Introduction
Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) is an established treatment for pseudomyxoma peritonei (PMP) from perforated low-grade appendiceal ...mucinous neoplasms (LAMN II). In a selected group of LAMN II patients without established PMP, CRS/HIPEC can be performed laparoscopically (L-CRS/HIPEC); however the short-term benefits and safety of this approach have yet to be determined. This study aims to determine the short-term outcomes from a series of L-CRS/HIPEC LAMN II patients compared to those who have undergone a similar open operation (O-CRS/HIPEC) for low-volume PMP.
Methods
LAMN II patients undergoing L-CRS/HIPEC at a UK national peritoneal tumour centre were compared to O-CRS/HIPEC patients (peritoneal cancer index ≤ 7). Outcomes of interest included Clavien–Dindo complication grade, operative time, blood transfusions, high dependency unit (HDU) admission, length of hospital stay, and histopathological findings.
Results
55 L-CRS/HIPEC were compared to 29 O-CRS/HIPEC patients (2003–2017). Groups were matched for age, sex, and procedures. Median operative time was 8.8 (IQR 8.1–9.5) h for L-CRS/HIPEC versus 7.3 (IQR 6.7–8) h for O-CRS/HIPEC (Mann–Whitney test
p
< 0.001). Post-operative HDU admission was 56% versus 97% (OR 0.04 95% CI 0.01–0.34) and median length of stay = 6 (IQR 5–8) versus 10 (IQR 8–11) days (
p
< 0.001) for L- versus O-CRS/HIPEC. Despite a normal pre-operative CT scan, 13/55 (23.6%) L-CRS/HIPEC patients had acellular mucin and 2/55 (3.5%) had mucin with epithelium present in their specimens. Residual appendix tumour was identified in 2/55 patients (3.6%). Clavien–Dindo Grade 1–4 complications were similar in both groups with no mortality.
Conclusion
L-CRS/HIPEC for LAMN II takes longer; however patients have significantly reduced length of HDU and overall stay, without increased post-operative complications. A significant proportion of LAMN II patients undergoing L-CRS/HIPEC have extra-appendiceal acellular mucin with some cases demonstrating residual cellular epithelium from the LAMN II. The risk of these patients developing PMP without surgery is under current review.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Mixed neuroendocrine non-neuroendocrine neoplasms (MiNENs) represent a rare diagnosis of the gastro-entero-pancreatic tract. Evidence from the current literature regarding their epidemiology, ...biology, and management is of variable quality and conflicting. Based on available data, the MiNEN has an aggressive biological behaviour, mostly driven by its (often high-grade) neuroendocrine component, and a dismal prognosis. In most cases, the non-neuroendocrine component is of adenocarcinoma histology. Due to limitations in diagnostic methods and poor awareness within the scientific community, the incidence of MiNENs may be underestimated. In the absence of data from clinical trials, MiNENs are commonly treated according to the standard of care for pure neuroendocrine carcinomas or adenocarcinomas from the same sites of origin, based on the assumption of a biological similarity to their pure counterparts. However, little is known about the molecular aberrations of MiNENs, and their pathogenesis remains controversial; molecular/genetic studies conducted so far point towards a common monoclonal origin of the two components. In addition, mutations in tumour-associated genes, including
,
and
, and microsatellite instability have emerged as potential drivers of MiNENs. This systematic review (91 full manuscripts or abstracts in English language) summarises the current reported literature on clinical, pathological, survival, and molecular/genetic data on MiNENs.
