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Pheochromocytoma: A Clinicopathologic and Molecular Study of 390 Cases From a Single Center
Liu, Zhonghua MD, PhD*; Ma, Junsheng PhD†; Jimenez, Camilo MD‡; Zhang, Miao MD, PhD*
doi : 10.1097/PAS.0000000000001768
September 2021 - Volume 45 - Issue 9 - p 1155-1165
Pheochromocytomas are rare neuroendocrine tumors arising from chromaffin cells in the adrenal medulla. They may occur sporadically or in the context of hereditary syndromes. All pheochromocytomas are considered to have malignant potential (defined as risk of metastasis, not local invasion). The use of grading systems with incorporated clinical and histopathologic parameters can help but not definitively predict the metastatic potential of pheochromocytomas. The recent discovery of susceptibility genes provided new insights into the pathogenesis and introduced additional approaches to estimate the metastatic risk of pheochromocytoma. However, the prevalence of these genetic signatures in pheochromocytomas has yet to be fully addressed. Therefore, in the present study, we retrospectively reviewed cases of pheochromocytoma from 1980 to 2018 in the archives of our institution. Three hundred ninety cases were identified, and their clinicopathologic characteristics and genetic statuses were analyzed. About 25% of the cases had metastases, which were more common in older patients (median, 49?y) than in younger ones. Univariate and multivariate analyses revealed that older age, Hispanic ethnicity, metastasis, and large primary tumor size were markedly associated with poor overall survival. In contrast, family history of pheochromocytoma, lack of symptoms, and bilateral adrenal involvement were associated with better survival. About 37% of the pheochromocytomas were associated with inherited syndromes. About 52% of tested patients had pathogenic mutations of pheochromocytoma susceptibility genes. Of these, succinate dehydrogenase B gene mutation had the strongest association with metastasis. These data support that genetic testing should be offered to all patients with pheochromocytoma.
ALK Rearrangements Characterize 2 Distinct Types of Salivary Gland Carcinomas: Clinicopathologic and Molecular Analysis of 4 Cases and Literature Review
Agaimy, Abbas MD*; Ban??ková, Martina MD†,‡; Ihrler, Stephan MD§,?; Mueller, Sarina K. MD¶; Franchi, Alessandro MD#; Hartmann, Arndt MD*; Stoehr, Robert PhD*; Skálová, Alena MD, PhD†,‡
doi : 10.1097/PAS.0000000000001698
September 2021 - Volume 45 - Issue 9 - p 1166-1178
The majority of salivary gland carcinomas are characterized by recurrent gene fusions that proved highly valuable diagnostically, but only rarely of therapeutic impact. Most of these fusion-positive carcinomas belong to the low-grade or intermediate-grade biological category. To date, only 5 cases of salivary gland carcinomas carrying an oncogenic ALK fusion have been reported in 4 recent studies, but their phenotypic spectrum and their nosological classification remain uncharacterized. We herein describe in detail the clinicopathologic and molecular features of 4 ALK–fusion-positive salivary carcinomas and review previously reported cases to assess if they could be classified into a defined World Health Organization (WHO) category. Patients were 3 men and 1 woman aged from 67 to 79 years (median: 70?y). All tumors originated in the parotid gland. Their size ranged from 1.1 to 3?cm (mean, 2?cm). Three tumors were de novo high-grade salivary duct carcinomas (SDCs) and 1 was a low-grade intercalated-type intraductal carcinoma. Histologically, high-grade tumors were predominantly solid, composed of intimately admixed basal (CK5+, androgen?) and luminal (CK5?, androgen+) components. The remarkable basal component showed squamoid basophilic pattern imparting an adenosquamous-like appearance in all cases. Conventional apocrine intraductal high-grade carcinoma was noted in 1 case. Prominent intraductal growth of the solid basal component (highlighted by p63 staining) was seen in all cases. The tumor cells expressed CK7 (3/3), mammaglobin (3/3, 1 focal), GATA3 (3/3, 1 focal), variably CK5 (3/3), and focally the androgen receptor (1/3), but lacked expression of HER2/neu, SOX10, MUC4, TTF1, S100, and Napsin A. The low-grade tumor showed classic histologic and immunophenotypic features of intercalated-type noninvasive intraductal carcinoma. Molecular profiling showed rearrangements involving exon 20 of ALK in all cases, confirmed by ALK immunohistochemistry (IHC and FISH). The fusion partner was EML4 (n=2) and STRN (n=1) in high-grade tumors and EML4 in the intraductal carcinoma. Two patients with high-grade tumors developed progressive disease (1 died at 9?mo; 1 alive under palliative therapy at 5?mo). This series and a review of 5 published cases indicate that ALK rearrangements characterize 2 distinct subsets of salivary gland carcinomas in the spectrum of high-grade androgen-poor, basal-like SDC (total reported: 5 cases) and low-grade intercalated-type intraductal carcinomas (4 cases). Given the therapeutic relevance of ALK fusions, inclusion of ALK IHC in any atypical-looking or androgen-poor SDC and in high-grade adenocarcinoma-not otherwise specified is recommended. Absence of aberrant ALK expression in genetically characterized secretory (n=15) and intraductal (n=9) carcinomas lacking ALK fusions underlines the value of ALK IHC as a diagnostic screening method for identifying potential cases.
