American Journal of Surgical Pathology最新文献

Staging of renal pelvic urothelial carcinoma can be challenging due to anatomic variation at the renal pelvis compared with ureter and bladder and calls into question the prognostic accuracy of the current TNM staging. In this study, we determined staging and cancer-specific survival (CSS) in 141 patients undergoing nephroureterectomy for renal pelvic urothelial carcinoma (pTa=50, pT1=29, pT2=10, pT3=36, and pT4=16). Under current staging criteria, we found no significant difference in CSS between adjacent staging categories step-wise across pTa, pT1, pT2, and pT3 tumors. When pT3 tumors were subcategorized into renal medulla, peripelvic adipose, or renal cortex invasion with or without peripelvic adipose invasion, we found that cortical invasion was associated with significantly worse CSS compared with medulla or peripelvic adipose invasion only. We next revised staging criteria such that pT1 correlated with invasion of lamina or muscularis propria (n=37), T2 with invasion of medulla or peripelvic adipose only (n=26), and pT3 with cortical invasion (n=12). Under the new criteria, better separation of survival curves was achieved; however, pT1 and pT2 remained statistically insignificant. When further redefining pT3 as invasive of cortex only (n=12) and combining medulla with lamina and muscularis propria invasion as a lower stage (pT1, n=63), there was further improvement in the prognostic stratification. Therefore, our data show that consideration of revised and simplified T staging criteria at the renal pelvis is warranted, wherein invasion of any anatomic structure up to the cortex shows a similar prognosis (combined pT1 category) and invasion of cortex showing significantly worse prognosis (pT3).

While the skin is a common target organ for sarcoidosis, cutaneous granulomatous vasculitis is rare among patients with sarcoidosis. Due to the lack of detailed studies on cutaneous sarcoid vasculitis, both dermatologists and pathologists remain unfamiliar with this rare but important vasculitic disorder. We clinicopathologically evaluated eight cases with biopsy-proven cutaneous vasculitis and cutaneous sarcoidosis and analyzed morphologic changes in the process of vasculitis for both small vessels and muscular vessels in detail. The various skin lesions ranged from papulonodular erythema, annular erythema, maculopapular erythema, livedo reticularis-like eruptions, erythema nodosum-like lesions, subcutaneous nodules to ulcerative lesions. The extremities were the most frequently affected sites. Bilateral hilar lymphadenopathy with pulmonary sarcoidosis was the most common extracutaneous comorbidity. Skin-limited sarcoidosis was identified in 3 cases. All cases demonstrated a common histopathologic feature with sarcoid granulomas impinging on the target vessels with resultant vessel destruction. Perivascular infiltration of sarcoid granulomas resulted in compression and destruction of small vessels. In muscular arteries and veins, sarcoid granulomas closely attached to the muscular vessel wall, infiltrated the muscular layers and either occupied or penetrated the vessel walls, eventually invading the vascular lumen and replacing the entire muscular layers. The intimal infiltration of sarcoid granulomas resulted in a marked luminal narrowing. The scarcity of reports on cutaneous sarcoid vasculitis may be due to the overlooking or misinterpretation of vascular destruction caused by sarcoid granuloma infiltration as a feature of sarcoid granuloma masses.

Intraoperative frozen section (FS) examination of oncologic surgical specimens is frequently performed to ensure complete surgical resection. Data on the gross evaluation of surgical margins are limited. We recently published a study suggesting the use of a macroscopic 2.0 cm tumor-margin cutoff during intraoperative evaluation to decrease the number of unnecessary FS. This study aimed to validate the safety and the clinical impacts of implementing a 2.0 cm tumor-margin threshold for FS diagnosis in evaluating surgical margins during oncologic lung surgery. This retrospective analysis included patients who underwent lung resection for primary or metastatic neoplasms between 2018 and 2022 at the Institut Universitaire de Cardiologie et de Pneumologie de Québec, following the implementation of this practice. Clinicopathological data were retrieved from the medical files. Univariate and multivariate analyses were used to identify the variables associated with positive margins. This study included 1575 tumors in 1299 patients. FS evaluations were performed in 24.4% of patients. No positive margins were observed when the tumor-margin distance was >2.0 cm. The incidence rate of positive margins was 2.95%, with parenchymal margins being the most affected. Multivariate analysis identified the tumor-margin distance as a significant predictor of positive margin status. This practice led to a 79.9% reduction in FS evaluations without compromising the margin assessment accuracy or patient safety. A 2.0 cm tumor-margin distance threshold for intraoperative FS evaluation in oncologic lung surgery is safe and effective in reducing unnecessary FS evaluations while maintaining accurate margin assessments.

