Clinical Focus


  • Pathology
  • Genitourinary Pathology
  • Surgical Pathology

Academic Appointments


  • Associate Professor - University Medical Line, Pathology

Administrative Appointments


  • Director of Genitourinary Pathology Fellowship, Department of Pathology (2018 - Present)
  • Director of Genitourinary Pathology Service, Department of Pathology (2017 - Present)

Honors & Awards


  • ASCP 40 under Forty, ASCP (2016)

Professional Education


  • Medical Education: Indiana University School of Medicine (2010) IN
  • Fellowship: Massachusetts General Hospital (2015) MA
  • Board Certification: American Board of Pathology, Pathology (2014)
  • Residency: Indiana University School of Medicine and Affilated Hospitals (2014) IN

Current Research and Scholarly Interests


Genitourinary tumors with a special interest in Testicular tumors

2022-23 Courses


All Publications


  • Molecular correlates of male germ cell tumors with overgrowth of components resembling somatic malignancies. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc Wyvekens, N., Sholl, L. M., Yang, Y., Tran, I., Vasudevaraja, V., Dickson, B. C., Al-Obaidy, K. I., Baniak, N., Collins, K., Gordetsky, J. B., Idrees, M. T., Kao, C. S., Maclean, F., Matoso, A., Ulbright, T. M., Wobker, S. E., Fletcher, C. D., Hirsch, M. S., Hornick, J. L., Snuderl, M., Acosta, A. M. 2022

    Abstract

    A small subset of male germ cell tumors (GCT) demonstrates overgrowth of histologic components that resemble somatic malignancies (e.g., sarcoma, carcinoma). The presence of so-called "somatic-type" malignancies (SM) in GCT has been associated with chemotherapy-resistance and poor clinical outcomes in prior studies. However, the molecular characteristics of these tumors remain largely undescribed. In this study, we performed a multi-platform molecular analysis of GCTs with SM diagnosed in 36 male patients (primary site: testis, 29 and mediastinum, 7). The most common histologic types of SM were sarcoma and embryonic-type neuroectodermal tumor (ENT, formerly known as "PNET"), present in 61% and 31% of cases, respectively. KRAS and TP53 mutations were identified by DNA sequencing in 28% of cases each, with enrichment of TP53 mutations in mediastinal tumors (86%). Gains in the short arm of chromosome 12 were seen in 91% of cases, likely reflecting the presence of isochromosome 12p. Numerous copy number changes indicative of widespread aneuploidy were found in 94% of cases. Focal homozygous deletions and amplifications were also detected, including MDM2 amplifications in 16% of cases. Sequencing of paired samples in 8 patients revealed similar mutational and copy number profiles in the conventional GCT and SM components. Oncogenic gene fusions were not detected using RNA sequencing of SM components from 9 cases. DNA methylation analysis highlighted the distinct methylation profile of SM components that sets them apart from conventional GCT components. In conclusion, GCT with SM are characterized by widespread aneuploidy, a distinct epigenetic signature and the presence of mutations that are otherwise rare in testicular GCT without SM. The similarity of the mutational and DNA methylation profiles of different histologic types of SM suggests that the identification of SM components could be more important than their precise histologic subclassification, pending confirmation by further studies.

    View details for DOI 10.1038/s41379-022-01136-1

    View details for PubMedID 36030288

  • Answer to April 2022 Photo Quiz. Journal of clinical microbiology Wang, H., Zhang, J., Kao, C., Budvytiene, I., Ho, D. Y., Mathison, B., Hogan, C. A. 2022; 60 (4): e0124721

    View details for DOI 10.1128/jcm.01247-21

    View details for PubMedID 35442073

  • Photo Quiz: A 25-Year-Old Man with Hematuria and a Bladder Nodule. Journal of clinical microbiology Wang, H., Zhang, J., Kao, C., Budvytiene, I., Ho, D. Y., Mathison, B., Hogan, C. A. 2022; 60 (4): e0124621

    View details for DOI 10.1128/jcm.01246-21

    View details for PubMedID 35442076

  • Clinicopathologic Spectrum of Secondary Solid Tumors of the Prostate of Nonurothelial Origin: Multi-institutional Evaluation of 85 Cases. The American journal of surgical pathology Acosta, A. M., Gordetsky, J. B., Collins, K., Osunkoya, A. O., Sangoi, A. R., Miyamoto, H., Kao, C. S., Trpkov, K., Van Leenders, G. J., Wobker, S. E., Maclean, F., Lal, P., Daniel, R. E., Brimo, F., Wasco, M., Hirsch, M. S., Baniak, N., Diaz-Perez, J. A., Cornejo, K. M., Choy, B., Mehra, R., Williamson, S. R., Epstein, J. I., Matoso, A. 2022

    Abstract

    Secondary involvement of the prostate by urothelial or hematolymphoid neoplasms is relatively common and well-described. In contrast, less is known about the clinicopathologic spectrum of secondary solid tumors of the prostate of nonurothelial origin. This study evaluated a series of secondary nonurothelial solid tumors of the prostate diagnosed at 21 institutions. Eighty-five patients with a median age at diagnosis of 64 years were included. Sixty-two patients had clinically manifest disease (62/85, 73%), 10 were diagnosed incidentally (10/85, 12%), and 13 (13/85, 15%) had no detailed clinical data available about symptomatology at presentation. Among patients with clinically manifest disease, the most common symptoms and signs were lower urinary tract symptoms (either obstructive of irritative; 36/62, 58%), abdominal or pelvic pain or discomfort (16/62, 26%), and hematuria (12/62, 19%). Metastasis and direct invasion occurred at roughly similar frequencies (47% vs. 42%) in this series, and in 11% of the cases, the mechanism of spread to the prostate was unclear/uncertain. Overall, among tumors with confirmed sites of origin, the most common primary sites were gastrointestinal tract (53/85, 62%), lung (9/85, 11%), skin (6/85, 7%), and testis (4/85, 5%). Among metastases, the most common tumor types were lung carcinomas (9/40, 23%), colorectal adenocarcinomas (7/40, 18%), melanoma (6/40, 15%), and germ cell tumors (6/40, 15%). This study demonstrated that secondary involvement of the prostate by solid tumors of nonurothelial origin is commonly symptomatic and that the most frequent sites of origin are the gastrointestinal tract, lung, skin, and testis. These findings are worth considering when lesions with unusual cytomorphology and/or architecture are encountered in prostate specimens.

    View details for DOI 10.1097/PAS.0000000000001907

    View details for PubMedID 35900850

  • Granulomas associated with renal neoplasms: A multi-institutional clinicopathological study of 111 cases. Histopathology Sangoi, A. R., Maclean, F., Mohanty, S., Hes, O., Daniel, R., Lal, P., Canete-Portillo, S., Magi-Galluzzi, C., Cornejo, K. M., Collins, K., Hwang, M., Falzarano, S. M., Feely, M. M., Dababneh, M., Harik, L., Tretiakova, M., Akgul, M., Manucha, V., Chan, E., Kao, C., Siadat, F., Arora, K., Barkan, G., Cheng, L., Hirsch, M., Lei, L., Wasco, M., Williamson, S. R., Acosta, A. M. 2022

    Abstract

    AIMS: Formal depiction of granulomatous inflammation associated with renal neoplasms has mainly consisted of case reports. Herein, we investigate the clinicopathological features and potential significance of granulomas associated with renal tumours from a large multi-institutional cohort.METHODS AND RESULTS: One hundred and eleven study cases were collected from 22 institutions, including 57 partial nephrectomies and 54 radical nephrectomies. Patient ages ranged from 27 to 85years (average=60.1years; male=61%). Renal neoplasms included clear cell renal cell carcinoma (RCC; 86%), papillary RCC (8%), chromophobe RCC (3%), clear cell papillary RCC (1%), mixed epithelial stromal tumour (1%) and oncocytoma (1%). Granulomas were peritumoral in 36%, intratumoral in 24% andboth in 40% of cases. Total granuloma count per case ranged from one to 300 (median=15) withsizes ranging from 0.15 to 15mm (mean= 1.9mm). Necrotising granulomas were seen in 14%of cases. Histochemical stains for organisms were performed on 45% of cases (all negative). Sixteen cases (14%) had a prior biopsy/procedure performed, and eight patients had neoadjuvant immunotherapy or chemotherapy. Eleven patients (10%) had a confirmed diagnosis of sarcoidosis, including five in whom sarcoidosis was diagnosed after nephrectomy.CONCLUSION: Based on this largest case-series to date, peri-/intratumoral granulomas associated with renal neoplasms may be more common than initially perceived. The extent of granulomatous inflammation can vary widely and may or may not have necrosis with possible aetiologies, including prior procedure or immunotherapy/chemotherapy.Although a clinical association with sarcoidosisis infrequent it can still occur, and the presence of granulomas warrants mention in pathology reports.

    View details for DOI 10.1111/his.14633

    View details for PubMedID 35347739

  • Molecular Characterization of Urachal Neoplasms Khan, O., Kunder, C., Kao, C., Sangoi, A. SPRINGERNATURE. 2022: 614-615
  • Molecular Correlates of Male Germ Cell Tumors with Overgrowth of Components Resembling "Somatic" Malignancies: Multi-Platform Analysis of a Collaborative Series Wyvekens, N., Sholl, L., Dickson, B., Idrees, M., Collins, K., Al-Obaidy, K., Gordetsky, J., Matoso, A., Maclean, F., Fletcher, C., Hornick, J., Baniak, N., Kao, C., Hirsch, M., Wobker, S., Acosta, A. SPRINGERNATURE. 2022: 700-701
  • Clear Cell Renal Cell Carcinoma with Psammomatous Calcifications: A Rare Occurrence Mimicking Translocation Carcinoma Sangoi, A., Al-Obaidy, K., Cheng, L., Kao, C., Chan, E., Sadasivan, S., Alvarado-Cabrero, I., Kunju, L., Dhillon, J., Tretiakova, M., Smith, S., Hes, O., Williamson, S. SPRINGERNATURE. 2022: 664
  • Clear Cell Renal Cell Carcinoma with Psammomatous Calcifications: A Rare Occurrence Mimicking Translocation Carcinoma Sangoi, A., Al-Obaidy, K., Cheng, L., Kao, C., Chan, E., Sadasivan, S., Alvarado-Cabrero, I., Kunju, L., Dhillon, J., Tretiakova, M., Smith, S., Hes, O., Williamson, S. SPRINGERNATURE. 2022: 664
  • Molecular Characterization of Urachal Neoplasms Khan, O., Kunder, C., Kao, C., Sangoi, A. SPRINGERNATURE. 2022: 614-615
  • Molecular Correlates of Male Germ Cell Tumors with Overgrowth of Components Resembling "Somatic" Malignancies: Multi-Platform Analysis of a Collaborative Series Wyvekens, N., Sholl, L., Dickson, B., Idrees, M., Collins, K., Al-Obaidy, K., Gordetsky, J., Matoso, A., Maclean, F., Fletcher, C., Hornick, J., Baniak, N., Kao, C., Hirsch, M., Wobker, S., Acosta, A. SPRINGERNATURE. 2022: 700-701
  • Association of renal cell carcinoma (RCC) metastatic to pancreas with a distinct molecular profile and immune cell population. Chiang, R. S., Ashok, A., Mauer, E., Barrett, A., Hoerner, C. R., Khan, O. A., Kao, C., Shah, S., Srinivas, S., Fan, A. C., Khaki, A. LIPPINCOTT WILLIAMS & WILKINS. 2022
  • Expanding the clinicopathological spectrum of succinate dehydrogenase-deficient renal cell carcinoma with a focus on variant morphologies: a study of 62 new tumors in 59 patients. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc Fuchs, T. L., Maclean, F., Turchini, J., Vargas, A. C., Bhattarai, S., Agaimy, A., Hartmann, A., Kao, C., Ellis, C., Bonert, M., Leroy, X., Kunju, L. P., Schwartz, L., Matsika, A., Williamson, S. R., Rao, P., Divatia, M., Guarch, R., Algaba, F., Balancin, M. L., Zhou, M., Samaratunga, H., da Cunha, I. W., Brimo, F., Ryan, A., Clouston, D., Aron, M., O'Donnell, M., Chan, E., Hirsch, M. S., Moch, H., Pang, C., Wah, C., Yin, W., Perry-Keene, J., Yilmaz, A., Chou, A., Clarkson, A., van der Westhuizen, G., Morrison, E., Zwi, J., Hes, O., Trpkov, K., Gill, A. J. 1800

    Abstract

    Most succinate dehydrogenase (SDH)-deficient renal cell carcinomas (RCCs) demonstrate stereotypical morphology characterized by bland eosinophilic cells with frequent intracytoplasmic inclusions. However, variant morphologic features have been increasingly recognized. We therefore sought to investigate the incidence and characteristics of SDH-deficient RCC with variant morphologies. We studied a multi-institutional cohort of 62 new SDH-deficient RCCs from 59 patients. The median age at presentation was 39 years (range 19-80), with a slight male predominance (M:F=1.6:1). A relevant family history was reported in 9 patients (15%). Multifocal or bilateral tumors were identified radiologically in 5 patients (8%). Typical morphology was present at least focally in 59 tumors (95%). Variant morphologies were seen in 13 (21%) and included high-grade nuclear features and various combinations of papillary, solid, and tubular architecture. Necrosis was present in 13 tumors, 7 of which showed variant morphology. All 62 tumors demonstrated loss of SDHB expression by immunohistochemistry. None showed loss of SDHA expression. Germline SDH mutations were reported in all 18 patients for whom the results of testing were known. Among patients for whom follow-up data was available, metastatic disease was reported in 9 cases, 8 of whom had necrosis and/or variant morphology in their primary tumor. Three patients died of disease. In conclusion, variant morphologies and high-grade nuclear features occur in a subset of SDH-deficient RCCs and are associated with more aggressive behavior. We therefore recommend grading all SDH-deficient RCCs and emphasize the need for a low threshold for performing SDHB immunohistochemistry in any difficult to classify renal tumor, particularly if occurring at a younger age.

    View details for DOI 10.1038/s41379-021-00998-1

    View details for PubMedID 34949766

  • EXTERNAL VALIDATION OF AN ARTIFICIAL INTELLIGENCE ALGORITHM FOR PROSTATE CANCER GLEASON GRADING AND TUMOR QUANTIFICATION Schmidt, B., Bhambhvani, H. P., Fan, R. E., Kunder, C., Kao, C., Higgins, J. P., Rusu, M., Sonn, G. A. LIPPINCOTT WILLIAMS & WILKINS. 2021: E1004
  • Nodular Maturation of the Testis: A Non-neoplastic Lesion of Boys That May Present as a Mass on Clinical and Ultrasound Examination. The American journal of surgical pathology Przybycin, C. G., Williamson, S. R., Kao, C., Reyes-Mugica, M., Ulbright, T. M., McKenney, J. K. 2021

    Abstract

    We have encountered a lesion of the pediatric testis, termed "nodular maturation," that clinically mimics a testicular neoplasm causing ultrasound abnormalities that may lead to surgical excision. To our knowledge, it has only been described anecdotally in textbooks without a series or description in the literature. We, therefore, report 8 cases in pediatric patients emphasizing the clinical presentation, ultrasound findings, histologic features, and clinical follow-up information. Patients ranged in age from 5 to 11 years (mean: 7.9 y). Precocious puberty was identified in 1 patient as isolated penile enlargement without other signs; another had a history of McCune-Albright syndrome, but did not have signs of precocious puberty; others had no clinical manifestations. All patients had testicular abnormalities on ultrasound; 6 had a discrete lesion and 2 showed diffuse testicular enlargement. In the 6 cases with available data, mean size of the lesion on ultrasound was 0.9 cm (range: 0.4 to 1.7 cm). In the 3 cases for which macroscopic descriptions were available, no gross abnormalities were noted in the testicular parenchyma, despite the ultrasound findings. Histologically, nodular maturation occurred as a zone of more mature testicular parenchyma having larger, lumen-bearing seminiferous tubules that contrasted with the smaller, immature cords of the remaining parenchyma. The mature tubules showed germ cell maturation (to the level of late spermatids/spermatozoa in 6 cases), mature Sertoli cells, and, in 4 cases, admixed nodules of mature Leydig cells. Of the 6 patients with available follow-up information, none developed a testicular neoplasm. Given its ability to cause a lesion on ultrasound leading to surgical intervention, pathologists, radiologists, and urologists should be aware of nodular maturation.

