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BACKGROUND Awareness of the potential global overtreatment of patients with appendiceal neuroendocrine tumours (NETs) of 1-2 cm in size by performing oncological resections is increasing, but the rarity of this tumour has impeded clear recommendations to date. We aimed to assess the malignant potential of appendiceal NETs of 1-2 cm in size in patients with or without right-sided hemicolectomy. METHODS In this retrospective cohort study, we pooled data from 40 hospitals in 15 European countries for patients of any age and Eastern Cooperative Oncology Group performance status with a histopathologically confirmed appendiceal NET of 1-2 cm in size who had a complete resection of the primary tumour between Jan 1, 2000, and Dec 31, 2010. Patients either had an appendectomy only or an appendectomy with oncological right-sided hemicolectomy or ileocecal resection. Predefined primary outcomes were the frequency of distant metastases and tumour-related mortality. Secondary outcomes included the frequency of regional lymph node metastases, the association between regional lymph node metastases and histopathological risk factors, and overall survival with or without right-sided hemicolectomy. Cox proportional hazards regression was used to estimate the relative all-cause mortality hazard associated with right-sided hemicolectomy compared with appendectomy alone. This study is registered with ClinicalTrials.gov, NCT03852693. FINDINGS 282 patients with suspected appendiceal tumours were identified, of whom 278 with an appendiceal NET of 1-2 cm in size were included. 163 (59%) had an appendectomy and 115 (41%) had a right-sided hemicolectomy, 110 (40%) were men, 168 (60%) were women, and mean age at initial surgery was 36·0 years (SD 18·2). Median follow-up was 13·0 years (IQR 11·0-15·6). After centralised histopathological review, appendiceal NETs were classified as a possible or probable primary tumour in two (1%) of 278 patients with distant peritoneal metastases and in two (1%) 278 patients with distant metastases in the liver. All metastases were diagnosed synchronously with no tumour-related deaths during follow-up. Regional lymph node metastases were found in 22 (20%) of 112 patients with right-sided hemicolectomy with available data. On the basis of histopathological risk factors, we estimated that 12·8% (95% CI 6·5 -21·1) of patients undergoing appendectomy probably had residual regional lymph node metastases. Overall survival was similar between patients with appendectomy and right-sided hemicolectomy (adjusted hazard ratio 0·88 [95% CI 0·36-2·17]; p=0·71). INTERPRETATION This study provides evidence that right-sided hemicolectomy is not indicated after complete resection of an appendiceal NET of 1-2 cm in size by appendectomy, that regional lymph node metastases of appendiceal NETs are clinically irrelevant, and that an additional postoperative exclusion of metastases and histopathological evaluation of risk factors is not supported by the presented results. These findings should inform consensus best practice guidelines for this patient cohort. FUNDING Swiss Cancer Research foundation.

ObjectiveWhile human papillomavirus (HPV) has been shown to play a significant role in cervical cancer carcinogenesis (HPV associated cases), a considerable percentage of cervical cancers occur independently of HPV status (HPV independent).MethodsIn this retrospective study of 254 locally advanced cervical cancer patients treated with chemoradiotherapy and radical surgery, HPV genotypes were determined using the Anyplex II HPV28 kit that uses multiplex, real time polymerase chain reaction technology. The primary endpoints of this study were to evaluate the complete response to chemoradiotherapy (pathologic complete response), the presence of microscopic (<3 mm, pathologic micro partial response, group 1) and macroscopic (>3 mm, pathologic macro partial response, group 2) residual carcinoma in the cervix, and the persistence of metastatic lymph nodes (group 3) in HPV independent cervical cancers. Secondary endpoints were evaluation of disease-free survival and overall survival.ResultsOf 254 patients studied, 21 cases (8.3%) of cervical cancer were determined to be HPV independent. The percentage of pathologic complete response was found to be higher in the HPV associated group compared with the HPV independent group (pConclusionsThis study showed that HPV status at diagnosis could be a relevant factor for clinical outcomes in locally advanced cervical cancer patients.

The prognostic role of perineural invasion (PNI) in vulvar squamous cell carcinoma (VSCC) has not been fully established since few studies on this topic are currently available in the literature. In the present study, we conducted a systematic review and metanalysis of literature data in order to determine if PNI could be an independent prognostic predictor of patient's survival in VSCC. Four electronic databases (PubMed, ISI Web of Science, Scopus and Google Scholar) were searched from their inception to December 2021 for all studies assessing the prognostic value of PNI in VSCC. Multivariate hazard ratios (HRs) for overall survival (OS), disease-specific survival (DSS), and progression-free survival (PFS) were pooled. Six studies with 1048 patients were included. PNI was significantly associated with decreased OS (HR = 2.687; p 0.001), DSS (HR = 2.375; p = 0.014) and PFS (HR = 1.757; p = 0.001), with no statistical heterogeneity among studies and no significant risk of bias across studies. The present meta-analysis highlights that PNI is independently associated with unfavorable prognosis in patients with VSCC. Therefore, PNI should be included in the pathological report of VSCC and considered in combination with other risk factors as a possible criteria for prognostic assessment adjuvant treatment planning inclusion.

