Cytoplasmic Pattern p53 Immunoexpression in Pelvic and Endometrial Carcinomas With TP53 Mutation Involving Nuclear Localization Domains

Rabban, Joseph T. MD, MPH; Garg, Karuna MD; Ladwig, Nicholas R. MD; Zaloudek, Charles J. MD; Devine, W. Patrick MD, PhD

doi : 10.1097/PAS.0000000000001713

November 2021 - Volume 45 - Issue 11 - p 1441-1451

A cytoplasmic pattern of p53 immunohistochemical expression has recently been reported in a rare subset of pelvic and endometrial cancers with a TP53 mutation involving domains affecting nuclear localization. This study reports the clinicopathologic features of 31 cases with a TP53 mutation involving nuclear localization, the largest study to date, emphasizing practical strategies for recognizing this uncommon variant and distinguishing it from the p53 wild-type pattern. The study also evaluates the prognostic significance of TP53 mutation involving nuclear localization in the ovarian high-grade serous carcinoma (HGSC) cohort of The Cancer Genome Atlas database. Most of the 31 tumors were advanced stage pelvic or endometrial HGSC. All TP53 mutations were predicted to result in loss of function. The p53 overexpression pattern was present in 6 tumors; the p53 null pattern in 3 and the p53 cytoplasmic pattern in 22 tumors. The p53 cytoplasmic pattern predominantly consisted of weak to moderate cytoplasmic staining in >95% of tumor cells as well as variable intensity nuclear staining involving a range of just a few cells to just under 80% of tumor cells. The p53 cytoplasmic pattern was observed in 100% of tumors with TP53 mutation in the nuclear localization domain and in 33% to 44% of tumors with a mutation in the adjacent tetramerization domain or nuclear exclusion sequence (P<0.01). p16 immunoexpression was present in 74% of tumors. In The Cancer Genome Atlas ovarian HGSC cohort, 9% of 471 nonredundant TP53-mutant cases had a nuclear localization domain, tetramerization domain, or nuclear exclusion sequence mutation but there was no significant difference in survival when compared to cases with TP53 mutation outside those domains (P>0.05). p53 cytoplasmic staining merits classification as an aberrant result despite coexisting nuclear staining that in some cases may resemble the p53 wild-type pattern. While positive p16 immunostaining may be of value to confirm diagnostically challenging cases of p53 cytoplasmic staining, a negative result is noninformative and molecular testing for TP53 mutation should be considered, if available.

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Accurate Distinction of Ovarian Clear Cell From Endometrioid Carcinoma Requires Integration of Phenotype, Immunohistochemical Predictions, and Genotype

Rodriguez, Monica MD*; Kang, Eun Young MD*; Farrington, Kyo MD*; Cook, Linda S. PhD†; Le, Nhu D. PhD‡; Karnezis, Anthony N. MD, PhD§; Lee, Cheng-Han MD, PhD?; Nelson, Gregg S. MD, PhD¶; Terzic, Tatjana MD*; Lee, Sandra MD*; Köbel, Martin MD*

doi : 10.1097/PAS.0000000000001798

November 2021 - Volume 45 - Issue 11 - p 1452-1463

Ovarian clear cell carcinoma (OCCC) and ovarian endometrioid carcinoma (OEC) are both associated with endometriosis but differ in histologic phenotype, biomarker profile, and survival. Our objectives were to refine immunohistochemical (IHC) panels that help distinguish the histotypes and reassess the prevalence of mismatch repair deficiency (MMRd) in immunohistochemically confirmed OCCC. We selected 8 candidate IHC markers to develop first-line and second-line panels in a training set of 344 OCCC/OEC cases. Interobserver reproducibility of histotype diagnosis was assessed in an independent testing cohort of 100 OCC/OEC initially without and subsequently with IHC. The prevalence of MMRd was evaluated using the testing cohort and an expansion set of 844 ovarian carcinomas. The 2 prototypical combinations (OCCC: Napsin A+/HNF1B diffusely+/PR?; OEC: Napsin A?/HNF1B nondiffuse/PR+) occurred in 75% of cases and were 100% specific. A second-line panel (ELAPOR1, AMACR, CDX2) predicted the remaining cases with 83% accuracy. Integration of IHC improved interobserver reproducibility (?=0.778 vs. 0.882, P<0.0001). The prevalence of MMRd was highest in OEC (11.5%, 44/383), lower in OCCC (1.7%, 5/297), and high-grade serous carcinomas (0.7%, 5/699), and absent in mucinous (0/126) and low-grade serous carcinomas (0/50). All 5 MMRd OCCC were probable Lynch syndrome cases with prototypical IHC profile but ambiguous morphologic features: 3/5 with microcystic architecture and 2/5 with intratumoral stromal inflammation. Integration of first-line and second-line IHC panels increases diagnostic precision and enhances prognostication and triaging for predisposing/predictive molecular biomarker testing. Our data support universal Lynch syndrome screening in all patients with OEC when the diagnosis of other histotypes has been vigorously excluded.

