Virchows Archiv European Journal of Pathology

Machine learning approaches for pathologic diagnosis Abstract Machine learning techniques, especially deep learning techniques such as convolutional neural networks, have been successfully applied to general image recognitions since their overwhelming performance at the 2012 ImageNet Large Scale Visual Recognition Challenge. Recently, such techniques have also been applied to various medical, including histopathological, images to assist the process of medical diagnosis. In some cases, deep learning–based algorithms have already outperformed experienced pathologists for recognition of histopathological images. However, pathological images differ from general images in some aspects, and thus, machine learning of histopathological images requires specialized learning methods. Moreover, many pathologists are skeptical about the ability of deep learning technology to accurately recognize histopathological images because what the learned neural network recognizes is often indecipherable to humans. In this review, we first introduce various applications incorporating machine learning developed to assist the process of pathologic diagnosis, and then describe machine learning problems related to histopathological image analysis, and review potential ways to solve these problems.

CD39 downregulation in chronic intervillositis of unknown etiology Abstract Chronic intervillositis of unknown etiology (CIUE) is a rare placental lesion associated with infiltration of mononuclear inflammatory cells into the intervillous space, poor perinatal outcomes (intrauterine fetal demise or fetal growth restriction), and high rates of recurrence. CD39 is the ectonucleotidase that protects tissues from inflammatory stress and cell injury, which is localized on the surface of villi in normal placentas; however, its expression and role in CIUE are unknown. The aims of this retrospective study were to determine the expression of CD39 in CIUE and its significance in pregnancy outcomes. We compared the number of CD68- and CD3-positive cells, CD39 expression, and complement 4d (C4d) and fibrin deposition in placental tissues from patients with CIUE (n = 22) and gestational age-matched controls (n = 20), and between CIUE pregnancies with poor and good outcomes. The numbers of CD68- or CD3-positive cells were significantly higher (P < 0.0001), whereas CD39 expression on the surface of villi and endothelial cells of the stem villi was significantly lower in the CIUE group than that in controls (45% vs. 95%, P < 0.0001 and 77% vs. 96%, P < 0.001, respectively). C4d and fibrin deposition were also significantly increased in CIUE compared with those of controls. Furthermore, CD39 downregulation and the number of CD68 cells were strongly associated with poor pregnancy outcomes (P < 0.01 and P < 0.05, respectively), but other histological parameters (CD3, C4d, and fibrin) did not show this association. Our study suggests that CD39 downregulation is a useful marker of CIUE and is associated with poor pregnancy outcomes in patients with CIUE.

Two cases of phenotypic switch of primary cutaneous T cell lymphoma after treatment with an aggressive course and review of the literature Abstract A "phenotypic switch" (PS) is a well-known phenomenon that occurs in hematopoietic neoplasms, often after treatment. However, in cutaneous T cell lymphoma (CTCL), this event has rarely been reported, and thus, very little is known about its relevance to disease prognosis. We report two cases of patients that were diagnosed with a CD4+ mycosis fungoides with positive T cell receptor gene rearrangement studies. Both patients originally responded to treatment, but subsequently, their CTCL came back with a different phenotype of a CD4− CTCL. Gene rearrangement studies were performed on the second occurrence in order to prove that this was the same lymphoma. Both patients died from their CTCL. Additionally, we collected seven cases of primary CTCL from the literature with tissue samples from before and after treatment with molecular studies confirming these neoplasms contained the same T cell clone, providing evidence of a true PS. This too revealed a poor prognosis in the majority of these cases. CTCL should be worked up to determine whether a PS has occurred after therapy since it could confuse management of patients and appears to portend a poor prognosis.

Identification of a novel PRR15L-RSPO2 fusion transcript in a sigmoid colon cancer derived from superficially serrated adenoma Abstract Superficially serrated adenoma (SuSA) is a recently proposed subtype of colorectal serrated lesion. We here report a sigmoid colon cancer derived from SuSA, which exhibited aggressive clinical behavior. Endoscopically, the tumor appeared as a superficial elevated lesion with a large nodule. Histological examination of the surgically resected material showed tubular adenocarcinoma associated with SuSA. Although tumor invasion was limited to the submucosal layer, lymph node and extranodal metastases were detected. The patient subsequently developed peritoneal metastases and died 15 months after surgery. Molecular analyses identified a KRASmutation and a novel PRR15L-RSPO2 fusion, which retains the entire coding region of RSPO2, in both SuSA and adenocarcinoma components. The present study demonstrates the malignant potential of SuSA and expands the spectrum of RSPO fusions in colorectal neoplasms.

