Virchows Archiv最新文献

Basal cell adenomas (BCAs) are benign epithelial tumors of the salivary gland, characterized by the proliferation of basaloid and luminal cells. In addition, a distinctive spindle cell stroma, that is immunohistochemically-positive for S100, is often observed in BCAs. Based on the ultrastructural findings, the S100-positive stroma was presumed to originate from neoplastic myoepithelial cells. However, immunohistochemical studies do not provide strong evidence supporting a myoepithelial origin, and the true nature of this stroma remains elusive. The aim of this study was to determine whether the S100-positive stroma was neoplastic through a molecular analysis. We selected 2 cases involving BCAs with at least one S100-positive stromal area within the tumor, measuring ≥ 0.2 × 0.2 mm. CTNNB1 I35T mutations were detected in both tumors by Sanger sequencing. Two areas of S100-positive stroma from these two tumors were successfully dissected by manual microdissection using a stereomicroscope without contamination from the surrounding neoplastic bilayered epithelial cells. Because of the small number of dissected stromal cells, the mutation status of these two areas was analyzed using digital PCR, and CTNNB1 I35T mutations were detected in both. In conclusion, this study demonstrated that the S100-positive stroma of BCAs exhibits a neoplastic nature from a molecular perspective. While future studies are needed to confirm whether the S100-positive stroma originates from myoepithelial cells, BCAs morphologically display tricellular differentiation, with neoplastic spindle-shaped stromal cells along with a bilayered neoplastic epithelium.

Amyloidosis is a rare disease that can affect genitourinary organs but the involvement of the prostate has been documented in a limited number of cases. We have reviewed morphologic and immunohistochemical features of prostate biopsies or surgical specimens in which an initial diagnosis of amyloidosis was made. Prostatic amyloidosis was diagnosed in 25 patients, 21 of them were needle biopsies (1.16% of these ones). Amyloid was observed inside vessel walls (25 cases) and the stroma (3). No significant differences in the number of affected biopsy samples between patients with and without cardiac amyloidosis were found. In prostatectomies, amyloid was visualized in all the regions of the prostate, being more abundant in the periphery and the posterolateral tissue. Three patients with abundant amyloid in the prostatectomy did not have cardiac amyloidosis. Immunohistochemically prostatic amyloid was positive for transthyretin and P amyloid (24 cases). A amyloid, kappa, and lambda chains were negative. The genetic analysis revealed transthyretin wild-type amyloidosis. Immunohistochemistry was not conclusive in one case of immunoglobulin light chain amyloidosis. In conclusion, prostate amyloidosis is an infrequent finding characterized by the deposition of amyloid inside small vessel walls, and less often in the stroma. It occurs mainly in the periphery of the gland. Amyloid deposits are often subtle and overlooked but relevant as this may be the first sample in which systemic amyloidosis is diagnosed. Immunohistochemistry can be used to subtype amyloid, although there are limitations when confronted with immunoglobulin light chain amyloidosis. Most cases have corresponded to wild-type transthyretin amyloidosis.

Lipoid pneumonia is a rare entity most often associated with inhalation of foreign material (i.e. "fire-eater's lung"), silicone injection, and severe trauma. We present the case of a 61-year old man who developed acute respiratory distress syndrome following endoscopic retrograde cholangiopancreatography (ERCP) for cholelithiasis. Intensive care supportive therapy included mechanical ventilation, dialysis, and total parenteral nutrition. Unresolved pneumothorax necessitated lobectomy. Histology of the lobectomy specimen demonstrated massive intra-alveolar haemorrhage and numerous alveolar septal macrophages with clear cytoplasmic vacuoles. These findings were diagnostic of interstitial lipoid pneumonia due to intravenous administration of lipid emulsions. The differential diagnosis is also discussed. Although rare, interstitial lipoid pneumonia should be considered in critically ill patients presenting with an interstitial pattern of lung disease after intravenous administration of lipid emulsions.