Squamous cell carcinoma of the vulva (vSCC) is currently categorized either as human papillomavirus (HPV) associated or independent. Immunohistochemical stains, p16 INK4a (p16) and p53 are helpful biomarkers to support the designation of vSCC into 1 of the 3 tumor pathways: (1) HPV-associated, (2) HPV-independent, TP53 mutant, or (3) HPV-independent, TP53 wild type. Recently, a framework of p53 expression patterns in vSCC was proposed. In this international and multi-institutional study, we evaluated the interrater agreement for p53 and p16 and tumor pathway classification in a cohort of 50 invasive vSCC across a variety of practice settings (private practice, academic medicine) and levels of expertise (trainees, gynecologic pathologists, dermatopathologists, private practice pathologists). Our study shows that the overall interrater agreement for the interpretation of p16 in vSCC is strong to near perfect, while the agreement for p53 and tumor pathway assignment is overall moderate. Interrater agreement for p53 and tumor pathway is higher (strong) in the academic practice setting. Pathologists without gynecologic subspecialty expertise benefited the most from a brief educational module, which fostered a better understanding and improved comfort level with the p16/p53 stain interpretation and tumor pathway designation in the diagnosis of vSCC. Some interpretative challenges remain, particularly in regard to select p53 patterns and high-risk HPV-in situ hybridization utilization, warranting additional research.

Fumarate hydratase tumor predisposition syndrome (FHTPS) is caused by germline fumarate hydratase (FH) pathogenic variants (PVs). Most women with FHTPS develop FH-deficient (FHD) uterine leiomyomas (ULs), which arise 10 to 15 years earlier than aggressive FHD-renal cell carcinoma. We evaluate a previously proposed FHTPS screening strategy for women with ULs. This 5-year, prospective and retrospective study performed FH and later S-(2-succino) cysteine immunohistochemistry (IHC) on all uterine smooth muscle (USM) tumors in patients 40 (later ≤30) years or younger and on all USM tumors with suggestive FHD morphology regardless of age. Patients with FHD tumors by IHC were referred to genetic counseling. Of 840 USM tumors, 112 FHD-tumors by IHC (13%) were identified, all with suggestive FHD-morphology; 44 patients (39%) underwent germline testing, and 15 harbored germline FH PVs (34.1% of germline tested, 13.4% of all FHD-tumors). While FHD tumors were seen across a wide age range (24 to 73 y), those with germline FH PVs were significantly younger (median 33 vs 44 years wild-type, P = 0.0032). Few (12.5%) patients ≥40 and no patients ≥50 had a germline FH PV, whereas a majority (60%) of patients <40 (86% of those <30) had a germline FH PV. We demonstrate that previously proposed resource-conscious screening involving morphology and IHC is effective for identifying women with FHTPS. We provide prospective data confirming patients presenting with FHD-ULs over age 50 are unlikely to harbor germline FH PVs and argue that for germline testing without consideration of other factors, a threshold of younger than 50 years may be appropriate.

The cholangioblastic variant of intrahepatic cholangiocarcinoma is a distinctive neoplasm that typically affects young women without underlying liver disease. Morphologically, it demonstrates solid, trabecular, and tubulocystic architecture, biphasic small cell-large cell cytology, and immunoreactivity for inhibin, neuroendocrine markers, and biliary but not hepatocellular markers. In 2021, our group identified a characteristic NIPBL::NACC1 gene fusion in cholangioblastic cholangiocarcinoma, and since then ~20 genetically confirmed cases have been reported in the literature. We report 2 additional cases, both of which caused diagnostic challenges. The first was previously published as a "biliary adenofibroma with malignant features" which we now show recurred as a high-grade adenocarcinoma. Re-review of the original lesion demonstrated the morphologic and immunohistochemical features of highly cystic cholangioblastic cholangiocarcinoma, whereas the high-grade recurrence lacked many of these features. In addition to the characteristic NIPBL::NACC1 gene fusion, the recurrence demonstrated loss of the RB1 and PTEN genes which were found in the highly cystic, bland areas of the original tumor, suggesting that the recurrence was derived from this bland component. The second case was originally misclassified as metastatic well-differentiated neuroendocrine neoplasm and only focally demonstrated the characteristic biphasic small cell-large cell cytology. In addition, a review of 7 cholangioblastic cholangiocarcinomas in our files demonstrates that loss of chromosome 13q14.2 (where the RB1 gene resides) and loss of chromosome 6q15-q16.3 are recurrent secondary changes in these neoplasms. Expression profiling demonstrated alterations in the transforming growth factor receptor beta superfamily, and overexpression of MYC which was validated by immunohistochemistry. Our findings expand the morphologic and genetic spectrum of this neoplasm and provide insight into secondary genetic changes associated with progression.

