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1.  Pseudomyxoma Peritonei: Is Disease Progression Related to Microbial Agents? A Study of Bacteria, MUC2 and MUC5AC Expression in Disseminated Peritoneal Adenomucinosis and Peritoneal Mucinous Carcinomatosis 
Annals of surgical oncology  2008;15(5):1414-1423.
Background and Aims
Pseudomyxoma peritonei (PMP) is characterized by peritoneal tumors arising from a perforated appendiceal adenoma or adenocarcinoma, but associated entry of enteric bacteria in the peritoneum has not been considered as a cofactor. Because Gram-negative organisms can upregulate MUC2 mucin gene expression, we determined whether bacteria were detectable in PMP tissues.
Methods
In situ hybridization was performed on resection specimens from five control subjects with noninflamed, nonperforated, non-neoplastic appendix and 16 patients with PMP [six with disseminated peritoneal adenomucinosis (DPAM) and 10 with peritoneal mucinous carcinomatosis (PMCA)]. Specific probes were designed to recognize: (1) 16S rRNA common to multiple bacteria or specific to H. pylori; (2) H. pylori cagA virulence gene; or (3) MUC2 or MUC5AC apomucins. Specimens from one patient with PMCA were examined by ultra-structural immunohistochemistry. Bacterial density and apomucin expression were determined in four histopathological compartments (epithelia, inflammatory cells, stroma, and free mucus).
Results
Enteric bacteria were detected in all specimens. Bacterial density and MUC2 expression were significantly (p < 0.05) higher in PMCA than in DPAM and controls and were highest in free mucin. MUC2 was also expressed in dysplastic epithelia and in associated inflammatory cells. MUC2 expression was significantly correlated with bacterial density.
Conclusions
Multiple enteric bacteria are present in PMP, and bacterial density and MUC2 expression is highest in the malignant form of PMP. Based on these observations, we propose that the bacteria observed in PMP may play a role in the mucinous ascites and perhaps promote carcinogenesis.
doi:10.1245/s10434-007-9778-9
PMCID: PMC2570966  PMID: 18299935
2.  Pseudomyxoma cutis; a new entity 
Pseudomyxoma (PM) implies an accumulation of a large amount of mucins which show myxomatous appearances. PM Peritonei (PMP) is famous and the only example of PM. PMP means excessive accumulation of mucins and mucin-secreting cells in the peritoneal cavity. The causes of PMP are mostly mucinous tumors, both benign and malignant, of ovaries and vermiform appendix. The author experienced excessive accumulation of mucins and mucin-producing cells in the subcutis and deep soft tissue. This situation very resembled PMP. Thus, the author termed the lesion as PM cutis (PMC). A 57-year-old man admitted to our hospital because of multiple subcutaneous large tumors in the perianal skin. The tumors were deeply seated and soft. No biopsy was performed. Very large skin and subcutis resection of the perianal region was done. Grossly, the material was skin and sot tissue flap measuring 25x25x5cm. The subcutis and deep soft tissue were resected. On cut surface, the tumor was slimy liquid. Microscopical examination revealed a large amount of mucins pools and mucin-producing intestinal epithelium with mild atypia. The author diagnosed it metastatic extremely well differentiated adenocarcinoma producing mucins, and pointed out anorectal primary. Thus, Miles operation was performed, which showed tumor formation in the anus. The tumor was located from the submucosa to adventitia, and composed of mucin pools and mucins producing intestinal-type epithelium with atypia. Mucins histochemistry showed that the mucin pools and epithelial cytoplasm contained neutral, carboxylated, and sulfated mucins. Immunohistochemically, the tumor cells were positive for CKAE1/3, CKCAM5.2, CK7, CK8, CK19, CK20, CEA, CA19-9,CD68, MET, p53, MUC2, MUC5AC, KIT, PDGFRA, chromogranin, and Ki-67 (76%). They were negative for CK34BE12, CK5/6, CK14, CK18, EMA, vimentin, desmin, smooth muscle actin, p63, CD34, ER, PgR, CA125, MUC1, MUC6, CD45, CD10, synaptophysin, surfactant Apo-A, TTF-1, NCAM, bcl-2, CDX-2. Although the atypia is mild, the author diagnosed primary anorectal extremely well differentiated adenocarcinoma with excessive production of mucins. The author considers the cutaneous mucins and tumor cells are metastatic or directly invading lesions of the anal tumor. Thus, the author termed pseudomyxoma cutis (PMC) for the cutaneous lesion.
PMCID: PMC3657373  PMID: 23696938
Pseudomyxoma; skin; anal; mucins; mucin producing tumor; immunohistochemistry
3.  Immunohistochemical and Biochemical Characterization of Mucin in Pseudomyxoma Peritonei: A Case Study 
We previously reported the presence of MUC2, MUC5AC and, for the first time, MUC5B in a 58-year-old male with pseudomyxoma peritonei (PMP). This is a report on the biochemical and immunohistochemical characterization of mucin in a 50-year-old female with the same rare illness. A right oophorectomy and appendicectomy and a resection of the involved omentum were performed. Approximately a litre of crude material in the sol and gel phases was obtained from the patient during laparotomy. This was briefly homogenized in 6 M guanidinium hydrochloride and proteolytic inhibitors and purified by density gradient centrifugation in caesium chloride. At laparotomy it was noted that the patient had appendiceal and ovarian masses as well as extensive mucinous deposits in the omentum and peritoneum. A mucinous adenocarcinoma of the appendix and ovary was confirmed on histology. The cells expressed both sulphated and non-sulphated acidic mucins. The presence of MUC2, MUC5AC, MUC5B and a-1-acid glycoprotein was shown by Western blotting and MUC4 by immunohistochemical staining. MUC1 and MUC6 were not detectable in the tissue. The study confirms that MUC2, MUC5AC and MUC5B are produced in the mucus of patients with PMP. The expression of MUC4 in this disease has not been previously reported.
doi:10.1159/000323137
PMCID: PMC3280478  PMID: 22347149
MUC; Mucin; Mucus; Pseudomyxoma peritonei; Ovary
4.  Chronic Anti-inflammatory Drug Therapy Inhibits Gel-Forming Mucin Production in a Murine Xenograft Model of Human Pseudomyxoma Peritonei 
Annals of surgical oncology  2012;19(5):1402-1409.