Objective The current IPMN risk stratification is based on clinical and histological features rather than molecular markers. We aimed to improve the current diagnostic criteria of IPMN performing spatial transcriptomic (ST) on lesions of different grade to identify novel markers that define IPMN degeneration to PDAC. Design We performed ST on two independent cohorts of IPMN samples grouped by morphology and degree of dysplasia using two innovative technologies: Visium ST on a discovery cohort of 18 samples from 14 patients: 4 low-grade IPMN (3 low-grade dysplasia (LGD), 1 intermediate dysplasia/Borderline), 9 high-grade IPMN characterized by a high-grade of dysplasia (HGD), including 4 invasive IPMN with associated PDAC, and 1 PDAC-associated normal duct). GeoMx ST on a validation cohort of 57 IPMN samples: 23 low-grade IPMN (6 low-grade dysplasia (LGD), 17 intermediate dysplasia/Borderline), 34 High-grade IPMN (13 HGD Gastric IPMN and 21 HGD Intestinal IPMN) from 40 patients. Results Novel subtype-specific markers were identified in the discovery cohort: HOXB3 and ZNF117 in LGD ; SPDEF, and gastric neck cell markers in Borderline; NKX6-2 and gastric isthmus cell markers in HGD Gastric IPMN. The spatial trajectory inference implicated NKX6-2 in progression of Gastric IPMN. Transcriptomic dissection highlighted the role of TNFα signalling and Myc activation in IPMN progression. The findings were confirmed in the independent validation cohort by GeoMx analysis. Conclusions Our results identify novel markers associated with IPMN morphology and dysplasia to be explored for clinical utility, to better delineate progression in patients, improve risk stratification and clinical management.

Herein, we present a clinicopathological and molecular analysis of four cases of endometrial carcinoma (EC) diffusely exhibiting dyshesive cells with wide eosinophilic and vacuolated cytoplasm (histiocyte-like tumor cells, HLTCs). We compared these HLTCs to similar cells found in microcystic, elongated and fragmented (MELF) pattern (n = 20) or after neoadjuvant chemotherapy (NAC) (n = 5). The four cases were endometrioid, serous, clear cell, and gastric-type; all were at FIGO stage ≥ III. HLTCs showed an epithelial Müllerian phenotype and at least focal CK20, HNF1β, and CK5/6 expression, with aberrant e-cadherin and β-catenin expression; two cases were MMR-deficient, and one was p53-abnormal; all were POLE wild type. MELF-associated and NAC-associated HLTCs showed similar morphological/immunophenotypical features. However, MELF-associated HLTCs were mainly intraglandular and inflammation-associated, did not form a distinct tumor component, and showed no relationship with lymph node metastases. In conclusion, different histotypes of EC may show a prominent HLTC component, which shows peculiar morphological/immunophenotypical features and appears associated with aggressive behavior.

Introduction: Poorly differentiated neuroendocrine carcinomas (NECs) are characterized by aggressive clinical course and poor prognosis. No reliable prognostic markers have been validated to date; thus, the definition of a specific NEC prognostic algorithm represents a clinical need. This study aimed to analyze a large NEC case series to validate the specific prognostic factors identified in previous studies on gastro-entero-pancreatic and lung NECs and to assess if further prognostic parameters can be isolated. Methods: A pooled analysis of four NEC retrospective studies was performed to evaluate the prognostic role of Ki-67 cut-off, the overall survival (OS) according to primary cancer site, and further prognostic parameters using multivariable Cox proportional hazards model and machine learning random survival forest (RSF). Results: 422 NECs were analyzed. The most represented tumor site was the colorectum (n = 156, 37%), followed by the lungs (n = 111, 26%), gastroesophageal site (n = 83, 20%; 66 gastric, 79%) and pancreas (n = 42, 10%). The Ki-67 index was the most relevant predictor, followed by morphology (pure or mixed/combined NECs), stage, and site. The predicted RSF response for survival at 1, 2, or 3 years showed decreasing survival with increasing Ki-67, pure NEC morphology, stage III–IV, and colorectal NEC disease. Patients with Ki-67 Conclusion: The most effective parameters to predict OS for NEC patients could be Ki-67, pure or mixed/combined morphology, stage, and site.

Ultrasound examination is an accurate method in the preoperative evaluation of the inguinofemoral lymph nodes when performed by experienced operators. The purpose of the study was to build a robust, multi-modular model based on machine learning to discriminate between metastatic and non-metastatic inguinal lymph nodes in patients with vulvar cancer. One hundred and twenty-seven women were selected at our center from March 2017 to April 2020, and 237 inguinal regions were analyzed (75 were metastatic and 162 were non-metastatic at histology). Ultrasound was performed before surgery by experienced examiners. Ultrasound features were defined according to previous studies and collected prospectively. Fourteen informative features were used to train and test the machine to obtain a diagnostic model (Morphonode Predictive Model). The following data classifiers were integrated: (I) random forest classifiers (RCF), (II) regression binomial model (RBM), (III) decisional tree (DT), and (IV) similarity profiling (SP). RFC predicted metastatic/non-metastatic lymph nodes with an accuracy of 93.3% and a negative predictive value of 97.1%. DT identified four specific signatures correlated with the risk of metastases and the point risk of each signature was 100%, 81%, 16% and 4%, respectively. The Morphonode Predictive Model could be easily integrated into the clinical routine for preoperative stratification of vulvar cancer patients.