Proliferations of neoplastic perivascular epithelioid cells (PECs) may occur within the lung and extrathoracic sites. The term "PEComatosis" is applied to multiple or diffuse microscopic proliferations of neoplastic PECs. Pulmonary diffuse PEComatosis is extremely rare, with only one case documented in the literature to date. We herein report a novel sclerosing variant of diffuse PEComatosis in a 68-year-old woman with clinical tuberous sclerosis complex (TSC), who underwent lung resection for evaluation of persistent, bilateral ground glass opacities. The patient had no respiratory complaints or ventilatory defects in pulmonary function tests. The morphologic features resembled the previous description of pulmonary diffuse PEComatosis, showing interstitial nodular and diffuse proliferation of predominantly clear epithelioid cells with PEC differentiation by immunohistochemistry. The PEComatous proliferation was accompanied by a pattern of sclerosis that overlapped with the sclerosing variant of PEComa. There was no evidence of lymphangioleiomyomatosis. The changes were complicated by neuroendocrine cell hyperplasia, which has not previously been reported in the lungs of patients with TSC.

Basal cell carcinomas (BCC) are driven primarily by cumulative ultraviolet (UV) radiation exposure resulting in activation of the Hedgehog (Hh) signaling pathway, often as a result of UV-mediated Patched-1 (PTCH1) gene inactivation. Accordingly, BCCs most commonly arise at sun-exposed sites such as the head and neck. Very rarely, BCCs can arise at sun-protected sites such as the genital skin and perianal area. This can pose significant diagnostic challenges not only due to the rarity of BCC at these sites but also due to the potential morphologic overlap with other entities such as basaloid squamous cell carcinoma, trichoblastic carcinoma, and even benign neoplasms such as trichoblastomas. Hh pathway alterations have not yet been described in BCCs arising at genital and perianal sites, and the role of UV radiation is uncertain at these anatomic locations. To address this ambiguity, we report the clinicopathologic features of a cohort of 14 BCCs arising at sun-protected sites (perianal n=7, vulva n=4, scrotum n=3). Furthermore, we use a next-generation DNA sequencing platform to investigate their pathogenesis and compare it to that of a cohort of 8 BCCs arising on sun-exposed skin. We find that BCCs arising on sun-protected sites display a spectrum of morphologic patterns, rarely recur, and do not metastasize. Both sun-protected and sun-exposed BCCs are characterized by recurrent PTCH1 alterations (93% and 100% of cases, respectively), supporting the classification of the tumors arising at sun-protected sites as bona fide BCCs. Notably, in contrast to conventional BCCs, none of the sun-protected BCCs harbored a UV mutation signature, suggesting an alternative mechanism of mutagenesis. Furthermore, the presence of upstream Hh pathway alterations in sun-protected BCCs supports their susceptibility to Hh pathway inhibitors such as vismodegib and sonidegib.

E-cadherin (E-cad) immunohistochemistry is commonly used to distinguish lobular carcinoma in situ (LCIS) from ductal carcinoma in situ in histologically uncertain or ambiguous cases. Although most LCIS cases show an absence of E-cad expression on the neoplastic cell membranes, some show aberrant E-cad expression which can lead to diagnostic confusion. Awareness and understanding of the frequency, patterns, and distribution of aberrant E-cad staining in LCIS is crucial to achieving a correct diagnosis. We studied 55 LCIS cases diagnosed on core needle biopsy, classified each case by WHO subtype (classic, pleomorphic, or florid), and evaluated the frequency and patterns of aberrant E-cad expression using 3 different E-cad antibodies targeting the N-terminal (N), extracellular (EC), and C-terminal domains (C). Aberrant E-cad expression in one or more of the E-cad domains was identified in 17 cases (31%) and was significantly more frequent among LCIS variants (10/19, 56%) than among classic cases (7/36, 19.4%) (P=0.02). Among these 17 cases, aberrant E-cad expression was seen for all 3 domains in 10 cases, for EC+C in 4, for EC+N in 2, and for N only in 1. These results indicate that about one-third of cases of LCIS can show aberrant E-cad expression, that this is more common in variants than classic types of LCIS, and that this may be seen in different E-cad domains, most often in combination. These different patterns of aberrant E-cad expression may reflect different mechanisms of E-cad alterations in LCIS, the underlying nature of which merits further studies.

According to histopathology and molecular genetics, there are 5 major subtypes of ovarian carcinomas: high-grade serous (70%), endometrioid (10%), clear cell (10%), mucinous (3% to 4%), and low-grade serous (<5%) carcinomas. These tumors, which constitute over 95% of cases, represent distinct diseases with different prognoses and therapy. This review outlines contemporary advances in molecular pathology, which have expanded our knowledge of the biology of epithelial ovarian cancer and are also important to patient management. We also comment on some controversial points of the FIGO staging classification that we proposed in 2014.