Virchows Archiv

doi: 10.1007/s00428-022-03352-1pmid: 35652997

Couvelard, Anne; Cros, Jérôme

doi: 10.1007/s00428-022-03306-7pmid: 35278097

Digestive neuroendocrine neoplasms (NENs) are a group of heterogeneous neoplasms found throughout the digestive tract, with different behaviour and genetic background. In the last few years, nomenclature and WHO/UICC classifications of digestive NENs have changed, and molecular classifications have emerged, especially in pancreatic locations. Increasing patho-molecular details are needed to diagnose the different categories of NEN, including the use of helpful immunohistochemical markers. In this review, we address these topics in three successive chapters. We first briefly review recent updates in classifications, discuss important grading and proliferating issues and advances in the molecular understanding of NEN. Then, we provide an update on diagnosis, including the most important differential diagnoses of NEN, with a focus on high-grade neoplasms and mixed tumours. Finally, we highlight a variety of currently used and next-generation predictive and prognostic biomarkers as well as biomarkers of tumour origin and describe some site specificities of gastrointestinal NEN. We specifically focus on biomarkers available to pathologists with the potential to change the way patients with NEN are diagnosed and treated.

Seyrek, Neslisah; Hollemans, Eva; Andrinopoulou, Eleni-Rosalina; Osanto, Susanne; Pelger, Rob C. M.; van der Poel, Henk G.; Bekers, Elise; Remmers, Sebastiaan; Schoots, Ivo G.; van Leenders, Geert J. L. H.

doi: 10.1007/s00428-022-03301-ypmid: 35157140

Percentage Gleason pattern 4, invasive cribriform and/or intraductal carcinoma (IC/IDC) and minor pattern 5 are recognized as independent parameters for prostate cancer outcome, but are not incorporated in current grade groups (GGs). Two proof-of-principle studies have proposed alternative grading schemes based on percentage Gleason pattern 4/5 (integrated quantitative Gleason score; IQ-Gleason) and IC/IDC presence (cribriform grade; cGrade). Our objective was to compare the performance of GG, IQ-Gleason and cGrade for predicting biochemical recurrence and metastasis after radical prostatectomy (RP). RP specimens of 1064 patients were pathologically reviewed and graded according to the three schemes. Discriminative power for prediction of biochemical recurrence-free (BCRFS) and metastasis-free (MFS) survival was compared using Harrell’s c-index. The GG distribution at RP was 207 (19.4%) GG1, 472 (44.4%) GG2, 126 (11.8%) GG3, 140 (13.2%) GG4 and 119 (11.2%) GG5. Grading according to 5-tier IQ-Gleason and cGrade systems led to categorical shifts in 49.8% and 29.7% of cases, respectively. Continuous IQ-Gleason had the best performance for predicting BCRFS (c-index 0.743, 95% confidence interval (CI) 0.715–0.771), followed by cGrade (c-index 0.738, 95%CI 0.712–0.759), 5-tier categorical IQ-Gleason (c-index 0.723, 95%CI 0.695–0.750) and GG (c-index 0.718, 95%CI 0.691–0.744). Continuous IQ-Gleason (c-index 0.834, 95%CI 0.802–0.863) and cGrade (c-index 0.834, 95%CI 0.808–0.866) both had better predictive value for MFS than categorical IQ-Gleason (c-index 0.823, 95%CI 0.788–0.857) and GG (c-index 0.806, 95%CI 0.777–0.839). In conclusion, the performance of prostate cancer grading can be improved by alternative grading schemes incorporating percent Gleason pattern 4/5 and IC/IDC.

Hladek, Luca; Bankov, Katrin; von der Grün, Jens; Filmann, Natalie; Demes, Melanie; Vallo, Stefan; Wild, Peter J.; Winkelmann, Ria

doi: 10.1007/s00428-022-03271-1pmid: 35024940

Penile squamous cell carcinomas are rare tumor entities throughout Europe. Early lymphonodal spread urges for aggressive therapeutic approaches in advanced tumor stages. Therefore, understanding tumor biology and its microenvironment and correlation with known survival data is of substantial interest in order to establish treatment strategies adapted to the individual patient. Fifty-five therapy naïve squamous cell carcinomas, age range between 41 and 85 years with known clinicopathological data, were investigated with the use of tissue microarrays (TMA) regarding the tumor-associated immune cell infiltrate density (ICID). Slides were stained with antibodies against CD3, CD8 and CD20. An image analysis software was applied for evaluation. Data were correlated with clinicopathological characteristics and overall survival. There was a significant increase of ICID in squamous cell carcinomas of the penis in relation to tumor adjacent physiological tissue. Higher CD3-positive ICID was significantly associated with lower tumor stage in our cohort. The ICID was not associated with overall survival. Our data sharpens the view on tumor-associated immune cell infiltrate in penile squamous cell carcinomas with an unbiased digital and automated cell count. Further investigations on the immune cell infiltrate and its prognostic and possible therapeutic impact are needed.

