Bleeding after childbirth / miscarriage - practical notes on the examination of biopsy material.

Postpartum haemorrhage is a significant cause of maternal morbidity and mortality worldwide. The pathologist encounters only a limited spectrum of causes leading to postpartum haemorrhage. The most common causes are retained placenta and placental site subinvolution. Both of these lesions can be diagnosed from material obtained by uterine curettage. Morbidly adherent placenta (placenta accreta spectrum) is a less frequent subject of investigation, the diagnosis of which can be reliably established only on the basis of histological examination of uterine specimens after hysterectomy.

Hydatidiform mole.

Hydatidiform mole is the most common form of gestational trophoblastic disease. It is an abnormally formed placental tissue with characteristic changes in karyotype, arising in fertilization disorders. The presence of abundant paternal genetic information plays a key role in the pathogenesis of complete and partial hydatidiform moles. These lesions are characterized by a relatively wide spectrum of morphological changes that may not be fully expressed, especially in the early stages of pregnancy. In addition, some changes can be observed in non-molar gravidities, which, unlike hydatidiform moles, lack any risk of malignant transformation. Although conventional histological examination still plays a key role in the diagnosis, it should be supplemented by other methods that reliably differentiate individual lesions. Accurate diagnosis of molar gravidities is important not only for determining the correct therapeutic approach, but the obtained data may also contribute to further research of these pathological entities.

Spontaneous abortion in the first trimester of pregnancy.

Spontaneous abortions in the first trimester of gravidity represent a clinically significant problem that can affect up to 15% of recognized pregnancies. The causes of early pregnancy loss are very heterogeneous and include genetic, environmental and immunological factors. Although the pathologist's main task is to exclude molar pregnancy, in some cases conventional histological examination can also contribute to the elucidation of the cause of miscarriage and the management of subsequent pregnancies, especially in the case of lesions with a high risk of recurrence that may lead to habitual abortion.

Molecular diagnosis of complete and partial hydatidiform moles.

Complete and partial hydatidiform moles are abnormal products of conception that can be identified by clinical, ultrasonographic, morphologic, histologic, and genetic methods. The diagnosis is usually confirmed only by histological examination. However, accurate diagnosis based on morphological criteria is difficult and some studies have shown that misclassifications are common, even when analysed by highly experienced pathologists. Misdiagnosis may mean that women are either not included in adequate ß-hCG follow-up with the risk that the hydatidiform mole progresses to choriocarcinoma or, conversely, are included in follow-up unnecessarily. A reliable complementary method to pathological interpretation may be genetic analysis of the conceptus to eliminate the diagnostic dilemma by distinguishing non-molar spontaneous abortions from hydatidiform moles and defining the type of hydatidiform mole. The aim of our short paper is to introduce the routine molecular analysis used in our laboratory to a wider range of clinical pathologists.

Pattern-based approach to duodenitis and duodenopathy.

Duodenum is currently the most popular site to obtain samples of intestinal mucosa for recognition of a disorder leading to malabsorption. Although there are significant overlaps between histological findings described in various non-neoplastic diseases of the duodenum, recognition of one of the six basic morphologic patterns, namely coeliac disease-like pattern, active chronic duodenitis, acute GvHD-like pattern, enteritis with predominant eosinophilic infiltration, enteritis with predominant infiltration by macrophages, and non-inflammatory enteropathy, usually allows diagnostic separation, especially if subtle histological details, clinical setting and serological investigation are taken into account.

Pattern-based approach to gastritis and gastropathy.

Histological investigation of non-neoplastic endoscopic biopsies of gastric mucosa is one of the most common tasks most pathologists have to face on daily basis. Although the most common clinical question is still being whether Helicobacter organisms are found, pathologists have to bear in mind the whole spectrum of causes and associated morphological patterns of gastritides and gastropathies, governed by characteristic combinations of various types of inflammatory infiltrate, alterative and reactive changes of epithelial component, vascular response, and variability of stromal composition. The association of histopathologic pattern with supposed etiology can be sometimes proved by direct detection of the cause of morphologic changes in the investigated endoscopic sample.