Background
Intraperitoneal accumulation of mucinous ascites in pseudomyxoma peritonei (PMP) promotes an inflammatory/fibrotic reaction that progresses to bowel obstruction and eventual patient demise. Cytokines and inflammation-associated transcription factor binding sites, such as glucocorticoid response elements and COX-2, regulate secretory mucin, specifically MUC2, production. We hypothesized that anti-inflammatory drugs targeting inflammation-associated pathways may reduce mucin production and subsequent disease morbidity in PMP.
Methods
The effects of dexamethasone and Celebrex were assessed in mucin-secreting human colon cancer LS174T cells in vitro and murine xenograft models of LS174T and human appendiceal PMP in vivo by serial parametric measurements, MUC2 transcripts via real-time RT-PCR, and MUC2 protein expression via immunofluorescence assays.
Results
Dexamethasone significantly inhibited basal MUC2 mRNA levels in LS174T cells, inhibited mucinous tumor accumulation in an intraperitoneal PMP xenograft model, and prolonged survival in a subcutaneous LS174T xenograft model. Celebrex significantly inhibited sodium butyrate-stimulated MUC2 mRNA levels in LS174T cells and demonstrated a statistically nonsignificant trend toward reduced mucinous tumor growth and prolonged survival in the xenograft models. MUC2 protein analysis by immunofluorescence demonstrated a dual effect of dexamethasone on mucin production and tumor cell count.
Conclusions
Inflammatory mediators are known to regulate mucin production and may promote overexpression of MUC2 by neoplastic cells with goblet cell phenotype in PMP. Anti-inflammatory drugs, dexamethasone and Celebrex, could inhibit extracellular mucin production in PMP by targeting inflammatory cascades and, therefore, may decrease compressive symptoms, increase the disease-free interval, and reduce the extent or frequency of morbid cytoreductive surgeries.
doi:10.1245/s10434-012-2242-5
PMCID: PMC4125010  PMID: 22302271
5.  Pseudomyxoma peritonei of 92 Chinese patients: Clinical characteristics, pathological classification and prognostic factors 
AIM: To assess the clinicopathologic features and its relationship with prognosis of pseudomyxoma peritonei (PMP) in Chinese patients.
METHODS: The clinicopathologic features and follow-up data of 92 patients with PMP were reviewed and retrospectively analyzed. The cases were categorized into three groups: disseminated peritoneal adenomucinosis (DPAM), peritoneal mucinous carcinomatosis (PMCA), and peritoneal mucinous carcinomatosis with intermediate or discordant features (PMCA-I/D). The log-rank test was used to analyze survival for each group and various clinicopathological parameters. Multivariate Cox proportional-hazard models were constructed to determine the important factors associated with survival.
RESULTS: The median age at diagnosis was 51.9 years (range: 22-76 years). The median follow up was 124 mo. The 3-, 5- and 10-year survival rates were 74.0%, 67.4% and 49.1%, respectively. There were 49 (53.2%) patients with DPAM, 26 (28.3%) with PMCA-I and 17 (18.5%) with PMCA. Patients with DPAM, PMCA-I/D and PMCA exhibited statistically significant difference in survival (P = 0.001). The 3 year survival for DPAM, PMCAI/D and PMCA was 97.0%, 80.0% and 67.0%, respectively; the 5 year survival was 80.0%, 67.0% and 50.0%, respectively; and the 10 year survival was 65.0%, 28.0% and 14.0%, respectively. Survival rate was significantly lowest in patients < 40 age years of age (P = 0.011). Appendiceal tumor and extra-ovarian parenchymal organ involvement were significantly related to overall survival. Patients with appendiceal mucinous adenocarcinoma (MACA) showed the significantly poorer prognosis (P = 0.011). Multivariate analysis showed that pathological classification, age, appendiceal tumor were significant related to overall survival.
CONCLUSION: The clinical process “PMP” should be pathologically classified into DPAM, PMCA and PMCA-I/D. Pathological classification, age, appendiceal MACA are survival independent predictors in Chinese patients with PMP.
doi:10.3748/wjg.v18.i24.3081
PMCID: PMC3386321  PMID: 22791943
Pseudomyxoma peritonei; Pathologic; Clinical; Classification; Prognosis
6.  Secreted mucins in pseudomyxoma peritonei: pathophysiological significance and potential therapeutic prospects 
Pseudomyxoma peritonei (PMP, ORPHA26790) is a clinical syndrome characterized by progressive dissemination of mucinous tumors and mucinous ascites in the abdomen and pelvis. PMP is a rare disease with an estimated incidence of 1–2 out of a million. Clinically, PMP usually presents with a variety of unspecific signs and symptoms, including abdominal pain and distention, ascites or even bowel obstruction. It is also diagnosed incidentally at surgical or non-surgical investigations of the abdominopelvic viscera. PMP is a neoplastic disease originating from a primary mucinous tumor of the appendix with a distinctive pattern of the peritoneal spread. Computed tomography and histopathology are the most reliable diagnostic modalities. The differential diagnosis of the disease includes secondary peritoneal carcinomatoses and some rare peritoneal conditions. Optimal elimination of mucin and the mucin-secreting tumor comprises the current standard of care for PMP offered in specialized centers as visceral resections and peritonectomy combined with intraperitoneal chemotherapy. This multidisciplinary approach has reportedly provided a median survival rate of 16.3 years, a median progression-free survival rate of 8.2 years and 10- and 15-year survival rates of 63% and 59%, respectively. Despite its indolent, bland nature as a neoplasm, PMP is a debilitating condition that severely impacts quality of life. It tends to be diagnosed at advanced stages and frequently recurs after treatment. Being ignored in research, however, PMP remains a challenging, enigmatic entity. Clinicopathological features of the PMP syndrome and its morbid complications closely correspond with the multifocal distribution of the secreted mucin collections and mucin-secreting implants. Novel strategies are thus required to facilitate macroscopic, as well as microscopic, elimination of mucin and its source as the key components of the disease. In this regard, MUC2, MUC5AC and MUC5B have been found as the secreted mucins of relevance in PMP. Development of mucin-targeted therapies could be a promising avenue for future research which is addressed in this article.