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Morphologic, Immunohistochemical, and Genetic Differences Between High-grade and Low-grade Fetal Adenocarcinomas of the Lung

Li, Yue MD*,†; Xi, Shao-yan MD*,‡; Yong, Juan-juan MD§; Wu, Xiao-yan MM*,†; Yang, Xin-hua MM*,†; Wang, Fang MD*,†

doi : 10.1097/PAS.0000000000001744

November 2021 - Volume 45 - Issue 11 - p 1464-1475

Fetal adenocarcinoma of the lung (FLAC) is a rare lung tumor classified into low-grade fetal adenocarcinoma of the lung (LG-FLAC) and high-grade fetal adenocarcinoma of the lung (HG-FLAC). It remains debatable whether HG-FLAC is a subset of FLAC or a distinct subtype of the conventional lung adenocarcinoma (CLA). In this study, samples of 4 LG-FLAC and 2 HG-FLAC cases were examined, and the clinicopathologic, immunohistochemical (IHC), and mutational differences between the 2 subtypes were analyzed using literature review. Morphologically, LG-FLACs had a pure pattern with complex glandular architecture composed of cells with subnuclear and supranuclear vacuoles, mimicking a developing fetal lung. In contrast, HG-FLACs contained both fetal lung-like (FLL) and CLA components. With regard to IHC markers, ?-catenin exhibited a nuclear/cytoplasmic staining pattern in LG-FLACs but a membranous staining pattern in HG-FLACs. Furthermore, p53 was expressed diffusely and strongly in HG-FLACs, whereas in LG-FLACs, p53 staining was completely absent. Using next-generation sequencing targeting a 1021-gene panel, mutations of CTNNB1 and DICER1 were detected in all 4 LG-FLAC samples, and a novel mutation, MYCN P44L, was discovered in 2 LG-FLAC samples. DNA samples of the FLL and CLA components of HG-FLACs were separately extracted and sequenced. The FLL component harbored no CTNNB1, DICER1, or MYCN mutations; moreover, the FLL genetic profile largely overlapped with that of the CLA component. The morphologic, IHC, and genetic features of HG-FLAC indicate that it is a variant of CLA rather than a subset of FLAC. Thus, HG-FLAC should be treated differently from LG-FLAC.

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Whole-exome Sequencing of Epstein-Barr Virus–associated Pulmonary Carcinoma With Low Lymphocytic Infiltration Shows Molecular Features Similar to Those of Classic Pulmonary Lymphoepithelioma-like Carcinoma

Yeh, Yi-Chen MD*,†,‡; Ho, Hsiang-Ling PhD*,§; Lin, Chia-I MD?; Chou, Teh-Ying MD, PhD*,¶; Wang, Yu-Chao PhD‡

doi : 10.1097/PAS.0000000000001722

November 2021 - Volume 45 - Issue 11 - p 1476-1486

Pulmonary lymphoepithelioma-like carcinoma (LELC) is a distinct type of Epstein-Barr virus (EBV)-associated non–small cell carcinoma characterized by a syncytial growth pattern with heavy lymphocytic infiltration. We recently identified a group of non–small cell carcinomas, which are also associated with EBV but lack significant lymphocytic infiltration. These EBV-associated pulmonary carcinomas with low lymphocytic infiltration morphologically resemble nonkeratinizing squamous cell carcinoma, but their patient characteristics are more similar to those of LELC, including female sex and nonsmoking status. To clarify the relationships between these disease entities, in this study, we explored the molecular characteristics of the EBV-associated carcinomas with low lymphocytic infiltration using whole-exome sequencing and compared their molecular profiles with those of classic LELC and pulmonary squamous cell carcinoma. We demonstrate that the molecular characteristics of EBV-associated carcinomas with low lymphocytic infiltration are highly similar to those of classic LELC. Both show low tumor mutational burden, lack of commonly mutated driver genes in other types of non–small cell lung cancer, similar mutational signature involving APOBEC-related mutations, and enrichment of CD274 (programmed death-ligand 1) amplification. These molecular characteristics are very different from those of pulmonary squamous cell carcinoma. The unique patient demographics and molecular characteristics shared by EBV-associated carcinomas with low lymphocytic infiltration and classic LELC suggest that these tumors represent one single disease entity defined by EBV association. This study supports the proposal for the usage of the term “EBV-associated pulmonary carcinoma” to encompass the entire morphologic spectrum of this distinct EBV-associated disease entity.