    View details for DOI 10.1097/PAS.0000000000001775

    View details for PubMedID 34881635

  • Immunohistochemical Characterization of 120 Testicular Sex Cord-Stromal Tumors With an Emphasis on the Diagnostic Utility of SOX9, FOXL2, and SF-1. The American journal of surgical pathology Lau, H. D., Kao, C., Williamson, S. R., Cheng, L., Ulbright, T. M., Idrees, M. T. 2021

    Abstract

    Sex cord-stromal tumors (SCSTs) account for the second most common category of testicular neoplasms and include several entities that may show overlapping morphologies and present diagnostic challenges. We analyzed a cohort of 120 testicular SCSTs and investigated the diagnostic utility of SRY-box transcription factor 9 (SOX9), forkhead box protein L2 (FOXL2), and steroidogenic factor 1 (SF-1) immunohistochemical stains. The results were compared with the more commonly used SCST markers, inhibin alpha, calretinin, and Wilms' tumor 1 (WT1). SF-1 was overall the most sensitive stain (91%), followed by inhibin alpha (70%), calretinin (52%), FOXL2 (50%), SOX9 (47%), and WT1 (37%), but sensitivities varied by tumor type. SOX9 and calretinin were more commonly positive in sex cord elements versus stromal elements (62% vs. 27% and 47% vs. 9%, respectively), whereas FOXL2 was more commonly positive in stromal elements versus sex cord elements (100% vs. 55%) when excluding Leydig cell tumors from the stromal category. Although no individual stain was diagnostically specific, some immunophenotypic patterns were noted that may help in the subclassification of SCSTs. We conclude that SOX9, FOXL2, and SF-1 are useful immunohistochemical stains for confirming sex cord-stromal differentiation in testicular tumors and provide increased sensitivity as well as additional diagnostic information, especially when combined with the more commonly used inhibin alpha, calretinin, and WT1 immunostains. Although morphology is paramount for subclassification of SCSTs, knowledge of certain immunohistochemical patterns may be helpful for diagnostically challenging cases.

    View details for DOI 10.1097/PAS.0000000000001704

    View details for PubMedID 34232606

  • Molekularpathologie bei urologischen Tumoren : Empfehlungen der Konsenskonferenz der Internationalen Gesellschaft fur Uropathologie (ISUP) 2019. Der Pathologe Hommerding, O., Allory, Y., Argani, P., Bismar, T. A., Bubendorf, L., Canete-Portillo, S., Chaux, A., Chen, Y., Cheng, L., Cubilla, A. L., Egevad, L., Gill, A. J., Grignon, D. J., Hartmann, A., Hes, O., Idrees, M. T., Kao, C., Knowles, M. A., Looijenga, L. H., Lotan, T. L., Pritchard, C. C., Rubin, M. A., Tomlins, S. A., Van der Kwast, T. H., Velazquez, E. F., Warrick, J. I., Williamson, S. R., Kristiansen, G. 2021

    Abstract

    Comprehensive understanding of molecular principles in cancer and the diversification of oncological therapy promise individual therapeutic concepts, which have not yet found their way into urogenital cancer therapy. In March 2019 the International Society of Urogenital Pathology (ISUP) therefore held aconsensus conference on recommendations for molecular diagnostics of genitourinary tumors, which were published in five separate manuscripts and are summarized in this article.In preparation for the conference, a comprehensive survey of current practices for molecular testing of urogenital tumors was carried out by members of the ISUP. At the conference, the results and the corresponding background information were presented by five working groups and recommendations for action for diagnostics were developed. An agreement between 66% of the conference participants was defined as consensus.

    View details for DOI 10.1007/s00292-020-00888-4

    View details for PubMedID 33398501

  • Large Cell Calcifying Sertoli Cell Tumour: A Contemporary Multi-Institutional Case Series Highlighting the Diagnostic Utility of PRKAR1A Immunohistochemistry. Histopathology Anderson, W. J., Gordetsky, J. B., Idrees, M. T., Al-Obaidy, K. I., Kao, C. S., Cornejo, K. M., Wobker, S. E., Cheville, J. C., Vargas, S. O., Fletcher, C. D., Hirsch, M. S., Acosta, A. M. 2021

    Abstract

    Large cell calcifying Sertoli cell tumour (LCCSCT) is a rare testicular sex cord-stromal tumour that primarily affects young patients and is associated with Carney complex. We sought to characterize the clinicopathological features of a series of LCCSCT and evaluate the diagnostic utility of PRKAR1A immunohistochemistry (IHC).The LCCSCT cohort (n=15) had a median age of 16 years (range: 2-30 years). Four patients were known to have Carney complex. PRKAR1A IHC was performed in each case. For comparison, PRKAR1A IHC was also assessed in other sex cord-stromal tumours, including Sertoli cell tumour, not otherwise specified (SCT, NOS; n=10), intratubular large cell hyalinizing Sertoli cell tumour (n=1), and Leydig cell tumour (n=23). Loss of cytoplasmic PRKAR1A expression was observed in all but one LCCSCT (14/15; 93%). PRKAR1A expression was retained in all SCTs, NOS (10/10; 100%), the majority of Leydig cell tumours (22/23; 96%), and an intratubular large cell hyalinizing Sertoli cell tumour (1/1; 100%). One Leydig cell tumour showed equivocal staining (multifocal weak expression).Overall, PRKAR1A loss is both sensitive (93%) and highly specific (97%) for the diagnosis of LCCSCT. PRKAR1A loss may aid its diagnosis, particularly in sporadic cases and those that are the first presentation of Carney complex.

    View details for DOI 10.1111/his.14599

    View details for PubMedID 34780072

  • Vasculogenic Mesenchymal Tumor: A Clinicopathologic and Molecular Study of 55 Cases of a Distinctive Neoplasm Originating From Mediastinal Yolk Sac Tumor and an Occasional Precursor to Angiosarcoma. The American journal of surgical pathology Levy, D. R., Agaram, N. P., Kao, C., Franks, S. E., Kesler, K. A., Stram, A. R., Einhorn, L. H., Bangs, C. D., Ulbright, T. M. 2020

    Abstract

    We report 55 postchemotherapy resections of primary nonseminomatous mediastinal germ cell tumors with prominent vasculogenic features showing the formation of rudimentary to well-developed neoplastic vessels within primitive mesenchyme. These cases represented 25% of a cohort of 221 such specimens. The patients were 19 to 49 years old (mean, 28y) and 98% had serological evidence of yolk sac tumor. The vasculogenic lesions, felt to represent a neoplastic reiteration of embryonic vasculogenesis in the splanchnic mesoderm of the yolk sac, were further subdivided into teratoma with vasculogenic stroma (n=9), vasculogenic mesenchymal tumor (VMT) (n=42, further classified into low grade [n=24] and high grade [n=18]), and angiosarcoma (n=4). The distinction of teratoma with vasculogenic stroma from VMT was based solely on the greater extent of VMT (exceeding 1 low power [*4 objective] microscopic field), with both categories showing a spectrum of vessels lined by atypical endothelium in a nonendothelial neoplastic stroma that often also generated vascular walls comprised of atypical smooth muscle. The angiosarcomas showed stratification of highly atypical endothelial cells or anastomosing vessels lined by nonstratified but cytologically similar endothelium. Immunohistochemical studies supported the generation of neoplastic vessels from the tumor stroma, most commonly by the development of stromal clefts showing reactivity for podoplanin, CD34, and occasionally ERG, followed by the gradual development from the clefts of thin-walled vessels that later became encircled by stromal cells showing smooth muscle differentiation by immunohistochemistry. Occasionally, round collections of stromal erythrocytes became surrounded by stromal cells to generate blood vessels. Fluorescence in situ hybridization showed chromosome 12p copy number increase in both the endothelial component and stromal component in 8/9 VMT cases and in 1/1 angiosarcoma. On follow-up, no patient with teratoma with vasculogenic stroma had evidence of a subsequent vascular tumor or sarcoma, whereas 8 of the 35 (23%) patients with VMTs (2 low grade and 6 high grade) and meaningful follow-up developed sarcoma (1 angiosarcoma, 2 rhabdomyosarcomas, and 5 not further characterized). The difference between low-grade and high-grade tumors was of borderline significance (P=0.058). Two of the 4 patients with angiosarcoma died of metastatic angiosarcoma, with the other 2 disease-free at 6.8 and 7 years. Compared with the 165 patients with follow-up and no vasculogenic lesions, there was a highly significant (P=4.3*10) association of any vasculogenic lesion with sarcomatoid tumors during the clinical course of VMT patients. In addition, 5/46 patients with follow-up and vasculogenic lesions (11%) died of either leukemia or myelodysplastic syndrome compared with 2 of 166 (1%) lacking them (P=0.0012). Three of the 5 patients had identifiable immature hematopoietic cells within their vasculogenic lesions, but 4 other VMT patients with these did not develop leukemia or myelodysplasia. We conclude: (1) vasculogenic lesions are frequent in postchemotherapy resections of primary mediastinal germ cell tumors with yolk sac tumor components; (2) they mostly consist of neoplastic vessels in a stroma that also generates neoplastic vascular walls of smooth muscle; (3) VMTs are associated with an increased incidence of sarcomas, even though most vasculogenic lesions in this context do not meet criteria for angiosarcoma; (4) the presence of vasculogenic lesions in postchemotherapy resections of primary mediastinal germ cell tumors place patients at increased risk for leukemia or myelodysplasia.

    View details for DOI 10.1097/PAS.0000000000001615

    View details for PubMedID 33136584

  • Histopathologic Characterization of Bladder Perivascular Epithelioid Cell Neoplasms (PEComa): A Series of 11 Cases With a Subset Having TFE3 Rearrangements. The American journal of surgical pathology Neumann, N. M., Haffner, M. C., Argani, P., Kao, C., Epstein, J. I. 2020

    Abstract

    Perivascular epithelioid cell neoplasms (PEComas) of the bladder are extremely rare, with ~30 case reports. A subset of PEComas contain TFE3 gene rearrangement, however, the distinct histomorphologic features of these translocation tumors has not been fully explored in bladder PEComas. In our series, 11 cases of bladder PEComas were collected, including 1 internal and 10 consults, with 1 case previously reported. There was a female predominance (9 female, 2 male) with a mean age of 44.2 years (24 to 61y). In only 1 of the 10 consult cases was PEComa considered in the differential diagnosis. In 10 of 11 cases, prominent epithelioid features were noted, with the final case having focal epithelioid morphology. Mitotic rate was increased in 2 of 11 cases, and 2 of 11 cases had cytological atypia. Two cases were malignant, with invasion into perivesicle tissue in 1 case, and metastases to lungs and brain followed by death in the other case. Immunohistochemically, there was strong, and diffuse staining for cathepsin K in 10/11 cases with the 1 negative case restained on a previously stained slide. HMB-45 was diffusely positive in 8/11 cases, while melan-A was present in only 1/10 cases. Muscle markers were variably expressed with positivity for both smooth muscle actin in 6/10 cases and desmin in 3/10 cases. Keratin AE1/3 was uniformly negative (0/11). In 5/8 cases where TFE3 was rearranged by fluorescence in situ hybridization, the morphology had a predominantly epithelioid, nested architecture. Overall, bladder PEComas are particularly difficult to diagnose given their rarity, are predominantly epithelioid and do not always express melanocytic markers. Diagnosis in the bladder requires a combination of morphologic characterization, exclusion of other diagnostic possibilities, positive Cathepsin K staining, variable melanocytic marker expression, with some cases showing a TFE3 gene rearrangement.

    View details for DOI 10.1097/PAS.0000000000001592

    View details for PubMedID 33002920

  • Report From the International Society of Urological Pathology (ISUP) Consultation Conference on Molecular Pathology of Urogenital Cancers IV: Current and Future Utilization of Molecular-Genetic Tests for Testicular Germ Cell Tumors AMERICAN JOURNAL OF SURGICAL PATHOLOGY Looijenga, L. J., Van der Kwast, T. H., Grignon, D., Egevad, L., Kristiansen, G., Kao, C., Idrees, M. T. 2020; 44 (7): E66–E79
  • Characterizing relaxin receptor expression and exploring relaxin's effect on tissue remodeling/fibrosis in the human bladder. BMC urology Diaz, E. C., Briggs, M., Wen, Y., Zhuang, G., Wallace, S. L., Dobberfuhl, A. D., Kao, C., Chen, B. C. 2020; 20 (1): 44

    Abstract

    BACKGROUND: Relaxin is an endogenous protein that has been shown to have antifibrotic properties in various organ systems. There has been no characterization of relaxin's role in the human bladder. Our objective was to characterize relaxin receptor expression in the human bladder and assess relaxin's effect on tissue remodeling/fibrosis pathways in bladder smooth muscle cells.METHODS: Relaxin family peptide receptor 1 (RXFP1) and RXFP2 expression was assessed using quantitative reverse transcriptase-PCR (qRT-PCR) and immunohistochemistry (IHC) on primary bladder tissue. Primary human smooth muscle bladder cells were cultured and stimulated with various concentrations of relaxin. Western blot, qRTPCR, ELISA, and zymogram assays were used to analyze fibrosis/tissue remodeling pathway proteins.RESULTS: There was universal mRNA transcript detection and protein expression of relaxin receptors in primary bladder specimens. Immunohistochemistry demonstrated RXFP1 and RXFP2 localizing to both urothelial and smooth muscle cell layers of the bladder. 24h of in vitro relaxin stimulation did not affect mRNA expression of selected proteins in human bladder smooth muscle cells. However, 48h of in vitro relaxin stimulation resulted in upregulation of active (p=0.004) and latent (p=0.027) MMP-2 in cell lysate, and upregulation of active MMP-2 in supernatant (p=0.04). There was a dose dependent relationship with increasing expression of MMP-2 with increasing relaxin concentration. Relaxin stimulation resulted in decreased levels of active and total TGF-beta1 in supernatant and extracellular matrix (p<0.005 with 100ng/mL relaxin stimulation).CONCLUSIONS: In the human bladder, relaxin receptors are expressed at the dome and trigone and localize to the urothelium and smooth muscle cell layers. Stimulation of human bladder SMCs with relaxin in vitro affects expression of MMP-2 and TGF-beta1.