doi:10.1186/1750-1172-9-71
PMCID: PMC4013295  PMID: 24886459
Pseudomyxoma peritonei; PMP; Mucin; MUC2; Goblet cells; Appendix
7.  Case of intraperitoneal sepsis secondary to rupture of the appendix on the background of pseudomyxoma peritonei 
Introduction
Pseudomyxoma peritonei (PMP) is characterised by gelatinous ascites and pools of mucin associated with neoplastic mucinous epithelium within the peritoneal cavity. It can rarely present as acute intraperitoneal sepsis, requiring urgent medical attention.
Presentation of case
A 59-year old male was referred to our centre in February 2014 following a diagnostic laparotomy, which showed jelly-like material with occasional epithelial cells. He was listed for peritonectomy in a month's time at our centre. Three weeks later, he was admitted urgently to our hospital due to generalised abdominal pain and watery diarrhoea. Examination at admission was unremarkable. On the following day, he became haemodynamically unstable and was suspected to have intraperitoneal sepsis due to infected PMP. At emergency laparotomy, we found gross intraperitoneal sepsis and did extensive debulking of tumour, appendectomy and extensive division of adhesions. Another laparotomy was done 24 h later for washout. He was discharged three weeks after.
Discussion
Although we have done 780 peritonectomy procedures, this was the first patient with this presentation of widerspread intraperitoneal sepsis. Continuous mucous production of appendiceal adenoma can lead to appendiceal rupture. The appendix may decompress by perforation and then reseal. However, one episode of appendiceal rupture can cause bacterial contamination of PMP, leading to sepsis.
Conclusion
Intraperitoneal sepsis secondary to appendiceal rupture is rare. Hence surgeons may face an emergency of intraperitoneal sepsis during waiting period of planned CRS or as a primary presentation. With combined therapy of CRS and PIC, the prognosis of mucinous appendiceal adenoma is excellent.
Highlights
•Intraperitoneal sepsis secondary to appendiceal rupture is rare.•Surgeons may face an emergency of intraperitoneal sepsis before the planned surgery or as a primary presentation.•With combined therapy, the prognosis of mucinous appendiceal adenoma is excellent.
doi:10.1016/j.amsu.2014.07.006
PMCID: PMC4323747
Pseudomyxoma peritonei; Intraperitoneal sepsis; Appendiceal mucinous adenoma
8.  A Comprehensive Expression Analysis of Mucins in Appendiceal Carcinoma in a Multicenter Study: MUC3 Is a Novel Prognostic Factor 
PLoS ONE  2014;9(12):e115613.
Background
Mucins are implicated in survival in various cancers, but there have been no report addressed on survival in appendiceal carcinoma, an uncommon disease with different clinical and pathological features from those of other colon cancers. We aimed to investigate the clinical implications of expression of mucins in appendiceal carcinoma.
Methods
Expression profiles of MUC1, MUC2, MUC3, MUC4, MUC5AC, MUC6, MUC16 and MUC17 in cancer tissue were examined by immunohistochemistry in 108 cases of surgically resected appendiceal carcinoma.
Results
The following relationships of mucins with clinicopathologic factors were identified: MUC1 with positive lymphatic invasion (p = 0.036); MUC2 with histological type (mucinous carcinoma, p<0.001), superficial invasion depth (p = 0.007), negative venous invasion (p = 0.003), and curative resection (p = 0.019); MUC3 with non-curative resection (p = 0.017); MUC5AC with histological type (mucinous carcinoma, p = 0.002), negative lymphatic invasion (p = 0.021), and negative venous invasion (p = 0.022); and MUC16 with positive lymph node metastasis (p = 0.035), positive venous invasion (p<0.05), and non-curative resection (p = 0.035). A poor prognosis was related to positive lymph node metastasis (p = 0.04), positive lymphatic invasion (p = 0.02), positive venous invasion (p<0.001), non-curative resection (p<0.001), and positive expression of MUC3 (p = 0.004). In multivariate analysis, positive venous invasion (HR: 6.93, 95% CI: 1.93–24.96, p = 0.003), non-curative resection (HR: 10.19, 95% CI: 3.05–34.07, p<0.001) and positive MUC3 expression (HR: 3.37, 95% CI: 1.13–10.03, p = 0.03) were identified as significant independent prognostic factors in patients with appendiceal carcinoma.
Conclusions
Expression of MUC3 in appendiceal carcinoma is an independent factor for poor prognosis and a useful predictor of outcome in patients with appendiceal carcinoma after surgery.
doi:10.1371/journal.pone.0115613
PMCID: PMC4281150  PMID: 25551773
9.  Laparoscopic Right Hemicolectomy for Mucocele Due to a Low-Grade Appendiceal Mucinous Neoplasm 
Tumors of the appendix are rare entities causing mucoceles. The majority of them are discovered incidentally during investigation for other conditions. Laparoscopic surgery for appendiceal tumors is still controversial, as inadvertent rupture of the lesion due to improper handling will cause pseudomyxoma peritonei. The patient was incidentally discovered to have an appendiceal tumor and referred to us for laparoscopy. Because the tumor involved the entire appendix, a laparoscopic right hemicolectomy was performed without directly handling the tumor. Postoperative recovery was uneventful. Pathological diagnosis was low-grade appendiceal mucinous neoplasm. The safety of laparoscopic appendectomy for the management of incidentally discovered appendiceal tumors has not yet been established. Several reports in the literature support both laparoscopic and open surgery. The main concerns to be addressed are the adequacy of resection and intraperitoneal rupture of the tumor. Our patient successfully underwent laparoscopic surgery without any complications. A formal right hemicolectomy was performed because the tumor involved the entire appendix. We now think laparoscopic surgery for appendiceal tumors is safe, feasible, and even may be beneficial.
