《美国外科病理学杂志》因其对人类外科病理学最新进展的出色报道而获得了全世界的认可。在每个月刊中，专家都会展示原创文章、评论文章、详细的病例报告和专题，并辅以精美的插图。覆盖范围包括技术方法、诊断辅助和冰冻切片诊断，以及对广泛疾病实体的详细病理学研究。 ARTHUR PURDY STOUT 外科病理学家协会和胃肠病理学协会的官方杂志。

The American Journal of Surgical Pathology is globally recognized for its outstanding reporting on the latest advancements in human surgical pathology. Each monthly issue features original research articles, review articles, detailed case reports, and special topics, complemented by high-quality illustrations. The scope includes technical methods, diagnostic aids, frozen section diagnosis, and in-depth pathological studies of a wide range of disease entities. It is the official journal of the ARTHUR PURDY STOUT Society of Surgical Pathologists and the Society for Gastrointestinal Pathology.

《美国外科病理学杂志》因其对人类外科病理学最新进展的卓越报道而获得全球认可。每期杂志中，专家们展示原创研究文章、评论、详细病例报告和专题，辅以精美插图。内容涵盖技术方法、诊断辅助、冰冻切片诊断，以及对多种疾病的详细病理学研究。该杂志是ARTHUR PURDY STOUT外科病理学家协会和胃肠病理学协会的官方出版物。

American Journal of Surgical Pathology

Lynch syndrome (LS) is defined by germline mutations in DNA mismatch repair (MMR) genes, and affected patients are at high risk for multiple cancers. Reflexive testing for MMR protein loss by immunohistochemistry (IHC) is currently only recommended for colorectal and endometrial cancers, although upper tract urothelial carcinoma (UTUC) is the third-most common malignancy in patients with LS. To study the suitability of universal MMR IHC screening for UTUC, we investigated MMR expression and microsatellite status in UTUC in comparison to bladder UC (BUC), and evaluated the clinicopathologic features of UTUC. We found that 9% of UTUC showed MMR IHC loss (8 MSH6 alone; 1 MSH2 and MSH6; 1 MLH1 and PMS2; n=117) compared with 1% of BUC (1 MSH6 alone; n=160) (P=0.001). Of these, 4/10 (40%) of UTUC (3% overall; 3 MSH6 alone; 1 MLH1 and PMS2) and none (0%) of BUC had high microsatellite instability on molecular testing (P=0.03). The only predictive clinicopathologic feature for MMR loss was a personal history of colorectal cancer (P=0.0003). However, UTUC presents at a similar age to colon carcinoma in LS and thus UTUC may be the sentinel event in some patients. Combining our results with those of other studies suggests that 1% to 3% of all UTUC cases may represent LS-associated carcinoma. LS accounts for 2% to 6% of both colorectal and endometrial cancers. As LS likely accounts for a similar percentage of UTUC, we suggest that reflexive MMR IHC screening followed by microsatellite instability testing be included in diagnostic guidelines for all UTUC.

Jennifer Y. Ju

Anne M. Mills

Mani S. Mahadevan

Jinbo Fan

Stephen H. Culp

Martha H. Thomas

Helen P. Cathro

The American Journal of Surgical Pathology

Universal Lynch Syndrome Screening Should be Performed in All Upper Tract Urothelial Carcinomas