    View details for DOI 10.1186/s12894-020-00607-4

    View details for PubMedID 32321501

  • Co-Manifestations of Genital Neurofibromatosis in a Patient with Neurofibromatosis Type 1. Urology Ku, S., Balasubramanian, A., Kao, C., Eisenberg, M. L., Skinner, E. C. 2020

    Abstract

    Genitourinary (GU) presentation of neurofibromatosis type 1 (NF-1) is rare, amongst which bladder involvement is the most common. Sporadic case reports do highlight infrequent external genitalia involvement in NF-1. We present a 21-year-old male with prior childhood history of partial cystectomy for an NF-1 related bladder tumor, who more recently presented with gross hematuria. Workup revealed multiple ganglioneuromas involving the bladder, prostate, and penis, and the patient underwent radical cystoprostatectomy and penile mass excision. Recurrences of previously excised urologic tumors or new tumors may appear many years later, and long-term monitoring of NF-1 patients with urologic involvement is necessary.

    View details for DOI 10.1016/j.urology.2020.03.030

    View details for PubMedID 32289361

  • Report From the International Society of Urological Pathology (ISUP) Consultation Conference on Molecular Pathology of Urogenital Cancers: IV: Current and Future Utilization of Molecular-Genetic Tests for Testicular Germ Cell Tumors. The American journal of surgical pathology Looijenga, L. H., Van der Kwast, T. H., Grignon, D., Egevad, L., Kristiansen, G., Kao, C., Idrees, M. T. 2020

    Abstract

    The International Society of Urological Pathology (ISUP) organized a Consultation Conference in March 2019 dealing with applications of molecular pathology in Urogenital Pathology, including testicular tumors (with a focus on germ cell tumors [GCTs]), preceded by a survey among its members to get insight into current practices in testicular germ cell tumor (TGCT) diagnostics and adoption of the ISUP immunohistochemical guidelines published in 2014. On the basis of the premeeting survey, the most commonly used immunomarker panel includes OCT3/4, placental alkaline phosphate, D2-40, SALL4, CD117, and CD30 for GCTs and the documentation of germ cell neoplasia in situ (GCNIS). Molecular testing, specifically 12p copy gain, is informative to distinguish non-GCNIS versus GCNIS related GCTs, and establishing germ cell origin of tumors both in the context of primary and metastatic lesions. Other molecular methodologies currently available but not widely utilized for TGCTs include genome-wide and targeted approaches for specific genetic anomalies, P53 mutations, genomic MDM2 amplification, and detection of the p53 inactivating miR-371a-3p. The latter also holds promise as a serum marker for malignant TGCTs. This manuscript provides an update on the classification of TGCTs, and describes the current and future role of molecular-genetic testing. The following recommendations are made: (1) Presence of GCNIS should be documented in all cases along with extent of spermatogenesis; (2) Immunohistochemical staining is optional in the following scenarios: identification of GCNIS, distinguishing embryonal carcinoma from seminoma, confirming presence of yolk sac tumor and/or choriocarcinoma, and differentiating spermatocytic tumor from potential mimics; (3) Detection of gain of the short arm of chromosome 12 is diagnostic to differentiate between non-GCNIS versus GCNIS related GCTs and supportive to the germ cell origin of both primary and metastatic tumors.

    View details for DOI 10.1097/PAS.0000000000001465

    View details for PubMedID 32205480

  • Development of a DNA Methylation-Based Diagnostic Signature to Distinguish Benign Oncocytoma From Renal Cell Carcinoma. JCO precision oncology Brennan, K. n., Metzner, T. J., Kao, C. S., Massie, C. E., Stewart, G. D., Haile, R. W., Brooks, J. D., Hitchins, M. P., Leppert, J. T., Gevaert, O. n. 2020; 4

    Abstract

    A challenge in the diagnosis of renal cell carcinoma (RCC) is to distinguish chromophobe RCC (chRCC) from benign renal oncocytoma, because these tumor types are histologically and morphologically similar, yet they require different clinical management. Molecular biomarkers could provide a way of distinguishing oncocytoma from chRCC, which could prevent unnecessary treatment of oncocytoma. Such biomarkers could also be applied to preoperative biopsy specimens such as needle core biopsy specimens, to avoid unnecessary surgery of oncocytoma.We profiled DNA methylation in fresh-frozen oncocytoma and chRCC tumors and adjacent normal tissue and used machine learning to identify a signature of differentially methylated cytosine-phosphate-guanine sites (CpGs) that robustly distinguish oncocytoma from chRCC.Unsupervised clustering of Stanford and preexisting RCC data from The Cancer Genome Atlas (TCGA) revealed that of all RCC subtypes, oncocytoma is most similar to chRCC. Unexpectedly, however, oncocytoma features more extensive, overall abnormal methylation than does chRCC. We identified 79 CpGs with large methylation differences between oncocytoma and chRCC. A diagnostic model trained on 30 CpGs could distinguish oncocytoma from chRCC in 10-fold cross-validation (area under the receiver operating curve [AUC], 0.96 (95% CI, 0.88 to 1.00)) and could distinguish TCGA chRCCs from an independent set of oncocytomas from a previous study (AUC, 0.87). This signature also separated oncocytoma from other RCC subtypes and normal tissue, revealing it as a standalone diagnostic biomarker for oncocytoma.This CpG signature could be developed as a clinical biomarker to support differential diagnosis of oncocytoma and chRCC in surgical samples. With improved biopsy techniques, this signature could be applied to preoperative biopsy specimens.

    View details for DOI 10.1200/PO.20.00015

    View details for PubMedID 33015531

    View details for PubMedCentralID PMC7529536

  • A Morphologic and Immunohistochemical Comparison of Nuclear β-Catenin Expressing Testicular Sertoli Cell Tumors and Pancreatic Solid Pseudopapillary Neoplasms Supporting Their Continued Separate Classification. The American journal of surgical pathology Kao, C. S., Ulbright, T. M. 2020

    Abstract

    Some recent reports suggested that many Sertoli cell tumors, not otherwise specified (SCTs-NOS) of the testis were analogs of the solid pseudopapillary neoplasm (SPN) of the pancreas. One of the most relied on pieces of information for this assertion was the shared occurrence in both neoplasms of exon 3 mutations of the CTNNB1 gene, which was reflected by nuclear β-catenin expression. We, therefore, compared the morphologic and immunohistochemical features of 18 SCTs-NOS with strong, diffuse nuclear β-catenin expression with 16 SPNs that also showed such positivity. Although there were clear similarities in the light microscopic features of these neoplasms, there were also significant differences that included, in SCT-NOS and SPN, respectively: hollow tubules (53% vs. 0%), sheet-like growth (44% vs. 94%), circumscription (79% vs. 25%), corded or trabecular patterns (81% vs. 31%), formation of papillae or pseudopapillae (24% vs. 69%), growth in nests or clusters (94% vs. 50%), perivascular pseudorosettes (13% vs. 56%), and rhabdoid cytology (6% vs. 50%). Commonly shared morphologic features included signet-ring cells, pale or foamy cytoplasm, myxoid stroma, cyst formation, perivascular hyalinization, and globular or band-like basement membrane deposits. On immunohistochemical study, sex cord markers were frequently positive in SCTs-NOS (steroidogenic factor-1-94%; FOXL2-87%; SOX9-69%; calretinin-60%; Wilms tumor-1-38%; inhibin-29%) whereas all of these markers were negative in the SPNs. We conclude that even though SCT-NOS and SPN share some morphologic features and nuclear immunoreactivity for β-catenin, there remain differences, both morphologically and immunohistochemically, between these neoplasms to the degree that SCT-NOS should not be equated with pancreatic SPN.

    View details for DOI 10.1097/PAS.0000000000001527

    View details for PubMedID 32604170

  • Fungal prostatitis due to endemic mycoses and Cryptococcus: A multicenter case series. The Prostate Epstein, D. J., Thompson, L. D., Saleem, A. n., Kao, C. S., Epstein, J. I. 2020

    Abstract

    Fungal prostatitis is exceedingly rare with mostly case reports.Electronic medical records at three medical centers were searched for cases of fungal prostatitis due to endemic mycoses and Cryptococcus over the preceding 10 years.Seven cases were identified from 105 600 prostate biopsies within the Southern California Permanente Medical Group for an incidence of 0.0066%. An additional eight cases were identified from two other health care systems. Excluding four patients without available clinical data, 11 patients were reviewed, most of whom underwent biopsy due to elevated prostate-specific antigen. Four were asymptomatic and the remainder had nonspecific signs or symptoms. All biopsies revealed granulomatous inflammation and fungal organisms. Seven patients had coccidioidomycosis, three patients had cryptococcosis (confirmed in two cases and suspected by organism morphology in the other), and one patient had likely histoplasmosis based on organism morphology. Prolonged antifungal treatment was standard; outcomes were favorable.Fungal prostatitis due to endemic mycoses and Cryptococcus is uncommon and associated with favorable outcomes but generally involves prolonged therapy.

    View details for DOI 10.1002/pros.24034

    View details for PubMedID 32572997

  • Identification of Diagnostic Metabolic Signatures in Clear Cell Renal Cell Carcinoma Using Mass Spectrometry Imaging. International journal of cancer Vijayalakshmi, K., Shankar, V., Bain, R. M., Nolley, R., Sonn, G. A., Kao, C., Zhao, H., Tibshirani, R., Zare, R. N., Brooks, J. D. 2019

    Abstract

    Clear cell renal cell carcinoma (ccRCC) is the most common and lethal subtype of kidney cancer. Intraoperative frozen section (IFS) analysis is used to confirm the diagnosis during partial nephrectomy (PN). However, surgical margin evaluation using IFS analysis is time consuming and unreliable, leading to relatively low utilization. In this study, we demonstrated the use of desorption electrospray ionization mass spectrometry imaging (DESI-MSI) as a molecular diagnostic and prognostic tool for ccRCC. DESI-MSI was conducted on fresh-frozen 23 normal-tumor paired nephrectomy specimens of ccRCC. An independent validation cohort of 17 normal-tumor pairs were analyzed. DESI-MSI provides two-dimensional molecular images of tissues with mass spectra representing small metabolites, fatty acids, and lipids. These tissues were subjected to histopathologic evaluation. A set of metabolites that distinguish ccRCC from normal kidney were identified by performing least absolute shrinkage and selection operator (Lasso) and log-ratio Lasso analysis. Lasso analysis with leave-one-patient-out cross validation selected 57 peaks from over 27,000 metabolic features across 37,608 pixels obtained using DESI-MSI of ccRCC and normal tissues. Baseline Lasso of metabolites predicted the class of each tissue to be normal or cancerous tissue with an accuracy of 94% and 76%, respectively. Combining the baseline Lasso with the ratio of glucose to arachidonic acid could potentially reduce scan time and improve accuracy to identify normal (82%) and ccRCC (88%) tissue. DESI-MSI allows rapid detection of metabolites associated with normal and ccRCC with high accuracy. As this technology advances, it could be used for rapid intraoperative assessment of surgical margin status. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1002/ijc.32843

    View details for PubMedID 31863456

  • Predicting Gonadal Germ Cell Cancer in People with Disorders of Sex Development; Insights from Developmental Biology. International journal of molecular sciences Looijenga, L. H., Kao, C., Idrees, M. T. 2019; 20 (20)

    Abstract

    The risk of gonadal germ cell cancer (GGCC) is increased in selective subgroups, amongst others, defined patients with disorders of sex development (DSD). The increased risk is due to the presence of part of the Y chromosome, i.e., GonadoBlastoma on Y chromosome GBY region, as well as anatomical localization and degree of testicularization and maturation of the gonad. The latter specifically relates to the germ cells present being at risk when blocked in an embryonic stage of development. GGCC originates from either germ cell neoplasia in situ (testicular environment) or gonadoblastoma (ovarian-like environment). These precursors are characterized by presence of the markers OCT3/4 (POU5F1), SOX17, NANOG, as well as TSPY, and cKIT and its ligand KITLG. One of the aims is to stratify individuals with an increased risk based on other parameters than histological investigation of a gonadal biopsy. These might include evaluation of defined susceptibility alleles, as identified by Genome Wide Association Studies, and detailed evaluation of the molecular mechanism underlying the DSD in the individual patient, combined with DNA, mRNA, and microRNA profiling of liquid biopsies. This review will discuss the current opportunities as well as limitations of available knowledge in the context of predicting the risk of GGCC in individual patients.

    View details for DOI 10.3390/ijms20205017

    View details for PubMedID 31658757

  • A Clinicopathologic and Molecular Analysis of Fumarate Hydratase-Deficient Renal Cell Carcinoma in 32 Patients. The American journal of surgical pathology Lau, H. D., Chan, E., Fan, A. C., Kunder, C. A., Williamson, S. R., Zhou, M., Idrees, M. T., Maclean, F. M., Gill, A. J., Kao, C. 2019

    Abstract

    Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a rare and recently described entity associated with hereditary leiomyomatosis and RCC syndrome. FH-deficient RCC may show variable clinical and pathologic findings, but commonly presents with locally advanced and metastatic disease and carries a poor prognosis. We identified 32 patients with FH-deficient RCC, confirmed by FH immunohistochemistry (IHC) and/or FH mutation analysis, and performed a retrospective review of the clinical and pathologic features. Median age at presentation was 43 years (range, 18 to 69y), and the M:F ratio was 2.2:1. Median tumor size was 6.5cm (range, 2.5 to 28cm), and 71% presented at stage ≥pT3a. After a median follow-up of 16 months (range, 1 to 118mo) in 26 patients, 19% showed no evidence of disease, 31% were alive with disease, and 50% were dead of disease. The vast majority of cases showed multiple histologic growth patterns, with papillary (52%) being the most common predominant pattern, followed by solid (21%), cribriform/sieve-like (14%), sarcomatoid (3%), tubular (3%), cystic (3%), and low-grade oncocytic (3%). Viral inclusion-like macronucleoli with perinucleolar clearing were present in almost all cases (96%). All cases were evaluated using FH IHC, and 3 cases (9%) showed retained FH expression. Nineteen cases had germline or tumor mutation analysis confirming a FH mutation, with 79% (11/14) of cases showing mutations within coding regions and 21% (3/14) showing mutations within intronic splice-sites. By IHC, 97% (32/33) of cases were negative for CK7, 93% (27/29) were negative for p63, and 52% (15/29) were negative for GATA3. All cases stained were positive for PAX8 and showed retained succinate dehydrogenase B expression. Our overall findings show that FH-deficient RCC is considerably heterogenous in morphology and frequently behaves aggressively. Suspicion for this entity should be raised even in the absence of predominantly papillary architecture and characteristic nucleolar features. We have included cases with uncommonly seen features, including 4 cases with predominantly cribriform/sieve-like architecture as well as one case with pure low-grade oncocytic morphology (9y of clinical follow-up without evidence of disease). Although FH IHC is a useful tool for identifying cases of FH-deficient RCC, not all cases of FH-deficient RCC show loss of FH staining, and FH mutation analysis should be considered for patients with suspicious clinical or pathologic features, even in cases with retained FH IHC expression.

    View details for DOI 10.1097/PAS.0000000000001372

    View details for PubMedID 31524643

  • 2 year outcome for 8 year old female managed with partial cystectomy for primary bladder clear cell carcinoma. Urology case reports Diaz, E. C., Velasquez, M. G., Kao, C., Wu, H. 2019; 26: 100948

    Abstract

    Bladder cancer is rare in the pediatric population, and clear cell carcinoma is extremely rare with one other pediatric case reported. Here we report the clinical outcome for a medically complicated pediatric patient with muscle invasive clear cell carcinoma treated with partial cystectomy without neoadjuvant or adjuvant therapy. Final pathology was stage T2bN0M0 with negative margins. At 2 years, there is no disease recurrence by cystoscopy, chest and abdominal imaging. Postoperative issues have been related to reduced bladder capacity and compliance and the patient is currently managed with continuous urinary diversion and will require future definitive lower tract reconstruction.