SARS-CoV-2 placentitis - report of two cases and review of the literature.

Covid-19 disease caused by severe acute respiratory syndrome 2 coronavirus (SARS-CoV-2) continues to be a global public health problem. Since the pandemic outbreak in early 2020, a number of cases have been reported in pregnant women whose infection has led to severe complications including preterm birth, miscarriage, intrauterine growth restriction or intrauterine fetal demise. The results of the current studies suggest that the transplacental transmission of infection from mother to fetus is a rare event and that the complications listed above are more likely due to damage of placental tissue. In this article, we describe two cases of SARS-CoV-2 placentitis with special consideration to the morphology and differential dia-gnosis of this newly defined entity.

SDHC Methylation Pattern in Patients With Carney Triad.

Carney triad is a multitumor syndrome affecting almost exclusively young women in a nonfamilial setting, which manifests by multifocal gastric gastrointestinal stromal tumors, paragangliomas, and pulmonary chondroma. The Carney triad-associated tumors are characterized by a deficiency of the mitochondrial succinate dehydrogenase enzymatic complex. Recently, it has been observed that the deficiency results from epigenetic silencing of the SDHC gene by its promoter hypermethylation. To elucidate anatomic distribution of SDHC promoter methylation in Carney triad patients and thus to shed some light on the possible natural development of this epigenetic change, both neoplastic and available non-neoplastic tissues of 3 patients with Carney triad were tested for hypermethylation at the SDHC promoter site. SDHC promoter hypermethylation was proven in all tumors studied. Lack of SDHC epigenetic silencing in the non-neoplastic lymphoid and duodenal tissue (ie, tissues not involved in the development of Carney triad-associated tumors) together with the finding of SDHC promoter hypermethylation in the non-neoplastic gastric wall favors the hypothesis of postzygotic somatic mosaicism as the biological background of Carney triad; it also offers an explanation of the multifocality of gastrointestinal stromal tumors of the stomach occurring in this scenario as well. However, the precise mechanism responsible for the peculiar organ-specific distribution of Carney triad-associated tumors is still unknown.

Morphologic findings in placenta associated with SARS-CoV-2 infection.

SARS-CoV-2 infection in pregnancy can cause a number of serious complications, including fetal growth restriction or intrauterine fetal death. It appears that transplacental transmission of infection is rare and the arising complications are due to damage of placental parenchyma. The aim of this article is to summarize the results of recent publications dealing with placental changes in COVID-19 disease, with special consideration to the morphology of the newly defined SARS-CoV-2 placentitis.

Placental mesenchymal dysplasia - morphology and differential diagnosis.

Placental mesenchymal dysplasia is a rare placental lesion characterized by placentomegaly, vascular abnormalities and formation of cystic structures in the placental parenchyma. It can be associated with various genetic abnormalities, fetal growth restriction or intrauterine fetal demise. Placental mesenchymal dysplasia needs to be distinguished from its main differential diagnosis, partial hydatidiform mole. The aim of this article is to provide readers with a basic overview of the morphology and differential diagnosis of this pathological entity.

Chronic non-infectious inflammations of the placenta.

In addition to the well-known group of inflammations of infectious etiology, placental inflammations arising on immunological basis are also encountered. The incidence of the latter far exceeds the group of infectious lesions of the placenta caused mainly by microorganisms of the TORCH group. Given the current knowledge of the possible complications of these inflammations, their precise diagnosis becomes more important not only from the clinicopathological point of view, but also because of potential forensic consequences. The aim of this article is to provide readers with a basic overview of the morphology, classification, presumed pathogenesis and clinical aspects of these entities.

Non-immune hydrops fetalis associated with two umbilical cord hemangiomas and vascular malformation of the transverse mesocolon. Case report.

Umbilical cord hemangioma is a rare tumor that can be associated with significant fetal and perinatal complications. Although usually described as a single anomaly, sometimes these tumors are reported in association with other vascular lesions. We report an unusual case of simultaneous occurrence of two umbilical cord hemangiomas and vascular malformation of the transverse mesocolon in a stillborn fetus with hydrops. To our knowledge, this is the first report of two simultaneously occurring umbilical cord hemangiomas. Moreover, presence of associated vascular malformation of transverse mesocolon could support the hypothesis of underlying predisposition to the development of vascular tumors.