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Pan-TRK Immunohistochemistry Is Highly Correlated With NTRK3 Gene Rearrangements in Salivary Gland Tumors

Csanyi-Bastien, Marie MD*; Lanic, Marie-Delphine BS†; Beaussire, Ludivine BS*; Ferric, Sandra BS*; François, Arnaud MD‡; Meseure, Didier MD, PhD§; Jardin, Fabrice MD, PhD†; Wassef, Michel MD?; Ruminy, Philippe PhD†; Laé, Marick MD*,†

doi : 10.1097/PAS.0000000000001718

November 2021 - Volume 45 - Issue 11 - p 1487-1498

Secretory carcinoma (SC) is characterized by ETV6 rearrangements, most often ETV6-NTRK3 fusion. Given its histologic overlap with other salivary gland tumors (SGTs), SCs can be difficult to diagnose without genetic confirmation. A recently developed pan?TRK (tropomyosin receptor kinase) antibody shows promise for identifying tumors with NTRK (neurotrophic tyrosine kinase receptor 3) fusions. The aim of this study was to evaluate the utility of pan?TRK immunohistochemistry in distinguishing SCs from mimics and selecting patients eligible for TRK inhibitor clinical trials. We examined whole?tissue sections from 111 SGTs with molecular characterization, including 26 SCs (23 with ETV6-NTRK3 fusion and 3 with ETV6-RET fusion detected by ligation-dependent reverse transcription-polymerase chain reaction, next-generation sequencing and 85 non-SC SGTs (no ETV6-NTRK3 fusion). Immunohistochemistry was performed with a pan?TRK rabbit monoclonal antibody. When any pan?TRK staining (nuclear or cytoplasmic with any staining intensity) was considered to indicate positivity, 22 of 23 SCs with ETV6-NTRK3 fusion (95.7%) and 33 of 85 non?SC (38.8%) salivary neoplasms were positive, mainly basal cell adenoma, pleomorphic adenomas, adenoid cystic carcinomas, and epithelial-myoepithelial carcinomas. All SCs with ETV6-RET fusion were entirely negative. When only nuclear pan-TRK staining with any staining intensity was considered positive, 18 of 23 SCs with ETV6-NTRK3 fusion (78.3%) were positive, 11 among them with diffuse staining (>30% of cells). All non-SCs and SCs with ETV6-RET fusion were entirely negative. In comparison to molecular analysis (ligation-dependent reverse transcription-polymerase chain reaction, next-generation sequencing), nuclear pan-TRK IHC has a sensitivity of 78.3% and a specificity of 100% for diagnosing SCs with ETV6-NTRK3 fusion, 69% and 100% for SCs (all fusions). Pan-TRK is a reasonable screening test for diagnosing SCs among SGTs when taking only nuclear staining into account. Although pan-TRK expression is not entirely sensitive for SCs, nuclear staining is highly specific for SCs with ETV6-NTRK3 fusion. The lack of pan-TRK immunoreactivity in a subset of SCs is suggestive of atypical exons 4 to 14 or exons 5 to 14 ETV6-NTRK3 fusion or non-NTRK alternative fusion partners such as ETV6-RET. Pan-TRK staining can serve as a strong diagnostic marker to distinguish SC from it mimics and to select patients eligible for TRK inhibitor clinical trials.