PMCID: PMC3016193  PMID: 18435897
Appendiceal tumor; Appendicitis; Mucinous cystadenoma; Laparoscopic right hemicolectomy
10.  Case of an appendiceal mucinous adenocarcinoma presenting as a left adnexal mass☆ 
INTRODUCTION
Appendiceal mucinous neoplasms represent an exceptionally rare form of pathology with an incidence rate ranging between 0.2 and 0.3% of all appendectomies.1,2 The most common presentation is right lower quadrant pain with a palpable abdominal mass present in 50% of cases.8–12 Patients may also present with nausea, vomiting, change in bowel habits, weight loss, appendicitis, intestinal obstruction, ureteral compression, or lower gastrointestinal bleeding. Early diagnosis and proper surgical precautions must be implemented to prevent iatrogenic rupture of the appendix and the widespread seeding of potentially malignant mucin-producing cells throughout the peritoneal cavity.
PRESENTATION OF CASE
A 50-year-old African-American female presented with complaints of left-sided pelvic pain. Pelvic examination revealed adnexal fullness with thickening behind the cervix. An adnexal mass was revealed on ultrasound and MRI. The patient was subsequently taken to the operating room for a planned robotic salpingectomy. During the procedure, she was unexpectedly found to have an abnormally large appendix displaced to the left lower quadrant. General surgery was consulted intra-operatively to perform an appendectomy. The final pathology report revealed a low-grade mucinous adenocarcinoma with mucin dissecting into the wall of the appendix.
DISCUSSION
Appendiceal mucinous cystadenomas are characterized by hyperplasia of glandular epithelium along with hypersecretion of mucous resulting in a grossly dilated appendix. The clinical manifestation of appendiceal mucoceles is often non-specific. The prevalence is higher in women than men (4:1) with the average age at the time of diagnosis being 54 years-old.14–17 Appendiceal mucinous cystadenomas can be particularly problematic for women as these tumors are commonly misdiagnosed pre-operatively as right-sided adnexal masses due to commonalities in clinical presentation and diagnostic findings.8–12 It is estimated that based on imaging studies only 15–29% of appendiceal mucinous cystadenomas are correctly diagnosed prior to surgical intervention.13
CONCLUSION
To the best of our knowledge, only one other case of appendiceal adenocarcinoma with left-sided presentation has been reported. Appendiceal carcinomas can create a diagnostic dilemma due to non-specific clinical findings and inadequate imaging studies. Early recognition and careful intra-operative precautions must be taken to maintain the integrity of the appendix to prevent iatrogenic rupture and the spread of potentially malignant mucin-producing cells throughout the peritoneal cavity.
doi:10.1016/j.ijscr.2013.12.008
PMCID: PMC3955234  PMID: 24568943
Appendiceal mucinous adenocarcinoma; Appendiceal neoplasm; Appendectomy; Left-lower quadrant pain; Left-sided mass; Adnexal mass
11.  Experience with adjuvant chemotherapy for pseudomyxoma peritonei secondary to mucinous adenocarcinoma of the appendix with oxaliplatin/fluorouracil/leucovorin (FOLFOX4) 
Background
Pseudomyxoma peritonei (PMP) is a rare condition characterized by mucinous tumors, disseminated intra-peritoneal implants, and mucinous ascites. So far its diagnosis remains challenging to most clinicians.
Case presentation
A 55-year-old male patient had suffered from acute onset of abdominal pain and abdominal distension for one day prior to his admission. Physical examination revealed tenderness over the right lower quadrant of the abdomen without diffuse muscle guarding. A large amount of ascites was identified by abdominal computed tomography (CT) scan. Paracentesis showed the appearance of sticky mucinous ascites. He underwent laparotomy under the impression of pseudomyxoma peritonei. There was a lot of mucinous ascites, one appendiceal tumor and multiple peritoneal implants disseminated from the subphrenic space to the recto-vesicle pouch. Pseudomyxoma Peritonei caused by mucinous adenocarcinoma of appendiceal origin, was confirmed by histopathology. We performed an excision of the appendiceal tumor combined with copious irrigation and debridement. After the operation, he received 10 cycles of systemic chemotherapy with FOLFOX4 regimen, without specific morbidity. Follow-up of abdominal CT and colonoscopy at post-operative 17 months showed excellent response without evidence of local recurrence or distal metastasis. He made an uneventful recovery (up to the present) for 21 months after the operation.
Conclusion
This case report emphasizes the possible new role of systemic chemotherapy in the treatment of patients with this rare clinical syndrome.
doi:10.1186/1477-7819-6-118
PMCID: PMC2615010  PMID: 19014441
12.  A specific cadherin phenotype may characterise the disseminating yet non-metastatic behaviour of pseudomyxoma peritonei 
British Journal of Cancer  2006;95(9):1258-1264.
Pseudomyxoma peritonei (PMP) is a rare neoplasm of mainly appendiceal origin, characterised by excess intra-abdominal mucin production leading to high morbidity and mortality. While histological features are frequently indolent, this tumour disseminates aggressively throughout the abdominal cavity, yet seldom metastasises. This study determined the expression of several markers of colorectal differentiation (carcinoembryonic antigen (CEA), cytokeratins (CK20 and CK7), epithelial membrane antigen), mucin production (MUC-2, interleukin-9 (IL-9), IL-9 receptor (IL-9Rα)), and cell adhesion (N- and E-cadherin, vimentin) in PMP tissue (n=26) compared with expressions in normal colonic mucosa (n=19) and colorectal adenocarcinoma (n=26). Expressions of CEA and cytokeratins were similar for PMP as those in colorectal adenocarcinomas with the exception that the CK20−/CK7− pattern was rare in PMP (Fisher's exact test: P=0.001). Similarly, expressions of mucin-related proteins were comparable for adenocarcinoma and PMP, with the exception that IL-9 expression was uncommon in adenocarcinoma (P=0.009). Pseudomyxoma peritonei demonstrated a specific pattern of adhesion-related protein expressions of increased N-cadherin, reduced E-cadherin, and increased vimentin (P=0.004), a phenotype suggesting a possible epithelial–mesenchymal transition state. Primary PMP cell cultures were successfully maintained and demonstrated marker expressions similar to those seen in in vivo tissues. These early characterisation studies demonstrate similarities between PMP and colorectal adenocarcinoma, but also reveal a specific cadherin phenotype that may characterise the distinct non-metastasising behaviour of PMP, and form the basis for future mechanistic and therapy-targeting research.
doi:10.1038/sj.bjc.6603398
PMCID: PMC2360585  PMID: 17031402
pseudomyxoma peritonei; cytokeratins; cadherin; vimentin
13.  Pseudomyxoma peritonei – two novel orthotopic mouse models portray the PMCA-I histopathologic subtype 
BMC Cancer  2007;7:116.
