Advances In Anatomic Pathology最新文献

Prostatic ductal adenocarcinoma (PDA) is a rare histological subtype of prostate carcinoma, first described by Melicow and Pachter in 1967 as "endometrial carcinoma of the uterus masculinus." The case for defining PDA as a separate entity rests on its distinctive morphology, aggressive clinical course, and, at times, unusual metastatic patterns. Yet, the frequent coexistence of PDA with acinar adenocarcinoma, together with molecular evidence pointing to a shared clonal origin-such as overlapping ERG rearrangements and other genomic alterations-suggests that PDA may instead represent a histologic variant of acinar prostate cancer. In this review, we explore what is currently known about PDA, tracing its epidemiology, clinical presentation, histopathology, molecular underpinnings, prognosis, and therapeutic challenges.

Over the last 2 to 3 decades, we have seen incremental movement from the "Rule of 10s" for pheochromocytomas, particularly those regarding tumor bilaterality, malignancy, and patterns of inheritance. The biology and prevalence of these tumors have not changed, but there has been a great deal of progress in terms of our understanding of tumor genetics, variable modes of acquiring of both pheochromocytomas and paragangliomas (PPGL), and our approach to clinical management of these unpredictable neoplasias. Although these non-epithelial neuroendocrine tumors are rare, they are clinically significant due to their hormonal activity, association with hereditary syndromes, and biological potential. Their detection has increased in recent decades with improved biochemical testing and advanced imaging modalities, yet predicting clinical behavior continues to be a major challenge. Histologically, PPGL typically shows classic neuroendocrine architecture but may display morphologic diversity, occasionally mimicking other adrenal or paraganglionic tumors. Immunohistochemistry remains essential for diagnostic confirmation and as a surrogate for genetic alterations, offering valuable genotype-phenotype correlations. With increasing knowledge of tumor genetics, additional emphasis has been placed on histology-based risk-stratification for these lesions, particularly those prone to metastasis or multifocality, and the 2022 WHO endorses no individual risk-stratification system, as none seems to be of definitive merit over another. Instead, it promotes a comprehensive approach integrating morphologic, molecular, and clinical factors. Approximately 40% of PPGL harbor germline mutations, whereas somatic alterations account for additional subsets. Mutations in SDHx, VHL, RET, NF1, and other susceptibility genes define molecular clusters with distinct signaling pathways and clinical behavior, underscoring the importance of multidisciplinary, lifelong management.

Tumors resembling conventional, somatic-type malignancies arise infrequently (<10%) in association with malignant, postpubertal-type testicular germ cell tumors, mainly at the metastatic sites (less frequently at primary), and often after treatment. Historically, the pathogenetic framework for these tumors, indeed their current classification and nomenclature under the WHO 5th Edition, contemplated their arising from (malignant) postpubertal-type teratomatous components undergoing oncogenic changes homologous to conventional somatic malignancies of the relevant tissue lineages. Recent scholarship questions the specificity of their provenance to postpubertal-type teratoma, with strong evidence relating them also to postpubertal-type yolk sac tumor as well. In tandem, molecular studies support a close relationship to their associated postpubertal-type testicular germ cell tumor rather than identifying any of the known molecular drivers of the somatic-type malignancies they resemble. The histologic patterns observed include sarcoma-like tumors, carcinoma-like tumors, primitive-appearing embryonic-type neuroectodermal tumor, nephroblastoma-like tumors, neuroglial-like neoplasms, leukemia-like malignancies, and combined forms incorporating 2 or more of the foregoing. Although greater experience will be required to validate the changing conceptualization of their origin, from a management standpoint when seen at metastatic sites these somatic tumors-like neoplasms may be poorly responsive to cisplatin-based chemotherapy regimens whereas when seen in the primary site they behave favorably. Surgical resection, if feasible, may provide the best chance for sure at metastatic sites.

Hereditary renal cancer syndromes account for approximately 5% to 8% of all renal cell carcinomas (RCCs) and are caused by germline alterations, mainly in tumor suppressor genes. Advances in molecular testing have led to the identification of new hereditary syndromes and expanded our understanding of the genetic landscape of renal neoplasia. This review summarizes both well-established and recently described hereditary renal cancer syndromes, highlighting their clinical, pathologic, and molecular features. Emphases are placed on genotype-phenotype correlations and the relationship between germline and somatic alterations in tumors. Understanding these correlations is critical for diagnosis, risk assessment, surveillance, and management and underscores the importance of a high index of clinical suspicion for early detection to optimize patient outcomes.

Micropapillary urothelial carcinoma is a well-recognized subtype of urothelial carcinoma that is associated with an aggressive clinical course. Its recognition is critical for optimal management; however, strict diagnostic criteria are not always applied, resulting in interobserver variability in recognition and reporting. The genomic profiles of micropapillary urothelial carcinoma overlap with those of classic urothelial carcinoma, but show higher rates of alterations in the cell cycle regulators TP53 and RB1 and the receptor tyrosine kinase ERBB2. Recently approved therapeutic agents targeting cell surface markers such as HER2 and NECTIN4 provide promising novel and potentially more effective therapies for micropapillary urothelial carcinoma.

