The histopathological classification, diagnosis and differential diagnosis of mucinous appendiceal neoplasms, appendiceal adenocarcinomas and pseudomyxoma peritonei

Carr, Norman J.; Bibeau, Frédéric; Bradley, Robert F.; Dartigues, Peggy; Feakins, Roger; Geisinger, Kim R.; Gui, Xianyong; Isaac, Sylvie; Milione, Massimo; Misdraji, Joseph; Pai, Reetesh K.; Rodriguez‐Justo, Manuel; Sobin, Leslie H.; Velthuysen, Marie‐Louise F. van; Yantiss, Rhonda K.

doi:10.1111/his.13324

Cited by 242 publications

(253 citation statements)

References 69 publications

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“…Serrated pathology of the appendix is an enigmatic subject . It is relatively common, and this study has shown that it is sometimes coincident with ADD and complicated ADD.…”

Section: Discussionmentioning

confidence: 78%

“…Nevertheless, we accept that the coexistence of the two entities may provide a route by which the neoplastic epithelium and associated mucin of LAMNs may reach the peritoneal surface, despite their indolent appearance, via one or more diverticula, essentially bypassing the muscularis propria . As an extension of this process, pseudomyxoma peritonei associated with LAMN is usually the result of rupture of the cystic neoplasm and seeding of mucin and neoplastic epithelium into the peritoneal cavity, rather than direct invasion …”

Section: Discussionmentioning

confidence: 97%

“…Tumours, especially neuroendocrine tumours, are not uncommon in the appendix, often in association with ADD, and they may cause obstruction or narrowing of the appendiceal lumen, leading to mucin accumulation, potentially exacerbating the changes of complicated ADD. Further mucin produced by coexistent LAMNs and by serrated lesions of the appendix may contribute to the formation of diverticula in the appendix and to the complications thereof. Such a theory is supported by the reported increased incidence of ADD in patients with cystic fibrosis …”

Section: Discussionmentioning

confidence: 99%

“…Hyperplastic changes associated with inflammatory pathology of the appendix can mimic serrated change. There is evidence that serrated lesions of the appendix differ from their colonic counterparts . They are more likely to be villous and more often demonstrate mutations in KRAS rather than BRAF, while ‘serrated adenomas’ are said to behave more aggressively in the appendix .…”

Section: Discussionmentioning

confidence: 99%

“…There is evidence that serrated lesions of the appendix differ from their colonic counterparts . They are more likely to be villous and more often demonstrate mutations in KRAS rather than BRAF, while ‘serrated adenomas’ are said to behave more aggressively in the appendix . Thus, the coincidence of complicated ADD and appendiceal serrated lesions causes difficulties, as we are currently ignorant of the implications of epithelium from serrated lesions reaching the serosal surface of the appendix and whether or not this may result in significant intraperitoneal disease.…”

Section: Discussionmentioning

confidence: 99%

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Complicated appendiceal diverticulosis versus low‐grade appendiceal mucinous neoplasms: a major diagnostic dilemma

et al. 2019

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Aims To research and identify how often complicated diverticular disease of the appendix [appendiceal diverticular disease (ADD)] shows histological mimicry of low‐grade appendiceal mucinous neoplasms (LAMNs) and to provide guidance on the useful histopathological features that allow the appropriate diagnosis to be made. Methods and results Seventy‐four cases of complicated appendiceal diverticular disease were identified from two specialist centres. Of the second opinion/consultation cases, 71% of the ADD cases had been diagnosed by referring pathologists as LAMNs. Salient pathological features were identified and agreed upon to reach the applicable diagnosis. For a diagnosis of complicated diverticulosis, particularly when associated with mucus cysts, the following morphological features were regarded as important: relative retention of the normal mucosal architecture with lamina propria and a maintained crypt architecture, crypts arranged in regular array, epithelial hyperplasia and a lack of nuclear abnormalities extending the length of the crypts. In a formal case–control study undertaken on 30 cases with each diagnosis, ADD and LAMN, loss of lamina propria, a filiform architecture and hypermucinosis were significantly associated with low‐grade appendiceal mucinous neoplasms. Mucosal neuromas were significantly associated with diverticular disease of the appendix. Conclusions To our knowledge, this study represents the largest series in the world literature and serves to highlight the important pathological features to distinguish complicated diverticular disease of the appendix from LAMNs, and emphasises the difficulties experienced by diagnostic pathologists in diagnosing complicated appendiceal diverticulosis. This is important, as LAMNs have a significant risk of transcoelomic spread, while complicated appendiceal diverticulosis has no such risk.