Immunohistochemical expression of mismatch repair proteins (MSH2, MSH6, MLH1, and PMS2) in prostate cancer: correlation with grade groups (WHO 2016) and ERG and PTEN status Abstract The role of DNA MMR genes in prostate cancer (PrCa) is controversial, as genetic alterations leading to microsatellite instability are incompletely defined in these tumors. ERG rearrangements and PTEN loss are concomitant events in PrCa. The aim of this study has been to analyze the immunohistochemical (IHC) expression of MSH2, MSH6, MLH1, PMS2, ERG, and PTEN and their potential association with the grade group (GG) grading system (WHO 2016) and PSA recurrence in a series of 200 PrCa (PSMAR-Biobank, Barcelona, Spain). MSH2, MLH1, PMS2, and PTEN losses were documented in 8%, 5%, 2%, and 36.5%, respectively. ERG expression was found in 48%. MSH6 showed an increase of expression with respect to basal levels in 42.1% of the cases. A statistical association between MSH6 overexpression and GG5 was found (p = 0.0281). ERG-wild-type cases were associated with single MSH2 loss (p = 0.024), and MSH2 and/or MLH1 loss (p = 0.019). The percentage of cases with PTEN loss was 20.5% (8/39) in GG1, 37.6% (53/141) of clustered GG2 to 4, and 60% (12/20) of GG5 (chi-square test, p = 0.01). Thus, PTEN expression loss was statistically more frequent in the upper-grade tumors. PMS2 loss was an infrequent event, but it was statistically associated with shorter time to PSA recurrence (p = 0.011). These results suggest the existence of an alternative non-ERG pathway associated with MSH2 or MLH1 expression loss. MSH6 overexpression could be a marker of aggressiveness in PrCa. The IHC assessment of DNA MMR proteins, ERG and PTEN, could identify different altered PrCa pathways, which could aid patient stratification.

Pathologist second opinion significantly alters clinical management of pT1 endoscopically resected colorectal cancer Abstract We retrospectively collected a series of 82 endoscopically removed early colorectal cancers. Histological specimens were revised by two gastrointestinal pathologists, performing a re-evaluation of all risk factors for lymph node metastasis. The comparison between second opinion and first pathological report revealed that lymphovascular invasion and tumor grading showed a lower level of concordance than other parameters. Our results demonstrated that second opinion modified risk assessment in about 10% of cases. It was mainly due to a lack in reporting of some parameters at the first diagnosis and a different evaluation in second opinion for updated guidelines. Considering the subgroup of patients with modified risk assessment, clinical data revealed that tumors, re-classified as low risk, did not develop lymph node metastasis that, conversely, occurred in patients identified as high risk by second opinion. In conclusion, second opinion significantly alters risk perception of endoscopically removed early colorectal carcinomas representing a valuable tool for their appropriate clinical management.

Recent advances in invasive adenocarcinoma of the cervix Abstract Endocervical adenocarcinomas (ECAs) are currently classified according to the 2014 World Health Organization (WHO) system, which is predominantly based on descriptive morphologic characteristics, considers factors bearing minimal etiological, clinical, or therapeutic relevance, and lacks sufficient reproducibility. The 2017 International Endocervical Adenocarcinoma Criteria and Classification (IECC) system was developed by a group of international collaborators to address these limitations. The IECC system separates ECAs into two major groups—those that are human papillomavirus-associated (HPVA) and those that are non-HPV-associated (NHPVA)—based on morphology (linked to etiology) alone, precluding the need for an expensive panel of immunohistochemical markers for most cases. The major types of HPVA ECA include the usual (with villoglandular and micropapillary architectural variants) and mucinous types (not otherwise specified [NOS], intestinal, signet-ring, and invasive stratified mucin-producing carcinoma). Invasive adenocarcinoma NOS is morphologically uninformative, yet considered part of this group when HPV positive. NHPVA ECAs include gastric, clear cell, endometrioid, and mesonephric types. The IECC system is supported by demographic and clinical features (HPVA ECAs develop in younger patients, are smaller, and are diagnosed at an earlier stage), p16/HPV status (almost all HPVA ECAs are p16 and/or HPV positive), prognostic parameters (NHPVA ECAs more often have lymphovascular invasion, lymph node metastases, and are Silva pattern C), and survival data (NHPVA ECAs are associated with worse survival). A move from the morphology-based WHO system to the IECC system will likely provide clinicians with an improved means to diagnose and classify ECAs, and ultimately, to better personalize treatment for these patients.