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Hypoplasia of Extrahepatic Biliary Tree and Intrahepatic Cholangiolopathy in Cystic Fibrosis Imperfectly Mimic Biliary Atresia in 4 Infants With Cystic Fibrosis and Kasai Portoenterostomy

Bove, Kevin E. MD*; Bernieh, Anas MD*; Picarsic, Jennifer MD*; Cox, Joseph P. MD†,?; Yang, Edmund MD‡; Mantor, Philip C. MD§; Thaker, Ameet MD?; Lazar, Lauren MD¶; Sathe, Meghana MD¶; Megison, Stephen MD#

doi : 10.1097/PAS.0000000000001803

November 2021 - Volume 45 - Issue 11 - p 1499-1508

Four male infants with cystic fibrosis and prolonged neonatal jaundice underwent Kasai procedure to relieve biliary obstruction due to apparent biliary atresia. The excised remnants had viscid mucus accumulation in hypoplastic gallbladders and distended peribiliary glands. Main hepatic ducts were narrow and/or malformed. Microscopic differences between the gallbladder and extrahepatic bile ducts in cystic fibrosis and sporadic biliary atresia were unequivocal, despite some histologic overlap; no erosive or fibro-obliterative lesions typical of biliary atresia were seen. Common in liver, biopsies were small duct cholangiopathy with intense focal cholangiolitis and massive accumulation of ceroid pigment within damaged cholangiocytes, and in portal macrophages, portal fibrosis, and unequivocal features of large duct obstruction were inconspicuous compared with biliary atresia. Plugs of bile in small ducts tended to be pale and strongly periodic acid–Schiff-reactive in cystic fibrosis. Distinguishing the liver lesion from that of biliary atresia is challenging but possible. Liver biopsies from 2 additional infants with cystic fibrosis and prolonged jaundice that spontaneously resolved showed a similar small duct cholangiopathy. Small gallbladders and extrahepatic ducts challenge surgical judgment as findings in liver biopsies challenge the pathologist. The decision to perform a Kasai procedure is reasonable when mimicry of biliary atresia is grossly complete. We hypothesize that a disorder of bile volume/flow during development and/or early infancy linked to the CFTR mutation alone or in combination with the stresses of neonatal intensive care causes destructive cholangiolitis and intrahepatic reduction of bile flow with secondary hypoplasia of extrahepatic biliary structures.

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Spread Through Air Spaces (STAS) in Non?Small Cell Lung Carcinoma

Gross, Daniel J. MD*; Hsieh, Min-Shu MD*,†; Li, Yan MD*,‡; Dux, Joseph MD*; Rekhtman, Natasha MD§; Jones, David R. MD*; Travis, William D. MD§; Adusumilli, Prasad S. MD*

doi : 10.1097/PAS.0000000000001788

November 2021 - Volume 45 - Issue 11 - p 1509-1515

Tumor spread through air spaces (STAS) is associated with locoregional recurrence in patients undergoing limited resection (LR) for non?small cell lung carcinoma (NSCLC). We hypothesized that the observation of STAS in both the initial LR specimen and the additional resection specimen from the same patient, processed using different knives, would provide evidence that STAS is an in vivo phenomenon contributing to locoregional recurrence. We retrospectively identified patients with NSCLC (9 adenocarcinoma, 1 squamous cell carcinoma) who underwent LR, had STAS in the LR specimen, and underwent additional resection (lobectomy or LR). The LR and additional resection specimens from each patient were processed at different times using different tissue-processing knives. All specimens were analyzed for STAS. All 10 patients underwent LR with negative margins (R0). All additional resection specimens had STAS: 8 patients had STAS clusters in their completion lobectomy specimens, and 2 had STAS in their additional LR specimens. In 2 patients, STAS was found in the completion lobectomy specimen only after extensive sampling (>10 sections) from the staple line adjacent to the initial LR. The presence of STAS in both the LR and the additional resection specimen processed using different knives supports the concept that STAS is an in vivo phenomenon, rather than an artifact from tissue processing. This observation indicates that occult STAS tumor cells can be present in the lung tissue of the remaining unresected lobe after LR and supports the concept that STAS is a contributing factor for locoregional recurrence following LR.

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TP53 Mutation and Extraneural Metastasis of Glioblastoma

Zhang, Xiaoming MD*; Katsakhyan, Levon MD*; LiVolsi, Virginia A. MD*; Roth, Jacquelyn J. PhD*; Rassekh, Christopher H. MD†; Bagley, Stephen J. MD‡; Nasrallah, MacLean P. MD, PhD*