    View details for DOI 10.1016/j.eucr.2019.100948

    View details for PubMedID 31293899

  • Plasmacytoid/diffuse urothelial carcinoma: a single-institution immunohistochemical and molecular study of 69 patients HUMAN PATHOLOGY Perrino, C. M., Eble, J., Kao, C., Whaley, R. D., Cheng, L., Idrees, M., Hashemi-Sadraei, N., Monn, M., Kaimakliotis, H. Z., Bandali, E., Grignon, D. 2019; 90: 27–36
  • Clinicopathologic Features and Chromosome 12p Status of Pediatric Sacrococcygeal Teratomas: A Multi-institutional Analysis PEDIATRIC AND DEVELOPMENTAL PATHOLOGY Mylonas, K. S., Kao, C., Levy, D., Lordello, L., Dal Cin, P., Masiakos, P. T., Oliva, E. 2019; 22 (3): 214–20
  • Urothelial Carcinoma in Situ Versus Early High-Grade Papillary Urothelial Carcinoma: A Survey of Pathologist and Urologist Interpretations Williamson, S., Sangoi, A., Kao, C., Deebajah, M., Barletta, J., Paner, G., Smith, S., Grignon, D., Comperat, E., Amin, M., Maclean, F., Shah, R., Iczkowski, K., Delprado, W., Cheng, L., Pan, C., McKenney, J., Ro, J., Khani, F., Montironi, R., Robinson, B., Al-Ahmadie, H., Epstein, J., Trpkov, K., Tretiakova, M., Shen, S., Alanee, S., Hirsch, M. NATURE PUBLISHING GROUP. 2019
  • Urothelial Carcinoma in Situ Versus Early High-Grade Papillary Urothelial Carcinoma: A Survey of Pathologist and Urologist Interpretations Williamson, S., Sangoi, A., Kao, C., Deebajah, M., Barletta, J., Paner, G., Smith, S., Grignon, D., Comperat, E., Amin, M., Maclean, F., Shah, R., Iczkowski, K., Delprado, W., Cheng, L., Pan, C., McKenney, J., Ro, J., Khani, F., Montironi, R., Robinson, B., Al-Ahmadie, H., Epstein, J., Trpkov, K., Tretiakova, M., Shen, S., Alanee, S., Hirsch, M. NATURE PUBLISHING GROUP. 2019
  • Renal Cell Carcinomas with Borderline Features of Eosinophilic Solid and Cystic Renal Cell Carcinoma are Most Likely Papillary Renal Cell Carcinomas Williamson, S., Al-Obaidy, K., Kao, C., Rogers, C., Grignon, D., Schwartz, L., Tretiakova, M., Antic, T., Cheng, L., Gupta, N. NATURE PUBLISHING GROUP. 2019
  • Clear Cell Renal Cell Carcinoma With a Poorly-Differentiated Component: A Novel Variant Causing Potential Diagnostic Difficulty Taneja, K., Cheng, L., Al-Obaidy, K., Kao, C., Barletta, J., Howitt, B., Wasco, M., Palanisamy, N., Gupta, N., Rogers, C., Carskadon, S., Chen, Y., Antic, T., Tretiakova, M., Williamson, S. NATURE PUBLISHING GROUP. 2019
  • Renal Cell Carcinomas with Borderline Features of Eosinophilic Solid and Cystic Renal Cell Carcinoma are Most Likely Papillary Renal Cell Carcinomas Williamson, S., Al-Obaidy, K., Kao, C., Rogers, C., Grignon, D., Schwartz, L., Tretiakova, M., Antic, T., Cheng, L., Gupta, N. NATURE PUBLISHING GROUP. 2019
  • Clear Cell Renal Cell Carcinoma With a Poorly-Differentiated Component: A Novel Variant Causing Potential Diagnostic Difficulty Taneja, K., Cheng, L., Al-Obaidy, K., Kao, C., Barletta, J., Howitt, B., Wasco, M., Palanisamy, N., Gupta, N., Rogers, C., Carskadon, S., Chen, Y., Antic, T., Tretiakova, M., Williamson, S. NATURE PUBLISHING GROUP. 2019
  • Native kidney cytomegalovirus nephritis and cytomegalovirus prostatitis in a kidney transplant recipient TRANSPLANT INFECTIOUS DISEASE Tan, S. K., Cheng, X. S., Kao, C., Weber, J., Pinsky, B. A., Gill, H. S., Busque, S., Subramanian, A. K., Tan, J. C. 2019; 21 (1)

    View details for DOI 10.1111/tid.12998

    View details for Web of Science ID 000457744400019

  • The asymptomatic bladder: gross and histological findings in a series of patients Briggs, M., Wen, Y., Zhuang, G., Kao, C., Wallace, S. L., Dobberfuhl, A. D., Chen, B., Diaz, E. C. WILEY. 2019: S37–S38
  • Plasmacytoid/diffuse urothelial carcinoma: a single institution immunohistochemical and molecular study of 69 patients. Human pathology Perrino, C. M., Eble, J. n., Kao, C. S., Whaley, R. D., Cheng, L. n., Idrees, M. n., Hashemi-Sadraei, N. n., Monn, M. F., Kaimakliotis, H. Z., Bandali, E. n., Grignon, D. n. 2019

    Abstract

    Accurate diagnosis of plasmacytoid urothelial carcinoma (PUC) is important given its poor prognosis and frequent presentation at high stage. We aim to assess the clinicopathologic features, molecular aberrations, and follow-up data in a series of PUC cases from a single tertiary cancer center. Seventy-two urinary bladder, ureteral, and renal pelvic specimens with urothelial carcinoma with plasmacytoid differentiation were identified. Immunohistochemical (IHC) stains were performed on 48 cases. Among urinary bladder origin markers, GATA3 was most sensitive (96%). Breast carcinoma markers (ER, mammaglobin) were usually negative, but PR stained 1 case (4%). Neuroendocrine markers CD56 and TTF-1 were each positive in 1 case (4% and 4%, respectively). Gastrointestinal adenocarcinoma marker CDX2 was positive in 4 cases (15%), but nuclear β-catenin was negative in all cases. CD138 was positive in 83% and e-cadherin expression was lost in 57% of cases. Fluorescence in situ hybridization (FISH) using the UroVysion Bladder Cancer Kit and FGFR3 mutational analysis using polymerase chain reaction (PCR) were performed on 15 cases; deletion of chromosome 9p21 was common (60%) and FGFR3 mutations were detected in 60% of cases (5 cases had both deletion 9p21 and FGFR3 mutations). Cases were divided into 3 morphologic groups: classic (29%), desmoplastic (35%), and pleomorphic (36%). The three morphologic subtypes had distinct survival outcomes (P=.083), with median survival for all patients 18 being months versus 10months for the desmoplastic group.

    View details for PubMedID 31054897

  • Optical biopsy of penile cancer with in vivo confocal laser endomicroscopy. Urologic oncology Shkolyar, E. n., Laurie, M. A., Mach, K. E., Trivedi, D. R., Zlatev, D. V., Chang, T. C., Metzner, T. J., Leppert, J. T., Kao, C. S., Liao, J. C. 2019

    Abstract

    Surgical management of penile cancer depends on accurate margin assessment and staging. Advanced optical imaging technologies may improve penile biopsy and organ-sparing treatment. We evaluated the feasibility of confocal laser endomicroscopy for intraoperative assessment of benign and malignant penile tissue.With institutional review board approval, 11 patients were recruited, 9 with suspected penile cancer, and 2 healthy controls. Confocal laser endomicroscopy using a 2.6-mm fiber-optic probe was performed at 1 or 2 procedures on all subjects, for 13 imaging procedures. Fluorescein was administered intravenously approximately 3 minutes prior to imaging for contrast. Video sequences from in vivo (n = 12) and ex vivo (n = 6) imaging were obtained of normal glans, suspicious lesions, and surgical margins. Images were processed, annotated, characterized, and correlated with standard hematoxylin and eosin histopathology.No adverse events related to imaging were reported. Distinguishing features of benign and malignant penile tissue could be identified by confocal laser endomicroscopy. Normal skin had cells of uniform size and shape, with distinct cytoplasmic membranes consistent with squamous epithelium. Malignant lesions were characterized by disorganized, crowded cells of various size and shape, lack of distinct cytoplasmic membranes, and hazy, moth-eaten appearance. The transition from normal to abnormal squamous epithelium could be identified.We report the initial feasibility of intraoperative confocal laser endomicroscopy for penile cancer optical biopsy. Pending further evaluation, confocal laser endomicroscopy could serve as an adjunct or replacement to conventional frozen section pathology for management of penile cancer.

    View details for DOI 10.1016/j.urolonc.2019.08.018

    View details for PubMedID 31537485

  • A Contemporary Review of Common Adult Non-germ Cell Tumors of the Testis and Paratestis. Surgical pathology clinics Mooney, K. L., Kao, C. 2018; 11 (4): 739–58

    Abstract

    This article provides a comprehensive review of non-germ cell tumors of the testis and paratestis in adults, incorporating the latest 2016 World Health Organization updates. Clinical features, gross pathologic findings, key morphologic details, immunohistochemical profiles, and differential diagnoses are covered, with an emphasis on how to resolve commonly encountered, and sometimes difficult, differential diagnoses.

    View details for PubMedID 30447839

  • A Clinicopathologic and Molecular Analysis of 34 Mediastinal Germ Cell Tumors Suggesting Different Modes of Teratoma Development AMERICAN JOURNAL OF SURGICAL PATHOLOGY Kao, C., Bangs, C. D., Aldrete, G., Cherry, A. M., Ulbright, T. M. 2018; 42 (12): 1662–73
  • A Case Report of Pediatric Clear Cell Carcinoma of the Urinary Bladder Associated With Polyomavirus AJSP-REVIEWS AND REPORTS Saleem, A., Brown, R. A., Higgins, J. T., Troxell, M. L., Kunder, C. A., Pinsky, B. A., Zambrano, E., Kao, C. 2018; 23 (6): 291–95
  • Adrenal Myelolipomas Involved by Plasma Cell Myeloma AMERICAN JOURNAL OF CLINICAL PATHOLOGY Lin, C., Levy, D., Higgins, J. T., Kunder, C. A., Kao, C. 2018; 150 (5): 406–14
  • P16 Expression in Extramammary Paget's Disease of the Vulva and Scrotum Is Not Human Papillomavirus Related INTERNATIONAL JOURNAL OF SURGICAL PATHOLOGY Al-Obaidy, K. I., Kao, C., Idrees, M. T. 2018; 26 (7): 617–20

    Abstract

    Extramammary Paget disease (EMPD) of the vulva has been shown to express p16 by immunohistochemistry (IHC), however, p16 expression in the vulva and scrotum has not been extensively studied in relation to human papillomavirus (HPV) within EMPD of both the vulva and scrotum.Twenty-two cases of EMPD (vulva, 16; scrotum, 6) were found in our laboratory information system. P16 and HPV IHC were performed. Any p16 reactivity less than 10% was considered negative. HPV in situ hybridization for both low- and high-risk HPV was also performed on all cases.Of the 6 scrotal EMPD, 3 (50%) showed weak to moderate positive reactivity for p16 by IHC. Of the 16 vulvar EMPD, 13 (81%) were positive for p16, with at least moderate (2+) intensity with a mean expression of 33.3% (range = 10% to 80%) and 62% (range = 20% to 95%) in scrotal and vulvar EMPD, respectively. None of the scrotal or vulvar cases showed positive reactivity for HPV either by IHC or in situ hybridization.Both vulvar and scrotal EMPD can express p16 by IHC, more commonly vulvar than scrotal; however, no HPV was detected either by IHC or in situ hybridization. EMPD of vulva and scrotum does not appear to be related to HPV, and p16 expression may be regulated through a different mechanism.

    View details for PubMedID 29745285

  • A Clinicopathologic and Molecular Analysis of 34 Mediastinal Germ Cell Tumors Suggesting Different Modes of Teratoma Development. The American journal of surgical pathology Kao, C., Bangs, C. D., Aldrete, G., Cherry, A. M., Ulbright, T. M. 2018

    Abstract

    Mediastinal teratomas are enigmatic; those in children and women are almost invariably benign but in men they may be benign or malignant. There are few data on the chromosome 12p status of mediastinal germ cell tumors (GCT), whereas increased 12p copy number is virtually uniform in malignant testicular GCTs. We therefore studied chromosome 12p copy number in 34 diverse mediastinal GCTs and correlated the results with morphology and follow-up to gain insight into possible pathogenesis. Four prepubertal (below 12y) children (3 females and 1 male), 7 postpubertal females (14 to 52y) and 6 postpubertal males (12 to 40y old) had pure, previously untreated teratomas; 15 were mature and 2 had low-grade immaturity. All lacked 12p copy number increase and cytologic atypia, and most (14/17) showed organoid morphology. On follow-up of 16, 1 died of postoperative complications and the remaining 15 were disease free (1 to 119mo, mean: 39mo). Eight postpubertal males (19 to 44y old) had pure teratomas in postchemotherapy resections; 5/8 showed 12p copy number increase. All 8 had distinct cytologic atypia, with organoid morphology in 3. On follow-up, 6 were disease free after surgical resection (1.5 to 94mo, mean 38mo); 1 died of disease at 14.5 months, and 1 was alive with metastases at 176 months. Two postpubertal patients, 1 male (29y) and 1 female (31y), had teratoma with secondary somatic-type malignancies, with positive 12p copy number increase in the former but not the latter. The man's tumor occurred after chemotherapy and was a nonorganoid teratoma with primitive neuroectodermal tumor and malignant glioma; the woman's was a previously untreated organoid teratoma with an undifferentiated carcinoma component. The man died of disease (16mo) and the woman was alive with metastases (27mo). Seven patients had resections for mixed GCTs (4) or pure nonteratomatous tumors, all after chemotherapy; 5/7 had positive 12p copy number increase. The teratoma component of the 2 cases having one showed distinct cytologic atypia and lacked organoid morphology. On follow-up, 1 died of disease (5mo), 2 were alive with disease (1, 1.5mo), 3 were disease free (1 to 43mo; mean: 18mo), and 1 was alive with unknown status (31mo). Our results support that mediastinal teratomas likely develop from 2 separate pathways. Those in children, women and some men arise as pure neoplasms from a nontransformed precursor cell and, therefore, lack 12p copy number increase, show no cytologic atypia, often have organoid morphology and are benign. Common 12p copy number increase, uniform atypia, infrequent organoid structures and malignant behavior support that pure teratomas after chemotherapy in postpubertal males derive from a malignantly transformed precursor cell. Interestingly, we identified organoid pancreatic differentiation only in the benign group and neuroglia more commonly in the malignant teratomas.