Intraoperative Frozen Section Biopsy of Uterine Smooth Muscle Tumors: A Clinicopathologic Analysis of 112 Cases With Emphasis on Potential Diagnostic Pitfalls
Lok, Johann MBChB, FHKCPath*; Tse, Ka Yu MBBS, FRCOG†; Lee, Elaine Yuen Phin MD, FRCR‡; Wong, Richard Wing Cheuk MBBS, FRCPA§; Cheng, Ivy Shui Ying MBBS, FRCPath?; Chan, Alice Ngot Htain MBBS, FRCPA¶; Leung, Charlotte Ka Lun MBBS, FHKCPath#; Cheung, Annie Nga Yin MD, FRCPath*; Ip, Philip Pun Ching MBChB, FRCPath*
doi : 10.1097/PAS.0000000000001746
September 2021 - Volume 45 - Issue 9 - p 1179-1189
Frozen sections of uterine smooth muscle tumors are infrequently required, and related diagnostic difficulties are seldom discussed. We analyzed the clinicopathologic features of 112 frozen sections of uterine smooth muscle tumors and determined the accuracy, reasons for deferrals, and causes of interpretational errors. Most patients (median age, 45?y) presented with pelvic mass symptoms (53%). The main reasons for a frozen section examination were an abnormal gross appearance including loss of the usual whorled pattern of leiomyoma (36 cases, 32.1%), and intraoperative discovery of an abnormal growth pattern and extrauterine extension of a uterine tumor (28 cases, 25%). There were 9 leiomyosarcomas and 103 leiomyomas, including 18 benign histologic variants. An accurate diagnosis of malignancy was achieved in all leiomyosarcomas, with the exception of a myxoid leiomyosarcoma. In 99 cases (88%), the frozen section diagnosis concurred with the permanent section diagnosis (false positives, 0.9%; false negatives, 0%). Misinterpretation of stromal hyalinization as tumor cell necrosis in a leiomyoma with amianthoid-like fibers was a major discrepancy. Two minor discrepancies did not lead to a change in management. The diagnosis was deferred in 10 cases (8.9%) because of stromal alterations, unusual cellular morphology, uncertain type of necrosis, and abnormal growth patterns. Thus, although various stromal and cellular alterations can cause diagnostic uncertainty, leading to deferrals, frozen section diagnosis of uterine smooth muscle tumors has a high accuracy rate. While a definitive frozen section diagnosis of malignancy may be made when there is unequivocal atypia, indisputable mitotic figures, and tumor cell necrosis, it is important to remember that nonmyogenic mesenchymal tumors may also mimic uterine smooth muscle tumors. In a frozen section setting, it would be sufficient to issue a diagnosis of “malignant mesenchymal tumor.” For tumors that do not meet the criteria for malignancy, issuing a frozen section diagnosis of “atypical mesenchymal tumor and defer the histologic subtyping to the permanent sections” is appropriate.
IDH2 R172 Mutations Across Poorly Differentiated Sinonasal Tract Malignancies: Forty Molecularly Homogenous and Histologically Variable Cases With Favorable Outcome
Glöss, Stefanie MD*,†; Jurmeister, Philipp MD†,‡; Thieme, Anne PhD*,†,§; Schmid, Simone MD*,†; Cai, Wei Y. BS?; Serrette, Rene N. BS?; Perner, Sven MD¶; Ribbat-Idel, Julika MD¶; Pagenstecher, Axel MD#; Bläker, Hendrik MD‡,**; Keber, Ursula MD#; Stadelmann, Christine MD††; Zechel, Sabrina MD††; Johann, Pascal D. MD‡‡,§§; Hasselblatt, Martin MD??; Paulus, Werner MD??; Thomas, Christian MD??; Dohmen, Hildegard MD¶¶; Baumhoer, Daniel MD##; Frank, Stephan MD***; Agaimy, Abbas MD†††; Schüller, Ulrich MD‡‡‡,§§§,???; Vasudevaraja, Varshini MS¶¶¶; Snuderl, Matija MD¶¶¶,###; Liu, Cheng Z. MD, PhD¶¶¶; Pfister, David G. MD****; Jungbluth, Achim A. MD, PhD?; Ghossein, Ronald A. MD?; Xu, Bin MD, PhD?; Capper, David MD*,§; Dogan, Snjezana MD?
