Virchows Archiv最新文献

Encapsulated thyroid gland lesions, defined by complete or partial confinement within a fibrous capsule, are common findings in endocrine pathology but frequently pose diagnostic challenges. The primary difficulty lies in distinguishing benign, low-risk, and malignant neoplasms, particularly within the spectrum of follicular-patterned tumors. Accurate classification can be hindered by pitfalls such as differentiating true tumor capsule from peritumoral fibrosis, identifying capsular or vascular invasion versus reactive changes from preoperative fine-needle aspiration, and accounting for histologic and cytologic heterogeneity. In this review, we discuss the definition of true capsule and vascular invasion and how to contrast from mimics. We describe the wide spectrum of both follicular and non-follicular lesions encountered in the thyroid, and we propose a systematic diagnostic approach to encapsulated thyroid neoplasms, integrating ultrasonographic, cytologic, histologic, immunohistochemical, and molecular data, in an effort to optimize diagnostic accuracy and guide appropriate clinical management.

The diagnosis of a non-metastatic parathyroid carcinoma requires the demonstration of invasive growth that defines malignancy. These include angioinvasion or vascular invasion (i.e., tumor penetrating the vessel wall and associated with thrombus or intravascular tumor cells intermixed with thrombus), lymphatic invasion, perineural (intraneural) invasion, and/or direct invasion into adjacent anatomical structures. However, the distinction of a pT1 disease (8th edition of UICC TNM staging system) which represents a localized disease (tumor confined to the parathyroid gland or showing minimal extra-parathyroidal soft tissue invasion without direct invasion into adjacent structures) often requires meticulous microscopic examination that couples multiple levels and biomarker studies. Although the diagnostic criteria of malignancy are clearly defined, the identification of harbingers of invasive growth and distinguishing them from their mimics can pose diagnostic challenges. Several artifacts and manipulations can simulate malignancy. For example, a prior biopsy, PTH washout, ethanol injection, or any form of surgical manipulation may result in fibrosis, crush (mechanical) artifacts, or tissue distortion, which can obscure histological details and mimic invasion. Peliosis-the presence of extravasated erythrocytes without an endothelial lining-may simulate vascular invasion. Other common mimics include mechanically displaced intravascular tumor cells unassociated with thrombus, which can occur at the time of specimen handling. Extension of the tumor into the adjacent irregular connective tissue or pseudo-capsule can be mistaken for invasive growth. Similarly, an intrathyroidal location of the parathyroid gland adds another layer of complexity. In such cases, the boundary between the parathyroid tissue and surrounding thyroid parenchyma may not be clearly discernible, making it difficult to determine whether there is genuine invasive growth into thyroid (pT2 disease, 8th edition of UICC TNM system) or simply anatomical proximity. In addition, parathyromatosis and contour irregularities associated with long-standing secondary or tertiary hyperparathyroidism are other challenging manifestations. Atypical parathyroid tumors (WHO 2022) should also be clearly delineated using appropriate criteria. In summary, pathologists must be aware of the potential pitfalls that may lead to overdiagnosis of parathyroid carcinoma. A consolidated diagnostic workup, which combines multiple levels and biomarkers, is necessary to ensure diagnostic accuracy in all parathyroid tumors. This review provides practical insights on these diagnostic difficulties, illustrating common artifacts and mimics. We also discuss the relevant clinical, histological, immunohistochemical, and molecular features associated with parathyroid carcinoma, with the goal of enhancing diagnostic accuracy.

Mixed neuroendocrine and non-neuroendocrine neoplasms (MiNEN) represent a heterogeneous group of bidirectionally differentiated epithelial malignancies that are, in most cases, highly aggressive. They are defined by the presence of morphologically distinct, yet clonally related, neuroendocrine and non-neuroendocrine components, each comprising at least 30% of the tumor mass according to current guidelines. Tumors that fall within the differential diagnostic spectrum of MiNEN include amphicrine carcinomas-characterized by the co-expression of neuroendocrine and non-neuroendocrine features within the same tumor cell-as well as conventional carcinomas that lack neuroendocrine morphology but exhibit immunohistochemical expression of neuroendocrine markers. However, these entities do not fulfill the current diagnostic criteria for MiNEN. In this review, we aim to outline the current diagnostic framework for MiNEN and examine the conceptual and classification boundaries of amphicrine carcinomas and conventional carcinomas with aberrant neuroendocrine marker expression in relation to what is presently defined as a MiNEN. In addition, we highlight key unresolved questions that should be addressed in future guidelines to streamline the diagnostic process and improve consistency. Finally, we provide an outlook on emerging technologies and future perspectives that may further refine the classification and clinical management of these complex neoplasms.

