary epithelial appendiceal lesions and the incidence and pathology history of patients with PMP. All regarded the 10-year period of 1995–2005.

Results

In the 10-year period 167,744 appendectomies were performed in the Netherlands. An appendiceal lesion was found in 1482 appendiceal specimens (0.9%). Nine percent of these patients developed PMP. Coincidentally, an additional epithelial colonic neoplasm was found in 13% of patients with an appendiceal epithelial lesion. A mucinous epithelial neoplasm was identified in 0.3% (73% benign, 27% malignant) of appendiceal specimens and 20% of these patients developed PMP. For mucocele and non-mucinous neoplasm the association with PMP was only 2% and 3%, respectively. From the nationwide database 267 patients (62 men and 205 women) with PMP were identified, which demonstrates an incidence of PMP in the Netherlands approaching 2 per million per year. The primary site was identified in 68% and dominated by the appendix (82%).

Conclusions

Primary epithelial lesions of the appendix are rare. One third of these lesions are mucinous epithelial neoplasms and especially these tumours may progress into PMP. The incidence of PMP seems to be higher than thought before. Furthermore there is a considerable risk of an additional colonic epithelial neoplasm in patients with an epithelial neoplasm at appendectomy.     

Prevalence of BRCA1 and BRCA2 mutations in unselected breast cancer patients from Greece

Carcinomas of the appendix are exceedingly rare tumors and have an annual age-adjusted incidence of around 0.4 cases per 100,000. Appendiceal adenocarcinoma accounts for < 0.5% of all gastrointestinal neoplasms and, of these, mucinous adenocarcinomas account for the majority. Published accounts of familial instances of primary appendiceal tumors are strikingly rare. We report two siblings who both developed primary mucinous adenocarcinomas. A genetics evaluation was conducted to determine if there was a recognizable underlying single gene disorder; no DNA mismatch repair defect was evident, and no other diagnosis was apparent. A review of appendiceal cancers seen at Mayo Clinic from l997 to the present was conducted to search for additional familial cases. Among 316 cases of primary appendiceal cancer of any histologic type, this sib pair was the only family reporting a second affected family member. The occurrence of appendiceal cancer in siblings may represent a random occurrence. An exceedingly rare predisposition syndrome cannot be ruled out.     

p53蛋白和增殖细胞核抗原在阑尾黏液性肿瘤和腹膜假黏液瘤中的表达及意义

  目的　研究p53蛋白和增殖细胞核抗原（Ki-67）表达与阑尾黏液性肿瘤临床病理特征之间的关系以及二者在肿瘤发生、发展中的作用。方法　选取解放军总医院病理科1993年5月至2007年10月收治的42例阑尾黏液性肿瘤患者手术标本组织蜡块,另取10例单纯性阑尾炎作为对照。应用PV6000免疫组织化学二步法,分别检测p53蛋白和Ki-67抗原的表达水平。结果　p53蛋白在阑尾黏液性肿瘤中表达阳性率[31.0 %（13／42）] 高于阑尾炎组[0（0／10）]（χ2＝4.127,P＝0.042）,在阑尾黏液腺癌组表达阳性率[40.0 %（12／30）]高于低级别黏液性肿瘤组[ 8.3 %（1／12）]（χ2＝4.0218,P＝0.044）。形成腹膜假黏液瘤组p53蛋白表达阳性率[45.5 %（10／22）]高于无腹膜假黏液瘤组[ 15.0 %（3／20）]（χ2＝4.5464,P＝0.033）。Ki-67抗原在阑尾黏液性肿瘤中标记阳性率[45.2 %（19／42）]高于阑尾炎组[10.0 %（1／10）]（χ2＝4.2374,P＝0.039）,而Ki-67抗原的表达与性别、年龄、是否形成腹膜假黏液瘤以及肿瘤病理类型等因素均无关（χ2值分别为0.0961、1.5910、1.6155、2.7776,均P＞0.05）。阑尾黏液性肿瘤中,p53蛋白阳性表达组Ki-67标记阳性率高于p53蛋白阴性组（χ2＝7.6299,P＝0.0057）。结论　p53基因的突变与阑尾黏液性肿瘤的发生、发展有一定关系 。Ki-67抗原表达可以反映出阑尾黏液性肿瘤增殖活性,但单独检测Ki-67不能作为鉴别肿瘤良性及判定恶性程度的指标。p53基因突变与Ki-67抗原表达存在相关性,联合检测p53蛋白、Ki-67抗原对于评估阑尾黏液性肿瘤的生物学行为,判断肿瘤恶性程度具有一定意义。     