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“…Serrated pathology of the appendix is an enigmatic subject . It is relatively common, and this study has shown that it is sometimes coincident with ADD and complicated ADD.…”

Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Complicated appendiceal diverticulosis versus low‐grade appendiceal mucinous neoplasms: a major diagnostic dilemma

et al. 2019

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Efficacy of Systemic Chemotherapy in Patients With Low-grade Mucinous Appendiceal Adenocarcinoma

et al. 2023

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ImportanceAppendiceal adenocarcinoma is a rare tumor, and given the inherent difficulties in performing prospective trials in such a rare disease, there are currently minimal high-quality data to guide treatment decisions, highlighting the need for more preclinical and clinical investigation for this disease.ObjectiveTo prospectively evaluate the effectiveness of fluoropyrimidine-based systemic chemotherapy in patients with inoperable low-grade mucinous appendiceal adenocarcinoma.Design, Setting, and ParticipantsThis open-label randomized crossover trial recruited patients at a single tertiary care comprehensive cancer center from September 2013 to January 2021. The data collection cutoff was May 2022. Enrollment of up to 30 patients was planned. Eligible patients had histological evidence of a metastatic low-grade mucinous appendiceal adenocarcinoma, with radiographic imaging demonstrating the presence of mucinous peritoneal carcinomatosis and were not considered candidates for complete cytoreductive surgery. Key exclusion criteria were concurrent or recent investigational therapy, evidence of bowel obstruction, and use of total parenteral nutrition. Data were analyzed from November 2021 to May 2022.InterventionsPatients were randomized to either 6 months observation followed by 6 months of chemotherapy, or initial chemotherapy followed by observation.Main Outcomes and MeasuresThe primary end point was the percentage difference in tumor growth in treatment and observation groups. Key secondary end points included patient-reported outcomes in the chemotherapy and observation periods, objective response rate, rate of bowel complications, and differences in overall survival (OS).ResultsA total of 24 patients were enrolled, with median (range) age of 63 (38 to 82) years, and equal proportion of men and women (eg, 12 men [50%]); all patients had ECOG performance status of 0 or 1. A total of 11 patients were randomized to receive chemotherapy first, and 13 patients were randomized to receive observation first. Most patients (15 patients [63%]) were treated with either fluorouracil or capecitabine as single agent; 3 patients (13%) received doublet chemotherapy (leucovorin calcium [folinic acid], fluorouracil, and oxaliplatin or folinic acid, fluorouracil, and irinotecan hydrochloride), and bevacizumab was added to cytotoxic chemotherapy for 5 patients (21%). Fifteen patients were available to evaluate the primary end point of difference in tumor growth during treatment and observation periods. Tumor growth while receiving chemotherapy increased 8.4% (95% CI, 1.5% to 15.3%) from baseline but was not significantly different than tumor growth during observation (4.0%; 95% CI, −0.1% to 8.0%; P = .26). Of 18 patients who received any chemotherapy, none had an objective response (14 patients [77.8%] had stable disease; 4 patients [22.2%] had progressive disease). Median (range) OS was 53.2 (8.1 to 95.5) months, and there was no significant difference in OS between the observation-first group (76.0 [8.6 to 95.5] months) and the treatment-first group (53.2 [8.1 to 64.1] months; hazard ratio, 0.64; 95% CI, 0.16-2.55; P = .48). Patient-reported quality-of-life metrics identified that during treatment, patients experienced significantly worse fatigue (mean [SD] score, 18.5 [18.6] vs 28.9 [21.3]; P = .02), peripheral neuropathy (mean [SD] score, 6.67 [12.28] vs 38.89 [34.88]; P = .01), and financial difficulty (mean [SD] score, 8.9 [15.2] vs 28.9 [33.0]; P = .001) compared with during observation.Conclusions and RelevanceIn this prospective randomized crossover trial of systemic chemotherapy in patients with low-grade mucinous appendiceal adenocarcinoma, patients did not derive clinical benefit from fluorouracil-based chemotherapy, given there were no objective responses, no difference in OS when treatment was delayed 6 months, and no difference in the rate of tumor growth while receiving chemotherapy.Trial RegistrationClinicalTrials.gov Identifier: NCT01946854

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Serum Tumor Markers and Outcomes in Patients With Appendiceal Adenocarcinoma