Pheochromocytoma and paraganglioma (PPGL) are rare tumors that occur in the adrenal medulla and extra-adrenal tissues, respectively. The prognosis and tumor microenvironment (TME) of pseudohypoxic PPGL as a major entity have not been fully described. Based on the clinical database of 65 patients with PPGL, we assessed the morphological features as well as the immunohistochemistry of pseudohypoxia-related proteins (SDHB and CAIX) and TME-related immune cell markers. Furthermore, we compared the relapse-free survival (RFS) rates in localized patients between the pathological subgroups. Among 50 available specimens, 84% and 30% of the cases exhibited at least one morphological adverse feature including vascular/capsular invasion and a Ki-67 index > 3%, respectively. The SDHB and CAIX positivity rates were 81% and 51%. Concerning the immune cell markers, the CD163-positive cell numbers were higher in hypoxia-associated PPGL composed of SDHB-negative or CAIX-positive cases than in non-hypoxia PPGL (median 66 vs. 23/mm²). Concerning prognosis, RFS rates were significantly lower in cases with Ki-67 indices > 3% and SDHB-negativity than in those with Ki-67 indices ≤ 3% and SDHB-positivity (3-year rate: 64% vs. 100%, P < 0.001; 57% vs. 100%, P = 0.03). In contrast, RFS was comparable between CAIX-positive and CAIX-negative PPGL cases. Our analyses suggested that SDHB-deficient PPGL exhibited a higher incidence of relapse. Furthermore, M2 macrophage infiltration in TME might be crucial in pseudohypoxic PPGL pathogenesis.

EWSR1/FUS::TFCP2-rearranged rhabdomyosarcoma (RMS) is a rare tumor with an aggressive clinical course, a predilection for craniofacial bones, spindled and/or epithelioid histomorphology, and positive immunohistochemistry (IHC) for epithelial and myogenic markers, along with variable ALK expression. Herein, we present four additional cases of primary cutaneous TFCP2-rearranged RMS. Notably, one tumor (case 1) displayed a varied pathological spectrum, initially presenting as a low-grade spindle cell neoplasm, but progressed into a high-grade spindle/epithelioid tumor. Another case (case 2) exhibited a predominant high-grade epithelioid/rhabdoid morphology. The third case (case 3) demonstrated a biphasic appearance of spindle and epithelioid cell proliferation, presenting with a low-grade morphology, and the last case (case 4) showed a predominant epithelioid morphology. All cases showed myogenic differentiation associated with keratins and ALK immunoreactivity. Interestingly, the two cases with high-grade and epithelioid morphology demonstrated CD30 immunoexpression. RNAseq or FISH revealed EWSR1 or FUS::TFCP2 gene fusion, and two cases with aggressive evolution showed ALK cluster-amplification as well, a finding that has not been previously reported. Two cases displayed aggressive behavior, with case 1 experiencing local recurrences and undergoing transformation into a high-grade epithelioid tumor, whereas case 2 initially presented as an epithelioid high-grade neoplasm, subsequently developing lymph node metastases and shortly thereafter distant metastases. In contrast, patients 3 and 4 are alive with no evidence of disease. The distinctive morphology and immunoprofile of this neoplasm may pose challenges in the differential diagnosis with cutaneous neoplasms showing keratins, ALK, and CD30 immunoreactivity. Nonetheless, ALK and CD30 overexpression may offer avenues for targeted therapy.

Clinical trials in oncology are important tools to identify and establish new effective drugs for cancer treatment. Since the development of the concept of precision oncology, a huge number of multi-centric biomarker-driven clinical trials have been performed and promoted by either academic institutions or pharmaceutical companies. In this scenario, the role of pathologists is essential in multiple aspects, with new challenges that should be addressed. In this position paper of the European Society of Pathology, the role of pathologists as contributors to the design of the clinical trial, as local collaborators, or as members of central review laboratories is discussed. Moreover, the paper emphasizes the important role of pathologists in guiding methods and criteria of tissue biomarker testing in the biomarker-driven clinical trials. The paper also addresses issues regarding quality control, training, and the possible role of digital pathology.