Background: Brain metastases (BMs) in patients with extra-pulmonary neuroendocrine neoplasms (EP–NENs) are rare, and limited clinical information is available. The aim of this study was to detail the ...clinicopathological features, management and outcomes in patients with EP–NENs who developed BMs. Methods: A retrospective single-centre analysis of consecutive patients with EP–NENs (August 2004–February 2020) was conducted. Median overall survival (OS)/survival from BMs diagnosis was estimated (Kaplan–Meier). Results: Of 730 patients, 17 (1.9%) had BMs, median age 61 years (range 15–77); 8 (53%) male, unknown primary NEN site: 40%. Patients with BMs had grade 3 (G3) EP–NENs 11 (73%), G2: 3 (20%), G1: 1 (7%). Eight (53%) had poorly differentiated NENs, 6 were well-differentiated and 1 was not recorded. Additionally, 2 (13%) patients had synchronous BMs at diagnosis, whilst 13 (87%) developed BMs metachronously. The relative risk of developing BMs was 7.48 in patients with G3 disease vs. G1 + G2 disease (p = 0.0001). Median time to the development of BMs after NEN diagnosis: 15.9 months (range 2.5–139.5). Five patients had a solitary BM, 12 had multiple BMs. Treatment of BMs were surgery (n = 3); radiotherapy (n = 5); 4: whole brain radiotherapy, 1: conformal radiotherapy (orbit). Nine (53%) had best supportive care. Median OS from NEN diagnosis was 23.6 months 95% CI 15.2–31.3; median time to death from BMs diagnosis was 3.0 months 95% CI 0.0–8.3. Conclusion: BMs in patients with EP–NENs are rare and of increased risk in G3 vs. G1 + G2 EP–NENs. Survival outcomes are poor, and a greater understanding is needed to improve therapeutic outcomes.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK, VSZLJ
Extra-pulmonary neuroendocrine carcinomas (EP-NECs) are lethal cancers with limited treatment options. Identification of contributing factors to the observed heterogeneity of clinical outcomes within ...the EP-NEC family is warranted, to enable identification of effective treatments. A multicentre retrospective study investigated potential differences in “real-world” treatment/survival outcomes between small-cell (SC) versus (vs.) non-SC EP-NECs. One-hundred and seventy patients were included: 77 (45.3%) had SC EP-NECs and 93 (54.7%) had non-SC EP-NECs. Compared to the SC subgroup, the non-SC subgroup had the following features: (1) a lower mean Ki-67 index (69.3% vs. 78.7%; p = 0.002); (2) a lower proportion of cases with a Ki-67 index of ≥55% (73.9% vs. 88.7%; p = 0.025); (3) reduced sensitivity to first-line platinum/etoposide (objective response rate: 31.6% vs. 55.1%, p = 0.015; and disease control rate; 59.7% vs. 79.6%, p = 0.027); (4) worse progression-free survival (PFS) (adjusted-HR = 1.615, p = 0.016) and overall survival (OS) (adjusted-HR = 1.640, p = 0.015) in the advanced setting. Within the advanced EP-NEC cohort, subgroups according to morphological subtype and Ki-67 index (<55% vs. ≥55%) had significantly different PFS (adjusted-p = 0.021) and OS (adjusted-p = 0.051), with the non-SC subgroup with a Ki-67 index of <55% and non-SC subgroup with a Ki-67 index of ≥55% showing the best and worst outcomes, respectively. To conclude, the morphological subtype of EP-NEC provides complementary information to the Ki-67 index and may aid identification of patients who could benefit from alternative first-line treatment strategies to platinum/etoposide.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
50
Background: Appendix goblet cell adenocarcinomas (GCA) are rare aggressive tumours with patients often presenting with peritoneal metastases. Cytoreductive surgery and heated intraperitoneal ...chemotherapy (CRS/HIPEC) can be curative treatment and the role of systemic chemotherapy less defined. There is a need to better understand factors that predict outcome alongside assessment of the latest WHO 2019 classification. Methods: Demographics, clinicopathological variables, treatment characteristics and survival of patients with GCA from a UK peritoneal tumour centre were identified through a prospective database (2005-2021). Patients were selected for CRS/HIPEC based on disease burden. Pathology records were reviewed and those previously classified by Tang grading were reclassified to WHO 2019. The primary endpoint was overall survival (OS). Analysis was by the Kaplan-Meier method. Results: We identified 177 patients with GCA who had a median follow-up of 67 months (m, 4-207). Mean age at diagnosis was 57 years (22-79) and 88 were female (50%). There were 99 patients (56%) who had localised disease (M0) and 74 (42%) who had metastatic disease (M1). There were 126 (71%) patients who had CRS and 115 (91%) had HIPEC (65% MMC, 25% Oxaliplatin); median peritoneal cancer index score was 1 (0-28) and 12 (10%) patients had M1 disease. There were 72 (41%) patients who had systemic chemotherapy (72% oxaliplatin with fluoropyrimidine) and of those who had CRS, four had neoadjuvant, 18 adjuvant and the rest palliative intent chemotherapy. Incomplete CRS resulted in shorter OS compared to complete CRS (median 23 v 103m, p<0.001). Patients