Background It is unknown whether there is an advantage to using the wet-suction or slow-pull technique during endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) with new-generation needles. We aimed to compare the performance of each technique in EUS-FNB. Methods This was a multicenter, randomized, single-blind, crossover trial including patients with solid lesions of ≥ 1 cm. Four needle passes with 22 G fork-tip or Franseen-type needles were performed, alternating the wet-suction and slow-pull techniques in a randomized order. The primary outcome was the histological yield (samples containing an intact piece of tissue of at least 550 μm). Secondary end points were sample quality (tissue integrity and blood contamination), diagnostic accuracy, and adequate tumor fraction. Results Overall, 210 patients with 146 pancreatic and 64 nonpancreatic lesions were analyzed. A tissue core was retrieved in 150 (71.4 %) and 129 (61.4 %) cases using the wet-suction and the slow-pull techniques, respectively (P = 0.03). The mean tissue integrity score was higher using wet suction (P = 0.02), as was the blood contamination of samples (P Conclusion Overall, the wet-suction technique in EUS-FNB resulted in a higher tissue core procurement rate compared with the slow-pull method. Diagnostic accuracy and the rate of samples with adequate tumor fraction were similar between the two techniques.

The aim of this study was to assess the relationship between endometrial metaplastic/reactive changes (EMRCs) and endometrial neoplastic lesions. Twenty cases of “simple” (without architecture complexity) EMRCs coexistent with endometrial malignant/premalignant lesions, twenty cases of neoplasia-unassociated EMRCs, and eight cases of complex metaplastic lesions were assessed by immunohistochemistry. EMRCs coexisted with endometrioid carcinoma (n = 12), atypical endometrial hyperplasia (n = 3), serous carcinoma (n = 2), and clear cell carcinoma (n = 3). Neoplasia-associated EMRCs showed a mean Ki67 labeling index of 12.6% (range 0–30%); with nuclear atypia in 16/20 (80%) cases; diffuse p16 expression in 15/20 (75%) cases; and heterogeneous ER, PR, and vimentin expression. Compared to the associated neoplasia, EMRCs showed a lower Ki67 expression (p < 0.001) and higher p16 expression (p < 0.001). No EMRC case showed mitotic activity, PTEN loss, MMR deficiency, nuclear β-catenin, p53-mutant pattern, Napsin A, or AMACR expression. No significant differences were found between neoplasia-associated and neoplasia-unassociated EMRCs. Complex metaplastic lesions showed a lower Ki67 expression than EMRCs (p = 0.044) and PTEN loss in 5/8 cases, even in the absence of nuclear atypia. In conclusion, neoplasia-associated simple EMRCs may show evident atypia and a worrisome immunophenotype, but no data support their involvement in endometrial carcinogenesis. Architectural complexity appears as a crucial factor to identify precancerous lesions.

BACKGROUND The global pandemic of the coronavirus disease 2019 represents a major concern for health services worldwide, and has also induced major changes in cytopathology practice. AIM We aimed to verify the diagnostic performance of cytological evaluation under a new safety protocol during the pandemic compared to the standard pre-pandemic procedure. We also aimed to assess how cytological diagnoses and sampling were impacted during the pandemic period compared to the pandemic-free period in 2019. MATERIALS AND METHODS Cytological samples of peritoneal washings taken during the first 10 months of the pandemic emergency in Italy (March 11, 2020 to January 11, 2021) were compared to samples from the preceding 10-month time frame (May 11, 2019 to March 10, 2020). RESULTS One hundred ninety-five specimens were analysed in the present study. We observed no noticeable differences in cytological diagnoses during the pandemic period compared to the pre-pandemic period. The case numbers by diagnostic category for the pre-pandemic vs pandemic periods, respectively, were as follows: non-diagnostic, 0 vs 0 cases; negative for malignancy, 86 vs 52 cases; atypia of uncertain significance, 7 vs 1 cases; suspicious for malignancy, 0 vs 2 cases; malignant, 42 vs 4 cases. CONCLUSION While a consistent reduction in the number of cytological examinations has been observed during the COVID-19 period, our institutional safety protocol for processing cytological samples did not affect the diagnostic reliability of peritoneal washing cytology.

Background The precursors of clear cell endometrial carcinoma (CC-EC) are still undefined. Here, we deal with the diagnostic issues related to CC-EC precursors by presenting a morphological, immunophenotypical and molecular study of two representative cases and discussing the relevant literature. Case presentation Our and previous cases suggest that clear cell endometrial intraepithelial carcinoma (CC-EIC) is a real entity, which may be distinguished from metaplastic/reactive changes and from its serous counterpart. CC-EIC appears associated with atrophic polyps and may be diagnosed based on morphological and immunophenotypical features of CC-EC in the absence of invasive disease. We described a p53-mutant putative precursor characterized by high-grade nuclei in the absence of other distinctive features. Two putative low-grade precursors resembled atypical tubal metaplasia and endometrial intraepithelial neoplasia, although immunohistochemistry could not support their relationship with CC-EC. Conclusions In conclusion, pathologists should be aware of the existence of CC-EIC, since its correct diagnosis may be crucial for a correct patient management. Although several putative earlier precursors have been described, they does not show univocal features that allow their recognition in the common practice. Further studies are necessary in this field.