Recommendations in the management of epithelial appendiceal neoplasms and peritoneal dissemination from mucinous tumours (pseudomyxoma peritonei)

The epithelial appendiceal neoplasms are uncommon and are usually detected as an unexpected surgical finding. The general surgeon should be aware of the diversity of its clinical manifestations and biological behaviors along with the significance of the surgical treatment on the progression of the illness and the prognosis of the patients. The operative findings and, especially, tumor histology, determine the type of surgery. Intestinal histologic subtype behaves and should be treated similarly to the right colon neoplasms; while mucinous tumors, often discordant between histology and its aggressiveness, can be treated with a simple appendectomy or require complex oncological surgeries. Mucinous tumors are often associated with the presence of mucin or tumor implants in the abdominal cavity, being the clinical syndrome known as pseudomyxoma peritonei (PMP). PMP tends to present an indolent but deadly evolution and requires a multimodal approach as a single treatment with curative potential: complete cytoreductive surgery plus hyperthermic Intra-peritoneal chemotherapy (CCRS + HIPEC) now considered the standard of care in this pathology. The general surgeon should be aware of the governing principles of the treatment of appendiceal neoplasms with or without peritoneal dissemination, know the therapeutic frontiers in every situation (avoiding unnecessary or counterproductive surgeries) and sending early these patients to specialised centres in the radical management of malignant diseases of the peritoneum in the conditions and with the necessary information to facilitate a possible radical treatment.     

Management and prognosis of low-grade appendiceal mucinous neoplasms: A clinicopathologic analysis of 50 cases

Background

Low-grade appendiceal mucinous neoplasms (LAMN) are poorly understood lesions characterized by their potential to spread to the peritoneal cavity as pseudomyxoma peritonei (PMP). The purpose of this study was to investigate the clinical and pathologic features and management of these tumors.

Challenges of Efficacy Assessments in Pseudomyxoma Peritonea

Several critical issues need to be considered in interpreting the results of the single-center observational study of the FOLFOX regimen in appendiceal pseudomyxoma peritonei reported by Pietrantonio et al.Several critical issues need to be considered in interpreting the results of the single-center observational study of the FOLFOX regimen in appendiceal pseudomyxoma peritonei (PMP) reported by Pietrantonio et al. [1].Clinical behavior of mucinous appendiceal neoplasms is variable and highly dependent on histological grade [2]. Currently, multiple histopathological grading systems exist [3–5]. Although the authors’ eligibility criteria describe inclusion of borderline mucinous tumors and well-differentiated appendiceal adenocarcinomas, the grading is reported as either low (n = 12) or high (n = 8). Because no reference grading system is provided, the meaning of high and low grade is unclear. According to the American Joint Committee on Cancer’s AJCC Cancer Staging Manual, 7th edition, high-grade mucinous appendiceal adenocarcinomas are defined as moderate to poorly differentiated tumors [6], and that is inconsistent with the inclusion criteria.Eligible patients were either unresectable (n = 6) or had relapsed following initial cytoreductive surgery (CRS; n = 14). It was reported that 2 of the 6 initially unresectable cases underwent cytoreductive surgery, but the rate of repeat CRS in the 14 patients who had initially relapsed following a complete CRS was not reported. Because repeated CRS in appendiceal PMP represents a proven approach [7, 8] the rate of a second CRS should be reported. Because both PFS and overall survival times are not censored at the time of a second CRS, the reported time-to-event analyses may best reflect an anticancer approach of chemotherapy followed by repeated CRS [9].Low-grade mucinous appendiceal neoplasms are known to have an indolent disease course; therefore, the presence of 7 cases with >20% growth at 3 months (progressive disease) is highly unusual for this disease type. Furthermore, the >30% shrinkage seen in 4 of these patients is unusual in the context of a median of 8 cycles (∼4 months) and a maximum of 12 (∼6 months). As a center that has conducted extensive research in appendiceal neoplasms, we disagree with the statement that a “decrease in the amount of mucus was invariably observed” and feel that the magnitude of radiographic change reported over a 3- to 6-month period for low-grade mucinous appendiceal neoplasms is not an accurate reflection of the disease biology under study. Prior reports documenting radiographic responses have all included more aggressive and higher grade appendiceal neoplasms and are not reflective of the population in this report [10, 11]. In part, we believe that the findings reported reflect the intrinsic challenges of both separating mucinous from more serous peritoneal accumulations and measuring geographically shaped mucinous implants that shift between scans. This latter point is amplified by the limitation of measuring only two peritoneal areas, as per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1.Prospective controlled studies are needed to clarify the role of chemotherapy in PMP. A clinical trial ({"type":"clinical-trial","attrs":{"text":"NCT01946854","term_id":"NCT01946854"}}NCT01946854) for unresectable low-grade mucinous appendiceal adenocarcinomas with PMP is ongoing at MD Anderson. In that trial, patients are randomized to either 6 months of chemotherapy followed by 6 months of observation or 6 months of observation followed by 6 months of chemotherapy. Within this study, a modified peritoneal RECIST measurement in which five locations are measured is being investigated. Because each patient serves as his or her own control, we hope this study will better clarify the true rate of radiographic change for this biologically unique tumor type.     