with involved nodes had shorter OS (32m v not reached, NR, p<0.001) compared to those with uninvolved nodes. WHO 2019 grade 2 predicts for longer OS than Tang B (median 118 v 54m, p=0.031). The table shows univariate survival according to grade and chemotherapy. Conclusions: This study represents the largest series of pure appendix GCA with long term follow-up data. Patients with positive lymph nodes and incomplete CRS had poor survival outcomes. The WHO 2019 classification had no direct prognostic correlation with the previous Tang classification. WHO 2019 grade 2 had longer OS compared to Tang B suggesting further stratification of the grade 2 group could be considered. Patients who had systemic chemotherapy had shorter OS and DFS as expected based on the selection of patients with higher grade, lymph node involvement and higher disease burden as part of clinical practice. Table: see text
Goblet cell carcinoids (GCCs) of the appendix are rare tumors, characterized by a carcinoid-like organoid growth pattern. Despite the term carcinoid, neuroendocrine features are inconspicuous, and ...its behavior is distinct from carcinoid. Its high-grade counterpart is designated as adenocarcinoma ex GCC. We conducted a retrospective study of 105 tumors to find prognostic values of a variety of clinicopathologic features. The tumors were subclassified as low grade, equivalent to classic type, and high grade, defined as loss of organoid pattern, and a proportion (%) of low and high grades were documented in each tumor. Correlations between survival and various clinicopathologic parameters were investigated. One-third were pure low grade, while the remainder contained variable high-grade component ranging from 5% to 95%. Neuroendocrine cell component ranged from 0% to 90% (median, 5), while mucus cell component ranged from 5% to 100% (median, 70). By univariate analysis, size, stage, high-grade component, nuclear grade, surgery, and chemotherapy correlated with cancer-related survival (CSS), and by multivariate analysis, stage (P=.001), high-grade component (P=.008), and tumor size (P=.005) correlated with CSS. There was significant difference in CSS when the cases were grouped by high-grade component: <40%, 40% to 90%, and ≤90% (P<.001). Our results indicate that staging and proportion of high-grade histology may provide important prognostic information. Neuroendocrine component was insignificant in both low- and high-grade areas. In light of our findings, this tumor type is best regarded as a variant of adenocarcinoma, and the term crypt cell adenocarcinoma more appropriately reflects the nature and origin of this tumor group.
•The goblet cell carcinoid tumor group can be simply subdivided into low- and high-grade morphology.•Staging and proportion of the high-grade component were shown to be important prognostic factors.•The term crypt cell adenocarcinoma more appropriately reflects the nature and origin of this tumor group.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Abstract Background Characterisation of human papilloma virus (HPV) infection in anal squamous cell carcinoma (ASCC) may have dual importance: first, aetiological; second, prognostic, informing ...outcome after chemo-radiotherapy (CRT). We undertook HPV genotyping, and allelic characterisations, to evaluate the aetiological role of HPV while simultaneously evaluating the impact of HPV genotyping on relapse-free (RFS) and overall survival (OS). Method Dual-primer HPV genotyping (subtypes 6, 11, 16, 18, 31, 33, 45, 52, 58) and DNA sequencing of HPV 16 positive tumours were analysed in 151 consecutively referred ASCCs, previously characterised by immunohistochemistry for p16 expression. In 110 patients treated with CRT, factors influencing RFS and OS were evaluated using univariate and multivariate models. Results HPV positivity was observed in 95%. HPV 16 accounted for 89%; of these, 64% harboured the T350G E6 variant. HPV 16 positivity was significantly correlated with improved 5-year RFS (62% versus 40%; p = 0.027) and OS (59% versus 38%; p = 0.019). p16 expression was also significantly correlated with improved 5-year RFS (positive versus negative: 65% versus 16%; p < 0.0001) and OS (63% versus 13%; p < 0.0001). In multivariable models that included HPV 16 status, p16 status, sex, and age, p16 expression remained an independent prognostic factor for RFS ( p < 0.0001) and OS ( p = 0.002). Conclusion In ASCC, near-universal HPV detection rates were demonstrated, higher than generally reported in the literature, and supporting the development of multivalent HPV vaccinations for prevention. By contrast, p16 negatively, but not HPV 16 genotype, is an independent adverse prognosticator after chemo-radiotherapy in patients with ASCC.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Mixed neuroendocrine non-neuroendocrine neoplasm (MiNEN) is a rare diagnosis, mainly encountered in the gastro-entero-pancreatic tract. There is limited knowledge of its epidemiology, prognosis and ...biology, and the best management for affected patients is still to be defined.