所有上尿路尿路上皮癌均应进行林奇综合征筛查

Different immunohistochemical sex cord-stromal markers have been previously studied in various types of ovarian sex cord-stromal tumors; however, the sensitivity for sex cord-stromal lineage may vary between markers, and some markers may not be as sensitive in some types of sex cord-stromal tumors compared with other tumors in this spectrum of neoplasms. The goals of this study were to determine which immunohistochemical markers are the most sensitive and immunohistochemically robust for sex cord-stromal lineage within a given type of ovarian sex cord-stromal tumor, and to establish whether there are substantial differences of expression of these markers between different types of sex cord-stromal tumors. Immunohistochemical stains for markers which have known variable specificity for sex cord-stromal lineage [inhibin, calretinin, MART-1/melan-A, CD99, steroidogenic factor 1 (SF-1, adrenal 4-binding protein), and WT1], were performed in 127 cases of 5 different types of ovarian sex cord-stromal tumors: adult granulosa cell tumor (n=32), Sertoli cell tumor (n=27), Sertoli-Leydig cell tumor (n=18), steroid cell tumor (n=25), and fibroma/fibrothecoma (n=25). All cases in each type of sex cord-stromal tumor expressed SF-1. Inhibin and calretinin were expressed in all groups of tumors but with a lesser frequency (56% to 100% and 36% to 100% of cases, respectively). All types of tumors except steroid cell tumor expressed WT1. Fibroma/fibrothecoma was the only type of tumor that did not express CD99. The only tumor groups that showed expression of MART-1 were Sertoli-Leydig cell tumor (restricted to the Leydig cell component) and steroid cell tumor (94% and 96% of cases, respectively). The type of sex cord-stromal tumor that was least frequently positive for several of the different markers studied was fibroma/fibrothecoma. Among all tumor groups combined, inhibin and WT1 were the 2 markers showing the most diffuse expression. Likewise, the single marker showing the most optimal combination of diffuse and strong staining (immunohistochemical composite score: possible range, 1 to 12) varied between tumors: adult granulosa cell tumor-inhibin (score 10.0); Sertoli cell tumor-WT1 (score 10.8); Sertoli-Leydig cell tumor (Sertoli cell component)-WT1 (score 10.4); steroid cell tumor-inhibin (score 11.2); and fibroma/fibrothecoma-WT1 (score 8.9). We conclude that most immunohistochemical sex cord-stromal markers have sufficient sensitivity for sex cord-stromal lineage. Although each of the different types of sex cord-stromal tumors has a slightly unique immunoprofile in terms of frequency and extent of expression, these differences are relatively minor for most types of tumors with certain exceptions (eg, WT1 is not diagnostically useful in steroid cell tumor; CD99 is not diagnostically useful in fibroma/fibrothecoma; the only sex cord-stromal tumor for which MART-1 is diagnostically useful is steroid cell tumor; inhibin and calretinin are less diagnostically useful in fibroma/fibrothecoma than in the other types of tumors, but expression in fibrothecoma was higher than in fibroma). SF-1 is the most sensitive sex cord-stromal marker among the most common types of sex cord-stromal tumors. Given the findings relating to sensitivity and extent of expression in this study, and known specificity in the literature, the most informative sex cord-stromal markers to be used for the distinction from nonsex cord-stromal tumors are inhibin, calretinin, SF-1, and WT1 (the exact number of markers to be used should be based on the degree of difficulty of the case and level of experience of the pathologist); however, the utility of immunohistochemistry for the diagnosis of fibroma/fibrothecoma is somewhat limited.

Chengquan Zhao

Tuyethoa N. Vinh

Kim McManus

David Dabbs

Ross Barner

Russell Vang

Identification of the Most Sensitive and Robust Immunohistochemical Markers in Different Categories of Ovarian Sex Cord-stromal Tumors

不同类别卵巢性索-间质肿瘤中最敏感和最稳定的免疫组化标志物的鉴定

Dyskeratosis congenita (DC) is a rare multisystemic disorder associated with defective telomere maintenance. Frequent clinical manifestations of DC include reticular skin pigmentation, dystrophic nails, oral leukoplakia, and bone marrow failure. Hepatic disturbances are reported to occur in 7% of DC patients. This study aimed to evaluate the histopathologic spectrum of hepatic involvement in this disorder. DC patients with liver tissue in the pathology database at Boston Children’s Hospital from 1995 to 2022 were identified. Clinical and pathologic information was documented. Thirteen specimens from 11 DC patients were included (M:F = 7:4; median age at the time of liver tissue evaluation: 18 y). DC-associated gene mutations were identified in 9 patients; TERF1-interacting nuclear factor 2 ( TINF2) was the most frequently represented gene mutation, seen in 4 patients. All patients had bone marrow failure, whereas dystrophic nails, cutaneous abnormal pigmentation, and oral leukoplakia were noted in 73%, 64%, and 55% of patients, respectively. Seven patients underwent bone marrow transplants before biopsy/autopsy (median interval of 45 mo). Histologically, 3 of 4 patients who presented with portal hypertension showed noncirrhotic changes (nodular regenerative hyperplasia and/or obliterative portal venopathy), whereas prominent central and sinusoidal fibrosis was noted in patients with intrahepatic shunting and those showing features of chronic passive congestion. All cases showed hepatocyte anisonucleosis. One patient developed hepatic angiosarcoma, and another 1 had colorectal adenocarcinoma metastatic to the liver. DC patients show heterogeneous histologic findings in their liver. The findings of noncirrhotic portal hypertension, intrahepatic shunting, and angiosarcoma suggest vascular functional/structural pathology as a possible unifying etiology of hepatic manifestations of DC.