Herein, we report a case of low-grade endometrial endometrioid carcinoma recurred on the vaginal stump, which showed a complete histotype shift toward a gastrointestinal-type carcinoma after chemotherapy. The recurrent tumor increased in volume during chemotherapy. Postchemotherapy histologic examination showed a pure mucinous signet-ring cell pattern with positivity for cytokeratin 20 and CDX2, focal SATB2 expression and negativity for cytokeratin 7 and estrogen and progesterone receptors. Such features led to consider a diagnosis of metastasis from a primary carcinoma of the gastrointestinal tract. The accurate exclusion of any primary lesions of gastrointestinal and of other sites allowed identifying the tumor as the recurrent endometrial carcinoma. Our case highlights that chemotherapy may induce a histotype shift from endometrioid carcinoma to gastrointestinal-type carcinoma; such occurrence might be a mechanism of resistance and might provide new insights on the sensitiveness of different histotypes to systemic therapies. Considering the possibility of a shift from endometrioid to gastrointestinal-type carcinoma may be useful for a correct diagnosis and an appropriate patient management.

Intraductal papillary mucinous neoplasms (IPMN) are one of the main precursor lesions of Pancreatic Ductal Adenocarcinoma (PDAC). The number of patients diagnosed with IPMN is constantly increasing. While in most of the cases IPMN present as indolent and nonmalignant entities, some degenerate into PDAC. The main mechanisms behind the IPMN progression to malignancy is still not fully understood.This is mainly due to the technological limit of the analyzes and to cysts heterogeneity whose malignant transformation potential is estimated based on size and degree of dysplasia without take in consideration the transformation time and therefore the real malignancy potential.Moreover, there is a general lack of consensus diagnostic markers to discern the Low-grade nonmalignant from High-grade malignant IPMN. In this study, we used two different Spatial Transcriptomic technologies (Visium, and GeoMx) to investigate the transcriptome of Low-grade dysplasia nonmalignant IPMN, Borderline IPMN, and High-grade dysplasia malignant IPMN to dissect the main mechanism that drives carcingenesis and to find specific markers associated to risk of tumor progression.We performed Visium spatial transcriptomics on two TMAs containing three Low-grade dysplasia nonmalignant IPMN, one Borderline IPMN, two High-grade dysplasia malignant IPMN, and two PDAC.We identified three specific epithelial cell clusters that characterize Low-grade dysplasia IPMN, Borderline IPMN, and High-grade dysplasia malignant IPMN and three transcription factors whose expression is associated with each grade. High-grade malignant IPMN were characterized by high expression levels ofNKX6-2and other markers of gastric isthmus cell lineage such asMUC5AC, PSCA, FERIL6.TheSPDEFhigh IPMN cluster was found in Borderline IPMN and spotted in some regions of High-grade malignant IPMN. This cluster was characterized by high expression levels ofSPDEFand other goblet cell lineage markers such asTFF2, AQP5,andMUC6.Low-grade nonmalignant IPMN were characterized by high expression levels ofHOXB3, HOXB5, ZNF117.The association of these markers with the different grades was validated by GeoMx spatial transcriptomics on 43 additional IPMN samples divided according to their grade of dysplasia and malignancy.To better understand the transcriptomic changes along IPMN progression we performed spatial trajectory inference and we found thatSPDEFhigh IPMN cluster cells are likely to evolve intoNKX6-2high malignant IPMN, and we found that this switch is characterized by the expression ofNKX6-2and other gastric markers.Taken together, the results presented here not only shed more light in to IPMN and PDAC oncogenesis, but also provided a plethora of novel malignancy-associated markers to be tested in diagnostic routine, to better delineate IPMN progression in patients and improve clinical management.

In the histological assessment of endometrial carcinoma, the presence of squamous differentiation is generally considered inconsistent with a serous histotype. Herein, we report a case of endometrial serous carcinoma with extensive squamous differentiation mimicking squamous cell carcinoma, with literature review. A 67-years-old-woman underwent hysterectomy, bilateral salpingo-oophorectomy, sentinel lymph node resection, omental and peritoneal biopsies, due to a 8 cm endometrial mass. Histologically, the tumor showed squamous carcinoma features with positivity for squamous cell markers (p40, p63, cytokeratin-5/6, cytokeratin-34βE12) and negativity for Müllerian markers (PAX8, estrogen receptor, progesterone receptor). No immunohistochemical/molecular alterations typical of endometrioid carcinoma (i.e., PTEN loss, mismatch repair deficiency, nuclear β-catenin expression, POLE mutation) were observed. P53 showed aberrant pattern and p16 showed basal positivity. The tumor infiltrated the myometrium full-thickness with extensive lymphovascular space invasion. Surprisingly, the sentinel lymph node metastasis showed overt serous carcinoma features. Additional sampling of the endometrial mass revealed a minor. In conclusion, serous carcinoma may show diffuse squamous differentiation. In the case of suspected primary endometrial squamous cell carcinoma, an extensive sampling is warranted.