Colorectal Adenocarcinomas Harboring ALK Fusion Genes: A Clinicopathologic and Molecular Genetic Study of 12 Cases and Review of the Literature.

This study determined the frequency and the clinicopathologic and genetic features of colorectal carcinomas driven by oncogenic fusions of the anaplastic lymphoma kinase gene (ALK). Of the 8150 screened tumors, 12 (0.15%) were immunohistochemically ALK-positive with D5F3 antibody. These cancers harbored CAD-ALK (n=1), DIAPH2-ALK (n=2), EML4-ALK (n=2), LOC101929227-ALK (n=1), SLMAP-ALK (n=1), SPTBN1-ALK (n=4), and STRN-ALK (n=1) fusions, as detected by an RNA-based next-generation sequencing assay. ALK fusion carcinomas were diagnosed mostly in older patients with a 9:3 female predominance (median age: 72 y). All tumors, except a rectal one, occurred in the right colon. Most tumors were stage T3 (n=7) or T4 (n=3). Local lymph node and distant metastases were seen at presentation in 9 and 2 patients. These tumors showed moderate (n=6) or poor (n=3) glandular differentiation, solid medullary growth pattern (n=2), and pure mucinous morphology (n=1). DNA mismatch repair-deficient phenotype was identified in 10 cases. Tumor-infiltrating lymphocytes were prominent in 9 carcinomas. In 4 carcinomas, tumor cells showed strong, focal (n=3), or diffuse programmed death-ligand 1 immunoreactivity. CDX2 expression and loss of CK20 and MUC2 expression were frequent. CK7 was expressed in 5 tumors. Four patients died of disease within 3 years, and 7 were alive with follow-up ranging from 1 to 8 years. No mutations in BRAF, RAS, and in genes encoding components of PI3K-AKT/MTOR pathway were identified. However, 1 tumor had a loss-of-function PTEN mutation. Aberration of p53 signaling, TP53 mutations, and/or nuclear accumulation of p53 protein was seen in 9 cases. ALK fusion colorectal carcinomas are a distinct and rare subtype of colorectal cancers displaying some features of mismatch repair-deficient tumors.

Targeted next generation sequencing of MLH1-deficient, MLH1 promoter hypermethylated, and BRAF/RAS-wild-type colorectal adenocarcinomas is effective in detecting tumors with actionable oncogenic gene fusions.

Oncogenic gene fusions represent attractive targets for therapy of cancer. However, the frequency of actionable genomic rearrangements in colorectal cancer (CRC) is very low, and universal screening for these alterations seems to be impractical and costly. To address this problem, several large scale studies retrospectivelly showed that CRC with gene fusions are highly enriched in groups of tumors defined by MLH1 DNA mismatch repair protein deficiency (MLH1d), and hypermethylation of MLH1 promoter (MLH1ph), and/or the presence of microsatellite instability, and BRAF/KRAS wild-type status (BRAFwt/KRASwt). In this study, we used targeted next generation sequencing (NGS) to explore the occurence of potentially therapeutically targetable gene fusions in an unselected series of BRAFwt/KRASwt CRC cases that displayed MLH1d/MLH1ph. From the initially identified group of 173 MLH1d CRC cases, 141 cases (81.5%) displayed MLH1ph. BRAFwt/RASwt genotype was confirmed in 23 of 141 (~16%) of MLH1d/MLH1ph cases. Targeted NGS of these 23 cases identified oncogenic gene fusions in nine patients (39.1%; CI95: 20.5%-61.2%). Detected fusions involved NTRK (four cases), ALK (two cases), and BRAF genes (three cases). As a secondary outcome of NGS testing, we identified PIK3K-AKT-mTOR pathway alterations in two CRC cases, which displayed PIK3CA mutation. Altogether, 11 of 23 (~48%) MLH1d/MLH1ph/BRAFwt/RASwt tumors showed genetic alterations that could induce resistance to anti-EGFR therapy. Our study confirms that targeted NGS of MLH1d/MLH1ph and BRAFwt/RASwt CRCs could be a cost-effective strategy in detecting patients with potentially druggable oncogenic kinase fusions.