Juan Putra

Suneet Agarwal

Alyaa Al-Ibraheemi

Ahmad I. Alomari

Antonio R. Perez-Atayde

Spectrum of Liver Pathology in Dyskeratosis Congenita

先天性角化不良肝脏病理谱

A fundamental controversy in using biomarkers to diagnose cervical cancer precursors [ie, squamous intraepithelial lesions (SIL)] is their lack of specificity for high-grade SIL [HSIL; cervical intraepithelial neoplasia grade 2/3 (CIN2/3)]. Stathmin-1 (STMN), a microtubule-destabilizing protein important in mitosis, is overexpressed in a variety of malignancies including those from the Müllerian tract and may be associated with poor outcome. However, the use of STMN as a diagnostic marker in cervical SILs has not been explored. A total of 193 cervical samples, including benign cervix and squamous and glandular lesions, were evaluated for STMN, p27 (a known cell cycle regulator inversely expressed with STMN in normal and many neoplastic tissues), p16, and Ki67 expression by immunohistochemical analysis. SILs were independently scored and classified as benign, low-grade SIL (LSIL/CIN1), and HSIL (separated into CIN2 or CIN3) on the basis of a majority diagnosis. Each diagnosis was correlated with biomarker expression independent of hematoxylin and eosin review. STMN was normally expressed in basal cells of the ectocervix and was absent in benign endocervix;"positive" STMN staining was defined as immunoreactivity in at least two thirds of the epithelial thickness. A majority hematoxylin and eosin diagnosis was obtained in 189/193 cases on initial independent review, with squamous epithelia ultimately classified as benign, CIN1, CIN2, and CIN3 in 25, 56, 11, and 16 cases, respectively. STMN was positive in 5/56 (9%) CIN1, 5/11 (45%) CIN2, 14/15 (93%) CIN3, all adenocarcinoma in situ (19/19), and all invasive squamous cell carcinoma (32/32) and adenocarcinoma (34/34) cases. In contrast, 40/56 (71%) CIN1, 11/11 (100%) CIN2, and 15/16 (94%) CIN3 lesions were p16 positive (defined as diffuse block staining in at least one third of the epithelial thickness). One CIN3 was negative for both p16 and STMN. Ki67 and p27 staining was variable in squamous lesions. These results demonstrate that STMN is overexpressed in virtually all cervical carcinomas and CIN3 lesions. In contrast to p16, which often stains LSIL and a small subset of reactive biopsies, STMN has greater specificity for CIN3 and has the potential to distinguish these latter lesions from the majority of low-grade precursors and negative/reactive cervical biopsies. STMN overexpression appears independent of proliferation, maturation, and human papilloma virus cytopathic effect and may be useful diagnostically in identifying HSIL. Further studies correlating STMN staining with lesion persistence or morphologic progression, in the context of CIN grade, are warranted.

Brooke E. Howitt

Marisa R. Nucci

Ronny Drapkin

Christopher P. Crum

Michelle S. Hirsch

Stathmin-1 Expression as a Complement to p16 Helps Identify High-grade Cervical Intraepithelial Neoplasia With Increased Specificity

Stathmin-1表达作为p16的补充有助于更特异性地识别高级别宫颈上皮内瘤变

Prostatic adenocarcinoma with focal pleomorphic giant cell features is rare with the only prior series consisting of 6 cases. From 2005 to 2018, we identified 29 cases from our consult service and 1 case from our own institution. Men ranged in age from 39 to 90 years (median=75.5). Diagnostic specimens consisted of needle biopsies (n=13); transurethral resections (n=7), urethral/bladder biopsies (n=8), radical prostatectomy (n=1), and orchiectomy (n=1). In all cases, there was usual acinar prostatic adenocarcinoma, where the highest grade in all cases was Gleason score 9 to 10 (Grade Group 5). On average, 68% of the involved cores had cancer with a maximum percent of cancer averaging 55%; on average, transurethral resections had 85% of the area involved by cancer. Areas of cancer showing pleomorphic giant cell features were focal (<5%). Two of the needle biopsies showed extraprostatic extension. The radical prostatectomy had seminal vesicle invasion and positive margins with lymphovascular invasion. Prostatic adenocarcinoma with focal pleomorphic giant cell features is always accompanied by extensive usual acinar prostate adenocarcinoma where the highest grade in all cases was Gleason score 9 to 10 (Grade Group 5). Although the pleomorphic component is focal, it can mimic urothelial carcinoma. IHC can be misleading as PSA staining is often negative or focal in both the pleomorphic and usual prostatic adenocarcinoma components. NKX3.1 is the most sensitive prostate marker, but was still focal in 1 usual prostatic adenocarcinoma and negative in 2 pleomorphic components. Prostatic adenocarcinoma with focal pleomorphic giant cell features has a dismal prognosis. In men with no prior diagnosis of prostate adenocarcinoma and >1-year follow-up, 7/19 (37%) were dead at a median of 8 months after diagnosis. Of the 7 men with a prior history of prostate adenocarcinoma, 4/7 (57%) were dead at a median of 7 months after diagnosis of recurrent prostate adenocarcinoma with pleomorphic giant cell features.