BACKGROUND. Intraductal papillary mucinous neoplasm (IPMN) are the most prevalent pancreatic cystic neoplasms which may progress to pancreatic ductal adenocarcinoma (PDAC), the most lethal solid malignancy. Therefore, patients suffering from this condition represent the ideal population where to address the efforts of identifying prevention or interception strategies. Here, we used spatial transcriptomics on IPMNs of different grade to identify mechanisms that are associated to the progression of those lesions toward invasive carcinomas. METHODS. We analysed 43 IPMNs grouped according to their dysplasia grade by digital spatial whole transcriptome analysis (GeoMX Human Whole Transcriptome Atlas). The high-resolution of the technology gave us the opportunity to define the genes activated along progression of IPMN to cancer, ruling out the background given by the non-neoplastic cells. The gene signature identified was validated for expression in an external validation cohort of IPMN patients and in TCGA dataset and as therapeutic target in in vitro 3D models and in in vivo syngeneic orthotopic model of PDAC. RESULTS. By spatial transcriptome profiling of IPMNs with different dysplasia grades, we identified more than 3000 genes differentially expressed between LGD-, HGD- IPMNs and during transformation into invasive carcinoma. One of the top differentially regulated gene signature, mucins-specific O-Glycosylation, was both validated in a cohort of patients (n=9) by immunofluorescence (IF) analysis and in TCGA dataset. Preclinical models of pancreatic cancer, including in vitro 3D and in vivo experiments confirmed the role of GCNT3 and mucins in protecting tumor cells from T-cells recognition. CONCLUSIONS. We identified more than 3000 genes differentially expressed between LGD- and HGD- IPMNs and along the transformation from IPMN into invasive carcinoma. These results shed light on the role of mucin-specific O-glycosylation in the IPMN progression and in PDAC offering suitable markers for the early diagnosis. Moreover, we demonstrated in in vitro 3D models and in vivo experiment that GCNT3, the main regulator of mucins post-translational modification, is an actionable target in PDAC, paving the way for the development of novel strategies to target the protective mucin barrier to enhance PDAC chemotherapy efficacy.

The four TCGA-based molecular prognostic groups of endometrial carcinoma (EC), i.e., POLE-mutant, mismatch repair (MMR)-deficient, p53-abnormal, and “no specific molecular profile” (NSMP), have recently been integrated into ESGO-ESTRO-ESP guidelines. The POLE-mutant and MMR-deficient groups are associated with high mutational load, morphological heterogeneity, and inflammatory infiltration. These groups are frequent in high-grade endometrioid, undifferentiated/dedifferentiated, and mixed histotypes. POLE-mutant ECs show good prognosis and do not require adjuvant treatment, although the management of cases at stage >II is still undefined. MMR-deficient ECs show intermediate prognosis and are currently substratified based on clinicopathological variables, some of which might not have prognostic value. These groups may benefit from immunotherapy. P53-mutant ECs are typically high-grade and often morphologically ambiguous, accounting for virtually all serous ECs, most carcinosarcomas and mixed ECs, and half of clear-cell ECs. They show poor prognosis and are treated with chemoradiotherapy; a subset may benefit from HER2 inhibitors or PARP inhibitors. The NSMP group is the most frequent TCGA group; its prognosis is highly variable and affected by clinicopathological/molecular factors, most of which are still under evaluation. In conclusion, the TCGA classification has improved diagnosis, risk stratification, and management of EC. Further studies are needed to resolve the points of uncertainty that still exist.

Corded and hyalinized endometrioid carcinoma (CHEC) typically shows low-grade features and "no specific molecular profile" (NSMP). This study aimed to perform a clinicopathological and molecular characterization of endometrial CHEC with high-grade features. Immunohistochemistry for cytokeratin AE1/AE3, e-cadherin, β-catenin, estrogen receptor, progesterone receptor, p53, p16, and mismatch repair proteins was performed. A next-generation sequencing kit was used to assess POLE, POLD1, APC, MLH1, MSH2, MSH6, PMS2, MUTYH, EPCAM, and CTNNB1. Molecular groups, i.e., POLE-mutant, mismatch repair deficient (MMRd), p53-abnormal, and NSMP, were assigned according to the TCGA classifier. Six high-grade endometrial CHECs were identified. The mean age was 57.5 years; 5/6 cases were uterine-confined. Five cases showed a diffusely and markedly atypical corded component and a MMRd or p53-abnormal signature; additional features included single-cell keratinization, necrosis, osteoid or myxoid/chondro-myxoid matrix, foci of anaplasia, and nuclear β-catenin expression. The remaining case showed a low mitotic count and a NSMP phenotype, with focal bizarre cells in an otherwise classical CH endometrioid carcinoma. All cases showed variably reduced expression of epithelial markers and hormone receptors in the corded component. No mutations were found in any of the analyzed genes. In conclusion, high-grade CHECs are a heterogeneous subset of biphasic endometrial carcinoma which show similarities and differences with classical CHEC and carcinosarcoma. These cases often show MMRd or p53-abnormal signatures.