    View details for PubMedID 30256256

  • Native Kidney Cytomegalovirus Nephritis and Cytomegalovirus Prostatitis in a Kidney Transplant Recipient. Transplant infectious disease : an official journal of the Transplantation Society Tan, S. K., Cheng, X. S., Kao, C., Weber, J., Pinsky, B. A., Gill, H. S., Busque, S., Subramanian, A. K., Tan, J. C. 2018: e12998

    Abstract

    We present a case of cytomegalovirus (CMV) native kidney nephritis and prostatitis in a CMV D+/R- kidney transplant recipient who had completed six months of CMV prophylaxis four weeks prior to the diagnosis of genitourinary CMV disease. The patient had a history of benign prostatic hypertrophy and urinary retention that required self-catheterization to relieve high post-voiding residual volumes. At 7 months post-transplant, he was found to have a urinary tract infection, moderate hydronephrosis of the transplanted kidney, and severe hydroureteronephrosis of the native left kidney and ureter, and underwent native left nephrectomy and transurethral resection of the prostate. Histopathologic examination of kidney and prostate tissue revealed CMV inclusions consistent with invasive CMV disease. This case highlights that CMV may extend beyond the kidney allograft to involve other parts of the genitourinary tract, including the native kidneys and prostate. Furthermore, we highlight the tissue-specific risk factors that preceded CMV tissue invasion. In addition to concurrent diagnoses, health care providers should have a low threshold for considering late-onset CMV disease in high-risk solid organ transplant recipients presenting with signs and symptoms of genitourinary tract pathology. This article is protected by copyright. All rights reserved.

    View details for PubMedID 30203504

  • Evaluation of Diagnostic Accuracy and a Practical Algorithmic Approach for the Diagnosis of Renal Masses by FNA. Cancer cytopathology Lau, H. D., Kong, C. S., Kao, C. 2018

    Abstract

    BACKGROUND: The classification of renal neoplasms is essential for oncologic risk stratification and clinical management, and an accurate pretreatment pathologic diagnosis can provide useful guidance for active surveillance, minimally invasive ablative therapy, or surgical resection and can reduce the incidence of overtreatment. Previous studies evaluating the diagnostic accuracy of fine-needle aspiration (FNA) and core-needle biopsy (CNB) for renal masses are limited and show variable results.METHODS: Two hundred forty-seven renal FNA cases with or without concurrent CNB performed and/or reviewed at the Stanford University School of Medicine over the course of 20 years were identified. Cytohistopathologic correlation was performed for 77 cases with subsequent resection specimens. All available case materials were reviewed, and select cases were worked up further and reclassified as necessary.RESULTS: Cytohistopathologic correlation showed 96% diagnostic specificity and 83% sensitivity for renal FNA with or without concurrent CNB. Discordant cases were mostly attributed to sampling errors or suboptimal specimens (79%) and also included 2 non-renal cell carcinoma entities (1 case of angiomyolipoma and 1 case of a benign peripheral nerve sheath tumor) and 1 case involving misclassification of the renal cell carcinoma subtype.CONCLUSIONS: There is considerable value in FNA/CNB for the initial diagnosis of renal masses because of the high diagnostic specificity and sensitivity. Sensitivity is predominantly dependent on sufficient sampling, and additional potential diagnostic pitfalls include nonepithelial and rare entities. Judicious use of ancillary techniques is encouraged, especially when one is presented with a limited specimen, and this article presents a practical algorithmic approach to the diagnosis of renal masses using salient morphologic features and results from ancillary studies. Fine-needle aspiration is an accurate method for the diagnosis of renal masses. A practical diagnostic algorithm, based on salient morphologic and ancillary findings, is presented.

    View details for PubMedID 30193011

  • Clinicopathologic Features and Chromosome 12p Status of Pediatric Sacrococcygeal Teratomas: A Multi-institutional Analysis. Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society Mylonas, K. S., Kao, C., Levy, D., Lordello, L., Dal Cin, P., Masiakos, P. T., Oliva, E. 2018: 1093526618798771

    Abstract

    Chromosome 12p gains are typically present in postpubertal male patients with testicular malignant germ cell tumors, including most teratomas, and absent in pure ovarian teratomas, both mature and immature. We sought to evaluate the clinicopathologic features and chromosome 12p status of pediatric patients with sacrococcygeal teratomas (SCTs) using the institutional databases of 2 tertiary medical centers. Seven mature teratomas (3 pure, 2 with yolk sac tumor, 1 with medulloepithelioma, and 1 with ependymoma) and 3 immature teratomas (2 pure: grade 2 and grade 3 and 1 mixed: grade 3 with yolk sac tumor) were identified. All patients underwent surgery and 2 received adjuvant chemotherapy. Fluorescence in situ hybridization analysis was performed to elucidate chromosome 12p gains, including isochromosome 12p. All 10 tumors analyzed lacked 12p gains regardless of the components. No patient had evidence of disease at their most recent interval follow-up (mean: 30, range: 7-91 months), irrespective of margin status or of receiving chemotherapy. Overall, our study suggests an absence of chromosome 12p abnormalities in clinically nonaggressive SCTs. Additional data are required to confirm these findings before definitive patient care recommendations can be made.

    View details for PubMedID 30176765

  • Serous Neoplasms of the Pancreas A Comprehensive Review ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE Charville, G. W., Kao, C. 2018; 142 (9): 1134–40
  • Evaluation of Diagnostic Accuracy and a Practical Algorithmic Approach for the Diagnosis of Renal Masses by FNA CANCER CYTOPATHOLOGY Lau, H. D., Kong, C. S., Kao, C. 2018; 126 (9): 782–96

    View details for DOI 10.1002/cncy.22037

    View details for Web of Science ID 000454533300006

  • Adrenal Myelolipomas Involved by Plasma Cell Myeloma. American journal of clinical pathology Lin, C., Levy, D., Higgins, J. P., Kunder, C. A., Kao, C. 2018

    Abstract

    Objectives: To report the presence and evaluate the frequency of plasma cell neoplasms within adrenal myelolipomas.Methods: Adrenal myelolipomas within our institution were reviewed for the presence of hematologic neoplasia, and a review of the literature was performed.Results: Two (9%) of 23 adrenal myelolipomas were involved by plasma cell myeloma. The patients were 71 and 81 years old, one woman and one man, with tumors measuring 7 cm and 8.5 cm, respectively. Both tumors contained large aggregates of dysplastic plasma cells occupying at least one *10 field and demonstrated light chain restriction. Neither had an established diagnosis of plasma cell neoplasm previously. After receiving therapy, one patient exhibited a stable clinical course 1 year after diagnosis while the other died of disease 3 years later.Conclusions: We report the first two cases of adrenal myelolipoma involved by plasma cell myeloma, a rare and subtle finding that has significant clinical implications.

    View details for PubMedID 30052719

  • Survival outcomes in plasmacytoid urothelial carcinoma: Results with contemporary systemic therapy. Hashemi-Sadraei, N., Perrino, C. M., Monn, M., Bandali, E., Cheng, L., Idrees, M., Bihrle, R., Koch, M. O., Eble, J., Kao, C., Adra, N., Pili, R., Grignon, D. A., Kaimakliotis, H. Z., Albany, C. AMER SOC CLINICAL ONCOLOGY. 2018
  • Expanding the Clinicopathological Spectrum of Succinate Dehydrogenase-Deficient Renal Cell Carcinoma: 42 Novel Tumors in 38 Patients Maclean, F., McKenney, J., Hes, O., Kao, C., Ellis, C. L., Turchini, J., Samaratunga, H., Jonathan, Z., Bhattarai, S., Ryan, A., Bonert, M., Leroy, X., Kunju, L., Schwartz, L., Williamson, S. R., Matsika, A., Rao, P., Divatia, M., Guarch, R., Algaba, F., Brimo, F., Agaimy, A., Balancin, M., da Cunha, I. W., Zhou, M., Trpkov, K., Gill, A. J. NATURE PUBLISHING GROUP. 2018: 362
  • Expanding the Clinicopathological Spectrum of Succinate Dehydrogenase-Deficient Renal Cell Carcinoma: 42 Novel Tumors in 38 Patients Maclean, F., McKenney, J., Hes, O., Kao, C., Ellis, C. L., Turchini, J., Samaratunga, H., Jonathan, Z., Bhattarai, S., Ryan, A., Bonert, M., Leroy, X., Kunju, L., Schwartz, L., Williamson, S. R., Matsika, A., Rao, P., Divatia, M., Guarch, R., Algaba, F., Brimo, F., Agaimy, A., Balancin, M., da Cunha, I. W., Zhou, M., Trpkov, K., Gill, A. J. NATURE PUBLISHING GROUP. 2018: 362
  • Clinicopathologic Characteristics of Fumarate Hydratase-Deficient and Hereditary Leiomyomatosis and Renal Cell Carcinoma-Associated Renal Cell Carcinoma: A Series of 10 Cases Lau, H., Williamson, S. R., Kunder, C., Fan, A. C., Kao, C. NATURE PUBLISHING GROUP. 2018: 358
  • The Significance of Isolated Linear Tumor Nests within the Tunica Albuginea in Stage I Seminoma: A Multi-Institutional Study Al-Obaidy, K., Kao, C., Levy, D. R., Trevino, K., Idrees, M., Ulbright, T. NATURE PUBLISHING GROUP. 2018: 324
  • The Significance of Isolated Linear Tumor Nests within the Tunica Albuginea in Stage I Seminoma: A Multi-Institutional Study Al-Obaidy, K., Kao, C., Levy, D. R., Trevino, K., Idrees, M., Ulbright, T. NATURE PUBLISHING GROUP. 2018: 324
  • Evaluation of Diagnostic Accuracy and a Practical Algorithmic Approach for the Diagnosis of Renal Masses by Fine Needle Aspiration Lau, H., Kong, C., Kao, C. NATURE PUBLISHING GROUP. 2018: 155
  • Clinicopathologic Characteristics of Fumarate Hydratase-Deficient and Hereditary Leiomyomatosis and Renal Cell Carcinoma-Associated Renal Cell Carcinoma: A Series of 10 Cases Lau, H., Williamson, S. R., Kunder, C., Fan, A. C., Kao, C. NATURE PUBLISHING GROUP. 2018: 358
  • Evaluation of Diagnostic Accuracy and a Practical Algorithmic Approach for the Diagnosis of Renal Masses by Fine Needle Aspiration Lau, H., Kong, C., Kao, C. NATURE PUBLISHING GROUP. 2018: 155
  • Plasmacytoid urothelial carcinoma: A clinicopathological study Hashemi-Sadraei, N., Perrino, C. M., Monn, M., Bandali, E., Cheng, L., Idrees, M., Bihrle, R., Koch, M. O., Eble, J., Kao, C., Albany, C., Pili, R., Grignon, D. A., Kaimakliotis, H. Z. AMER SOC CLINICAL ONCOLOGY. 2018
  • Serous Neoplasms of the Pancreas: A Comprehensive Review. Archives of pathology & laboratory medicine Charville, G. W., Kao, C. S. 2018; 142 (9): 1134–40

    Abstract

    Serous neoplasms are uncommon, usually cystic tumors that account for less than 1% of all primary pancreatic lesions. They consist predominantly of a monomorphic epithelial cell population with a glycogen-rich, clear cytoplasm, reminiscent of clear cell renal cell carcinoma, with which serous neoplasms share an association with underlying VHL loss-of-function mutations. Serous neoplasms have no metastatic potential. Accurate recognition of this entity, including its various architectural subtypes, is critical to appropriate prognostication and treatment. Immunohistochemical detection of inhibin and calponin expression, along with the absence of both estrogen and progesterone receptors and nuclear β-catenin, can help to distinguish serous neoplasms from mimics. With the advent of minimally invasive and molecularly driven diagnostic techniques, the pathologist's role in the assessment and management of serous neoplasms has become increasingly complex and important. We provide an update on the histologic, immunohistochemical, and molecular features of pancreatic serous neoplasms for the practicing pathologist.

    View details for PubMedID 30141993

  • Do Nonseminomatous Germ Cell Tumors of the Testis With Lymphovascular Invasion of the Spermatic Cord Merit Staging as pT3? AMERICAN JOURNAL OF SURGICAL PATHOLOGY Gordetsky, J., Sanfrancesco, J., Epstein, J. I., Trevino, K., Xu, H., Osunkoya, A., Xiao, G. Q., Kao, C., Unger, P., Hashemi-Sadraei, N., Albany, C., Jorns, J. M., Lu, D. Y., Matoso, A., Rais-Bahrami, S., Schwartz, L. E., Ulbright, T. M., Idrees, M. T. 2017; 41 (10): 1397–1402

    Abstract

    The staging of testicular nonseminomatous germ cell tumors (NSGCTs) with lymphovascular invasion (LVI) of the spermatic cord in the absence of cord parenchymal involvement remains controversial. Our previous study showed that tumors with spermatic cord LVI present at a higher clinical stage than tumors with LVI confined to the testis (pT2). We compared NSGCTs with LVI of the spermatic cord without direct involvement of the spermatic cord soft tissues to pT3 tumors to help clarify the appropriate staging of this histologic finding. A retrospective, multi-institutional review was performed to identify cases of NSGCTs with LVI in the spermatic cord without soft tissue invasion of the cord. The clinical-pathologic findings were compared with NSGCTs with spermatic cord soft tissue invasion (pT3). We identified 38 pT2 NSGCTs with LVI in the spermatic cord without soft tissue invasion of the cord and 89 pT3 tumors. There were no significant differences in patient age, tumor size, or clinical stage at presentation between the 2 groups. There were no significant differences in dominant histologic subtype, rete testis invasion, hilar soft tissue invasion, or margin status. There were no significant differences in disease recurrence/progression (P=0.63), recurrence/progression after chemotherapy (P=0.35), or death (P=0.51) between patients with only spermatic cord LVI versus patients with cord soft tissue invasion. In patients with pT2 NSGCTs according to the current staging, LVI in the spermatic cord without cord soft tissue invasion is comparable with pT3 tumors in terms of clinical stage at presentation as well as disease recurrence and survival.

    View details for Web of Science ID 000410661700010

    View details for PubMedID 28719463

  • Variant morphology in upper urinary tract urothelial carcinoma: a fourteen-year case series of biopsy and resection specimens. Human pathology Hayashi, H., Mann, S., Kao, C., Grignon, D., Idrees, M. T. 2017

    Abstract

    Upper urinary tract urothelial carcinoma exhibiting variant morphology, especially in higher-grade tumors, is a recognized phenomenon but has not been comparatively studied in biopsy versus resection material. We studied the morphologic patterns and clinicopathological features, and provide a comparison between biopsy and resection specimens. Consultation cases were evaluated separately to investigate for possible consultation bias. A total of 383 in-house cases from 352 patients including 314 resection specimens and 69 biopsies from 2001-2014 were reviewed from a single institution. Histologic type, tumor grade, invasion, pathologic stage, nodal status, metastasis, and the presence and type of variant morphology for each case were evaluated. Variant morphology was identified in 5 biopsy specimens (7.2%) and 42 resection specimens (13.4%). The most common variant morphologic pattern was squamous differentiation (16 cases, 4.5%) followed by an inverted growth pattern (8 cases, 2.2%). The presence of variant morphology in resection specimens had a significant association with higher tumor grade, higher pT stage, and non-papillary configuration. Out of 69 patients with biopsies, 31 had a subsequent resection. In comparison, 181 consultation cases from 168 patients showed variant morphology in six biopsies (7.1%) and twenty-seven resections (28.1%). In conclusion, the frequency of recognizing variant morphology in biopsies is about one-half of that in resections. The inclusion of consultation cases can inflate the incidence of variant morphology. As a result, the frequency of variant morphology in our in-house cases is lower than the percentage reported in the literature, most likely secondary to a consultation bias.