doi : 10.1097/PAS.0000000000001697
September 2021 - Volume 45 - Issue 9 - p 1190-1204
IDH2 R172 mutations occur in sinonasal undifferentiated carcinoma (SNUC), large-cell neuroendocrine carcinoma (LCNEC), sinonasal adenocarcinomas, and olfactory neuroblastoma (ONB). We performed a clinical, pathologic, and genetic/epigenetic analysis of a large IDH2-mutated sinonasal tumor cohort to explore their distinct features. A total 165 sinonasal/skull base tumors included 40 IDH2 mutants studied by light microscopy, immunohistochemistry, and genome-wide DNA methylation, and 125 IDH2 wild-type tumors used for comparison. Methylation profiles were analyzed by unsupervised hierarchical clustering, t-distributed stochastic neighbor embedding dimensionality reduction and assessed for copy number alterations (CNA). Thirty-nine histologically assessable cases included 25 (64.1%) SNUC, 8 (20.5%) LCNEC, 2 (5.1%) poorly differentiated adenocarcinomas, 1 (2.7%) ONB, and 3 (7.7%) IDH2-mutated tumors with ONB features. All cases were high-grade showing necrosis (82.4%), prominent nucleoli (88.9%), and median 21 mitoses/10?HPFs. AE1/AE3 and/or CAM 5.2 were positive in all and insulinoma-associated protein 1 (INSM1) in 80% cases. All IDH2 mutants formed one distinct group by t-distributed stochastic neighbor embedding dimensionality reduction separating from all IDH2 wild-type tumors. There was no correlation between methylation clusters and histopathologic diagnoses. Recurrent CNA included 1q gain (79.3%), 17p loss (75.9%), and 17q gain (58.6%). No CNA differences were observed between SNUC and LCNEC. IDH2 mutants showed better disease-specific survival than SMARCB1-deficient (P=0.027) and IDH2 wild-type carcinomas overall (P=0.042). IDH2-mutated sinonasal tumors are remarkably homogeneous at the molecular level and distinct from IDH2 wild-type sinonasal malignancies. Biology of IDH2-mutated sinonasal tumors might be primarily defined by their unique molecular fingerprint rather than by their respective histopathologic diagnoses.
Primary Cilia Are Preserved in Cellular Blue and Atypical Blue Nevi and Lost in Blue Nevus–like Melanoma
Sheahon, Kathleen M. MD*; Jankowski, Tyler DO*; Yeh, Iwei MD, PhD*,†; North, Jeffrey P. MD*,†; Pincus, Laura B. MD*,†; LeBoit, Philip E. MD*,†; McCalmont, Timothy H. MD*,†; Lang, Ursula E. MD, PhD*,‡
doi : 10.1097/PAS.0000000000001739
September 2021 - Volume 45 - Issue 9 - p 1205-1212
Distinguishing cellular blue nevi (CBNs) and atypical CBNs from blue nevus–like melanoma (BNLM) can be diagnostically challenging. Immunohistochemistry may inform the diagnosis in a subset of cases but is not always diagnostic. Further, ancillary molecular testing is expensive and often requires significant tissue to complete. Primary cilia are cell-surface organelles with roles in signal transduction pathways and have been shown to be preserved in conventional melanocytic nevi but lost in melanoma. Immunofluorescence staining of primary cilia can be performed using a single standard-thickness formalin-fixed paraffin-embedded tissue section and has a turnaround time similar to immunohistochemistry. The percentage of tumoral melanocytes retaining a primary cilium is quantified and reported as the ciliation index. In the current study, we explored the utility of the ciliation index in a series of 31 blue nevus–like lesions, including CBNs (12), atypical CBNs (15), and BNLM (4). The average ciliation index for the CBNs was 59±18%, with a median of 60 (range: 28 to 87). The average ciliation index for atypical CBNs was 59±23, with a median of 59 (range: 20 to 93). The average ciliation index for BNLM was 4±3, with a median of 3 (range: 1 to 8). There was no significant difference in ciliation index between the CBN and atypical CBN categories. There was a significant difference between CBN and BNLM and between atypical CBNs and BNLM (P<0.001 for each). Here, we show that ciliation index is a quantitative diagnostic tool useful in the setting of blue nevus–like neoplasms, with benefits including cost and time efficiency.