Up to now, a vaginal well-differentiated neuroendocrine tumor (NET) has never been well described in the literature. A 2-cm vaginal nodule morphologically revealed a proliferation of mild to moderately atypical eosinophilic epithelioid cells, without tumor cell necrosis. Immunohistochemistry (IHC) showed positivity for CK (AE1/AE3), chromogranin A, and synaptophysin, focal positivity for CDX2, and negativity for PAX8 and TTF1. Metastatic origin was excluded by imaging and the morphological context with benign mucinous glands as present in the surgical resection specimen. Considering mitotic index and Mib1/Ki67 (8 mitoses/2 mm2; >20%), the case was diagnosed as vaginal NET G2 in the light of the WHO 2020 grading system for the gynecologic neuroendocrine neoplasms (NENs). Ranges of Mib1-Ki67 are not yet standardized. Currently, mitotic index and tumor cell necrosis were taken into consideration for the grading system. Gynecologic NENs still represent a diagnostic challenge. A clinico-radiologic workup and an appropriate diagnostic path ruling out the metastatic nature are mandatory to achieve the diagnosis.

Endometrial clear cell carcinoma (CCC) shows morphological overlap with endometrioid and serous carcinoma. We aimed to assess the accuracy of immunohistochemical diagnostic markers of CCC, i.e. HNF1β, Napsin A and P504S/Alpha-Methylacyl-CoA Racemase (AMACR). A systematic review and meta-analysis was conducted by searching 4 electronic databases from their inception to April 2022 for all studies assessing HNF1β, Napsin A and/or AMACR in endometrial CCC vs endometrioid/serous carcinomas. Diagnostic accuracy was assessed as sensitivity, specificity, positive and negative likelihood ratios (LR+ and LR-), diagnostic odds ratio (DOR) and area under the curve (AUC) on sROC curves. Eleven studies were included. HNF1β positivity (any expression) showed sensitivity= 0.78; specificity= 0.81; LR+ =2.46; LR-= 0.38; DOR= 5.96; AUC= 0.79. Diffuse HNF1β expression showed sensitivity= 0.53; specificity= 0.95; LR+ =9.68; LR-= 0.51; DOR= 18.02; AUC= 0.40. Napsin A positivity (any expression) showed sensitivity= 0.76; specificity= 0.97; LR+ =18.79; LR-= 0.27; DOR= 73.31; AUC= 0.81. Diffuse Napsin A expression showed sensitivity= 0.52; specificity= 0.99; LR+ =14.50; LR-= 0.55; DOR= 24.93; AUC= 0.98. AMACR positivity (any expression) showed sensitivity= 0.76; specificity= 0.86; LR+ =4.86; LR-= 0.30; DOR= 13.56; AUC was not assessable due to the presence of only 2 studies. In conclusion, HNF1β, Napsin A and AMACR show moderate accuracy in identifying endometrial CCC. Considering only a diffuse expression of these markers as positive leads to high specificity but low sensitivity. In particular, Napsin A appears as the most specific marker of endometrial CCC.

Neuroendocrine neoplasms (NENs) of the major and minor ampulla are rare diseases with clinico-pathologic features distinct from non-ampullary-duodenal NENs. However, they have been often combined and the knowledge on prognostic factors specific to ampullary NENs (Amp-NENs) is limited. The aim of this study was to identify factors associated with metastatic potential and patient prognosis in Amp-NENs. We clinically and histologically investigated an international series of 119 Amp-NENs, comprising 93 ampullary neuroendocrine tumors (Amp-NETs) and 26 neuroendocrine carcinomas (Amp-NECs). Somatostatin-producing tubulo-acinar NET represented the predominant Amp-NET histologic subtype (58 cases, 62%, 12 associated with type 1 neurofibromatosis). Compared to Amp-NETs, Amp-NECs arose in significantly older patients and showed a larger tumor size, a more frequent small vessel invasion, a deeper level of invasion and a higher rate of distant metastasis, and, importantly, a tremendously worse disease-specific patient survival. In Amp-NETs, the WHO grade proved to be a strong predictor of disease-specific survival (hazard ratio: 12.61, p 60 years, small vessel invasion, pancreatic invasion, and distant metastasis at diagnosis. Although nodal metastatic disease was not associated with survival by itself, patients with > 3 metastatic lymph nodes showed a worse outcome in comparison with the remaining Amp-NET cases with lymphadenectomy. Tumor epicenter in the major ampulla, small vessel invasion, and tumor size > 16 mm were independent predictors of nodal metastases in Amp-NETs. In conclusion, we identified prognostic factors, which may eventually help guide treatment decisions in Amp-NENs.