卵巢来源腹膜假黏液瘤临床病理分析

  目的  探讨卵巢来源腹膜假黏液瘤（pseudomyxoma peritonei,PMP）的临床病理学特征及免疫组织化学表型。  方法  回顾性分析2010年1月至2019年1月272例于首都医科大学附属北京世纪坛医院确诊为PMP患者的临床资料,研究PMP肿瘤来源,复阅病理切片并行免疫组织化学标记,标记抗体包括CK7、CK20、CEA、Villin、CDX2、SATB2、CA125、ER、PR、PAX8、MUC1、MUC2等。  结果  272例PMP中阑尾来源245例（90.1%）、非阑尾来源27例（9.9%）。卵巢来源PMP仅5例（1.8%）,其中4例为黏液性囊腺瘤、1例为交界性黏液性囊腺瘤,均发生在单侧,5例中2例合并成熟性囊性畸胎瘤;腹膜播散肿瘤中2例为无细胞性黏液、2例为低级别腹膜黏液癌、1例为高级别腹膜黏液癌。免疫组织化学法检测显示,5例PMP患者组织中CK20、CEA、Villin、CDX2均阳性,2例黏液性囊腺瘤合并畸胎瘤患者的SATB2部分阳性、2例SATB2阴性、1例SATB2灶状阳性。  结论  卵巢来源PMP罕见,需对阑尾全部取材或对可疑组织块行连续切片,以排除阑尾黏液性肿瘤,并结合临床症状体征、影像学表现、手术所见、组织学特征及免疫组织化学法检测进行综合分析。      

COX-2 expression in pseudomyxoma peritonei

COX-2 expression was studied using an immunohistochemical method in 75 patients with pseudomyxoma peritonei (PMP). Twenty-five patients presented with disseminated peritoneal adenomucinosis (DPAM) and 50 with peritoneal mucinous carcinomatosis (PMCA). COX-2 was expressed in neoplastic mucinous epithelium of 30 cases (40%): 20 in PMCA (40%), 10 in DPAM (40%). Weak COX-2 expression was also noted in four of five patients with appendiceal mucinous neoplasms without peritoneal dissemination. In addition, COX-2 was detected in stromal, endothelial, inflammatory cells and reactive mesothelium. This preliminary information indicates a potential for the use of COX-2 inhibitors in patients with PMP.     

Loss of chromosome 18q and DPC4 (Smad4) mutations in appendiceal adenocarcinomas

Appendiceal adenocarcinomas are uncommon, and the genetic alterations present in these tumors are not well characterized. We studied genetic alterations including loss of chromosome 18q (location of DCC, DPC4, and JV-18 genes), and mutations of the DPC4 (SMAD4) and beta-catenin genes in 28 appendiceal adenocarcinomas, consisting of 17 mucinous and 11 nonmucinous carcinomas. Chromosome 18q loss was present in 57% (12/21) of appendiceal carcinomas including 54% (7/13) of mucinous and 63% (5/8) of nonmucinous carcinomas. Mutation of the DPC4 gene was present in 14% (three of 22) of the carcinomas occurring in one tumor with chromosome 18q loss and in two with unassessed chromosome 18q status. beta-catenin gene mutation was present in 0% (0 of 25) of the carcinomas. Chromosome 18q loss status was not associated with any clinicopathological features. The presence of chromosome 18q loss and DPC4 mutations in appendiceal adenocarcinomas suggests involvement of DPC4 and nearby genes on chromosome 18q (DCC and/or JV-18) in the pathogenesis of appendiceal adenocarcinomas.     

Whole-genome allelotyping identified distinct loss-of-heterozygosity patterns in mucinous ovarian and appendiceal carcinomas.