Human Leukocyte Antigen Class I Deficiency in Gastric Carcinoma: An Adaptive Immune Evasion Strategy Most Common in Microsatellite Instable Tumors
Iwasaki, Akiko MD, PhD*; Shinozaki-Ushiku, Aya MD, PhD*; Kunita, Akiko PhD*; Yamazawa, Sho MD, PhD*; Sato, Yasuyoshi MD, PhD†; Yamashita, Hiroharu MD, PhD‡; Fukayama, Masashi MD, PhD§; Seto, Yasuyuki MD, PhD†; Ushiku, Tetsuo MD, PhD*
doi : 10.1097/PAS.0000000000001779
September 2021 - Volume 45 - Issue 9 - p 1213-1220
Immune checkpoint inhibitor therapy is effective only for a subset of patients with gastric cancer. Impaired neoantigen presentation caused by deficiency of human leukocyte antigen class I (HLA-I) has been reported as a common mechanism of immune evasion which is associated with resistance to immune checkpoint blockade. To elucidate the significance of HLA-I deficiency in gastric cancer with special focus on microsatellite instable (MSI) and Epstein-Barr virus (EBV)-positive tumors, we examined HLA-I expression on tumor cells and correlated the results with clinicopathologic features, programmed death-ligand 1 (PD-L1) expression, and degree of tumor-infiltrating immune cells. This study included 58 MSI, 44 EBV-positive, and 107 non-EBV non-MSI tumors for comparison. The frequency of HLA-I deficiency (?1% tumor cells) was significantly higher in MSI tumors (52%) compared with EBV-positive tumors (23%) and the other tumors (28%). In contrast, PD-L1 expression levels were highest in EBV-positive tumors, followed by MSI tumors, with the lowest prevalence in the other tumors in both Tumor Proportion Score and Combined Positive Score. HLA-I deficiency was significantly more frequent in advanced tumors (pT2-4) than in early tumors (pT1) in MSI and non-EBV non-MSI subtypes. In addition, the degree of CD8-positive cells infiltration was significantly reduced in HLA-I deficient tumor areas compared with HLA-I preserved tumor area within a tumor. Based on our observations, HLA-I, as well as PD-L1, should be considered as a common mechanism of immune escape especially in the MSI subtype, and therefore could be a biomarker predicting response to immune checkpoint inhibitor therapy in gastric cancer.
NUT Is a Specific Immunohistochemical Marker for the Diagnosis of YAP1-NUTM1-rearranged Cutaneous Poroid Neoplasms
Macagno, Nicolas MD, PhD*,†,‡; Kervarrec, Thibault MD, PhD*,§; Sohier, Pierre MD, PhD*,?,¶; Poirot, Brigitte PharmD, PhD#,**; Haffner, Aurélie MD†; Carlotti, Agnès MD*,?; Balme, Brigitte MD*,††; Castillo, Christine MD‡‡; Jullie, Marie-Laure MD*,§§; Osio, Amélie MD*,??; Lehmann-Che, Jacqueline PharmD, PhD¶,#,**; Frouin, Eric MD*,¶¶,##; Battistella, Maxime MD, PhD*,¶,**,??
doi : 10.1097/PAS.0000000000001693
September 2021 - Volume 45 - Issue 9 - p 1221-1227
YAP1-NUTM1 fusion transcripts have been recently reported in poroma and porocarcinoma. NUTM1 translocation can be screened by nuclear protein in testis (NUT) immunohistochemistry in various malignancies, but its diagnostic performance has not been thoroughly validated on a large cohort of cutaneous epithelial neoplasms. We have evaluated NUT immunohistochemical expression in a large cohort encompassing 835 cases of various cutaneous epidermal or adnexal epithelial neoplasms. NUT expression was specific to eccrine poromas and porocarcinoma, with 32% of cases showing NUT expression. All other cutaneous tumors tested lacked NUT expression, including mimickers such as seborrheic keratosis, Bowen disease, basal cell carcinoma, squamous cell carcinoma, Merkel cell carcinoma, nodular hidradenoma, and all other adnexal tumors tested. Remarkably, NUT expression was more frequent in a distinct morphologic subgroup. Indeed, 93% of poroid hidradenoma (dermal/subcutaneous nodular poroma, 13/14) and 80% of poroid hidradenocarcinoma cases (malignant poroid hidradenoma, 4/5) showed NUT expression, in contrast to 17% and 11% of classic poroma (4/23) and porocarcinoma cases (4/35), respectively. RNA sequencing of 12 NUT-positive neoplasms further confirmed the presence of a YAP1-NUTM1 fusion transcript in all cases, and also an EMC7-NUTM1 gene fusion in a single case. In the setting of a cutaneous adnexal neoplasm, nuclear expression of NUT accurately and specifically diagnosed a specific subgroup of benign and malignant poroid tumors, all associated with a NUTM1 fusion, which frequently harbored a poroid hidradenoma morphology.