    View details for DOI 10.1016/j.humpath.2017.05.001

    View details for PubMedID 28506733

  • Immunohistochemical Assessment of 23 Immature Ovarian Teratomas Charville, G., Longacre, T., Vogel, H., Ulbright, T. M., Kao, C. NATURE PUBLISHING GROUP. 2017: 279A–280A
  • Adrenal Gland Myelolipomas with Plasma Cell Neoplasms Levy, D., Lin, C., Higgins, J. P., Kunder, C. A., Kao, C. NATURE PUBLISHING GROUP. 2017: 149A
  • Plasmacytoid Urothelial Carcinoma: A Single Institution Immunohistochemical and Molecular Study of 26 Cases Perrino, C., Cheng, L., Idrees, M., Eble, J. N., Kao, C., Grignon, D. NATURE PUBLISHING GROUP. 2017: 248A
  • A Comparative Study of pT3 versus pT2 Testicular Germ Cell Tumors, Including Evaluation of Lymphovascular Invasion (LVI) in the Spermatic Cord Sanfrancesco, J., Trevino, K., Osunkoya, A., Xiao, G. Q., Kao, C., Gordetsky, J., Unger, P., Ulbright, T. M., Idrees, M. NATURE PUBLISHING GROUP. 2017: 255A–256A
  • A Clinicopathologic and Molecular Analysis of 34 Mediastinal Germ Cell Tumors (GCT) Supporting a Dual Histogenesis for Teratomas Kao, C., Bangs, D., Ulbright, T. M. NATURE PUBLISHING GROUP. 2017: 482A
  • Plasmacytoid Urothelial Carcinoma: A Single Institution Immunohistochemical and Molecular Study of 26 Cases Perrino, C., Cheng, L., Idrees, M., Eble, J. N., Kao, C., Grignon, D. NATURE PUBLISHING GROUP. 2017: 248A
  • A Comparative Study of pT3 versus pT2 Testicular Germ Cell Tumors, Including Sanfrancesco, J., Trevino, K., Osunkoya, A., Xiao, G. Q., Kao, C., Gordetsky, J., Unger, P., Ulbright, T. M., Idrees, M. NATURE PUBLISHING GROUP. 2017: 255A–256A
  • A Clinicopathologic and Molecular Analysis of 34 Mediastinal Germ Cell Tumors (GCT) Supporting a Dual Histogenesis for Teratomas Kao, C., Bangs, D., Ulbright, T. M. NATURE PUBLISHING GROUP. 2017: 482A
  • Adrenal Gland Myelolipomas with Plasma Cell Neoplasms Levy, D., Lin, C., Higgins, J. P., Kunder, C. A., Kao, C. NATURE PUBLISHING GROUP. 2017: 149A
  • Immunohistochemical Assessment of 23 Immature Ovarian Teratomas Charville, G., Longacre, T., Vogel, H., Ulbright, T. M., Kao, C. NATURE PUBLISHING GROUP. 2017: 279A–280A
  • Evidence of a dual histogenetic pathway of sacrococcygeal teratomas HISTOPATHOLOGY Emerson, R. E., Kao, C., Eble, J. N., Grignon, D. J., Wang, M., Zhang, S., Wang, X., Fan, R., Masterson, T. A., Roth, L. M., Cheng, L. 2017; 70 (2): 290-300

    Abstract

    Sacrococcygeal teratomas are rare tumours that occur most frequently in neonates, although adult cases also occur. The molecular pathogenesis of these tumours and their long-term prognosis is uncertain. We investigated the i(12p) status of a large number of primary sacrococcygeal teratomas in both children and adults, including cases with malignant germ cell tumour elements.Fifty-four sacrococcygeal teratoma specimens from 52 patients were identified, and available follow-up information was obtained. Fluorescence in-situ hybridization analysis was performed to identify isochromosome 12p [i(12p)] abnormalities on paraffin blocks of the tumours. Among the 48 paediatric patients, there were 44 teratomas and four tumours with combined teratoma and yolk sac tumour (one of whom also had primitive neuroectodermal tumour). The teratomas included 37 mature teratomas and 11 immature teratomas (four grade 1, two grade 2, and five grade 3). The 44 teratomas lacking a yolk sac tumour component were all negative for i(12p). The four tumours with a yolk sac tumour component were all positive for i(12p). The four adult cases all lacked non-teratomatous germ cell tumour components, immature elements, and i(12p). Follow-up information was available for 32 patients. Two patients with teratoma had recurrence, but were alive with no evidence of disease after long-term follow-up. One patient with combined teratoma and yolk sac tumour had recurrence 7 months after resection. The other patients were alive with no evidence of disease at last follow-up.Our data suggest that paediatric sacrococcygeal teratomas should be considered as two distinct groups with divergent histogenetic pathways. The prognosis of these tumours is excellent, despite rare recurrence.

    View details for DOI 10.1111/his.13062

    View details for Web of Science ID 000394982000017

  • "Dissecting Gonadoblastoma" of Scully: A Morphologic Variant That Often Mimics Germinoma. American journal of surgical pathology Kao, C., Idrees, M. T., Young, R. H., Ulbright, T. M. 2016; 40 (10): 1417-1423

    Abstract

    Dr Robert E. Scully, who recognized and defined gonadoblastoma (GB), used the term "dissecting gonadoblastoma" (DGB) to describe variants with either an infiltrative type or diffuse pattern instead of the usual small nested arrangement. These patterns have not been emphasized in the literature. To investigate the features of DGB we examined 50 GBs microscopically and performed immunohistochemistry (IHC) in some. DGB was found in 38 (76%) GBs and was represented by 3 patterns. The most frequent was solid/expansile (n=26), consisting of large coalescent nests of germ cells, often (92%) interrupted by fibrovascular septa, with usually minor numbers of sex cord cells. Less frequent were small anastomosing nests (n=24) and cord-like arrangements (n=22) of germ cells irregularly distributed in a prominent stroma and with mostly inconspicuous sex cord cells. Most DGBs (24) showed >1 pattern and demonstrated the characteristic globular deposits of basement membrane, although these were often subtle. The germ cells in all patterns varied from spermatogonium-like to seminoma-like; OCT3/4 was positive only in the latter (7/7). The sex cord cells were small with dense, oval or angulated nuclei, inconspicuous nucleoli, and positivity for inhibin (9/9, strong), FOXL2 (9/9, strong), SF1 (8/9, strong), SOX9 (9/9, weak and focal), WT1 (5/7, variable), and calretinin (3/7, variable). Granulomas were present in 84% of germinoma foci, 13% of DGB foci, and 8% of classic GB foci. Twenty two of 38 DGBs had associated germinoma; 3 also had embryonal carcinoma, yolk sac tumor, and choriocarcinoma, respectively. Follow-up of 2 cases lacking an invasive tumor showed that both patients were disease free at 13 and 4.8 years after bilateral gonadectomy. We conclude that DGB is commonly seen with classic GB and displays identical IHC features, supporting it as a morphologic variant of GB. It appears likely that cord-like DGB is the earliest phase in a GB developmental continuum that may proceed successively into anastomosing, nested (classic GB), and solid/expansile patterns. DGB often mimics germinoma because of the large size of the nests, pseudoinfiltrative pattern of some cases, and inconspicuous sex cord cells. The presence of sex cord cells (identification aided by IHC for sex cord markers), the heterogenous morphology of the germ cells, and globules of basement membrane are useful differential features. The lack of a granulomatous reaction also favors DGB over germinoma. Mistaking DGB for GB with invasive germinoma may result in more aggressive therapy than warranted. The likely relationship of DGB to the relatively recently described concept of so-called "undifferentiated gonadal tissue" is discussed herein.

    View details for DOI 10.1097/PAS.0000000000000704

    View details for PubMedID 27454939

  • Nonchoriocarcinomatous Trophoblastic Tumors of the Testis The Widening Spectrum of Trophoblastic Neoplasia AMERICAN JOURNAL OF SURGICAL PATHOLOGY Idrees, M. T., Kao, C., Epstein, J. I., Ulbright, T. M. 2015; 39 (11): 1468-1478

    Abstract

    Tumors of trophoblastic derivation other than choriocarcinoma are very rare in the testis but have been reported on occasion in association with other germ cell tumors. Their morphologic spectrum is analogous to the trophoblastic tumors of the female genital tract including epithelioid trophoblastic tumor (ETT) and placental site trophoblastic tumor (PSTT). Herein we report our experience with 8 cases of trophoblastic tumors of testicular origin that lacked the features of choriocarcinoma; these included 4 ETTs, 1 PSTT, 1 unclassified trophoblastic tumor (UTT), 1 partially regressed choriocarcinoma with a monophasic morphology, and 1 hybrid tumor showing a mixture of adenocarcinoma and a UTT. All tumors occurred in young men 19 to 43 years old. Five arose de novo within the testis (2 ETTs, 1 UTT, 1 regressing choriocarcinoma, and the hybrid tumor) as a component of mixed germ cell tumors, and 3 (2 ETTs and 1 PSTT) were found in metastatic sites after chemotherapy. The trophoblastic component was minor (5% to 10%) in 6 tumors but was 95% of 1 metastatic tumor (ETT) and 50% of the hybrid tumor. Other germ cell tumor elements were identified in all cases, most commonly teratoma. The ETTs consisted of nodules and nests of squamoid trophoblast cells showing abundant eosinophilic cytoplasm, frequent apoptotic cells, extracellular fibrinoid material, and positivity for p63 and negativity for human placental lactogen (HPL). The PSTT showed sheets of discohesive, pleomorphic, mononucleated trophoblast cells that invaded blood vessels with fibrinoid change and were p63 negative and HPL positive. The UTT showed a spectrum of small and large trophoblast cells, some multinucleated but lacking distinct syncytiotrophoblasts, and was patchily positive for both p63 and HPL. The hybrid tumor had ETT-like and adenocarcinomatous areas that coexpressed inhibin and GATA3 but were negative for p63 and HPL, leading to classification of the trophoblastic component as UTT. Seven of the patients were alive and well on follow-up (8 to 96 mo; median, 39 mo), whereas the patient with the hybrid tumor died of liver metastases at 2 years. Our study verifies that trophoblastic neoplasms often having the features of nonchoriocarcinomatous gestational trophoblastic tumors may arise from the testis, occur either in the untreated primary tumor or in metastases after chemotherapy, and should be distinguished from choriocarcinoma given what appears to be a less aggressive clinical course.

    View details for DOI 10.1097/PAS.0000000000000509

    View details for Web of Science ID 000363375900003

    View details for PubMedID 26457351

  • Juvenile Granulosa Cell Tumors of the Testis A Clinicopathologic Study of 70 Cases With Emphasis on Its Wide Morphologic Spectrum AMERICAN JOURNAL OF SURGICAL PATHOLOGY Kao, C., Cornejo, K. M., Ulbright, T. M., Young, R. H. 2015; 39 (9): 1159-1169

    Abstract

    The clinical and pathologic features of 70 juvenile granulosa cell tumors (JGCTs) of the testis are presented. The patients were from 30 weeks gestational age to 10 years old; 60 of 67 (90%) whose ages are known to us were 6 months old or younger. Sixty-two underwent gonadectomy, 6 wedge excision, and 2 only biopsy. Twenty-six tumors were left sided and 22 right sided. Six occurred in an undescended testis and 2 in dysgenetic gonads. The most common presentation was a testicular mass (65%), followed by an "enlarging testis" (25%). Six of 14 patients in whom it was measured had "elevated" serum α-fetoprotein (AFP), likely physiologically, and 1 had gynecomastia. The tumors measured 0.5 to 5 cm (mean, 1.7 cm; median, 1.5 cm) and were most commonly well circumscribed and typically yellow-tan; approximately 2/3 had a cystic component, whereas 1/3 were entirely solid. Microscopic examination typically showed a lobular growth, punctuated in 67 cases by variably sized and shaped follicles containing material that was basophilic (21%), eosinophilic (44%), or of both characters (35%); 3 lacked follicles. In nonfollicular areas, the tumor cells typically grew diffusely but occasionally had a corded arrangement (26%) or reticular appearance (29%). The stroma was either fibrous or fibromyxoid; hemorrhage associated with hemosiderin-laden macrophages was focally seen in 16%. The tumor cells were mostly small to medium sized with round to oval nuclei containing inconspicuous nucleoli and moderate to abundant, but occasionally scant, pale to lightly eosinophilic, sometimes vacuolated, cytoplasm; nuclear grooves were infrequent (6%). Focal columnar morphology was seen in 27% of the tumors. Mitoses were plentiful in 37%, and apoptosis was prominent in 46%. Intratubular tumor was seen in 43% and entrapped seminiferous tubules in 70%. Lymphovascular invasion was present in 2 cases, rete testis involvement in 4, and necrosis in 1. Rare features/patterns included: regressed tumor with hyalinization and prominent blood vessels (13%), papillary growth (4%), basaloid morphology (1%), spindle cell predominance (1%), microcystic foci (1%), adult granulosa cell-like (1%) patterns, and hyaline globules (1%). Inhibin (16/18), calretinin (8/9), WT1 (6/7), FOXL2 (12/12), SF-1 (12/12), and SOX9 (6/11) were positive, whereas SALL4 and glypican-3 were consistently negative in the neoplastic granulosa cells. Only 1 of 10 tumors was focally positive for α-fetoprotein. JGCT is a rare neoplasm with a wide morphologic spectrum that also occurs rarely in undescended testes and dysgenetic gonads. The solid and reticular patterns may pose diagnostic challenges, but the lobular appearance and follicular differentiation are characteristic. Immunohistochemical stains may aid in its distinction from other tumors of young male individuals, particularly yolk sac tumor, a neoplasm that peaks at a somewhat later age. Twenty-four patients with follow-up, including 4 of 6 patients treated with wedge resection/biopsy, had no evidence of disease (2 to 348 mo; mean, 83 mo; median, 61 mo). One additional patient was alive at 260 months, but the disease status is unknown. The benign clinical course of all cases of JGCT with follow-up, despite often frequent mitotic activity, supports testis sparing surgery when technically feasible.

    View details for DOI 10.1097/PAS.0000000000000450

    View details for Web of Science ID 000360590000001

    View details for PubMedID 26076062

  • Fine-Needle Aspiration Cytology of Metastatic Plasmacytoid Urothelial Carcinoma: Report of Four Cases Including a Case of Mixed Plasmacytoid and Micropapillary Morphology ACTA CYTOLOGICA Wu, H. H., Kao, C., Grignon, D. J. 2015; 59 (3): 248-252

    Abstract

    The aim of this study was to report a small series of fine-needle aspiration (FNA) cytology of the plasmacytoid variant of urothelial carcinoma (PVUC).A computerized search of our laboratory information system was performed for the 5-year period between January 2008 and January 2013 to identify all FNA cases in which the corresponding surgical pathology cases were diagnosed as PVUC.The 4 cases identified were from 2 men (aged 56 and 64 years) and 2 women (aged 72 and 46 years). The FNA smears demonstrated low-to-moderate cellularity and consisted predominantly of single and dyshesive, medium-sized tumor cells with eccentrically located nuclei and a moderate-to-abundant dense cytoplasm. The nuclei were oval with slightly irregular nuclear membranes and contained coarse granular chromatin with inconspicuous or small nucleoli. There was moderate nuclear variation in size. The nuclear-to-cytoplasmic ratio ranged from <1 to 3. Binucleation, cytoplasmic vacuoles, and perinuclear hof were occasionally seen.FNA cytology of PVUC shares features with plasma cell neoplasms, lobular carcinoma of the breast, and signet ring cell carcinoma of the stomach. Being aware of the patient's clinical history and the potential diagnostic pitfall of this rare variant of urothelial carcinoma is important for an accurate diagnosis on FNA biopsy.