PURPOSE: Mucinous adenocarcinoma of the ovary is one of the common histologic types of ovarian cancer. Its pathogenesis is largely unknown. In addition, the differential diagnosis of metastatic mucinous carcinomas to the ovaries, particularly those originating from the appendix, remains challenging. The purpose of this study is to identify molecular biomarkers for mucinous ovarian adenocarcinoma and compare them with those of appendiceal origin. EXPERIMENTAL DESIGN: Genome-wide loss-of-heterozygosity (LOH) analysis was done on DNA isolated from 28 microdissected primary mucinous ovarian carcinomas and five appendiceal adenocarcinomas. Markers from high-loss regions were selected for further analysis on a total of 32 ovarian and 14 appendiceal cancers. RESULTS: High levels of LOH rates (>40%) were detected on chromosome arms 9p, 17p, and 21q in mucinous ovarian carcinoma cases. The frequency of allelic loss was similar between high-grade and low-grade mucinous ovarian carcinoma cases but was significantly higher in ovarian versus appendiceal cases. In addition, LOH rates on five chromosomal loci were statistically different between ovarian and appendiceal carcinomas. CONCLUSION: A high frequency of LOH can be found in mucinous ovarian adenocarcinomas independent of grade. Despite histologic similarities between mucinous ovarian carcinomas and metastatic appendiceal carcinomas, they have distinct LOH profiles, which may be used for distinguishing the two diseases.     

The etiology, clinical presentation, and management of pseudomyxoma peritonei

PMP is a rare condition, which, although of "borderline malignancy," is invariably fatal. Difficulties exist with the definition of PMP. It has been broadly applied to include a heterogenous group of pathologic lesions that present clinically with "jelly belly" due to mucinous ascites. The relatively few reports in the literature commonly use different pathologic definitions, and there is no consensus on the point of separation between PMP and carcinomatosis secondary to a mucinous adenocarcinoma. Sugarbaker has suggested "the term pseudomyxoma peritonei syndrome be strictly applied to a pathologically and prognostically homogenous group of cases characterized by histologically benign peritoneal tumors that are frequently associated with an appendiceal mucinous adenoma." This definition excludes all cases with mucinous adenocarcinoma. The optimal treatment is undoubtedly complete tumor excision, by complex surgical peritonectomy procedures, taking on average 10 hours. Surgery is usually combined with intraperitoneal, and now intraoperative heated chemotherapy. These techniques have a high morbidity and mortality. The rarity of the condition, together with the risks associated with definitive treatment, suggests that such treatment ought to be centralized in a few centers, covering a large population. The search continues for safer, less aggressive treatments, but is hampered by a lack of hard evidence and the absence of experimental animal or human models to evaluate emerging strategies.     

阑尾黏液性肿瘤临床病理分析

目的:探讨阑尾黏液性肿瘤的临床病理特征.方法:对2例阑尾黏液性肿瘤的临床、病理和免疫学表型进行观察、分析及文献复习.结果:例1为-47岁女性,症状主要为阴道不规则出血四月,病理确诊为阑尾交界性黏液性乳头状囊腺瘤.例2为-66岁女性,症状主要为右下腹痛一天,病理确诊为阑尾高分化黏液性囊腺癌.结论:阑尾黏液性肿瘤是一种少见的疾病,临床及影像学检查容易误诊,确诊依靠病理检查.     

Immunological reactivity of mucinous and serous ovarian adenocarcinomas

Comparison of immunological reactivity of glycoprotein antigens extracted from individual cases of mucinous and serous ovarian adenocarcinomas was performed taking into account the immunological relationship with carcinoembryonic antigen (CEA), nonspecific cross-reacting antigen (NCA), alpha-1-antichymotrypsin, and alpha-1-acid glycoprotein. In all immunological tests, the specific immune sera against perchloric acid extracts of ovarian mucinous and serous cystadenocarcinomas and antisera against the reference antigens mentioned above were used. It was established that: 1) ovarian mucinous and serous adenocarcinomas are immunologically different and possess various tumor-associated antigens, 2) ovarian mucinous adenocarcinomas contain considerable amounts of CEA and NCA, whereas serous type neoplasms show negligible amounts or lack of these antigens; and 3) in both types of tumors, alpha-1-antichymotrypsin and alpha-1-acid glycoprotein activities are found. Immunological data indicate that ovarian mucinous and serous adenocarcinomas derive from separate lineages of epithelium.     