Background
Pseudomyxoma peritonei (PMP) is a rare malignant disease, most commonly originating from appendiceal lesions and characterized by accumulation of mucinous tumor tissue in the peritoneal cavity. Since the disease is infrequent, the task of carrying out studies of treatment efficacy and disease biology in the clinical setting is challenging, warranting the development of relevant in vitro and in vivo PMP models.
Methods
Human tumor tissue was implanted in the peritoneal cavity of nude mice to establish two orthotopic models exhibiting noninvasive intraperitoneal growth without metastasis development.
Results
Xenograft tissues have retained essential properties of the original human tumors, such as macro- and microscopic growth patterns, mucin production as well as expression of carcinoembryonal antigen, cytokeratins 20 and 7 and the proliferation marker pKi67. Upon microscopic examination, the human tumors were categorized as the PMCA-I (peritoneal mucinous carcinomatosis of intermediate features) subtype, which was conserved through 14 examined passages in mice, for the first time modeling this particular histopathologic category.
Conclusion
In conclusion, two novel orthotopic models of human PMP have been established that consistently portray a distinct histopathologic subtype and reflect essential human tumor properties. Xenografts can easily and reproducibly be transferred to new generations of mice with acceptable passage periods, rendering the models as attractive tools for further studies of PMP biology and treatment.
doi:10.1186/1471-2407-7-116
PMCID: PMC1920528  PMID: 17603904
14.  Appendiceal Mucocele and Pseudomyxoma Peritonei; The Clinical Boundaries of a Subtle Disease 
Patient: Male, 70 • Male, 84
Final Diagnosis: Appendiceal mucocele and pseudomyxoma peritonei
Symptoms: —
Medication: —
Clinical Procedure: —
Specialty: Surgery
Objective:
Rare disease
Background:
Mucocele of the appendix is an uncommon cystic lesion characterized by distension of the appendiceal lumen with mucus. Most commonly, it is the result of epithelial proliferation, but it can also be caused by inflammation or obstruction of the appendix. When an underlying mucinous cystadenocarcinoma exists, spontaneous or iatrogenic rupture of the mucocele can lead to mucinous intraperitoneal ascites, a syndrome known as pseudomyxoma peritonei.
Case Report:
We report 2 cases that represent the clinical extremities of this heterogeneous disease; an asymptomatic mucocele of the appendix in a 70-year-old female and a case of pseudomyxoma peritonei in an 84-year-old male. Subsequently, we review the current literature focusing to the optimal management of both conditions.
Conclusions:
Mucocele of the appendix is a rare disease, usually diagnosed on histopathologic examination of appendectomized specimens. Due to the existing potential for malignant transformation and pseudomyxoma peritonei caused by rupture of the mucocele, extensive preoperative evaluation and thorough intraoperative gastrointestinal and peritoneal examination is required.
doi:10.12659/AJCR.890837
PMCID: PMC4156334  PMID: 25163976
Appendix; Mucocele; Pseudomyxoma Peritonei
15.  A core microbiome associated with the peritoneal tumors of pseudomyxoma peritonei 
Background
Pseudomyxoma peritonei (PMP) is a malignancy characterized by dissemination of mucus-secreting cells throughout the peritoneum. This disease is associated with significant morbidity and mortality and despite effective treatment options for early-stage disease, patients with PMP often relapse. Thus, there is a need for additional treatment options to reduce relapse rate and increase long-term survival. A previous study identified the presence of both typed and non-culturable bacteria associated with PMP tissue and determined that increased bacterial density was associated with more severe disease. These findings highlighted the possible role for bacteria in PMP disease.
Methods
To more clearly define the bacterial communities associated with PMP disease, we employed a sequenced-based analysis to profile the bacterial populations found in PMP tumor and mucin tissue in 11 patients. Sequencing data were confirmed by in situ hybridization at multiple taxonomic depths and by culturing. A pilot clinical study was initiated to determine whether the addition of antibiotic therapy affected PMP patient outcome.
Main results
We determined that the types of bacteria present are highly conserved in all PMP patients; the dominant phyla are the Proteobacteria, Actinobacteria, Firmicutes and Bacteroidetes. A core set of taxon-specific sequences were found in all 11 patients; many of these sequences were classified into taxonomic groups that also contain known human pathogens. In situ hybridization directly confirmed the presence of bacteria in PMP at multiple taxonomic depths and supported our sequence-based analysis. Furthermore, culturing of PMP tissue samples allowed us to isolate 11 different bacterial strains from eight independent patients, and in vitro analysis of subset of these isolates suggests that at least some of these strains may interact with the PMP-associated mucin MUC2. Finally, we provide evidence suggesting that targeting these bacteria with antibiotic treatment may increase the survival of PMP patients.
Conclusions
Using 16S amplicon-based sequencing, direct in situ hybridization analysis and culturing methods, we have identified numerous bacterial taxa that are consistently present in all PMP patients tested. Combined with data from a pilot clinical study, these data support the hypothesis that adding antimicrobials to the standard PMP treatment could improve PMP patient survival.
doi:10.1186/1750-1172-8-105
PMCID: PMC3729368  PMID: 23844722
PMP; Pseudomyxoma peritonei; Peritoneal cancer; Microbiome; Microbiota
16.  Pseudomyxoma Peritonei Originating from an Intestinal Duplication 
Case Reports in Pathology  2013;2013:608016.