doi : 10.1097/PAS.0000000000001762

November 2021 - Volume 45 - Issue 11 - p 1516-1526

Extraneural metastases of glioblastoma (GBM), although rare, are becoming an increasingly recognized occurrence. Currently, the biological mechanism underlying this rare occurrence is not understood. To explore the potential genomic drivers of extraneural metastasis in GBM, we present the molecular features of 4 extraneural metastatic GBMs, along with a comprehensive review and analysis of previously reported cases that had available molecular characterization. In addition to our 4 cases, 42 patients from 35 publications are reviewed. To compare the molecular profiles between GBM cases with extraneural metastasis and the general GBM population, genomic data from GBM samples in The Cancer Genome Atlas (TCGA) database were also analyzed. We found that 64.5% (20/31) of the cases with extraneural metastasis that were tested for TP53 changes had at least 1 TP53 pathogenic variant detected in either 1 or both primary and metastatic tumors. In contrast, TP53 mutation was significantly less frequent in the unselected GBM from TCGA (22.6%, 56/248) (P=0.000). In addition, O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation was more common in unselected TCGA GBM cases (48.6%, 170/350) than in cases with extraneural metastasis (31.8%, 7/22), although not statistically significant. Although isocitrate dehydrogenase (IDH) mutation is a rare occurrence in high-grade astrocytomas, IDH-mutant grade 4 astrocytomas are at least as likely to metastasize as IDH wild-type GBMs; 3 metastatic cases definitively harbored an IDH1 (p.R132H) mutation in our analysis. Our findings not only provide potential biomarkers for earlier screening of extraneural metastasis, but could also suggest clues to understanding biological mechanisms underlying GBM metastasis, and for the development of therapeutic modalities.

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Intraductal Carcinoma of the Prostate

Samaratunga, Hemamali MBBS, FRCPA*,†; Delahunt, Brett MD, FRCPA*,‡; Yaxley, John W. MBBS, FRACS†,§; Johannsen, Shulammite MSc*; Egevad, Lars MD, PhD?

doi : 10.1097/PAS.0000000000001776

November 2021 - Volume 45 - Issue 11 - p 1527-1533

High-grade prostatic adenocarcinoma involving duct/acinar structures is labeled intraductal carcinoma of the prostate (IDCP). As numerous studies have shown that IDCP is associated with high stage disease with a significant negative impact on cancer-specific survival, accurate diagnosis is crucial to ensure appropriate patient management. The definition of IDCP recommended by 2016 World Health Organization (WHO) classification suggests that cases of IDCP with micropapillary or loose cribriform architecture without comedonecrosis should have cells with ?6× nuclear enlargement. It is unclear how this size criterion was derived and which of the parameters of nuclear size (nuclear diameter, nuclear surface area, or nuclear perimeter) it relates to. To evaluate the extent of nuclear enlargement in IDCP, we performed morphometric analyses relating to each of these parameters in 100 radical prostatectomy specimens. One hundred nuclei from foci of IDCP and 50 nuclei from foci of normal luminal epithelium were examined for each patient. Diagnosis of IDCP was based on cells with definite features of carcinoma present within duct/acinar structures. Comparing the means of each of the parameters between IDCP cells and benign luminal cells, there was a statistically significant enlargement in nuclear perimeter (P<0.0005), nuclear area (P<0.0005), and nuclear diameter (P<0.0005); however, the difference in mean nuclear size was limited to factors of 1.3×, 1.6×, and 1.3×, respectively. Three patients each had rare large nuclei (largest perimeter 45, 45, and 44??m; maximum nuclear area 135, 136, and 136??m2; and the largest diameter 18?µm in each). For these rare cells, the nuclear size difference, when compared with benign nuclei was; nuclear perimeter 2.0×, 2.1×, and 2.1×; nuclear area 3.6×, 3.8×, and 3.8×; and nuclear maximum diameter 3.0×, 2.5×, and 2.5×. The definition of nuclear enlargement of ?6× was not reached in any of our cases, all of which clearly showed features of duct invasive carcinoma. In these cases, reliance on nuclear size criteria would have resulted in underdiagnosis of IDCP. This is of concern as failure to recognize IDCP, particularly in needle biopsies, could lead to delays in the timely treatment of aggressive high-grade prostate cancer, resulting in cancer progression and suboptimal patient oncological outcomes.