Atypical Teratoid/Rhabdoid Tumor (AT/RT) With Molecular Features of Pleomorphic Xanthoastrocytoma
Thomas, Christian MD*; Federico, Aniello PhD†,‡; Sill, Martin PhD†,‡; Bens, Susanne MD§; Oyen, Florian?; Nemes, Karolina MD¶; Johann, Pascal D. MD†,‡,¶; Hartmann, Christian MD#; Hartmann, Wolfgang MD**; Sumerauer, David MD††; Paterno, Vincenzo MD‡‡; Samii, Amir MD‡‡; Kordes, Uwe MD?; Siebert, Reiner MD§; Frühwald, Michael C. MD¶; Paulus, Werner MD*; Kool, Marcel PhD†,‡,§§; Hasselblatt, Martin MD*
doi : 10.1097/PAS.0000000000001694
September 2021 - Volume 45 - Issue 9 - p 1228-1234
Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant central nervous system tumor predominantly occurring in infants that may also arise in older children and adults. Rare secondary AT/RT developing from other tumors such as pleomorphic xanthoastrocytoma (PXA) are on record, but AT/RT presenting with molecular features of PXA have not been described. Here, we report 3 malignant central nervous system tumors in children (10, 13, and 18?y old). All tumors were located in the temporal lobe. In 2 cases, there was no history of a low-grade precursor lesion; in 1 case anaplastic PXA had been diagnosed 3 months earlier. Histopathologically, all tumors were composed of RT cells and showed frank signs of malignancy as well as loss of nuclear SMARCB1/INI1 protein expression. Two cases displayed homozygous deletions of the SMARCB1 region while the third case showed an exon 7 mutation (c.849_850delGT; p.Met283Ilefs*77). Of note, DNA methylation profiles did not group with AT/RT or other tumor entities using the Heidelberg Brain Tumor Classifier (version v11b4). By unsupervised t-distributed stochastic neighbor embedding analysis and hierarchical clustering analysis, however, all tumors clearly grouped with PXA. Genome-wide copy number analysis revealed homozygous CDNK2A/B deletions and gains of whole chromosome 7. BRAF V600E mutations could be demonstrated in all cases. In conclusion, the possibility of AT/RT with molecular features of PXA needs to be taken into account and warrants molecular characterization of AT/RT especially in older children. Since treatments targeting mutated BRAF are available, identification of such cases may also have therapeutic consequences.
Prevalence and Predictors of Bacterial Contamination in Excisional Lymph Node Biopsies: Implications for Diagnosis and Management
Hergott, Christopher B. MD, PhD*; Craig, Jeffrey W. MD, PhD†; Hornick, Jason L. MD, PhD*; Weinberg, Olga K. MD‡
doi : 10.1097/PAS.0000000000001699
September 2021 - Volume 45 - Issue 9 - p 1235-1244
Routine tissue handling exposes lymph node specimens to microbial contamination that can confound microbiological culture results and interfere with diagnosis. The scope and impact of this problem remain poorly understood. We combined over 13 years of lymph node pathology, culture data, and patient records to define the prevalence, predisposing factors, microbiology, and clinical management of false-positive lymph node cultures at a large academic medical center. Nearly one third (31.9%) of 216 cultured lymph nodes yielded bacterial growth. Approximately 90% of positive bacterial cultures grew 1 of 2 common skin-resident taxa—coagulase-negative Staphylococcus and Cutibacterium acnes—with well-documented predispositions for contamination in other clinical settings. Lymph nodes excised from axillary, cervical, and inguinal regions yielded higher positive culture rates than nodes excised from the mediastinum, suggesting proximity to the skin surface may increase contamination risk. Accordingly, cultures from thoracoscopic pulmonary resections displayed contamination rates over 5-fold lower than those from percutaneously accessed lymph nodes. Lymph nodal tissue allocated for culture in the operating room yielded unexpectedly high contamination rates, significantly higher than cultures sent from the frozen section processing area. A significant minority of contamination events were noted in the clinical record and prompted antibiotic therapy on multiple occasions. Collectively, our results illuminate the risk factors contributing to bacterial contamination and argue that routine lymph node bacterial cultures provide minimal clinical benefit for adult patients. This widespread bacterial contamination also warrants cautious implementation of increasingly sensitive molecular microbiology tools for excised tissues.