Yousef,

Zeineddine

et al. 2024

JAMA Netw Open

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ImportanceSerum tumor markers carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), and cancer antigen 125 (CA125) have been useful in the management of gastrointestinal and gynecological cancers; however, there is limited information regarding their utility in patients with appendiceal adenocarcinoma.ObjectiveTo assess the association of serum tumor markers (CEA, CA19-9, and CA125) with clinical outcomes and pathologic and molecular features in patients with appendiceal adenocarcinoma.Design, Setting, and ParticipantsThis is a retrospective cohort study at a single tertiary care comprehensive cancer center. The median (IQR) follow-up time was 52 (21-101) months. Software was used to query the MD Anderson internal patient database to identify patients with a diagnosis of appendiceal adenocarcinoma and at least 1 tumor marker measured at MD Anderson between March 2016 and May 2023. Data were analyzed from January to December 2023.Main Outcomes and MeasuresAssociation of serum tumor markers with survival in patients with appendiceal adenocarcinoma. Cox proportional hazards regression analyses were also performed to assess associations between clinical factors (serum tumor marker levels, demographics, and patient and disease characteristics) and patient outcomes (overall survival).ResultsA total of 1338 patients with appendiceal adenocarcinoma were included, with a median (range) age at diagnosis of 56.5 (22.3-89.6) years. The majority of the patients had metastatic disease (1080 patients [80.7%]). CEA was elevated in 742 of the patients tested (56%), while CA19-9 and CA125 were elevated in 381 patients (34%) and 312 patients (27%), respectively. Individually, elevation of CEA, CA19-9, or CA125 were associated with worse 5-year survival; elevated vs normal was 81% vs 95% for CEA (hazard ratio [HR], 4.0; 95% CI, 2.9-5.6), 84% vs 92% for CA19-9 (HR, 2.2; 95% CI, 1.4-3.4), and 69% vs 93% for CA125 (HR, 4.6; 95% CI, 2.7-7.8) (P &lt; .001 for all). Quantitative evaluation of tumor markers was associated with outcomes. Patients with highly elevated (top 10th percentile) CEA, CA19-9, or CA125 had markedly worse survival, with 5-year survival rates of 59% for CEA (HR, 9.8; 95% CI, 5.3-18.0), 64% for CA19-9 (HR, 6.0; 95% CI, 3.0-11.7), and 57% for CA125 (HR, 7.6; 95% CI, 3.5-16.5) (P &lt; .001 for all). Although metastatic tumors had higher levels of all tumor markers, when restricting survival analysis to 1080 patients with metastatic disease, elevated CEA, CA19-9, or CA125 were all still associated worse survival (HR for CEA, 3.4; 95% CI, 2.5-4.8; P &lt; .001; HR for CA19-9, 1.8; 95% CI, 1.2-2.7; P = .002; and HR for CA125, 3.9; 95% CI, 2.4-6.4; P &lt; .001). Interestingly, tumor grade was not associated with CEA or CA19-9 level, while CA-125 was slightly higher in high-grade tumors relative to low-grade tumors (mean value, 18.3 vs 15.0; difference, 3.3; 95% CI, 0.9-3.7; P &lt; .001). Multivariable analysis identified an incremental increase in the risk of death with an increase in the number of elevated tumor markers, with an 11-fold increased risk of death in patients with all 3 tumor markers elevated relative to those with none elevated. Somatic mutations in KRAS and GNAS were associated with significantly higher levels of CEA and CA19-9.Conclusions and RelevanceIn this retrospective study of serum tumor markers in patients with appendiceal adenocarcinoma, CEA, CA19-9, and CA125 were associated with overall survival in appendiceal adenocarcinoma. Given their value, all 3 biomarkers should be included in the initial workup of patients with a diagnosis of appendiceal adenocarcinoma.

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The histopathological classification, diagnosis and differential diagnosis of mucinous appendiceal neoplasms, appendiceal adenocarcinomas and pseudomyxoma peritonei

Cited by 242 publications

References 69 publications

Complicated appendiceal diverticulosis versus low‐grade appendiceal mucinous neoplasms: a major diagnostic dilemma

Complicated appendiceal diverticulosis versus low‐grade appendiceal mucinous neoplasms: a major diagnostic dilemma

Efficacy of Systemic Chemotherapy in Patients With Low-grade Mucinous Appendiceal Adenocarcinoma

Serum Tumor Markers and Outcomes in Patients With Appendiceal Adenocarcinoma

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