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Genetic and Clinical Studies of Patients With Increased Multinucleated Megakaryocytes in Bone Marrow as an Isolated Finding

Zheng, Gang MD, PhD*,†; He, Rong MD†; Reichard, Kaaren K. MD†; Peterson, Jess F. MD*; Olteanu, Horatiu MD, PhD†; Oliveira, Jennifer L. MD†; Rangan, Aruna MBBS†; Chen, Dong MD, PhD†; Shi, Min MD, PhD†

doi : 10.1097/PAS.0000000000001732

November 2021 - Volume 45 - Issue 11 - p 1534-1540

The presence of increased multinucleated megakaryocytes (aka osteoclast-like) is considered a dysplastic feature in myelodysplastic syndrome; however, its clinical significance in isolation is uncertain. Herein, we report the clinicopathologic and genetic features of 18 such cases of 40,539 bone marrow biopsies spanning 10 years. All 18 patients had ?25% multinucleated megakaryocytes in otherwise normal bone marrow biopsies, which were evaluated for plasma cell neoplasms (n=9), lymphoma (n=4), or anemia/neutropenia (n=5). None of the 17 patients tested showed acquired cytogenetic abnormalities. Sixteen patients underwent targeted gene panel next-generation sequencing: 9 patients had no pathogenic mutations; 3 harbored a single pathogenic mutation with variant allele frequencies of 7.5%, 7.6%, and 10.7%, likely representing clonal hematopoiesis of indeterminate potential; 1 had 2 pathogenic mutations, 1 of which had a variant allele frequency >20%. Fourteen of 18 patients had a follow-up period >6 months (median: 36.5?mo, range: 7 to 110?mo) and no patients developed a new-onset cytopenia, a progressive cytopenia, or a myeloid neoplasm. The patient with 2 mutations had persistent anemia, worrisome for an emerging MDS. However, given the absence of thrombocytopenia, increased multinucleated megakaryocytes in this patient could be an unrelated incidental finding. Our study indicates that increased multinucleated megakaryocytes as an isolated finding is a rare phenomenon, and this sole morphologic finding is not diagnostic of myelodysplastic syndrome. Diagnostic approaches in the presence of increased multinucleated megakaryocytes are proposed based on different clinical and pathologic scenarios.

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Recurrent YAP1-TFE3 Gene Fusions in Clear Cell Stromal Tumor of the Lung

Agaimy, Abbas MD*; Stoehr, Robert PhD*; Michal, Michael MD†,‡; Christopoulos, Petros MD§,?; Winter, Hauke MD?,¶; Zhang, Lei MD#; Stenzinger, Albrecht MD**; Michal, Michal MD†,‡; Mechtersheimer, Gunhild MD**; Antonescu, Cristina R. MD#

doi : 10.1097/PAS.0000000000001719

November 2021 - Volume 45 - Issue 11 - p 1541-1549

Clear cell (hemangioblastoma-like) stromal tumor of the lung (CCST-L) is a recently described distinctive rare pulmonary neoplasm of unknown histogenesis and molecular pathogenesis. Only 7 cases have been reported in 2 recent studies, although additional cases might have been reported under the heading of extraneural pulmonary hemangioblastoma. We herein describe 4 CCST-L cases, 3 of them harboring a YAP1-TFE3 fusion. The fusion-positive tumors occurred in 3 women, aged 29, 56, and 69 years. All presented with solitary lung nodules measuring 2.3 to 9.5?cm. Histologically, all tumors showed similar features being composed of relatively uniform medium-sized epithelioid to ovoid cells with clear cytoplasm and small round monomorphic nuclei. Scattered larger cells with enlarged hyperchromatic nuclei and marked pleomorphism were noted in 2 cases. The tumors were associated with a hypervascularized stroma with variable but essentially subtle resemblance to capillary hemangioblastoma and perivascular epithelioid cell tumor (PEComa). Immunohistochemistry was negative for all lineage-specific markers. Targeted RNA sequencing showed a YAP1-TFE3 fusion in 3 of 4 cases. All 3 tumors showed homogeneous nuclear TFE3 immunoreactivity. Two patients were disease free at 36 and 12 months. The third patient had biopsy-proven synchronous renal and hepatic metastases, but extended follow-up is not available (recent case). The fourth case lacking the fusion affected a 66-year-old woman and showed subtle histologic differences from the fusion-positive cases, but had comparable TFE3 immunoreactivity. CCST-L represents a distinctive entity unrelated to hemangioblastoma and likely driven by recurrent YAP1-TFE3 fusions in most cases. The relationship of our cases to the recently reported “hemangioblastoma-like” CCST-L remains to be determined. Analysis of larger series is paramount to delineate the morphologic spectrum and biological behavior of this poorly characterized entity.