Patients with inborn errors of immunity/primary immunodeficiency (IEI/PID) frequently present with reactive lymphadenopathy which is biopsied to rule out lymphoma or infection. We asked whether reactive lymphoid tissue from an international cohort of 35 patients with IEI/PID contains diagnostic clues to the underlying immune dysfunction as compared to 13 control pediatric patients. To this end, we investigated abnormalities of B-cell follicle architecture and Immunoglobulin G (IgG) + class-switched (CS) versus IgM/IgD + non-IgG-CS Ig production. Abnormalities of B-cell follicles including absent or naked germinal centers (GCs) and/or increased T follicular helper(TFH) cells within GCs were seen in 45.7% (16/35) of IEI/PIDs and 15.4% (2/13) of controls (X² = 3.7520, p = 0.054). There was a statistically significant association of B-cell follicle abnormalities with infectious (X² = 5.148, p = 0.023) but not autoimmune history. Abnormal IgM + , IgD + , IgG + and/or CD138 + plasmablast/plasma cell (PB/PC) density was observed in 79.4% of IEI/PIDs (27/34) as compared to 7.7% of controls (1/13, X² = 20.085, p < 0.001). Isolated deficiency of IgG CS PB/PC was present in 42% (12/33) of IEI/PID biopsies and in no control patients, 0% (0/13, X² = 6.396, p = 0.011). There was a strong and highly statistically significant positive correlation between IgG + PB/PC density and serum IgG (Kendall's tau-b 0.567, asymptotic standard error 0.129, approximate significance < 0.001). There was also a statistically significant association of PB/PC abnormalities with infectious (X² = 12.024, p < 0.001) but not autoimmune history. Assessment of B-cell follicle architecture and Ig production may play a role in identifying patients with unexplained reactive lymphadenopathy who would benefit from immunologic evaluation.

Adamantinoma-like Ewing sarcoma (ALES) is a rare malignant neoplasm currently classified as a subtype of Ewing sarcoma (ES) and is similarly molecularly defined by a FET-ETS translocation. However, ALES demonstrates some morphologic and immunohistochemical features distinct from conventional ES. In this case report, we present the clinico-pathological features of a case of ALES in the nasal septum of a 75-year-old lady, with a hitherto unreported NRAS Q61R mutation. Further studies are required to investigate the prevalence and clinical significance of the NRAS Q61R mutation in ALES.

RREB1::MRTFB fusion-positive extra-glossal mesenchymal neoplasm is a recently recognized tumor so far mostly described in the head and neck area and in the mediastinum. At least some of these neoplasms are potentially related to ectomesenchymal chondromyxoid tumor of the tongue since they share an identical gene fusion and overlapping morphological features in some cases. Herein we describe for the first time two cases with RREB1::MRTFB fusion located in the skin and subcutis. The cases occurred in 36-year-old male with a cutaneous mass on the nose and in 65-year-old woman with a large subcutaneous mass involving the lower leg. Histopathologically, both cases consisted of bland ovoid cells in a myxoid stroma. Immunohistochemically, one of the two cases showed diffuse S100 positivity. RREB1::MRTFB fusion was confirmed in both cases. In summary, the two reported cases expand the anatomical spectrum and improve our understanding of this rare emerging entity.

SMARCA4, encoding the BRG1 protein, is a crucial component of the SWI/SNF chromatin remodeling complex, essential for regulating gene expression and maintaining genomic integrity; our knowledge regarding the role of these genes continues to evolve. Deficiency or loss of SMARCA4 expression has been implicated in the development and progression of various gynecological neoplasms, notably small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), SMARCA4-deficient uterine sarcoma, and some subtypes of endometrial carcinoma such as undifferentiated or dedifferentiated carcinoma. Given its central role in oncogenesis, targeting SMARCA4-deficient tumors has become an area of active research, with potential therapeutic strategies above all in these aggressive gynecological tumor subtypes. This review summarizes current knowledge of the role of SMARCA4 deficiency in gynecological cancers, discussing the morphological and immunophenotypic characteristics of the different entities, emphasizing clinical implications and potential targeted therapies. Further understanding of its structure, function, and therapeutic vulnerabilities is crucial for improving patient outcomes.

HER2 overexpression and amplification occur in a subset of endometrial serous carcinomas (ESC) and carcinosarcomas, but HER2 testing remains unsettled due to the lack of tumor-specific guidelines. We retrospectively evaluated 113 tumors with serous morphology (95 ESC, 4 mixed carcinomas, 13 carcinosarcomas) diagnosed between 2001 and 2022 at two tertiary centers. HER2 immunohistochemistry was assessed using four scoring systems: ASCO/CAP 2007 breast, ASCO/CAP 2023 breast, ASCO/CAP/ASCP 2016 gastric, and an ESC-specific algorithm. All equivocal and discordant cases underwent in situ hybridization (ISH). HER2 positivity ranged from 15% with the 2007 breast and ESC-specific systems to 20% with the 2023 breast and 24% with the gastric criteria, and it was significantly associated with patient age > 70 years (p = 0.016). Concordance was excellent between the 2007 breast and ESC-specific systems (K = 0.98), good between the 2023 breast and 2007/ESC systems (K = 0.71-0.73), and excellent between the 2023 breast and gastric criteria (K = 0.95). Eight discordant tumors were resolved by ISH, confirming ERBB2 amplification in five. Intratumoral heterogeneity was observed in 13 cases (12%), including one carcinosarcoma with focal gene amplification. The prevalence of HER2-low tumors varied markedly, from 16 (14%) with gastric criteria to 26 (23%) with ESC-specific scoring. These findings demonstrate that the choice of scoring system substantially impacts HER2 classification in ESC. While 2007 breast and ESC-specific criteria remain the only ones validated for trastuzumab, gastric criteria are required for trastuzumab-deruxtecan eligibility. Standardized, therapy-specific algorithms integrating IHC and ISH are essential to optimize patient selection, including candidates with HER2-low tumors.