Mesothelial lesions of the testis and paratestis encompass a spectrum of reactive, benign, and malignant processes that may overlap morphologically with one another and with other intra- and extratesticular neoplasms, including Müllerian-type tumors as well as Sertoli cell and yolk sac tumors. Providing an accurate diagnosis has important consequences for patient care, dictating significant changes in treatment modality. While immunohistochemical stains specific to mesothelial cells are helpful in differentiating mesothelial from nonmesothelial lesions, the distinction between benign and malignant processes has only recently been facilitated by molecular testing and immunohistochemical staining for BAP1 and MTAP. Although benign mesothelial lesions are usually easily classified with routine histopathologic evaluation, certain cases of florid reactive mesothelial hyperplasia and infarcted adenomatoid tumors may pose a diagnostic challenge. Well-differentiated papillary mesothelial tumors are bland papillary tumors with indolent behavior and TRAF7 or CDC42 mutations. Architecturally more complex forms within this spectrum exist and have been labelled as having "uncertain malignant potential." Malignant mesothelioma of the tunica vaginalis is an uncommon but aggressive tumor that may show loss of BAP1 or MTAP immunostaining, supporting a distinct molecular pathogenesis. This review summarizes the clinicopathologic, immunohistochemically, and molecular features of mesothelial lesions of the paratestis, emphasizing their morphologic overlap, diagnostic pitfalls, and evolving framework for classification.

Since the initial recognition of unique renal cell carcinomas (RCC) with the ASPCR1::TFE3 gene fusion, the category of MiT-family RCC has evolved to include TFE3-rearranged RCC, TFEB-rearranged RCC, and TFEB-amplified RCC, 3 entities with significant intracategory and intercategory variation in morphology and clinical behavior. Given their ability to mimic one another as well as more common RCC subtypes, we present a review here that summarizes relevant morphologic, immunohistochemical, and molecular findings as well as a practical approach to diagnosis. Accurate diagnosis of TFE-altered RCCs is critical to provide patients and treating clinicians with pertinent prognostic information and inform treatment decisions in the event of advanced disease.

Intraepithelial penile lesions encompass non-neoplastic and preneoplastic lesions. Non-neoplastic lesions comprise condyloma acuminatum, including giant condyloma acuminatum, also known as Buschke-Löwenstein tumor. It is usually the low-risk human papillomavirus (HPV) types 6 and 11 that are most prevalent in penile condylomas. However, high-risk HPV types can be detected along with low-risk types in a subset of patients. Penile intraepithelial neoplasia (PeIN) is a preneoplastic lesion that is either HPV-associated or HPV-independent. HPV-associated PeIN represents the majority of PeIN in regions where the incidence of penile cancer is lower, as in North America and Europe. HPV-associated PeIN is subdivided into basaloid, warty, and mixed subtypes and, less commonly, into pagetoid, clear-cell, and spindle-cell subtypes based on morphologic characteristics. HPV-associated PeIN is positive for immunohistochemical stain p16 and high-risk HPV in situ hybridization (ISH). Immunohistochemical stain p53 usually exhibits a wild-type staining pattern. HPV-independent PeIN/differentiated PeIN is more frequent in countries with a high incidence of penile cancer and an uncircumcised population. It is usually associated with predisposing factors like lichen sclerosus and chronic inflammatory conditions such as lichen planus, lichen simplex chronicus, and phimosis. The degree of atypia in differentiated PeIN ranges from subtle to full-thickness proliferation of markedly atypical pleomorphic cells. Many cases are associated with TP53 mutations and other alterations involving PIK3CA and HRAS. Recently, it has been proposed to further subclassify differentiated PeIN. Extramammary Paget disease (EMPD) can involve the skin of the penis and glans mucosa in elderly men. It is either primary or secondary, and when secondary, it can be associated with prostate or urothelial carcinoma. Lastly, rare case reports of primary penile melanoma in situ have been reported. The lesions can involve either the skin or mucosa, with the glans penis being the most commonly reported site.

Penile squamous cell carcinomas (pSCC) are broadly divided into two subgroups based on their etiopathogenesis: Human Papillomavirus (HPV)-associated and HPV-independent. HPV-associated pSCC is driven by high-risk HPV and commonly overexpresses p16 by immunohistochemistry (IHC), making it a widely used surrogate for HPV presence. HPV-associated pSCC encompasses multiple histologic subtypes, including basaloid, warty, mixed (warty-basaloid), clear cell, lymphoepithelioma-like, and medullary carcinomas. Although most of these have a distinct morphology, a "block" or "diffuse" staining pattern of p16 IHC is recommended for categorically classifying them as HPV-associated pSCC. Molecular diagnostics (e.g., HPV DNA or RNA assays) are rarely employed for the classification of pSCC. The prognostic relevance of HPV status and p16 overexpression remains under investigation, but preliminary findings suggest that HPV-associated / p16-positive tumors may have a more favorable prognosis, with better survival outcomes, and may also dictate the choice of therapy in advanced cases. Larger multicentric datasets from regions of higher incidence, harmonized criteria for p16 IHC interpretation, and standardized HPV detection methods are needed to further understand the utility of these biomarkers in pSCC. Finally, the relevance and impact of HPV vaccination on HPV-associated pSCC are not well documented, largely because male vaccination is not yet accepted globally.

Pulmonary large cell neuroendocrine carcinoma (LCNEC) represents a controversial entity that has been associated with difficulties for diagnosis. The sources for these difficulties are multiple, including lack of stringent morphologic criteria, variable immunohistochemical profile, and variable molecular profile that share overlap with other tumors of the lung. There appears to exist a spectrum of lesions in the lung that have the potential to overlap with LCNEC, compounding the difficulties inherent in making a diagnosis for what is essentially a rare lesion that most general pathologists have limited experience with. Moreover, the broad definition of LCNEC by the World Health Organization (WHO) has the potential for classifying tumors that may not clearly belong in this group under this category. Herein we will discuss the criteria for light microscopic, immunohistochemical, and molecular diagnostic features of LCNEC along with a discussion of some of the problems encountered in the interpretation of these tumors. The differential diagnosis is also discussed, including tumors that may show similar neuroendocrine-like morphology.