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A Novel NIPBL-NACC1 Gene Fusion Is Characteristic of the Cholangioblastic Variant of Intrahepatic Cholangiocarcinoma

Argani, Pedram MD*; Palsgrove, Doreen N. MD†; Anders, Robert A. MD, PhD*; Smith, Steven C. MD, PhD‡; Saoud, Carla MD*; Kwon, Regina MD, MPH*; Voltaggio, Lysandra MD*; Assarzadegan, Naziheh MD*; Oshima, Kiyoko MD*; Rooper, Lisa MD*; Matoso, Andres MD*; Zhang, Lei MD§; Cantarel, Brandi L. PhD?; Gagan, Jeffrey MD, PhD†; Antonescu, Cristina R. MD§

doi : 10.1097/PAS.0000000000001729

November 2021 - Volume 45 - Issue 11 - p 1550-1560

We report a novel NIPBL-NACC1 gene fusion in a rare primary hepatic neoplasm previously described as the “cholangioblastic variant of intrahepatic cholangiocarcinoma.” The 2 index cases were identified within our consultation files as morphologically distinctive primary hepatic neoplasms in a 24-year-old female and a 54-year-old male. The neoplasms each demonstrated varied architecture, including trabecular, organoid, microcystic/follicular, and infiltrative glandular patterns, and biphasic cytology with large, polygonal eosinophilic cells and smaller basophilic cells. The neoplasms had a distinctive immunoprofile characterized by diffuse labeling for inhibin, and patchy labeling for neuroendocrine markers (chromogranin and synaptophysin) and biliary marker cytokeratin 19. RNA sequencing of both cases demonstrated an identical fusion of NIBPL exon 8 to NACC1 exon 2, which was further confirmed by break-apart fluorescence in situ hybridization assay for each gene. Review of a tissue microarray including 123 cases originally diagnosed as well-differentiated neuroendocrine neoplasm at one of our hospitals resulted in identification of a third case with similar morphology and immunophenotype in a 52-year-old male, and break-apart fluorescence in situ hybridization probes confirmed rearrangement of both NIPBL and NACC1. Review of The Cancer Genome Atlas (TCGA) sequencing data and digital images from 36 intrahepatic cholangiocarcinomas (www.cbioportal.org) revealed one additional case with the same gene fusion and the same characteristic solid, trabecular, and follicular/microcystic architectures and biphasic cytology as seen in our genetically confirmed cases. The NIPBL-NACC1 fusion represents the third type of gene fusion identified in intrahepatic cholangiocarcinoma, and correlates with a distinctive morphology described herein.

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Morphologic Spectrum of Lymphadenopathy in Adult-onset Immunodeficiency (Anti-interferon-? Autoantibodies)

Thingujam, Bipin MD*,†; Syue, Ling-Shan MD‡; Wang, Ren-Ching MD§; Chen, Chih-Jung MD§,?; Yu, Shan-Chi MD¶; Chen, Chien-Chin MD#; Medeiros, L.J. MD**; Liao, I-Chuang MD*; Tsai, Jen-Wei MD††; Chang, Kung-Chao MD, PhD*,‡‡,§§

doi : 10.1097/PAS.0000000000001736

November 2021 - Volume 45 - Issue 11 - p 1561-1572

Adult-onset immunodeficiency syndrome (AOIS) caused by anti-interferon-? autoantibodies is an emerging disease. Affected patients present typically with systemic lymphadenopathy, fatigue, and fever. We studied 36 biopsy specimens, 31 lymph nodes, and 5 extranodal sites, of AOIS confirmed by serum autoantibody or QuantiFERON-TB Gold In-Tube assay. We describe the morphologic features and the results of ancillary studies, including special stains, immunohistochemistry, and molecular testing. The overall median age of these patients was 60.5 years (range, 41 to 83?y) with a male-to-female ratio of 20:16. All biopsy specimens showed nontuberculous mycobacterial infection, and most cases showed the following histologic features: capsular thickening with intranodal sclerosing fibrosis, irregularly distributed ill-formed granulomas or histiocytic aggregates with neutrophilic infiltration, interfollicular expansion by a polymorphic infiltrate with some Hodgkin-like cells that commonly effaces most of the nodal architecture and proliferation of high endothelial venules. In situ hybridization analysis for Epstein-Barr virus–encoded RNA showed scattered (<1%) to relatively more common (4% to 5%) positive cells in 29 of 30 (97%) tested specimens, reflecting immune dysregulation due to an interferon-? defect. In the 31 lymph node specimens, 23 (74%) cases showed increased immunoglobulin G4–positive plasma cells (4 to 145/HPF; mean, 49.7/HPF) with focal areas of sclerosis reminiscent of immunoglobulin G4–related lymphadenopathy, 4 (13%) cases resembled, in part, nodular sclerosis Hodgkin lymphoma, and 9 (29%) cases mimicked T-cell lymphoma. Among 33 patients with available clinical follow-up, 20 (61%) showed persistent or refractory disease despite antimycobacterial therapy, and 1 patient died of the disease. We conclude that the presence of ill-defined granulomas, clusters of neutrophils adjacent to the histiocytic aggregates, and some Epstein-Barr virus–positive cells are features highly suggestive of AOIS. A high index of clinical suspicion and awareness of the morphologic features and differential diagnosis of AOIS are helpful for establishing the diagnosis.