Pathogenic alterations, namely, fusions and amplifications, of the GLI1 gene have been identified in various mesenchymal tumors, including pericytoma with t(7;12), plexiform fibromyxoma, gastroblastoma, and other malignant mesenchymal neoplasms arising in the soft tissues, as well as in various visceral organs. However, only three cases of GLI1-rearranged renal tumors have been reported to date, comprising two low-grade spindle cell tumors with GLI1::FOXO4 fusion along with one GLI1-rearranged case with an unknown fusion partner. In this study, we analyzed three cases with GLI1::FOXO4 fusion and overlapping morphology. One of the cases was reported previously, but an extended clinical and immunohistochemical information is provided. The studied cases occurred in 2 female and 1 male patients aged 35, 55, and 62 years (mean 51 years). All three tumors affected the renal parenchyma and grew as unencapsulated but well-circumscribed solid masses containing occasional entrapped and dilated renal tubules. The tumor cells were organized in cords, nests, or fascicles, had a round to spindled shape, and exhibited only mild nuclear atypia and minimal mitotic activity. They had a sparse eosinophilic to clear cytoplasm and were embedded in myxocollagenous stroma. Immunohistochemically, all cases expressed GLI1 (albeit with variable intensity) and harbored GLI1::FOXO4 fusion. All three patients were treated solely by complete surgical excision. Case 1 was alive with unknown disease status, case 2 was alive without evidence of disease, and case 3 died of unrelated causes. Our study doubles the number of reported cases with GLI1::FOXO4 fusion. The so far absolute predilection of this fusion for renal tumors, coupled with the absence of reports of other GLI1 fusions in tumors of the kidney, might indicate the potential existence of a distinct renal subtype with morphological features similar to other GLI1-altered tumors. All four reported cases had an uneventful follow-up which, together with their low-grade morphological features, suggests that these tumors might have a favorable prognosis.

Molecular classification of endometrial carcinomas (EC) divides these neoplasms into four distinct subgroups based on their molecular background. Given its clinical significance, genetic examination is becoming integral to the diagnostic process. This study aims to share our experience with the molecular classification of EC using immunohistochemistry (IHC) and next-generation sequencing (NGS). We included all ECs diagnosed at two institutions from 2020 to the present. All cases were prospectively examined by IHC for MMR proteins and p53, followed by NGS using a customized panel covering 18 genes, based on which ECs were classified into four molecular subgroups: POLE mutated, hypermutated (MMR deficient), no specific molecular profile (NSMP), and TP53 mutated. The cohort comprised 270 molecularly classified ECs: 18 (6.6%) POLE mutated, 85 (31.5%) hypermutated, 137 (50.7%) NSMP, and 30 (11.1%) TP53 mutated. Twelve cases (4.4%) were classified as 'multiple classifier' EC. Notably, most of these cases with available follow-up (6/9) behaved aggressively. Within the POLEmut EC group, 3/4 cases had advanced tumors, including one patient who died of the disease. Similarly, in the MMRd/TP53mut group, 3/5 patients with available follow-up had metastatic disease, leading to death of the patient in 1 case. ECs of NSMP showed multiple genetic alterations, with the most common mutations being PTEN (44% within the group of NSMP), followed by PIK3CA (30%), ARID1A (21%), and KRAS (9%). Our findings suggest that combining immunohistochemistry with NGS offers a more reliable classification of ECs, including 'multiple classifier' cases, which, based on our observations, tend to exhibit aggressive behavior. Additionally, our data highlight the complex genetic background of NSMP ECs, which can facilitate further stratification of tumors within this group and potentially help select patients for dedicated clinical trials.

Role of BRCA2 gene mutation in renal tumorigenesis remains largely unclear. There are only two case reports of renal cell carcinoma (RCC) with BRCA2 mutation, both of which showed a high-grade RCC with various architectural patterns including tubulopapillary and solid. The tumor cells were described as having eosinophilic cytoplasm and prominent nucleoli. The current study describes another case of high-grade RCC with somatic BRCA2 mutation with various architectural patterns and cells with eosinophilic cytoplasm and prominent nucleoli. Immunohistochemical staining showed co-expression of PAX8, CAIX, CD10, CK7, CK20, and P504S. This unusual co-expression of the commonly used IHC stains during the workup of RCC could serve as a potential diagnostic pitfall. Although very rare, it is important for pathologists to be aware of this form of RCC due to its aggressive clinical behavior, possibility of a germline mutation, and current therapeutic options for tumors with BRCA2 mutation.