    View details for DOI 10.1159/000435828

    View details for Web of Science ID 000421583900004

    View details for PubMedID 26279415

  • Lymph node metastases in patients with urothelial carcinoma variants: Influence of the specific variant on nodal histology UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS Rice, K. R., Koch, M. O., Kao, C., Pedrosa, J. A., Kaimakliotis, H. Z., Masterson, T. A., Bihrle, R., Cheng, L. 2015; 33 (1): 20.e23-20.e29

    Abstract

    The effect that the presence of urothelial variant (UV) histologies has on the behavior of urothelial carcinoma remains poorly defined. The goal of this study is to examine the relationship between different histologic variants and the presence and histology of lymph node metastases.Our institutional bladder cancer database was examined for all patients demonstrating UV at cystectomy performed between 2001 and 2012. Patients with primary bladder sarcoma, primary bladder adenocarcinoma, and squamous cell carcinoma were excluded. The cystectomy and nodal pathology reports were reviewed in node-positive cases with the goal of determining the relative percentages of UVs in the bladder and lymph nodes.Overall, 292 patients demonstrated UV at cystectomy. After excluding patients with primary adenocarcinoma, sarcoma, and squamous variants, 141 patients remained, of which 65 demonstrated node-positive disease. Of these node-positive patients, 57 had slides available for review. Node positivity was most common in the micropapillary (MP), clear cell urothelial carcinoma (CC), and plasmacytoid (PC) variants. Remaining variants demonstrated node-positive rates ranging from 11.1% to 37.5%. When nodes were positive, the variants found in the nodal metastases most commonly were MP, CC, glandular, nested, and lymphoepitheliomalike. Median lymph node density was highest in PC (33%) and CC (35%) variants, although these differences were not statistically significant. Variant histology predominated the nodal metastases regardless of predominance in bladder for the MP (84%) and CC (100%) variants. The PC variant exhibited the high incidence of positive surgical margins.Lymph node metastases were most common in the MP, CC, and PC variants. Variant histology was present and predominated nodal histology in most MP and CC cases. These results suggest that the variant histology itself may be driving lymphatic spread in MP and CC cases. Conversely, the PC variant may be a marker for locally advanced and aggressive disease rather than specifically influencing lymphatic spread.

    View details for DOI 10.1016/j.urolonc.2014.06.012

    View details for Web of Science ID 000370975300015

    View details for PubMedID 25047418

  • Gonadoblastoma: an immunohistochemical study and comparison to Sertoli cell nodule with intratubular germ cell neoplasia, with pathogenetic implications HISTOPATHOLOGY Kao, C., Ulbright, T. M., Idrees, M. T. 2014; 65 (6): 861-867

    Abstract

    To investigate the immunohistochemical properties of the sex cord cells of gonadoblastoma and Sertoli cell nodule with intratubular germ cell neoplasia unclassified (IGCNU) as a means of objective distinction and to provide insight into the pathogenesis.Immunohistochemical stains for SOX9, FoxL2 and SF-1 were performed on 10 gonadoblastomas (all phenotypical females) and 14 Sertoli cell nodules with IGCNU in normal phenotypical males with coexisting germ cell tumours. The sex cord cells of gonadoblastomas showed strong, diffuse FoxL2 and SF-1 positivity and focal weak to moderate SOX9 reactivity, whereas those of Sertoli cell nodules with IGCNU were uniformly, strongly positive for SOX9 and SF-1, while negative for FoxL2.Coexpression of SOX9 and FoxL2 in the sex cord cells of gonadoblastomas provides evidence that these morphologically ambiguous sex cord cells are incompletely differentiated. The strong, diffuse SOX9 and SF-1 positivity and absence of FoxL2 reactivity in the Sertoli cell nodules with IGNCU support full Sertoli cell differentiation of the sex cord cells and distinguish them from gonadoblastomas. Deficient SOX9 expression in gonadoblastoma supports a current model of pathogenesis where immature germ cells, in the absence of well-formed Sertoli cells, retain a fetal phenotype and susceptibility to malignant transformation.

    View details for DOI 10.1111/his.12444

    View details for Web of Science ID 000345574400014

    View details for PubMedID 24766183

  • Myoid Gonadal Stromal Tumor A Clinicopathologic Study of Three Cases of a Distinctive Testicular Tumor AMERICAN JOURNAL OF CLINICAL PATHOLOGY Kao, C., Ulbright, T. M. 2014; 142 (5): 675-682

    Abstract

    To report three new cases of testicular myoid gonadal stromal tumor to better characterize its features.The clinicopathologic findings (including follow-up) were evaluated and a review of the literature was performed.The patients were 38, 43, and 59 years old, and tumor sizes were 1.2, 1.3, and 3.2 cm. All were unilateral, well circumscribed, adjacent to the rete testis, and composed exclusively of spindled cells with elongated nuclei and occasional nuclear grooves arranged in fascicles with admixed variably ectatic blood vessels. Nucleoli were inconspicuous, and the cytoplasm was scant, ill-defined, and pale/lightly eosinophilic. No sex cord component was present. Mitotic figures ranged from zero to five per 10 high-power fields. Significant atypia, lymphovascular invasion, and necrosis were absent. All were consistently positive for smooth muscle actin, S100 protein, FOXL2, and steroidogenic factor 1 but negative for h-caldesmon, calretinin, and SOX9. Inhibin and calponin were focally positive. All patients were alive and well at 5, 31, and 58 months postorchiectomy. Combining our cases with those previously reported (n = 6) shows that this neoplasm occurs mostly in younger men (mean, 37 years), and all follow-up thus far (mean, 25 months) has been benign.Myoid gonadal stromal tumors are small (<4 cm) indolent testicular tumors distinctly different from other sex cord-stromal tumors and are adequately managed by orchiectomy.

    View details for DOI 10.1309/AJCPGSCD1DGNZ0QO

    View details for Web of Science ID 000343687100016

    View details for PubMedID 25319984

  • "Somatic-type" Malignancies Arising From Testicular Germ Cell Tumors A Clinicopathologic Study of 124 Cases With Emphasis on Glandular Tumors Supporting Frequent Yolk Sac Tumor Origin AMERICAN JOURNAL OF SURGICAL PATHOLOGY Magers, M. J., Kao, C., Cole, C. D., Rice, K. R., Foster, R. S., Einhorn, L. H., Ulbright, T. M. 2014; 38 (10): 1396-1409

    Abstract

    Somatic-type malignancies (SMs) in patients with testicular germ cell tumors (GCT) are rare and mostly attributed to "transformation" of teratoma, although yolk sac tumor (YST) origin has also been proposed. We studied 124 cases of "SM" of testicular GCT origin from 106 patients to evaluate their morphology, immunohistochemical features (especially the utility of SALL4), and relationship to YST. Primitive neuroectodermal and nephroblastomatous tumors were excluded because of prior studies. Patients ranged in age from 15 to 68 years (mean, 33 y). The tumors ranged from 0.7 to 30 cm (mean, 7.6 cm) and involved the retroperitoneum (64%), abdomen/pelvis (10%), lung (10%), mediastinum (6%), supraclavicular region/neck (4%), testis (4%), and thigh (1%). Most initial diagnoses were sarcomas (n=68) or carcinomas (n=51). On review and immunohistochemical analysis, 7 of 45 adenocarcinomas were reclassified as glandular YSTs (GYST) on the basis of glypican-3 (GPC3) and/or α-fetoprotein positivity and scant/absent reactivity for EMA and CK7. These occasionally (29%) had subnuclear and sometimes supranuclear vacuoles (endometrioid-like), whereas adenocarcinomas were more frequently mucinous (17%) or enteric-type (11%) than endometrioid-like (9%). Both expressed CDX2 frequently (83% and 63%, respectively). MUC protein 2, 4, 5, and 6 expression was more common in adenocarcinomas (7% to 36%) than in GYSTs (0% to 20%) but was infrequent. Both were often positive for SALL4, BerEP4, and MOC31; all were negative for TTF-1. On follow-up (GYST: range, 23 to 169 mo; mean, 81mo; adenocarcinoma: range, 1 to 170 mo; mean, 55 mo), 50% and 33% of patients with GYST and adenocarcinoma, respectively, died of disease. We reclassified 26 of 76 sarcomatoid tumors as sarcomatoid YSTs (SYST) on the basis of positive reactivity for both AE1/3 and GPC3. These tumors often had spindled and epithelioid cells in a fibromyxoid stroma. SYSTs were often (60%) SALL4 positive, whereas sarcomas were all negative. On follow-up (SYST: range, 1 to 259 mo; mean, 62 mo; sarcoma: range, 1 to 327 mo; mean, 70 mo), 50% and 29% of patients with SYST and sarcoma, respectively, died of disease, with most mortality occurring in those with high-grade tumors. We conclude that, on the basis of a panel of immunoreactivities, a significant number of "SMs" in testicular GCT patients are more accurately classified as either GYSTs or SYSTs. Ambiguous glandular tumors should be evaluated for GPC3, α-fetoprotein, CK7, and EMA reactivity and sarcomatoid ones for GPC3, AE1/3, and SALL4 reactivity.

    View details for Web of Science ID 000342001800011

    View details for PubMedID 24921638

  • The utility of immunostaining for NUT, GAGE7 and NY-ESO-1 in the diagnosis of spermatocytic seminoma HISTOPATHOLOGY Kao, C., Badve, S. S., Ulbright, T. M. 2014; 65 (1): 35-44

    Abstract

    To identify specific positive immunohistochemical markers for spermatocytic seminoma (SS).We studied the reactivity of 94 (total) cases of SS, seminoma, embryonal carcinoma and solid yolk sac tumour with antibodies against nuclear protein in testis (NUT) and two cancer/testis antigens, GAGE7 and NY-ESO-1. When tumour positivity was defined as an extent plus intensity score of ≥ 4, NUT was positive in 71% of SSs, 19% of seminomas, and 5% of solid yolk sac tumours. GAGE7 was positive in 67% of SSs and 4% of seminomas. NY-ESO-1 was positive in 82% of SSs, 13% of seminomas, and 5% of solid yolk sac tumours. The sensitivity and specificity, respectively, of these antibodies for SSs were as follows: NUT, 71% and 92%; GAGE7, 67% and 99%; and NY-ESO-1, 82% and 94%. When positivity criteria were stricter, NUT and GAGE7 positivity occurred exclusively in SS, but the sensitivity decreased to 41% and 60%, respectively, and NY-ESO-1 was 59% sensitive and 97% specific. Neither the sarcomatous component of three SSs nor any embryonal carcinoma showed reactivity with any antibody.All three antibodies are variably sensitive for SS, and high specificity is attained when there is multifocal and strong nuclear labelling.

    View details for DOI 10.1111/his.12365

    View details for Web of Science ID 000337694700004

    View details for PubMedID 24393139

  • Testicular Embryonal Carcinoma A Morphologic Study of 180 Cases Highlighting Unusual and Unemphasized Aspects AMERICAN JOURNAL OF SURGICAL PATHOLOGY Kao, C., Ulbright, T. M., Young, R. H., Idrees, M. T. 2014; 38 (5): 689-697

    Abstract

    A total of 180 consecutive testicular cancers containing a component of embryonal carcinoma (EC) were reviewed to assess the morphologic features of the EC component. EC mostly (84%) occurred as a component of a mixed germ cell tumor, but 16% were pure. Solid (55%), glandular (17%), and papillary (11%) were the most common primary patterns (predominant architectural pattern occupying at least 50%), whereas other less common primary patterns included nested (3%), micropapillary (2%), anastomosing glandular (1%), sieve-like glandular (<1%), pseudopapillary (<1%), and blastocyst-like (<1%). Occasionally, EC developed predominantly in the context of polyembryoma-like (6%) and diffuse embryoma-like ("necklace" pattern) (3%) proliferations. In all, 69% had secondary architectural patterns, the most frequent being glandular (31%), papillary (14%), and solid (12%). An appliqué appearance, in which smudged and degenerate-appearing EC cells appear "applied" to the tumor periphery, was common (67%). EC cells with clear cytoplasm and distinct cell membranes (seminoma-like) were present in 11%, and dense lymphocytic infiltration and granulomatous inflammation were seen in 7% and 3%, respectively. Features simulating yolk sac tumor and teratoma were also seen: pseudoendodermal sinuses (34%), columnar cells (20%), and secretory-type subnuclear cytoplasmic vacuoles (6%). Syncytiotrophoblast cells were frequent (46%). Intratubular EC, typically partly necrotic and calcified, occurred in 24%. The associated stroma was more often non-neoplastic (53%) than neoplastic (29%). The rarity of some poorly characterized patterns of EC (micropapillary, blastocyst-like, anastomosing glandular, and sieve-like glandular) and some that overlap with those of other germ cell tumors, as well as some uncommon cytologic features, may result in misinterpretation, potentially impacting management. The association with other more common patterns and typical cytologic features, together with simple awareness of these variant morphologies, are helpful in establishing an accurate diagnosis of EC.

    View details for DOI 10.1097/PAS.0000000000000171

    View details for Web of Science ID 000334933700013

    View details for PubMedID 24503753

  • Idiopathic granulomatous orchitis: morphology and evaluation of its relationship to IgG4 related disease HUMAN PATHOLOGY Karram, S., Kao, C., Osunkoya, A. O., Ulbright, T. M., Epstein, J. I. 2014; 45 (4): 844-850

    Abstract

    Idiopathic granulomatous orchitis (IGO) is rare, thought to result from an autoimmune reaction to spermatogenic elements. Its relationship to IgG4-related disease (IgG4-RD) has not been evaluated. Sixteen orchiectomy specimens (1984-2012) with a prominent intratubular granulomatous reaction were reviewed: IGO (n = 6); intratubular germ cell neoplasia unclassified (IGCNU) with a granulomatous reaction and associated seminoma (GS, n = 6); and unclassified intratubular granulomatous orchitis not fitting into a specific entity (UGO, n = 4). Men with IGO were 32 to 86 years old, presenting with a mass suspicious for malignancy. Only one patient had a history of an inflammatory disease. Clinical follow-up was available for 2 patients with IGO, and both had no evidence of systemic IgG4-RD. All IGO cases had an epithelioid granulomatous reaction confined to seminiferous tubules, an extensive interstitial lymphoplasmacytic inflammation, 3 of 6 had prominent interstitial fibrosis, and 3 of 6 cases had plasma cells with an IgG4+/IgG+ ratio >40%. In GS, 10% to 100% of tubules with IGCNU had a granulomatous reaction, which in 3 cases replaced IGCNU cells. In contrast to IGO, GS had more intratubular multinucleated giant cells, more peritubular sclerosis, fewer interstitial plasma cells, and no interstitial fibrosis. Of the 4 UGO cases, most had predominantly interstitial with less intratubular granulomatous inflammation. Only 1 non-IGO case had elevated tissue IgG4 (GS case). It is critical and sometimes difficult to distinguish GS from IGO. IGO shares some features with IgG4-RD, yet current evidence does not support its classification as a localized manifestation of IgG4-RD occurring in the testis.