Le neoplasie neuroendocrine (NEN) sono una famiglia ampia ed eterogenea di neoplasie osservabili in molte sedi dell’organismo. Seppure condividano aspetti morfologici, i loro nomi e i criteri classificativi variano nelle diverse sedi anatomiche di insorgenza. I diversi nomenclatori oggi forniti dall’Organizzazione Mondiale della Sanita (OMS), seppure ben definiti ed efficaci, possono talora generare confusione, ostacolando potenzialmente il corretto inquadramento della malattia e l’efficace gestione dei pazienti. L’Agenzia Internazionale per la Ricerca su Cancro (AIRC) dell’OMS nel 2018 ha proposto un modello di classificazione universale per le neoplasie neuroendocrine (AIRC-OMS 2018). Questo modello si fonda su basi precise. Le neoplasie neuroendocrine sono composte da cellule con uno specifico fenotipo caratterizzato dell’espressione di marcatori neuroendocrini. Il fenotipo neuroendocrino connota una ben definita categoria neoplastica chiamata in tutti gli organi “neoplasia neuroendocrina”. Le neoplasie neuroendocrine possono essere ben differenziate o scarsamente differenziate, con incidenza e prevalenza diverse nei differenti distretti anatomici. E stato proposto che le forme ben differenziate siano universalmente definite “tumori” neuroendocrini (NET) e le forme scarsamente differenziate “carcinomi neuroendocrini” (NEC). Sistemi di grading basati sulla proliferazione con conta mitotica, valore percentuale di Ki67 e/o presenza di necrosi, si sono dimostrati efficaci nel predire la prognosi dei pazienti con tumori neuroendocrini ben differenziati in sedi diverse. Si e proposto di utilizzare questo approccio per il grading dei NET in ogni sede definendo, tuttavia, valori soglia sede-specifici. In ogni caso e riconosciuto il fatto che esistono differenze di comportamento biologico significative e specifiche per ogni sede. Questi caratteristici aspetti sede-specifici vanno sempre tenuti in conto per il corretto inquadramento diagnostico di queste neoplasie. Si raccomanda, pertanto, di utilizzare sia la definizione classica sia la definizione fornita da questa classificazione universale. La proposta di classificazione universale AIRC-OMS 2018 ha lo scopo di uniformare il nomenclatore delle neoplasie neuroendocrine delle diverse sedi anatomiche, nella speranza di favorire la definizione di un analogo sistema classificativo genetico.

Highlights • Integration of PIPAC to systemic chemotherapy can have good tolerance profile. • Repeated biopsies performed during PIPAC allowed therapy-response monitoring. • Analysis of biopsies performed during PIPAC allowed tailoring of chemotherapy. • Integration of PIPAC to systemic chemotherapy can permit good quality of life., Introduction Pancreatic ductal adenocarcinoma (PDAC) with peritoneal metastases (PM) has a dismal prognosis and palliative systemic chemotherapy, which represents the standard treatment option, has significant pharmacokinetics limitations and low efficacy. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a new method of drug delivery that is expected to maximize exposure of peritoneal nodules to antiblastic agents. A combination of systemic chemotherapy and PIPAC may be valuable. Presentation of case A 55 years old male affected by PDAC with synchronous PM underwent a multimodal treatment comprising systemic chemotherapy and PIPAC without any procedural-related adverse events. Tumor genomic profiling evaluation from peritoneal biopsies addressed further tailored systemic chemotherapy. Discussion The presented case illustrates the possibility of adding PIPAC to systemic chemotherapy with a fair tolerance profile and good quality of life while allowing monitoring of therapy-response and tailoring of the antiblastic treatment.

Background: Additional prognostic factors and personalized therapeutic alternatives for vulvar squamous cell carcinoma (VSCC), especially for advanced stages with poor prognosis, are urgently needed. Objectives: To review and assess literature regarding underlying molecular mechanisms of VSCC target therapeutic and prognostic approaches. Methods: We performed a narrative literature review from the inception of the database up to January 2020 limited to English language, organizing knowledge in five main fields: extracellular and intracellular cell cycle deregulation, tumor immune microenvironment, tumor angiogenesis and hormones. Results: EGFR immunohistochemical overexpression/gene amplification, representing early events in VSCC carcinogenesis, have been correlated with a worse prognosis and led to inclusion of erlotinib in cancer guidelines. p16 expression and HPV positivity are linked to a better prognosis, while p53 overexpression is linked to a worse prognosis; thus, biomarkers could help tailoring conventional treatment and follow-up. The implications of PD-L1 positivity in reference to HPV status and prognosis are still not clear, even though pembrolizumab is part of available systemic therapies. The role of tumor angiogenesis emerges through data on microvessel density, immunohistochemical VEGF staining and evaluation of serum VEGF concentrations. Few data exist on hormonal receptor expression, even though hormonal therapy showed great manageability. Conclusions: We suggest adding p16, p53 and HPV status to routine hystopathological examination of vulvar biopsies or surgical specimens. Predictive biomarkers for anti-EGFR and anti-PD-1/PD-L1 drugs are needed. Enough preclinical data supporting anti-angiogenic target therapies in clinical trials are existing. Hormonal receptor expression deserves further investigation.

Endometrial morular metaplasia (MorM) can show cytoplasm clarification, which may mimic clear cell carcinoma (CCC), especially on biopsy. We aimed to assess the expression of CCC markers in MorM.Twenty cases of MorM with areas of cytoplasmic clarification were assessed by immunohistochemistry for HNF1β, Napsin A, and P504S/alpha-Methylacyl-CoA racemase (AMACR); 60 tumors were selected as controls (20 classical MorM, 20 conventional squamous differentiation and 20 CCC).Eighteen cases (90%) showed overt squamous/keratinizing areas within MorM, and 11 cases (55%) showed isolated ghost cells which might mimic the hyaline globules of CCC. All cases (100%) showed expression of AMACR, which was mostly diffuse and strong; in all cases, the expression was restricted to the prototypical MorM areas, while glandular areas and overtly squamous areas were negative. Twelve cases (60%) showed HNF1β expression, which was focal/multifocal and/or weak; the expression was found in all tumor components. No case showed Napsin A expression in any component. Classical MorM showed similar immunophenotype, while conventional squamous differentiation did not show AMACR expression. Most CCC expressed AMACR (70%), HNF1β (85%), and Napsin A (75%), mostly with diffuse and strong positivity.MorM may show features that mimic CCC and consistently expresses AMACR, which may be accompanied by HNF1β expression; Napsin A is consistently negative instead. These findings should be considered to avoid overdiagnosis.