Utility of SOX6 and DAB2 for the Diagnosis of Malignant Mesothelioma
Naso, Julia R. MD, PhD*,†; Cheung, Simon BSc*; Ionescu, Diana N. MD‡; Churg, Andrew MD*,†
doi : 10.1097/PAS.0000000000001712
September 2021 - Volume 45 - Issue 9 - p 1245-1251
The separation of malignant mesothelioma from non–small cell lung carcinomas can be a difficult problem. Sex-determining region Y box 6 (SOX6) and disabled homolog 2 (DAB2) have recently been proposed as sensitive/specific markers of mesothelial lineage, but have not yet been independently tested for utility in mesothelioma diagnosis. Using tissue microarrays containing mesotheliomas (epithelioid: n=40, sarcomatoid: n=23) and non–small cell lung carcinomas (adenocarcinoma: n=52, squamous cell carcinoma: n=57, large cell carcinoma: n=12) we evaluated the performance of SOX6 and DAB2 by themselves, in conjunction with other established mesothelioma markers (calretinin, WT1, D2-40, CK5/6, HEG1) and combined with 3 broad-spectrum established carcinoma markers: claudin-4, MOC31, and BerEP4. For epithelioid mesothelioma, SOX6 and DAB2 had sensitivities of 85% and 98%, respectively. For sarcomatoid mesothelioma, SOX6 had a sensitivity of 13% and DAB2 could not be assessed due to background stromal staining. For SOX6 alone, specificity for mesothelioma versus adenocarcinoma, squamous cell carcinoma, and large cell carcinoma was 94%, 79%, and 92%, respectively, while for DAB2 specificity was 77%, 86%, and 67%. Combinations of SOX6 and established mesothelioma markers produced sensitivities of 95% or greater. A combination of SOX6 positive/claudin-4 negative staining was 95% to 100% specific for mesothelioma versus carcinoma with a sensitivity of 85%. SOX6 is a promising marker for the diagnosis of mesothelioma and potentially could be combined with other mesothelial markers or a broad-spectrum carcinoma marker to reach an accurate diagnosis with relatively few immunostains, The relatively low specificity and difficulty of interpreting DAB2 staining limits its utility for mesothelioma diagnosis.
Steatotic and Steatohepatitic Hepatocellular Carcinomas: Features in a Series With Predominantly Viral Etiology
Aykutlu, Umut MD*; Argon, Asuman MD†; Orman, Mehmet PhD‡; Ulukaya, Sezgin MD§; Zeytunlu, Murat MD?; Karasu, Zeki MD¶; Gün?ar, Fulya MD¶; Nart, Deniz MD#; Akarca, Ulus MD¶; Yilmaz, Funda MD#
doi : 10.1097/PAS.0000000000001714
September 2021 - Volume 45 - Issue 9 - p 1252-1263
Hepatocellular carcinomas (HCCs) with steatohepatitis and steatosis are reported with varying definitions and clinicopathologic features. We aimed to search the attributes of steatohepatitic hepatocellular carcinoma (SH-HCC) and steatotic-HCC in our series. A retrospective clinicopathologic analyses of 150 HCCs and immunostaining for C-reactive protein (CRP) and serum amyloid A (SAA) were performed. Tumors were reclassified as all SH-HCC, limited SH-HCC, typical SH-HCC (steatohepatitic features in >5%, 5% to 50%, and ?50% of the tumor, respectively), steatotic-HCC, and classic HCC (C-HCC). Group comparisons were made using Kruskal-Wallis and Kaplan-Meier tests. The background etiology in all SH-HCCs was pure viral in 51.4%, nonalcoholic steatohepatitis (NASH)/alcoholic liver disease (ALD) alone/mixed in 34.3%, and unidentified in normal liver in 14.3%. All SH-HCCS (n=35, 23.3%) and typical SH-HCCs (n=13, 8.6%) had higher NASH/ALD. Limited SH-HCCs (n=22, 14.6%) had higher ALD (all P<0.05). Typical SH-HCCs tended to have more NASH (P=0.054). Steatotic-HCCs (n=13, 9%) and C-HCCs (n=102, 68%) had higher pure viral etiology and serum CRP (all P<0.05). CRP and SAA were positive in 69% and 27% of the tumors, respectively. SAA positivity correlated with ALD (P=0.026). In the overall group disease-free survival rates at 1, 5, 10, and 20 years were 97.0%, 82.3%, 79.6%, and 77.2%, respectively. Demographics, tumor characteristics, CRP and SAA positivity, and survival were similar between the groups (P>0.05). SH-HCC is heterogenous in terms of underlying etiologies, and can be seen in NASH/ALD, pure viral and noncirrhotic/normal background. The ?50% cutoff for the definition of SH-HCC can lead to overlook ALD-related SH-HCC. Steatotic-HCC seems more similar to C-HCC rather than SH-HCC, but none of them feature as a different prognostic group.