Alimentary tract duplications are rare congenital anomalies. They most often become symptomatic in childhood and rarely undergo malignant transformation. Pseudomyxoma peritonei (PMP) is an equally uncommon condition, most frequently originating from a primary appendiceal mucinous neoplasm. We report an extremely unusual case of PMP arising from an intestinal duplication. A 67-year-old woman presented with vague upper abdominal pain, and, unexpectedly, explorative laparoscopy revealed diffuse jelly-like peritoneal implants. The histopathological diagnosis of a low-grade PMP or “disseminated peritoneal adenomucinosis” was made. At that moment, no primary tumor was found. During later surgery, a cystic lesion located in the mesentery of the small bowel could be resected. Histologically, the cyst wall clearly showed the concentric layering of a normal bowel wall. The mucosa, however, displayed a diffuse low-grade villous adenoma. We concluded that this histological picture was most consistent with a small intestinal duplication, containing a low-grade villous adenoma. The adenoma caused a mucocele, which subsequently leaked or ruptured, giving rise to noninvasive mucinous peritoneal implants or low-grade PMP, also known as “disseminated peritoneal adenomucinosis” (DPAM).
doi:10.1155/2013/608016
PMCID: PMC3760268  PMID: 24024058
17.  Two Cases of Mucinous Cystadenoma of the Appendix Successfully Treated by Laparoscopy 
Two cases of mucinous cystadenoma of the appendix successfully treated by laparoscopy are reported. An 81-year-old woman with lower right back pain was diagnosed with mucinous cystadenoma of the appendix or appendiceal carcinoma and underwent elective laparoscopic surgery. The other case involved a 70-year-old man with hematochezia who was diagnosed with mucinous cystadenoma. He also underwent elective laparoscopic surgery. In these two cases, gauze was folded around the tumors rather than grasping them directly. The postoperative courses were uneventful, and these patients had no recurrent disease at 2-year follow-up. In such cases, surgical excision of the tumor without rupture is of paramount importance because rupture of the lesion can cause pseudomyxoma peritonei. Though appendiceal mucinous cystadenoma has been considered a contraindication of laparoscopic resection, it was possible to achieve this by using a laparoscopic procedure with a gauze technique.
doi:10.1159/000346299
PMCID: PMC3573785  PMID: 23467399
Mucinous cystadenoma of the appendix; Laparoscopic surgery
18.  Pathobiological Implications of Mucin (MUC) Expression in the Outcome of Small Bowel Cancer 
PLoS ONE  2014;9(4):e86111.
Mucins have been associated with survival in various cancer patients, but there have been no studies of mucins in small bowel carcinoma (SBC). In this study, we investigated the relationships between mucin expression and clinicopathologic factors in 60 SBC cases, in which expression profiles of MUC1, MUC2, MUC3, MUC4, MUC5AC, MUC6 and MUC16 in cancer and normal tissues were examined by immunohistochemistry. MUC1, MUC5AC and MUC16 expression was increased in SBC lesions compared to the normal epithelium, and expression of these mucins was related to clinicopathologic factors, as follows: MUC1 [tumor location (p = 0.019), depth (p = 0.017) and curability (p = 0.007)], MUC5AC [tumor location (p = 0.063) and lymph node metastasis (p = 0.059)], and MUC16 [venous invasion (p = 0.016) and curability (p = 0.016)]. Analysis of 58 cases with survival data revealed five factors associated with a poor prognosis: poorly-differentiated or neuroendocrine histological type (p<0.001), lymph node metastasis (p<0.001), lymphatic invasion (p = 0.026), venous invasion (p<0.001) and curative resection (p<0.001), in addition to expression of MUC1 (p = 0.042), MUC5AC (p = 0.007) and MUC16 (p<0.001). In subsequent multivariate analysis with curability as the covariate, lymph node metastasis, venous invasion, and MUC5AC and/or MUC16 expression were significantly related to the prognosis. Multivariate analysis in curative cases (n = 45) showed that SBC with MUC5AC and/or MUC16 expression had a significantly independent high hazard risk after adjusting for the effects of venous invasion (hazard ratio: 5.6, 95% confidence interval: 1.8–17). In conclusion, the study shows that a MUC5AC-positive and/or MUC16-positive status is useful as a predictor of a poor outcome in patients with SBC.
doi:10.1371/journal.pone.0086111
PMCID: PMC3982950  PMID: 24722639
19.  Diagnosis of Pancreatic Neoplasms Using a Novel Method of DNA Methylation Analysis of Mucin Expression in Pancreatic Juice 
PLoS ONE  2014;9(4):e93760.
Mucins (MUC) play crucial roles in carcinogenesis and tumor invasion in pancreatic ductal adenocarcinoma (PDAC) and intraductal papillary mucinous neoplasms (IPMNs). Our immunohistochemistry (IHC) studies have shown a consensus position on mucin expression profiles in pancreatic neoplasms as follows: MUC1-positive but MUC2-negative expression in PDACs; MUC1-negative but MUC2-positive expression in intestinal-type IPMNs (dangerous type); MUC1-negative and MUC2-negative expression in gastric-type IPMNs (safe type); High MUC4 expression in PDAC patients with a poor outcome; and MUC4-positive expression in intestinal-type IPMNs. We also showed that three mucin genes (MUC1, MUC2 and MUC4) expression in cancer cell line was regulated by DNA methylation. We have developed a novel ‘methylation-specific electrophoresis (MSE)’ method to analyze the DNA methylation status of mucin genes by high sensitivity and resolution. By using the MSE method, we evaluated pancreatic juice samples from 45 patients with various pancreatic lesions. The results were compared with final diagnosis of the pancreatic lesions including IHC of mucin expression in the paired pancreatic tissues. The results indicated that the DNA methylation status of MUC1, MUC2 and MUC4 in pancreatic juice matched with the mucin expression in tissue. Analyses of the DNA methylation status of MUC1, MUC2 and MUC4 were useful for differential diagnosis of human pancreatic neoplasms, with specificity and sensitivity of 87% and 80% for PDAC; 100% and 88% for intestinal-type IPMN; and 88% and 77% for gastric-type IPMN, respectively. In conclusion, MSE analysis of human pancreatic juice may provide useful information for selection of treatment for pancreatic neoplasms.