Background: Several pathological parameters, including tumor size, depth of stromal invasion, lympho-vascular space invasion and lymph node status, have been proposed as prognostic predictors in cervical cancer. However, given the high mortality and recurrence rate of cervical cancer, novel parameters that are able to provide additional prognostic information are needed in order to allow a better prognostic stratification of cervical cancer patients. Methods: A search was conducted on PubMed to identify relevant literature data regarding prognostic factors in cervical cancer. The key words “cervical cancer”, “prognostic factors”, “pathology”, and “outcome” were used. Results: The novel pathological grading system based on tumor budding and cell nest size appeared the most relevant prognostic factor in primary neoplasms. Moreover, other potentially useful prognostic factors were tumor size, depth of stromal invasion, lympho-vascular space invasion, perineural invasion, tumor-free distance and tumor-infiltrating lymphocytes. Prognostic factors related to advanced-stage cervical cancer, including lymph-nodes status, endometrial and cervical involvement as well as distant metastases, were also taken into consideration. Conclusions: According to our findings, tumor budding and cell nest size grading system, depth of stromal invasion, lympho-vascular space invasion, perineural invasion, tumor-free distance and tumor-infiltrating lymphocytes appeared the most relevant factors included in the pathology report.

Purpose to correlate somatostatin receptor (SSTR) and proliferative activity profile (SSTR2, SSTR5, Ki-67) at immunohistochemistry (IHC) with SSTR-PET/CT imaging features in a retrospective series of lung neuroendocrine neoplasms (NEN). Proliferative activity by Ki-67 and 18F-FDG-PET/CT parameters (when available) were also correlated. Methods Among all consecutive patients who underwent SSTR-PET/CT with 68Ga-DOTA-somatostatin analogs (SSA) between July 2011 and March 2020 for lung NEN, 35 patients with a confirmed diagnosis were included. For 16 of them, 18F-FDG-PET/CT studies were available. PET/CT images were reviewed by qualitative and semi-quantitative analyses. Immunohistochemistry for SSTR2, SSTR5, and Ki-67 was assessed. An inferential analysis was performed including kappa statistic and Spearman's rank correlation test. Results Definitive diagnosis consisted of 32 low-intermediate-grade NEN (26 typical carcinoids-G1 and six atypical carcinoids-G2) and 3 high-grade NEN. Positive SSTR2-IHC was found in 63% of samples while SSTR5-IHC positivity was 17.6%. A correlation between SSTR2-IHC and SSTR-PET/CT was found in 26/35 cases (74.3%, p=0.003): 22 were concordantly positive, 4 concordantly negative. For positive IHC, 100% concordance with SSTR-PET/CT (both positive) was observed, while for negative IHC concordance (both negative) was 30.8%. In 9 cases, IHC was negative while SSTR-PET/CT was positive, even though with low-grade uptake in all but one. A significant correlation between SUVmax values at SSTR-PET/CT and the SSTR2-IHC scores was found, with low SUVmax values corresponding to negative IHC and higher SUVmax values to positive IHC (p=0.0007). When correlating 68Ga-DOTA-SSA or 18F-FDG SUVmax values with Ki-67, a significant result was found for 18F-FDG only (p=0.015). Conclusion This retrospective study showed an overall good agreement between SSTR2-IHC and tumor uptake at SSTR-PET/CT in lung NENs. SSTR-PET/CT SUVmax values can be used as a parameter of SSTR2 density. SSTR2-IHC may be proposed as surrogate of SSTR-PET/CT in selected lung NEN patients for clinical decision making when SSTR-PET/CT is not available.

Herein, we present a morphological, immunohistochemical, and molecular analysis of three cases of endometrial giant cell carcinoma (EGCC) with a literature review. Patient age was 55 to 76 years. The tumors were limited to the uterus and showed dyshesive, bizarre giant cells with numerous atypical mitoses. Minor components were low-grade endometrioid, spindled/myxoid (case nos. 1 and 2), serous (case no. 3), and undifferentiated (all cases). The giant cells were e-cadherin-, cytokeratins/EMA + (focal/multifocal), hormone receptors + (focal/multifocal), vimentin + , p16 + (diffuse), CD68-, α-FP-, β-HCG-, muscle markers-, CD10-, and ERG-. Case no. 3 was p53-abnormal. All cases were mismatch repair-proficient and microsatellite-stable. No POLE mutations were detected. Based on our and previous reports, EGCC is often accompanied by a conventional carcinomatous component (mostly endometrioid) and shows partial loss epithelial markers and negativity for specific differentiation markers. EGCC shows evident similarities to both undifferentiated/dedifferentiated carcinoma and carcinosarcoma and should be managed similarly. Unlike the latter two, EGCC might preferentially derive from “no-specific-molecular-profile” carcinomas.