Polónia, António; Canelas, Carolina; Caramelo, Ana

doi: 10.1007/s00428-022-03290-ypmid: 35137279

We aimed to document the pathological characteristics of breast cancer (BC) cases with different scores of HER2 by immunohistochemistry (IHC), as well as to establish a relationship between HER2 expression and HER2 amplification by in situ hybridization (ISH). A cohort of 258 primary BC cases was evaluated for HER2 gene amplification with bright-field ISH. All HER2-negative and HER2-positive cases by IHC were concordant with the ISH classification. BC cases with score of 0 had lower average of HER2 copy number compared to cases with score of 1 + . HER2-equivocal cases by IHC had intermediate pathological characteristics between HER2-negative and HER2-positive cases. About 12% of HER2-equivocal cases were classified as ISH-positive. HER2-equivocal cases with HER2 gene amplification had proliferation index, HER2/CEP17 ratio, and average of HER2 copy number between HER2-equivocal cases without HER2 gene amplification and HER2-positive cases by IHC. Additionally, HER2-equivocal cases with HER2 amplification had score of 2 + in at least 50% of the total tumor area, with a proportion of ISH-positive cases increasing with the amount of score of 2 + present in the tumor. The quantification of score of 2 + in the tumor predicted the ISH classification with an AUC of 0.902. A logistic regression model using the same HER2 quantification and the nuclear score was able to increase the abovementioned prediction to an AUC of 0.929. As such, we were able to link HER2 quantification by IHC and morphological analysis with HER2 amplification by ISH.

Tomimori, Kayo; Kodama, Yuki; Tanaka, Hiroyuki; Yamashita, Atushi; Gi, Toshihiro; Asada, Yujiro; Doi, Koutarou; Katsuragi, Shinji; Sato, Yuichiro

doi: 10.1007/s00428-022-03289-5pmid: 35199205

Transient abnormal myelopoiesis (TAM), also known as transient myeloproliferative disorder or transient leukemia, is a self-regressing neoplasia that afflicts infants with trisomy 21. A recent review article documented “myeloid cell thrombus (MCT)” and “fetal vascular malperfusion (FVM)” in placentas with TAM, although the characteristic TAM placental findings have not been clarified. Here, we compared the clinical and pathological placental findings between trisomy 21 patients with or without TAM. In 13 cases of trisomy 21, we identified six placentas with TAM and seven placentas without TAM. The six placentas with TAM included two stillborn cases. Microscopically, MCT was noted in all the cases, and a high incidence of FVM (50%) was observed in TAM cases. Immunohistochemically, MCT was found to be a platelet-rich thrombus. The placentas were grouped according to the presence or absence of TAM and subsequently compared. Clinically, the incidences of abnormal fetal heart rate pattern and fetal or neonatal death were significantly higher in TAM cases. Pathologically, placenta in TAM cases weighted more than those in cases without TAM, and the incidence of MCT was significantly higher in placentas with TAM. Moreover, the incidence of FVM was higher in placentas with TAM, but this difference was not statistically significant. We propose that MCT is a diagnostic feature of placentas with TAM and may be associated with poor fetal outcomes.

Sakihama, Kukiko; Koga, Yutaka; Yamamoto, Takeo; Shimada, Yuki; Yamada, Yutaka; Kawata, Jun; Shindo, Koji; Nakamura, Masafumi; Oda, Yoshinao

doi: 10.1007/s00428-022-03277-9pmid: 35066614

Mucinous cystic neoplasm (MCN) of the pancreas rarely progresses to invasive carcinoma, but few studies have analyzed genomic alterations involved in its malignant transformation. The relationships of ring finger protein 43 (RNF43) mutations with cytological atypia, RNF43 protein expression, and Wnt signaling proteins in MCN remain unclear. This study included 106 MCN cases, classified into 89 low-grade dysplasia (LG), 9 high-grade dysplasia (HG), and 8 invasive carcinoma (INV). We analyzed HG/INV and LG lesions of 9 HG/INV cases and LG lesions of 9 LG cases using targeted sequencing and confirmed the protein expression of RNF43 and β-catenin. The frequency of RNF43 mutations was significantly higher in HG/INV cases than in LG cases. Furthermore, HG/INV lesions (56%) and LG lesions (33%) of HG/INV cases possessed RNF43 mutation, whereas no such mutation was detected in any LG cases. The expression of RNF43 was reduced in 71% of HG/INV cases and significantly correlated with histological grade and aberrant expression of β-catenin. In 3 of 5 RNF43-mutated cases, the expression of RNF43 was reduced, but there was no significant correlation between RNF43 mutation and protein expression. MCNs frequently harbored KRAS mutations, at rates of 100% in HG/INV lesions and 50% in LG lesions of HG/INV and LG cases. There was no significant difference in mutation frequency in LG lesions between HG/INV and LG cases. These results suggest that RNF43 mutations may be involved in and predictive of malignant transformation from an early stage of MCN.