doi:10.1371/journal.pone.0093760
PMCID: PMC3979708  PMID: 24714692
20.  Management of appendiceal pseudomyxoma peritonei diagnosed during pregnancy 
Background
The incidence of cancer during pregnancy is approximately 1 in 1000. The most common types encountered during pregnancy are cervical, breast and ovarian. Epithelial tumors of the appendix on the other hand are rare and account for only approximately 1% of all colorectal neoplasms; the occurrence of this neoplasm during pregnancy is extremely rare.
Case Presentation
The medical history of a 30 year old woman diagnosed at 17 weeks gestation with an appendiceal mucinous tumor with large volume pseudomyxoma peritonei was presented. Her pregnancy was preserved and she had an early vaginal delivery of a healthy baby at 35 weeks. At 2 1/2 weeks postpartum the patient underwent extensive cytoreductive surgery and intraperitoneal chemotherapy. She remains disease-free 5 years after her initial diagnosis. A literature review of this clinical situation and a discussion of treatment plans were presented.
Conclusion
The management of an appendiceal tumor with pseudomyxoma peritonei diagnosed during pregnancy requires full knowledge of the natural history of this disease to achieve a balance of concern for maternal survival and fetal health.
doi:10.1186/1477-7819-7-48
PMCID: PMC2688488  PMID: 19454019
21.  MUC1 expression and anti-MUC1 serum immune response in head and neck squamous cell carcinoma (HNSCC): a multivariate analysis 
BMC Cancer  2006;6:253.
Background
HNSCC progression to adjacent tissue and nodes may be mediated by altered glycoproteins and glycolipids such as MUC1 mucin. This report constitutes a detailed statistical study about MUC1 expression and anti-MUC1 immune responses in relation to different clinical and pathological parameters which may be useful to develop new anti HNSCC therapeutic strategies.
Patients and methods
Fifty three pre treatment HNSCC patients were included: 26 (49.1%) bearing oral cavity tumors, 17 (32.1%) localized in the larynx and 10 (18.8%) in the pharynx. Three patients (5.7%) were at stage I, 5 (9.4%) stage II, 15 (28.3%) stage III and 30 (56.6%) at stage IV. MUC1 tumor expression was studied by immunohistochemistry employing two anti-MUC1 antibodies: CT33, anti cytoplasmic tail MUC1 polyclonal antibody (Ab) and C595 anti-peptidic core MUC1 monoclonal antibody. Serum levels of MUC1 and free anti-MUC1 antibodies were detected by ELISA and circulating immune complexes (CIC) by precipitation in polyethylene glycol (PEG) 3.5%; MUC1 isolation from circulating immune complexes was performed by protein A-sepharose CL-4B affinity chromatography followed by SDS-PAGE and Western blot. Statistical analysis consisted in Multivariate Principal Component Analysis (PCA); ANOVA test (Tukey's test) was employed to find differences among groups; nonparametrical correlations (Kendall's Tau) were applied when necessary. Statistical significance was set to p < 0.05 in all cases.
Results
MUC1 cytoplasmic tail was detected in 40/50 (80%) and MUC1 protein core in 9/50 (18%) samples while serum MUC1 levels were elevated in 8/53 (15%) patients. A significant statistical correlation was found between MUC1 serum levels and anti-MUC1 IgG free antibodies, while a negative correlation between MUC1 serum levels and anti-MUC1 IgM free antibodies was found. Circulating immune complexes were elevated in 16/53 (30%) samples and were also statistically associated with advanced tumor stage. MUC1 was identified as an antigenic component of IgG circulating immune complexes. Moreover, poorly differentiated tumors were inversely correlated with tumor and serum MUC1 detection and positively correlated with node involvement and tumor mass.
Conclusion
Possibly, tumor cells produce MUC1 mucin which is liberated to the circulation and captured by IgG antibodies forming MUC1-IgG-CIC. Another interesting conclusion is that poorly differentiated tumors are inversely correlated with tumor and serum MUC1 detection.
doi:10.1186/1471-2407-6-253
PMCID: PMC1633744  PMID: 17064405
22.  The role of intratumoral lymphovascular density in distinguishing primary from secondary mucinous ovarian tumors 
Clinics  2014;69(10):660-665.
OBJECTIVE:
Ovarian mucinous metastases commonly present as the first sign of the disease and are capable of simulating primary tumors. Our aim was to investigate the role of intratumoral lymphatic vascular density together with other surgical-pathological features in distinguishing primary from secondary mucinous ovarian tumors.
METHODS:
A total of 124 cases of mucinous tumors in the ovary (63 primary and 61 metastatic) were compared according to their clinicopathological features and immunohistochemical profiles. The intratumoral lymphatic vascular density was quantified by counting the number of vessels stained by the D2-40 antibody.
RESULTS:
Metastases occurred in older patients and were associated with a higher proportion of tumors smaller than 10.0 cm; bilaterality; extensive necrosis; extraovarian extension; increased expression of cytokeratin 20, CDX2, CA19.9 and MUC2; and decreased expression of cytokeratin 7, CA125 and MUC5AC. The lymphatic vascular density was increased among primary tumors. However, after multivariate analysis, the best predictors of a secondary tumor were a size of 10.0 cm or less, bilaterality and cytokeratin 7 negativity. Lack of MUC2 expression was an important factor excluding metastasis.