Significance of Alpha-inhibin Expression in Pheochromocytomas and Paragangliomas
Mete, Ozgur MD*,†,‡; Pakbaz, Sara MD*,†; Lerario, Antonio M. MD, PhD§; Giordano, Thomas J. MD, PhD§,?; Asa, Sylvia L. MD, PhD¶
doi : 10.1097/PAS.0000000000001715
September 2021 - Volume 45 - Issue 9 - p 1264-1273
Alpha-inhibin expression has been reported in pheochromocytomas and paragangliomas (PPGLs). We analyzed alpha-inhibin immunohistochemistry in 77 PPGLs (37 pheochromocytomas [PCCs] and 40 paragangliomas) and correlated the results with catecholamine profile, tumor size, Ki-67 labeling index, succinate dehydrogenase B subunit and carbonic anhydrase IX (CAIX) staining, and genetic pathogenesis. PPGLs were classified as pseudohypoxic cluster 1 disease with documented VHL mutation or SDHx mutation or biochemical phenotype, whereas NF1-driven and RET-driven PPGLs and those with a mature secretory (adrenergic or mixed adrenergic and noradrenergic) phenotype were classified as cluster 2 disease. The Cancer Genome Atlas data on INHA expression in PPGLs was examined. Alpha-inhibin was positive in 43 PPGLs (56%). Ki-67 labeling indices were 8.07% and 4.43% in inhibin-positive and inhibin-negative PPGLs, respectively (P<0.05). Alpha-inhibin expression did not correlate with tumor size. Alpha-inhibin was expressed in 92% of SDHx-related and 86% of VHL-related PPGLs. CAIX membranous staining was found in 8 of 51 (16%) tumors, including 1 SDHx-related PCC and all 5 VHL-related PCCs. NF1-driven and RET-driven PPGLs were negative for alpha-inhibin and CAIX. Alpha-inhibin was expressed in 77% of PPGLs with a pseudohypoxia signature, and 20% of PPGLs without a pseudohypoxia signature (P<0.05). PPGLs with a mature secretory phenotype were negative for CAIX. The Cancer Genome Atlas data confirmed higher expression of INHA in cluster 1 than in cluster 2 PPGLs. This study identifies alpha-inhibin as a highly sensitive (90.3%) marker for SDHx/VHL-driven pseudohypoxic PPGLs. Although CAIX has low sensitivity, it is the most specific biomarker of VHL-related pathogenesis. While alpha-inhibin cannot replace succinate dehydrogenase B subunit immunohistochemistry for detection of SDHx-related disease, it adds value in prediction of cluster 1 disease. Importantly, these data emphasize that alpha-inhibin is not a specific marker of adrenal cortical differentiation, as it is also expressed in PCCs.
PD-L1 Expression in Metaplastic Breast Carcinoma Using the PD-L1 SP142 Assay and Concordance Among PD-L1 Immunohistochemical Assays
Grabenstetter, Anne MD*; Jungbluth, Achim A. MD, PhD*; Frosina, Denise BS*; Hoda, Raza MD*; Dos Anjos, Carlos H. MD†; Patil, Sujata PhD‡; Sevilimedu, Varadan MBBS, DrPH‡; Weigelt, Britta PhD*; Reis-Filho, Jorge S. MD, PhD*; Zhang, Hong MD, PhD*; Traina, Tiffany MD†; Robson, Mark E. MD†; Brogi, Edi MD, PhD*; Wen, Hannah Y. MD, PhD*
doi : 10.1097/PAS.0000000000001760
September 2021 - Volume 45 - Issue 9 - p 1274-1281
Immunotherapy for the treatment of programmed death-ligand 1 (PD-L1) positive locally advanced or metastatic triple negative breast cancer may benefit patients with metaplastic breast cancer (MpBC). Previous study of PD-L1 in MpBC scored tumor cells (TCs), different from Food and Drug Administration-approved scoring methods. We sought to define PD-L1 expression in MpBCs and to evaluate concordance of 3 PD-L1 assays. Primary, treatment naive MpBC treated at our Center from 1998 to 2019 were identified. PD-L1 expression was assessed using SP142, E1L3n, and 73-10. We evaluated PD-L1 expression on tumor infiltrating immune cells (IC) and also in TCs. For each assay, we scored PD-L1 expression using ?1% IC expression according to the IMpassion130 trial criteria and using combined positive score (CPS) ?10 according to the KEYNOTE-355 trial cutoff. A total of 42 MpBCs were identified. Most MpBC had PD-L1 positivity in ?1% IC with all 3 assays (95%, 95%, 86%) in contrast to a maximum 71% with a CPS ?10. PD-L1 IC expression was comparable between the SP142 and 73-10 assays and was lowest with E1L3n. PD-L1 TC expression was lowest using SP142. The overall concordance for IC scoring was 88% while 62% had concordant CPS. For each assay, the results of the 2 scoring algorithms were not interchangeable. The SP142 assay showed distinct expression patterns between IC (granular, dot-like) and TC (membranous) while 73-10 and E1L3n showed membranous and/or cytoplasmic expression in both IC and TC. Most MpBC in our cohort were positive for PD-L1 indicating eligibility for anti-PD-L1/programmed death-1 immunotherapy.