Pathogenesis of histologic variations of appendiceal mucinous neoplasms

BackgroundIn order for peritoneal metastases from a primary appendiceal mucinous neoplasm to occur, the wall of the appendix must perforate to allow mucus with tumor cells access to the peritoneal spaces. With progression the peritoneal metastases show a broad spectrum of tumor biology varying from indolent to aggressive activity.MethodsThe histopathology of peritoneal tumor masses was determined from the clinical material resected at the time of cytoreductive surgery (CRS). All groups of patients were treated by a uniform strategy that involved complete CRS and perioperative intraperitoneal chemotherapy. Overall survival was determined.ResultsFrom a database of 685 patients, four histologic subtypes were identified and long-term survival determined. Four hundred and fifty patients (66.0%) had low-grade appendiceal mucinous neoplasm (LAMN), 37 patients (5.4%) had mucinous appendiceal adenocarcinoma of intermediate subtype (MACA-Int), 159 patients (23.2%) had mucinous appendiceal adenocarcinoma (MACA), and 39 patients (5.4%) had a mucinous appendiceal adenocarcinoma with positive lymph nodes (MACA-LN). The mean survival of the four groups was 24.5, 14.8, 11.2 and 7.4 years, respectively (p < 0.0001). These four subtypes of mucinous appendiceal neoplasms were shown to have distinct survival estimates.ConclusionsThe estimated survival of these four histologic subtypes in patients having a complete CRS plus HIPEC is of value to the oncologist managing these patients. A mutations and perforations hypothesis was offered in an attempt to explain the broad spectrum of mucinous appendiceal neoplasms that exist. Inclusion of MACA-Int and MACA-LN as standalone subtypes was thought to be necessary.     

Primary malignant neoplasms of the appendix: a population-based study from the surveillance,epidemiology and end-results program, 1973-1998

BACKGROUND: 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. METHODS: 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. RESULTS: 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).CONCLUSIONS: 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 Role of Microorganisms in Appendiceal Pseudomyxoma Peritonei: A Review

Pseudomyxoma peritonei (PMP) is a rare clinical syndrome. It originates from neoplasms of the appendix and leads to the formation of peritoneal implants and the accumulation of mucinous ascites. PMP represents a spectrum of low to high-grade disease. Despite aggressive management, many PMP patients recur, leading to debilitating symptoms and few treatment options. Therefore, scientists have continued to look for ways to improve treatment and further understand disease pathogenesis. Microorganisms were previously hypothesized to play a role in PMP progression and development. Hence, antibacterial treatment was suggested by some authors, but the data were limited. In this paper, we review the current data on the role of bacteria in PMP, discuss the significance, and suggest possible solutions to the inherent challenges in these studies. Given the limitations of the discussed studies, we remain skeptical about introducing novel antibacterial treatment into clinical practice at this time; however, the available data are valuable and indicate that more research into the molecular mechanisms of PMP is needed.     

Pseudomixoma peritonei: a case report

Pseudomixoma Peritonei (PMP) is an uncommon neoplasm characterised by mucinous ascites and multifocal amorphous mucous substances involving the peritoneal surface, omentum and bowel loops. Although the origin of the Pseudomixoma Peritonei is still unclear, it could be due to the perforation of an ovarian mucinous cystoadenoma or an appendiceal mucocele. The further pelvic dissemination of the endotumor material, which adhere itself into the peritoneal surface, may induce an intra-abdominal transformation of the peritoneal mesothelium into mucin-producing tissue. A case of Pseudomyxoma Peritonei (PMP) which occurred in a young woman is reported.     

Splenic metastases from mucinous neoplasms of the appendix and colon

AIMS AND BACKGROUND: Splenic metastases associated with mucinous intraabdominal tumors have been an enigma in the radiologic and oncology literature. These focal parenchymal defects from a non-metastasizing malignancy within an organ that rarely develops metastatic foci, even with high-grade cancer, were studied. METHODS: Information on 9 patients who underwent splenectomy with intraparenchymal splenic masses associated with appendiceal or colorectal mucinous tumors with peritoneal dissemination was collected. The CT scan, the histopathology and the clinical parameters of these patients were studied. A literature review searching for prior reports of this subject was performed. RESULTS: Eight of these patients had mucinous appendiceal tumors and 1 a mucinous sigmoid colon cancer. All patients had mucinous carcinomatosis at some time in their clinical course. These splenic tumor masses had a CT image compatible with metastases and not compatible with mucinous tumor layered out of the splenic capsule. None of the patients had evidence of metastases to other sites such as liver or lymph nodes. All patients had a mucinous histopathology. Splenectomy may be associated with prolonged survival. CONCLUSIONS: From our review of the clinical information available on these 9 patients, these splenic lesions were thought to be an entrapment of mucinous tumor within splenic surface trabeculae, which expand into the splenic parenchyma resembling metastatic disease. These CT findings may be more accurately referred to as splenic pseudometastases.