CONCLUSIONS:
The higher intratumoral lymphatic vascular density in primary tumors when compared with secondary lesions suggests differences in the microenvironment. However, considering the differential diagnosis, the best discriminator of a secondary tumor is the combination of tumor size, laterality and the pattern of expression of cytokeratin 7 and MUC2.
doi:10.6061/clinics/2014(10)02
PMCID: PMC4221329  PMID: 25518016
Mucinous Ovarian Tumors; Ovarian Metastasis; Lymphatic Vascular Density; D2-40; Immunohistochemistry
23.  Appendiceal intussusception to the cecum caused by mucocele of the appendix: Laparoscopic approach 
INTRODUCTION
Appendiceal intussusception is a very rare disease that is found in only 0.01% of patients who have undergone an appendectomy. Clinical symptoms vary and some patients are asymptomatic. Laparoscopic surgery for appendiceal tumors is still controversial. We present a case of intussusception of the appendix with a mucinous cystadenoma treated by laparoscopic surgery.
PRESENTATION OF CASE
We report a case of 47 year-old-women patient who presented with a six month history of intermittent right lower abdominal pain. Abdominal computer tomography CT showed appendiceal mass with intussusception. A laparoscopic right hemicolectomy was performed because the tumor involved the entire appendix. Histopathological examination revealed mucocele due to mucinous cystadenoma of appendix.
DISCUSSION
Appendiceal intussusception to the cecum caused by mucocele of the appendix is extremely rare. It is very difficult to diagnose the presence of an intussuscepted appendix pre-operatively and investigations will usually include colonoscopy and CT scan. An appendicular intussusception should not be reduced by colonoscopy. Laparoscopic surgery for appendiceal tumors is still controversial; the main concerns to be addressed are the adequacy of resection and intraperitoneal rupture of the tumor. Our patient successfully underwent laparoscopic surgery without any complications.
CONCLUSION
Appendiceal intussusception to the cecum caused by mucocele of the appendix is a rare cause of abdominal pain and difficult to diagnose. The laparoscopic surgery for appendiceal tumors is safe, feasible, and even may be beneficial.
doi:10.1016/j.ijscr.2012.04.019
PMCID: PMC3397288  PMID: 22706297
Appendix intussusception; Multidetector CT; Laparoscopic surgery; Mucinous cystadenoma
24.  Efficacy of a novel mucolytic agent on pseudomyxoma peritonei mucin, with potential for treatment through peritoneal catheters 
Compared to current treatment for pseudomyxoma peritonei (PMP), the extraction of solubilised mucin through peritoneal catheter can be minimally invasive. However, mucin has variable appearance that may influence mucolysis. Hence, we investigated the mucolysis of 36 mucin samples with a novel agent. Using visual inspection and hardness index, PMP mucin was classified into three grades. The mucin pathological category was identified from patient record. Subsequently, the dissolution of the samples was tested. For in vitro, 1 g of mucin was treated to the mucolytic agent in 10 ml TRIS buffer at 37 deg. Celsius for 3 hours, with weighing of residual mucin. Control treatment was similar but received TRIS buffer. For in vivo, 2 g of implanted intra-peritoneal mucin in nude rats was treated to mucolytic (2 X 500 ul/24 hr, over 48 hours, plus another treatment before sacrifice at 56 hours, with weighing of residual mucin. Controls were treated but only with TRIS buffer. Six animals were used for each mucin grade (3 mucolytic treated & and 3 controls). Grades of mucin were soft mucin (62%), semi hard (20%) and hard mucin (18%). Diffuse peritoneal adenomucinosis had 50% of soft mucin and peritoneal mucinous carcinoma had 11% (P = 0.0382). In vitro and in vivo absolute disintegration was 100% for soft, 57.38% and 48.67% for semi hard, 50% and 28.67% for hard mucin. Majority of mucin were soft with complete disintegration, the rest showed variable disintegration, suggesting that the mucolytic has potential for treating PMP.
PMCID: PMC4163614  PMID: 25232491
Pseudomyxoma peritonei; mucin; mucolytic; disintegration
25.  HN125: A Novel Immunoadhesin Targeting MUC16 with Potential for Cancer Therapy 
Journal of Cancer  2011;2:280-291.
Background: The mucin MUC16 expresses the repeating peptide epitope CA125 that has been known for decades to be a well-validated cancer marker that is overexpressed on the cell surface of ovarian cancers and other malignant tumors. In spite of recent efforts to make mouse monoclonal antibodies to MUC16 to treat ovarian cancer, a human monoclonal antibody against this mucin has not been described. MUC16 interacts with mesothelin, a protein that mediates heterotypic cancer cell adhesion, indicating that MUC16 and mesothelin play an important role in the peritoneal implantation and metastasis of ovarian tumors. Therefore, a suitable candidate for therapeutic targeting of MUC16 would functionally block the interaction of MUC16 and mesothelin.
Methodology/Principal Findings: Here we report the generation of a novel immunoadhesin, HN125, against MUC16 that consists of a functional MUC16 binding domain of mesothelin (IAB) and the Fc portion of a human antibody IgG1. The yield for purified HN125 proteins is over 100 µg/mL of HEK-293 culture supernatant. We show that HN125 has high and specific affinity for MUC16-expressing cancer cells by flow cytometry and immunohistochemistry. HN125 has the ability to disrupt the heterotypic cancer cell adhesion mediated by the MUC16-mesothelin interaction. Moreover, it elicits strong antibody-dependent cell mediated cytotoxicity against MUC16-positive cancer cells in vitro.
Conclusion/Significance: This report describes a novel human immunotherapeutic agent highly specific for MUC16 with potential for treating ovarian cancer and other MUC16-expressing tumors. Because of its lower immunogenicity in patients, a fully human protein is the most desirable format for clinical applications. We believe that the methods developed here may apply to the generation of other tumor-targeting immunoadhesins when it is difficult to obtain a human monoclonal antibody to a given antigen for clinical applications. The resultant immunoadhesins can have advantages usually found in monoclonal antibodies such as ease of purification, high binding affinity and effector functions.
PMCID: PMC3100680  PMID: 21611109
immunoadhesin; human Fc fusion; mesothelin; mucin MUC16/CA125; antibody-dependent cellular cytotoxicity (ADCC); ovarian cancer; mesothelioma.

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