To investigate clinical-pathological characteristics, treatment modalities and survival outcomes of a retrospective cohort of patients with a diagnosis of MiNEN.
Consecutive patients with a histologically proven diagnosis of MiNEN were identified at 5 European centres. Patient data were retrospectively collected from medical records. Pathological samples were reviewed to ascertain compliance with the 2017 World Health Organisation definition of MiNEN. Tumour responses to systemic treatment were assessed according to the Response Evaluation Criteria in Solid Tumours 1.1. Kaplan-Meier analysis was applied to estimate survival outcomes. Associations between clinical-pathological characteristics and survival outcomes were explored using Log-rank test for equality of survivors functions (univariate) and Cox-regression analysis (multivariable).
Sixty-nine consecutive patients identified; Median age at diagnosis: 64 years. Males: 63.8%. Localised disease (curable): 53.6%. Commonest sites of origin: colon-rectum (43.5%) and oesophagus/oesophagogastric junction (15.9%). The neuroendocrine component was; predominant in 58.6%, poorly differentiated in 86.3%, and large cell in 81.25%, of cases analysed. Most distant metastases analysed (73.4%) were occupied only by a poorly differentiated neuroendocrine component. Ninety-four percent of patients with localised disease underwent curative surgery; 53% also received perioperative treatment, most often in line with protocols for adenocarcinomas from the same sites of origin. Chemotherapy was offered to most patients (68.1%) with advanced disease, and followed protocols for pure neuroendocrine carcinomas or adenocarcinomas in equal proportion. In localised cases, median recurrence free survival (RFS); 14.0 mo (95%CI: 9.2-24.4), and median overall survival (OS): 28.6 mo (95%CI: 18.3-41.1). On univariate analysis, receipt of perioperative treatment (
surgery alone) did not improve RFS (
= 0.375), or OS (
= 0.240). In advanced cases, median progression free survival (PFS); 5.6 mo (95%CI: 4.4-7.4), and median OS; 9.0 mo (95%CI: 5.2-13.4). On univariate analysis, receipt of palliative active treatment (
best supportive care) prolonged PFS and OS (both,
< 0.001).
MiNEN is most commonly driven by a poorly differentiated neuroendocrine component, and has poor prognosis. Advances in its biological understanding are needed to identify effective treatments and improve patient outcomes.
Objectives
To assess the use of MRI-determined tumour regression grading (TRG) in local response assessment and detection of salvageable early local relapse after chemoradiotherapy (CRT) in patients ...with anal squamous cell carcinoma (ASCC).
Methods
From a prospective database of patients with ASCC managed through a centralised multidisciplinary team, 74 patients who completed routine post-CRT 3- and 6-month MRIs (2009–2012) were reviewed. Two radiologists blinded to the outcomes consensus read and retrospectively assigned TRG scores 1 (complete response) to 5 (no response) and related these to early local relapse (within 12 months) and disease-free survival (DFS).
Results
Seven patients had early local relapse. TRG 1/2 scores at 3 and 6 months had a 100 % negative predictive value; TRG 4/5 scores at 6 months had a 100 % positive predictive value. All seven patients underwent salvage R0 resections. We identified a novel ‘tram-track’ sign on MRI in over half of patients, with an NPV for early local relapse of 83 % at 6 months. No imaging characteristic or TRG score independently prognosticated for late relapse or 3-year DFS.
Conclusions
Post-CRT 3- and 6-month MRI-determined TRG scores predicted salvageable R0 early local relapses in patients with ASCC, challenging current clinical guidelines.
Key Points
•
Post-chemoradiotherapy MRI (3 and 6 months) helps local response assessment in ASCC
.
•
The MRI-TRG system can be used reproducibly in patients with ASCC
.
•
The TRG system facilitates patient selection for examination under anaesthesia and biopsy
.
•
The use of MRI-TRG predicts for detection of salvageable early local relapses
.
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The TRG system allows for a standardised follow-up pathway
.
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