Morphological features useful in the differential diagnosis between undifferentiated carcinoma and gastrointestinal stromal tumor.

Undifferentiated (sarcomatoid) carcinomas may closely mimic gastrointestinal stromal tumors (GISTs) due to possible histological and immunohistochemical overlap between these two entities. To avoid unnecessary employment of a wide spectrum of immunohistochemical stainings and molecular genetics and thus decrease costs, finding simple morphological features to target further investigation of such neoplasms of the gastrointestinal tract would be helpful. Five cases classified as undifferentiated (sarcomatoid) carcinomas with a definite proof of the diagnosis, i. e. the presence of a differentiated carcinomatous component, were retrieved from archives of several institutions. For comparison, 84 cases of GIST mutated in KIT or PDGFRA genes served as the control group. Hematoxylin and eosin stained slides were evaluated for the presence of patterns which might discriminate between sarcomatoid carcinoma and GIST. Lymphatic invasion and entrapment of fat tissue strongly favor the diagnosis of undifferentiated carcinoma, as it was found in all or almost all cases of undifferentiated carcinoma, but in no GIST. Alternation of low- and high- grade areas, formation of angiosarcomatous-like spaces, and the presence of yolk sac-like areas were also detected in all cases of undifferentiated carcinoma, but only in 1.2%, 2.4% and 7.2% of the GISTs, respectively. Furthermore, DOG1 was negative in all cases of undifferentiated carcinoma. According to this study, the presence of the histological findings listed above should prompt extensive tumor sampling in order to find a differentiated carcinomatous component. However, due to the small number of cases of undifferentiated carcinoma available for the study, a larger multi-institutional study is warranted.

Comments on the 5th edition of WHO classification of digestive system tumors - Part 1. Gastrointestinal tract.

The new 2019 WHO classification of digestive system tumors reflects some important advancements in our understanding of etiopathogenesis and molecular background of selected neoplastic diseases of the gastrointestinal tract, offers more integrated review of non-epithelial neoplasms and updates the spectrum of genetic tumor syndromes of the digestive system. Recently recognized conditions, such as gastroblastoma and “gastric adenocarcinoma and proximal poly-posis of the stomach” are described, including molecular alterations associated with these entities. On the other hand, the new interpretation of some topics, mainly grading of serrated lesions or ICD-O coding of adenomas and dysplasia, is rather controversial. Last but not least, the definition of pTis in the large intestine according to WHO conflicts its definition according to AJCC/UICC TNM classification, 8th edition, issued in 2017.

Immunohistochemistry and molecular genetics in the differential diagnostics of mesenchymal lesions of gastrointestinal tract.

Although, in routine practice, the differential diagnostics of mesenchymal tumors of the gastrointestinal tract is still focused mainly on the correct diagnosis of gastrointestinal stromal tumor and its further therapeutic management based on predictive diagnostics, recent progress in the development of endoscopic techniques has led to increased detection of other mesenchymal lesions, which were previously commonly neglected due to their small size or absence of symptoms requiring surgical exploration. Diagnosis of some of these lesions may be reached based on their histologic pattern alone, while others may be recognized with the use of tissue specific antibodies related to the probable lineage of differentiation of the neoplastic cells. Finally, a subset of tumors, commonly with uncertain lineage of differentiation, is defined by pathognomonic genetic alterations of neoplastic cells. Recognition of such alterations, based either on methods of molecular genetics or immunohistochemical detection of an altered protein product, enables a precise diagnosis in a growing number of these cases. However, regarding the fact that most of these alterations are not unique to a single tumor type, but are often shared by more neoplastic entities, the diagnosis must still be based on a complex diagnostic attitude, reflecting histological, immunohistochemical and molecular genetic features of the investigated tumor.