Constitutional abnormality of nuclear membrane proteins in small cell lung carcinoma Abstract Nuclear membrane proteins reportedly play important roles in maintaining nuclear structures and coordinating cell activities. Studying profiles of nuclear membrane proteins may help us evaluate the biological and/or clinical nature of malignant tumors. Using immunohistochemistry with antibodies for emerin, lamin A/C, lamin B, and LAP2, we examined 105 lung cancer tissues from 33 small cell lung carcinomas (SCLCs) and 72 non-SCLCs (34 adenocarcinomas, 30 squamous cell carcinomas, and 8 large cell carcinomas). Emerin had negative or local/weak positivity in 79% of SCLCs and 1% of non-SCLCs, and lamin A/C had similar positivity in 91% of SCLCs and 3% of non-SCLCs. LAP2's expression was similar between SCLCs and non-SCLCs. RT-PCR analyses for these four nuclear membrane proteins over 7 cell lines showed that mRNA of emerin and lamin A/C were distinctly downregulated in the SCLC cell lines, supporting the immunohistochemical results. In conclusion, we suggest that downregulation of the nuclear membrane proteins emerin and lamin A/C is characteristic of SCLC cells, and this constitutional abnormality of the nuclear membrane may be related to the biological and/or clinical nature of SCLC. In addition, knowing the nuclear protein profile in SCLC cells may contribute to our understanding of nuclear fragility known as the crush artifact in pulmonary biopsy specimens.

Follicular dendritic cells display microvesicle-associated LMP1 in reactive germinal centers of EBV+ classic Hodgkin lymphoma Abstract Expression of the latent membrane protein-1 (LMP1) of Epstein-Barr virus (EBV) was investigated in 153 cases of EBV+ classic Hodgkin lymphoma (cHL); 120 cases were pediatric patients (< 14 years of age) from Iraq, and 33 cases were adult patients from Italy. We describe for the first time the presence of LMP1 protein in EBV-encoded RNA (EBER)-negative follicular dendritic cells (FDCs) of reactive germinal centers (GC) associated with EBV+ cHL. Presence of LMP1+ GCs was independent of geographic region and age of patients. Variable numbers of reactive GCs were present in 22.2% of cases (34 of 153), whereas LMP1 staining of FDCs was present in about a third of cases (10 of 34) with reactive GC. Most cases with LMP1+ GC were mixed-cellularity (MC) subtype, but some nodular sclerosis (NS) was also present. GC cells with LMP1+ FDCs were surrounded by numerous EBV-infected cells which were positive for EBER, LMP1, and CD30. Double immunolocalization analysis revealed that LMP1 was associated with CD63, an exosomal marker, and with CD21. The possibility is discussed that peri-follicular EBV-infected cells release LMP1 protein, perhaps through exosomes, and that the protein is then captured by FDCs and is presented to EBER-negative GC B cells.

Spread through air spaces (STAS) is a predictor of poor outcome in atypical carcinoids of the lung Abstract Spread through air spaces (STAS) have been recently recognized as a prognostic factor for adenocarcinoma and squamous cell carcinoma of the lung. Pulmonary neuroendocrine neoplasms (NENs) include tumors with different morphology and a heterogeneous clinical behavior. Among atypical carcinoids (ACs), new prognostic factors able to refine prognosis are needed. In the present study, a retrospective series of 91 surgically resected ACs was investigated, in parallel with 191 control cases of typical carcinoids (TCs) and of high-grade small- and large-cell neuroendocrine carcinomas, to assess the presence and potential prognostic role of STAS. STAS was defined by the presence of neoplastic nests or single cells in air spaces beyond the tumor edge. Clinicopathological parameters and survival were correlated by univariate and multivariate analyses. STAS was identified in 48% of ACs (44/91) compared to 20.5% of TCs and 71–88% of high-grade large- and small-cell carcinomas in the control group. In the carcinoid group, presence of STAS was significantly correlated with unfavorable parameters, such as high tumor stage, positive nodal status, high Ki-67 index, presence of angioinvasion, and with adverse disease outcome, shorter overall survival, and time to progression. In conclusion, the presence of STAS is an additional relevant adverse prognostic factor in pulmonary AC that currently has the most unpredictable outcome and the most controversial treatment strategy.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com