de Bitter, Tessa J. J.; Trapman, Daan M.; Simmer, Femke; Hugen, Niek; de Savornin Lohman, Elise A. J.; de Reuver, Philip R.; Verheij, Joanne; Nagtegaal, Iris D.; van der Post, Rachel S.

doi: 10.1007/s00428-022-03314-7pmid: 35357569

BackgroundMetastases to the gallbladder (GBm) are rare and pose a unique diagnostic challenge because they can mimic a second primary tumor. This study aimed to gain insight into the clinicopathological and epidemiological characteristics of GBm.MethodsA comprehensive literature review was performed (literature cohort) and compared with a nationwide cohort of GBm patients diagnosed between 1999 and 2015 in the Netherlands, collected via two linked registries (population cohort). Overall survival (OS) was estimated by Kaplan–Meier. Hazard ratios were determined by a Cox proportional hazard model.ResultsThe literature cohort and population cohort consisted of 225 and 291 patients, respectively. In the literature cohort, melanoma was the most frequent origin (33.8%), while colorectal cancer was the most frequent origin in the population cohort (23.7%). Prognosis was poor with median OS ranging from 6.0 to 22.5 months in the literature and population cohorts, respectively. Age, timing of GBm (synchronous/metachronous) and primary tumor origin were independent prognostic factors for OS.DiscussionMetastases to the gallbladder are rare and carry a poor prognosis. Differences between both cohorts can be attributable to the biased reporting of tumor types that are more easily recognized as GBm because of distinct histological features.

Pichler Sekulic, Simona; Sekulic, Miroslav

doi: 10.1007/s00428-022-03269-9pmid: 35013774

Lymphangiomas are comprised of aggregates of lymphatic vessels, considered to represent either aberrant embryogenic remnants or developing secondary to obstruction. Lymphangiomas primary to the heart and pericardial are exceedingly rare, and to date sparingly reported in individual case reports. In this study, the histopathologic, clinical, and radiologic features of 35 cases of cardiac/pericardial lymphangiomas described in the literature to date together with four cases from our own institution (39 cases in total) are examined to provide clinicopathologic characterization. Cardiac/pericardial lymphangiomas were identified in both children and adults, with two cases initially discovered in utero. If presenting with symptoms, patients most commonly exhibited respiratory distress/dyspnea. By X-ray, a widened cardiac silhouette could be noted, and echocardiogram generally showed an echogenic mass with cystic and septal components. On computed tomography (CT) and magnetic resonance imaging (MRI), cystic and septal components were again observed, with CT showing an absence of calcifications or macroscopic fat. Most lymphangiomas were pericardial (specifically visceral) based, and frequently situated in the right atrioventricular groove. A majority of cases proceeded to surgical resection, with no evidence of recurrence post-operatively. Grossly, lesions had a median size of 6 cm and in almost all cases were multicystic/multilocular. Microscopically, the lymphangiomas were composed of lymphatic spaces lined by endothelial cells that specifically express podoplanin (D2-40) with immunoperoxidase staining. Further investigation with a larger and more uniformly organized cohort is required to better characterize the clinicopathologic features of lymphangiomas of this unusual anatomic location.

Marletta, Stefano; Luchini, Claudio; Sperandio, Nicola; Torresani, Evelin; Sorio, Alessandro; Girolami, Ilaria; Scarpa, Aldo; Eccher, Albino; Ghimenton, Claudio

doi: 10.1007/s00428-022-03304-9pmid: 35212813

Meningiomas are common tumors of the central nervous system. Although their histological diagnosis is usually straightforward, their differential diagnosis versus other tumors may be challenging at times. The objective of this study is to assess the diagnostic value of CD13 immunoexpression in the differential diagnosis between meningiomas and their morphological mimics. Immunohistochemical analysis for CD13, epithelial membrane antigen, SOX10, and STAT6 was carried out in a large cohort of primary meningeal tumors comprising 225 meningiomas, 15 schwannomas, and 20 solitary fibrous tumor/hemangiopericytomas. Within the meningioma group, the expression of CD13 and epithelial membrane antigen was distinguished in three categories using a semiquantitative score. Most of meningiomas expressed CD13 (94%) and epithelial membrane antigen (96%) while none of the schwannomas nor of the solitary fibrous tumor/hemangiopericytomas was positive for either the two markers. Diffuse positivity for CD13 and epithelial membrane antigen was more common in low-grade meningiomas than in anaplastic ones, which were also more often negative for such markers, especially for CD13 (32%). CD13 is a helpful immunohistochemical marker for the differential diagnosis of meningiomas and their mimics, achieving in combination with epithelial membrane antigen maximal sensitivity (100%) and showing statistically relevant difference of expression in comparison with both schwannomas (p < 0.0001) and solitary fibrous tumor/hemangiopericytomas (p < 0.0001). Furthermore, loss of CD13 expression could be related to outcome as it is associated with worrisome histological findings, mainly in the setting of anaplastic meningiomas.