Atypical Pleomorphic Lipomatous Tumor: Expanding Our Current Understanding in a Clinicopathologic Analysis of 64 Cases
Anderson, William J. MBChB; Fletcher, Christopher D.M. MD, FRCPath; Jo, Vickie Y. MD
doi : 10.1097/PAS.0000000000001706
September 2021 - Volume 45 - Issue 9 - p 1282-1292
Atypical pleomorphic lipomatous tumor (APLT) is a recently recognized adipocytic neoplasm that lies on a spectrum with atypical spindle cell lipomatous tumor (ASCLT). APLT/ASCLT are included together in the fifth edition World Health Organization Classification of Soft Tissue and Bone Tumours; however limited data on APLT have emerged since its first description in 2017. This study aims to further define the clinicopathologic features of APLT in a large series of 64 cases. Histologic features and ancillary studies were reviewed, and clinical and follow-up data were obtained from referring institutions. Immunohistochemistry for MDM2, CDK4, CD34, Rb, S100, and desmin was performed in cases with available material. Patients were 24 females and 40 males, and the median age was 61 years (range, 20 to 89?y). Tumors arose in upper limb (33%), lower limb (31%), trunk (23%), head and neck (8%), breast (3%), and inguinal region (2%), with a median size of 5.4?cm (range, 1.5 to 14.5?cm). Tumor depth was mostly subcutaneous or deep/subfascial. Microscopically, APLTs were variably composed of atypical spindle and pleomorphic cells, adipocytes, and lipoblasts, often showing infiltrative growth, myxoid or collagenous stroma, and multinucleate floret cells. Mitoses were infrequent and necrosis was consistently absent. By immunohistochemistry, tumors expressed CD34 (63%), S100 (19%), and desmin (28%). APLT showed frequent loss of Rb (79%; 46/58). Rare cases showed staining for MDM2 (2%) or CDK4 (12%); however, fluorescence in situ hybridization was negative for MDM2 amplification in all cases tested (0/22). Follow-up in 28 patients (median duration: 21?mo) revealed a single patient with local recurrence (4%); no patient developed metastatic disease. Despite its frequently infiltrative growth, nuclear pleomorphism, and hypercellularity which can mimic sarcoma, APLT behaves in an indolent manner and should be distinguished from its more aggressive mimics, including atypical lipomatous tumor/well-differentiated liposarcoma and pleomorphic liposarcoma. Immunohistochemistry for CD34, S100, desmin, and Rb (demonstrating loss), as well as exclusion of MDM2 amplification, can support the diagnosis.
PD-1 and PD-L1 Immunohistochemistry as a Diagnostic Tool for Classic Hodgkin Lymphoma in Small-volume Biopsies
Uccella, Silvia MD, PhD*; Magnoli, Francesca MD, PhD†; Vivian, Lisa F. MD*; Marchiori, Deborah MD*; Leoni, Eleonora MD*; Tibiletti, Maria G. BD†; Sessa, Fausto MD*
doi : 10.1097/PAS.0000000000001654
September 2021 - Volume 45 - Issue 9 - p 1293-1296
Response To: PD-1 and PD-L1 Immunohistochemistry as a Diagnostic Tool for Classic Hodgkin Lymphoma in Small-volume Biopsies
Volaric, Ashley K. MD*,†; Gru, Alejandro A. MD†
doi : 10.1097/PAS.0000000000001743
September 2021 - Volume 45 - Issue 9 - p 1296-1297