Abdullah M. Alharbi

Angelo M. De Marzo

Jessica L. Hicks

Tamara L. Lotan

Jonathan I. Epstein

Prostatic Adenocarcinoma With Focal Pleomorphic Giant Cell Features

前列腺腺癌伴局灶性多形性巨细胞特征

Primary biliary cholangitis (PBC) with early cholestasis and extensive bile duct loss but no significant fibrosis or cirrhosis is rare and underrecognized. We aimed to clarify the clinicopathology features and prognosis of these variants of patients with early-stage PBC with ductopenia. From January 2009 to January 2023, we retrospectively collected the laboratory and pathologic data of patients with early-stage PBC and recorded their liver-related events with a median follow-up of 4.5 years. Finally, a total of 141 patients with PBC in the early stage were included and divided into 2 groups: one with ductopenia (n = 36) and the other without ductopenia (n = 105). The median age of the participants was 50 years, with 90.8% being female. The ductopenia group exhibited significantly elevated alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transpeptidase, total bilirubin﻿﻿, total bile acid, and total cholesterol (CHOL). Conversely, they showed a reduced biochemical response to ursodeoxycholic acid according to the Paris II, Barcelona, and Rotterdam criteria. A relatively poorer prognosis was observed in patients with early-stage PBC with ductopenia but with no statistical difference (11.8% vs 4.9%, P = 0.352). Baseline total CHOL levels were identified as an independent factor for the presence of ductopenia in early-stage PBC (odds ratio = 1.771, 95% CI: 1.264-2.479, P = 0.001). In conclusion, ductopenia was a significant risk factor for worse biochemical profiles and poor treatment response in patients with early-stage PBC. High levels of total CHOL at baseline are associated with the presence of ductopenia in early-stage PBC.

Haitian Yu

Tingting Lv

Shuxiang Li

Sha Chen

Min Li

Jimin Liu

Weijia Duan

Jidong Jia

Xinyan Zhao

Clinicopathologic Features of a Rare and Underrecognized Variant of Early-stage Primary Biliary Cholangitis With Ductopenia

早期原发性胆汁性胆管炎伴胆管缺失的罕见且易忽视的临床病理特征

Immature PIT1-lineage pituitary neuroendocrine tumors (PitNETs)/adenomas (Immature PIT1-lineage tumors) are a rare and underrecognized subtype of PitNETs that exhibits distinct cytologic atypia features and aggressive clinical potential. This study characterizes the clinical, radiological, histologic, and immunohistochemical features of 15 immature PIT1-lineage tumors identified from 1084 PitNETs patients over 5 years. Our cohort of 6 males and 9 females had a median age of 37.00 years (range: 23 to 68 y). All patients presented with pituitary macrotumors with an average size of 27.13×22.60×22.13 mm (length×width×height). The invasive growth pattern was identifiable, with 40.00% of tumors presenting with advanced stage (Knosp type 3 and 4) disease, followed by 20.00% Knosp type 2, 26.67% type 1, and 13.33% type 0. Clinical follow-up in 11 patients (median duration: 10.91 mo) revealed local recurrence in 1 case (9.09%). Microscopically, immature PIT1-lineage tumors comprised epithelioid (n=14) or spindle-shaped (n=1) chromophobic or weak basophilic cells with marked cytologic atypia, macronucleoli, and nuclear pseudoinclusions. By immunohistochemistry, most cases showed a consistent stain for PIT1 but limited expression of PIT1 family hormones in conjunction with diffuse or focal expression of CK8/18 (Cam 5.2), whereas none of the mimics showed a similar stain pattern in such a distinct way. We corroborate that immature PIT1-lineage tumors are rare, aggressive, and morphologically unique PitNETs/adenomas with cytologic atypia features. Immunohistochemistry may facilitate diagnosis in the distinction from histologic mimics.