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p16 Immunoreactivity Correlates With Morphologic Diagnosis of HPV-associated Anal Intraepithelial Neoplasia

Liu, Yuxin MD, PhD*; McCluggage, W. Glenn FRCPath†; Darragh, Teresa M. MD‡; Farhat, Nada MD§; Blakely, Morgan MD?; Sigel, Keith MD, PhD¶; Zheng, Wenxin MD#; Westra, William H. MD*; Gaisa, Michael M. MD, PhD**

doi : 10.1097/PAS.0000000000001769

November 2021 - Volume 45 - Issue 11 - p 1573-1578

p16 is the most useful diagnostic marker for human papillomavirus (HPV)-associated anogenital lesions. In the cervix, the pattern of p16 immunoreactivity generally correlates with lesion severity. p16 expression in anal intraepithelial neoplasia (AIN) is far less studied. Whether such correlation holds true has to be determined. We correlated the degree and pattern of p16 immunohistochemistry (IHC) results with morphologic diagnoses of 1000 anal squamous and transitional zone biopsy specimens. Using the Lower Anogenital Squamous Terminology criteria, p16 IHC results were classified as block staining, partial staining, or negative. Among 150 samples without morphologic evidence of AIN, p16 was negative in 85% and partial staining in 15%. AIN 1 (n=400) revealed diverse results: 28% negative, 35% partial, and 37% block staining. Among AIN 2 (n=298), 89% were block, 9% partial staining, and 2% negative. AIN 3 (n=152) revealed block (95%) or partial staining (5%). For the detection of AIN 2/3, p16 block staining yielded 91% sensitivity, 73% specificity, 80% positive predictive value, 91% negative predictive value, and a Youden Index of 0.64. Combining block staining and partial staining slightly increased sensitivity (99%) and negative predictive value (98%), but significantly decreased specificity (43%), positive predictive value (59%) and Youden Index (0.42, P<0.001). As with the cervix, p16 immunoreactivity correlates with morphologic diagnoses of AIN. Block staining offers the optimal diagnostic value for AIN 2/3. Caution is required since AIN 1 frequently exhibits block staining; the prognostic value of p16 warrants further investigation.

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OGT-rearranged Acral Mesenchymal Neoplasms

Lee, Jen-Chieh MD, PhD*; Hsieh, Tsung-Han PhD†; Kao, Yu-Chien MD‡,§

doi : 10.1097/PAS.0000000000001679

November 2021 - Volume 45 - Issue 11 - p 1579-1581

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Cutaneous Primary NUT Carcinoma With BRD3-NUTM1 Fusion

Nishimura, Yuuki MD*; Ryo, Eijitsu PhD†; Yamazaki, Naoya MD, PhD‡; Yatabe, Yasushi MD, PhD*,†; Mori, Taisuke DMD, PhD*,†

doi : 10.1097/PAS.0000000000001801

November 2021 - Volume 45 - Issue 11 - p 1582-1584

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Reply to: Expanding the Spectrum of Primary Cutaneous Carcinoma With BRD3-NUTM1 Fusion

Kervarrec, Thibault MD, PhD*,†,‡; Amatore, Florent MD§,?; Pissaloux, Daniel PhD¶,#; Paindavoine, Sandrine MSc¶; Legrand, Elodie BSc¶; Lehmann-Che, Jacqueline PharmD, PhD**,††; Battistella, Maxime MD, PhD*,**,‡‡; Macagno, Nicolas MD, PhD*,¶,§§,??

doi : 10.1097/PAS.0000000000001796

November 2021 - Volume 45 - Issue 11 - p 1584-1586

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