Yuejiao Lang

Shaolei Guo

Ying Tuo

Tian Tian

Yuefeng Wang

Qiming Li

Yingqian Chen

Wenli Chen

Yonghong Zhu

Dawei Liu

Immature PIT1-lineage Pituitary Neuroendocrine Tumors/Adenomas, a Morphologically Unique Pituitary Neuroendocrine Tumors/Adenomas Commonly With Cytologic Atypia Features and a Predilection for Aggressive Clinical Potential

不成熟的PIT1系垂体神经内分泌肿瘤/腺瘤：一种形态学独特的垂体神经内分泌肿瘤/腺瘤，常伴有细胞学异型特征，并具有侵袭性临床潜能的倾向

Isabel Trias

Ferran Algaba

Inés de Torres

Adela Saco

Lorena Marimon

Núria Peñuelas

Laia Diez-Ahijado

Lia Sisuashvili

Katarzyna Darecka

Alba Morató

Marta Del Pino

Carla Ferrándiz-Pulido

María José Ribal

Tarek Ajami

Juan Manuel Corral

Josep Maria Gaya

Oscar Reig

Oriol Ordi

Inmaculada Ribera-Cortada

Adriana García-Herrera

Natalia Rakislova

Am J Surg Pathol

p53 Immunohistochemistry Defines a Subset of Human Papillomavirus-independent Penile Squamous Cell Carcinomas With Adverse Prognosis

p53 免疫组织化学定义了一组与人乳头瘤病毒无关的阴茎鳞状细胞癌，具有不良预后

Gastric-type endocervical adenocarcinomas (GAS) are aggressive HPV-independent neoplasms with molecular alterations in TP53 , STK11 , CDKN2A, and SMAD4 . Claudin-18 (CLDN18) has emerged as a useful marker to distinguish GAS from HPV-associated neoplasia. Its role in separating GAS from benign proliferations and exuberant endocervical glands is unknown. We studied the utility of immunohistochemistry for CLDN18, progesterone receptor (PR), and mutation surrogate stains (P53, STK11/LKB1, MTAP, SMAD4/DPC4) in 46 GAS, 12 benign gastric-type endocervical lesions, 54 benign Mullerian endocervical populations, and 11 HPV-associated endocervical adenocarcinomas. PD-L1 and HER2 immunostains were evaluated in GAS. Gastric-type lesions were more often positive for CLDN18 (100% benign, 78% GAS, most often well to moderately differentiated) compared to benign Mullerian endocervical specimens (all negative) and HPV-associated neoplasia (18%, always focal). Conversely, PR was negative in all gastric-type lesions and positive in 92% of benign Mullerian endocervical populations. GAS revealed aberrant/mutant expression of P53 in 35%, STK11/LKB1 in 25%, MTAP in 23%, and SMAD4/DPC4 in 9% of cases. Abnormal staining in at least one of these 4 mutation surrogate markers was present in 63% of GAS. HER2 score of 3+ was seen in 25% of GAS, and PD-L1 was positive in 37% based on a combined positive score. CLDN18 is a sensitive and highly specific marker of gastric-type benign and malignant endocervical lesions. Once a gastric-type phenotype is confirmed, mutation surrogate immunostains can be used to support a diagnosis of GAS. PD-L1 and HER2 expression is seen in a subset of GAS offering therapeutic options for this aggressive tumor.

Lawrence Hsu Lin

Harsimar Kaur

David L. Kolin

Carlos Parra-Herran

Claudin-18 and Mutation Surrogate Immunohistochemistry in Gastric-type Endocervical Lesions and their Differential Diagnoses

Claudin-18及突变替代性免疫组化在胃型宫颈内膜病变及其鉴别诊断中的应用

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.

Susanne K. Jeffus

Jacob T. Wooldridge

Lynn Hoang

Mugahed Hamza

Miki Lindsey

Meredith Verret

Nicholas Zoumberos

Bradley Fogel

Autumn Wyeth

João Gama

Charles M. Quick

Interpretation of p16 and p53 in the Classification of Squamous Cell Carcinoma of the Vulva—An Interobserver Agreement Study

外阴鳞状细胞癌分类中p16和p53的解读——一项观察者间一致性研究

Abbreviation	Am. J. Surg. Pathol.
Journal Impact	4.51
Quartiles(Global)	SURGERY(Q1)

ISSN	0147-5185, 1532-0979
h-index	240
Top Journals	Yes

Publication Information	Publisher: Wolters Kluwer Health，Publishing cycle: Monthly，Journal Type: journal，Open Access Journals: No
Basic data	Year of publication: 1977，Proportion of original research papers: 95.56%，Self Citation Rate:6.70%， Gold OA Rate: 6.01%
Average review cycle	网友分享经验：平均1月
Average recruitment ratio	网友分享经验：约5%

American Journal of Surgical Pathology

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