    View details for DOI 10.1016/j.humpath.2013.12.003

    View details for Web of Science ID 000333659800021

    View details for PubMedID 24656095

  • Sclerosing Sertoli Cell Tumor of the Testis A Clinicopathologic Study of 20 Cases AMERICAN JOURNAL OF SURGICAL PATHOLOGY Kao, C., Kum, J. B., Idrees, M. T., Ulbright, T. M. 2014; 38 (4): 510-517

    Abstract

    Sclerosing Sertoli cell tumor (SSCT) of the testis is rare, with only 22 previously reported cases. Most have been small, circumscribed masses, and none has had a malignant clinical course; however, follow-up is limited. We have examined 20 new SSCTs to better characterize their features and report long-term follow-up. At least focal tubule formation by sex cord cells in a dense, hypocellular fibrous stroma occupying at least 50% of the lesion was required. The patient age ranged from 23 to 52 years (mean, 37; median, 39). All SSCTs were unilateral with 11 left sided and 9 right sided. The average size was 1.7 cm (range, 0.5 to 6 cm). In most cases, the stroma represented 50% to 70% of the mass but was at least 80% in 2. The Sertoli cells formed cords, trabeculae, small nests, focal tubules (sometimes with a vague pseudovascular or retiform appearance), and rarely single cells. Most tumor cells had small, round, oval to polygonal nuclei with finely granular chromatin, small nucleoli, and modest amounts of pale, eosinophilic cytoplasm. No mitotic figures, significant atypia, or necrosis was seen. All tumors but 1 were circumscribed and lacked lymphovascular invasion. Follow-up in 15 patients (3 mo to 16 y; mean, 6.1 y) showed 9 alive and free of disease, 5 alive with unknown disease status, and 1 patient, who presented with bone metastases, dead of disease at 27 months. The only features in the malignant case that differed from all others in our study were lymphovascular invasion and lack of circumscription. Combining our cases with previously reported ones shows that SSCTs are unilateral, usually small (80% <2 cm) tumors that occur in a wide age range (18 to 80 y old; mean, 35 y) and lack necrosis. Only 1 of 31 with follow-up (mean, 4.4 y) metastasized; this tumor was 3.8 cm and had lymphovascular invasion and invasive growth. We conclude that SSCTs<2 cm with the typical features and lacking those associated with malignancy in Sertoli cell tumors, not otherwise specified, have a negligible risk of metastasis and are adequately managed by orchiectomy alone.

    View details for DOI 10.1097/PAS.0000000000000132

    View details for Web of Science ID 000333391300008

    View details for PubMedID 24552667

  • Merkel Cell Carcinoma Exhibiting Cytoplasmic OCT4 Staining: A Potential New Diagnostic Immunohistochemical Marker AMERICAN JOURNAL OF DERMATOPATHOLOGY Kao, C., Warren, S., Idrees, M. T. 2014; 36 (3): 274-276

    View details for DOI 10.1097/DAD.0b013e3182932aed

    View details for Web of Science ID 000337303600018

    View details for PubMedID 23863554

  • Testicular Hemorrhage, Necrosis, and Vasculopathy Likely Manifestations of Intermittent Torsion That Clinically Mimic a Neoplasm AMERICAN JOURNAL OF SURGICAL PATHOLOGY Kao, C., Zhang, C., Ulbright, T. M. 2014; 38 (1): 34-44

    Abstract

    We report 30 cases of testicular hemorrhage and/or necrosis with associated vascular damage that caused clinical concern for a neoplasm and that raised the question of a vasculitis syndrome on pathologic examination. The patients were 12 to 66 years old (median, 33 y) and presented with pain (n=15), mass (n=12), or both (n=2); 1 case had no available clinical information. Ultrasonographic interpretations included a neoplasm in the differential diagnoses in 14 of 18 cases in which this information was available, and most (n=24) had orchiectomy because of this possibility. Only 4 were clinically suspected to represent testicular infarction. Circumscribed, hemorrhagic lesions occurred in 10 cases, less demarcated hemorrhagic foci in 5, and discrete nodules or ill-defined foci of varying color and consistency in the remainder. No clear testicular lesion was described in 2, with 1 of these having a "dusky" appearance. On microscopic examination all but 1 case showed damaged blood vessels (vasculopathy), with either associated hemorrhage/hematoma (n=24) and/or areas of parenchymal necrosis (n=21). One case showed only segmental tubular atrophy with interstitial inflammation and vasculopathy; no infarct or hemorrhage was identified. A variety of vascular changes was identified, including prominent intimal thickening in arteries (n=22) and fibrinoid change in both arteries (n=5) and vessels of indeterminate type (n=8). Medial fibrosis was present in veins (n=12) and vessels of indeterminate type (n=4), whereas thrombi (remote, recanalized, and/or recent) occurred in arteries (n =7), veins (n=9), and vessels of indeterminate type (n=11). Dilated, blood-filled vessels were present in the testis and/or paratestis in 15 cases. In addition, 7 cases showed arteriolar hyalinization, and 19 had inflammation of blood vessels. The latter was lymphohistiocytic and mostly light but occasionally prominent (n=5). Interstitial inflammation was seen adjacent to damaged testicular parenchyma in all 30 cases. Clinical follow-up in 20 patients (4 to 131 mo, mean 38 mo) showed no evidence of recurrence in the contralateral testis or later development of systemic vasculitis. The histologic findings were compared with those in 11 orchiectomies resected for clinical acute torsion. All clinical acute torsion cases showed both parenchymal and fibrinoid vascular necrosis, and 10 had hemorrhage/hematoma; they lacked vasculitis, interstitial inflammation, and chronic vascular changes. Testicular vasculopathy, characterized by acute and chronic vascular injury, commonly occurs in testes with parenchymal hemorrhage and necrosis that clinically mimic a tumor. It shares the acute features of recent torsion but also has findings indicative of chronic injury. Testicular vasculopathy is most likely a result of chronic intermittent torsion that leads to localized hemorrhage/necrosis and should be distinguished from cases of systemic vasculitis given the significantly different clinical implications.

    View details for DOI 10.1097/PAS.0b013e31829c0206

    View details for Web of Science ID 000338983000004

    View details for PubMedID 24061519

  • NUT protein is not expressed in undifferentiated (anaplastic) thyroid carcinoma HISTOPATHOLOGY Kao, C., Badve, S. 2013; 63 (3): 429-430

    View details for DOI 10.1111/his.12142

    View details for Web of Science ID 000323257200015

    View details for PubMedID 23701453

  • Tubular adenoma of the urinary tract: a newly described entity HUMAN PATHOLOGY Kao, C., Epstein, J. I. 2013; 44 (9): 1890-1894

    Abstract

    Tubular adenomas in the urinary tract with the same appearance as those in the gastrointestinal tract have not yet been described in the literature. We herein report 4 cases of tubular adenomas in the urinary tract encountered within our consult practice. This lesion was defined by the presence of a collection of small round tubular glands with intestinal-type epithelium showing moderate dysplasia, identical to the histology of tubular adenomas in the intestinal tract. Patients ranged in age from 37 to 63 years (mean, 45 years), with 3 of the 4 being male (male-to-female ratio, 3:1). The locations were urinary bladder, prostatic urethra and ureter with hematuria, polyps, and obstructive mass as their presentations, respectively. One lesion was large measuring 1.4 cm associated with pseudoinvasion as well as invasive adenocarcinoma. Immunohistochemically, the tubular adenomas stained positive for CDX2 and CK20, while negative for GATA3 and CK7. One case showed positive nuclear β-catenin staining. Tubular adenoma of the urinary tract is a rare lesion, and recognition of this entity will encourage further reports and help to better understand the relation of tubular adenoma to concurrent and subsequent urinary tract malignancies.

    View details for DOI 10.1016/j.humpath.2013.02.017

    View details for Web of Science ID 000324152500024

    View details for PubMedID 23664485

  • A case report of adrenocortical carcinosarcoma with oncocytic and primitive neuroectodermal-like features HUMAN PATHOLOGY Kao, C., Grignon, D. J., Ulbright, T. M., Idrees, M. T. 2013; 44 (9): 1947-1955

    Abstract

    Adrenocortical carcinosarcomas are rare aggressive neoplasms; only a few have been reported to date, all with dismal prognosis. These were reported as having varying morphology. We have encountered a case of adrenal carcinosarcoma with an undifferentiated component bearing similarities to primitive neuroectodermal tumors and other areas of oncocytic differentiation. The 48-year-old woman patient presented with abdominal pain and unintended, excessive weight loss. Computed tomographic imaging revealed a tumor located adjacent to the liver and kidney necessitating a partial nephrectomy and hepatectomy. Histologically, the tumor exhibited malignant features. Melan-A, inhibin, calretinin, cytokeratin AE1/AE3, synaptophysin, and neuron-specific enolase were positive immunohistochemically. The patient developed metastasis within 2 months of surgery and is currently alive with disease after chemotherapy. Adrenal carcinosarcoma is a rare highly aggressive malignancy with a wide morphologic spectrum. Recognition of variant morphology and applying correct immunohistochemical studies will aid in reaching an accurate diagnosis.

    View details for DOI 10.1016/j.humpath.2013.01.019

    View details for Web of Science ID 000324152500032

    View details for PubMedID 23574783

  • Testicular Fibrothecoma A Morphologic and Immunohistochemical Study of 16 Cases AMERICAN JOURNAL OF SURGICAL PATHOLOGY Zhang, M., Kao, C., Ulbright, T. M., Epstein, J. I. 2013; 37 (8): 1208-1214

    Abstract

    Benign intratesticular spindle cell lesions are rare. Herein, we report the morphology, immunohistochemical characteristics, and prognosis of 16 cases of testicular fibrothecoma. The mean age at diagnosis was 44 years (16 to 69 y). Of 15 patients with information, 14 presented with a palpable testicular mass and 1 with heaviness in the scrotum. Medical histories included bilateral orchidopexy as a child (n=1) and testicular atrophy receiving testosterone replacement (n=1). The average size was 1.8 cm (median 2 cm; range, 0.5 to 7.6 cm). All cases were intratesticular, although 13 were abutting the tunica albuginea with others centered on the rete testis (n=2), or were indeterminate on biopsy (n=1). Eleven cases were relatively well circumscribed, although not encapsulated, with 1 being infiltrative and 4 not evaluable. Four tumors showed entrapment of seminiferous tubules. Half of the fibrothecomas showed a mixed storiform pattern and short fascicles, with 6 storiform only and 2 short fascicles only. One half of the tumors were very hypercellular. Cases were equally split between having plumper ovoid as opposed to spindled pointed nuclei, with all cases lacking prominent nucleoli. Eleven cases had 0 to 2 mitoses per 10 HPF, 3 had 4 to 5 mitoses per 10 HPF, and 2 had 9 to 10 mitoses per 10 HPF. Collagen deposition either in bands or investing single cells ranged from none to extensive, with 10/16 cases having at least a moderate amount. Immunohistochemical positivity was as follows: inhibin (11/13, patchy to diffuse); calretinin (5/9); Melan-A (4/4); pan keratin (5/8); BCL2 (3/4); CD34 (3/8); S100 (4/8); muscle-specific actin (4/4); and desmin (5/8). Patients were followed up for a mean of 71.8 months (range, 3 to 144 mo). All were well with no evidence of disease. Of the 2 men with 9 to 10 mitoses per 10 HPF, 1 died of other causes 5 years and 8 months later, and the other had no evidence of disease at 4 years and 10 months after surgery. In summary, testicular fibrothecomas are rare with somewhat variable histology and can have worrisome histologic features such as minimal invasion into surrounding testis, high cellularity, and increased mitotic rate. Their immunoprofile is variable and typically not diagnostic. Despite some worrisome histologic features, they appear uniformly benign in their behavior.

    View details for Web of Science ID 000330428500010

    View details for PubMedID 23715159

  • Nephrogenic Adenomas in Pediatric Patients: A Morphologic and Immunohistochemical Study of 21 Cases PEDIATRIC AND DEVELOPMENTAL PATHOLOGY Kao, C., Kum, J. B., Fan, R., Grignon, D. J., Eble, J. N., Idrees, M. T. 2013; 16 (2): 80-85

    Abstract

    Similar to nephrogenic adenomas in adults, those in children are rare benign lesions that often occur in the setting of previous surgery or chronic irritation of the urinary tract. These lesions often present with hematuria and/or as polypoid or papillary lesions on cystoscopy, which may indicate malignancy. We sought to evaluate the various patterns of nephrogenic adenoma occurring in the pediatric population and better characterize the immunophenotype of these lesions. We reviewed 21 cases of nephrogenic adenomas from urinary bladder biopsies of 16 patients. Most patients had a history of urinary bladder augmentation with recurrent urinary stones and urinary tract infections. Many cases presented as a papillary or polypoid mass on cystoscopy. The most common morphologic patterns are papillary, tubulocystic, and a mixed pattern of papillary and tubulocystic, followed by cystic and tubular. On immunostaining, PAX-2, PAX-8, CK7, and MUC-1 provided the most diffuse and intense positive reactivity for nephrogenic adenoma, whereas CD10 and P504S were focal and lesser in intensity when positive. p63 and PAX-5 were consistently negative. We conclude that, although rare in children, nephrogenic adenoma should be included in the differential diagnosis of papillary/polypoid lesions in the urinary tract, especially in the context of previous surgery, chronic irritation from recurrent urinary tract infections, or stones. The immunohistochemistry profile of nephrogenic adenomas in our study also provides evidence that these are derived from distal renal tubular cells. In difficult cases, an immunohistochemical panel consisting of cytokeratin 7, PAX-2, PAX-8, and MUC-1 may be useful.

    View details for DOI 10.2350/12-10-1261-OA.1

    View details for Web of Science ID 000317833200004

    View details for PubMedID 23597251

  • Solid Pattern Yolk Sac Tumor: A Morphologic and lmmunohistochemical Study of 52 Cases AMERICAN JOURNAL OF SURGICAL PATHOLOGY Kao, C., Idrees, M. T., Young, R. H., Ulbright, T. M. 2012; 36 (3): 360-367

    Abstract

    Yolk sac tumors may exhibit numerous patterns. One that has received little attention overall, yet is not uncommon, is a solid pattern, which is especially prone to misinterpretation, usually as seminoma, in biopsy specimens from metastatic or mediastinal sites. This distinction is of critical importance as the 2 tumors are treated differently. To determine features useful in the diagnosis of solid yolk sac tumor we reviewed 52 germ cell tumors (28 testicular primaries, 21 metastases from the testis, and 3 mediastinal primaries) that had a yolk sac tumor component with foci of solid growth, defined as a sheet-like arrangement of tumor cells occupying >2 mm and with no or only rare microcysts. Solid yolk sac tumor was almost always associated with other patterns, most commonly microcystic/reticular (75%), glandular (35%), and myxoid (25%). The solid foci consisted of sheets of cells with usually abundant cytoplasm that was mostly (85%) pale to clear and frequently had intercellular basement membrane deposits (75%), rare microcysts (67%), significant nuclear pleomorphism (65%), and hyaline globules (65%). In 2 cases (4%), the cells were small with scant cytoplasm (blastema-like variant). A myxoid background (39%), lymphocytic infiltrate (17%), and an appliqué pattern (8%) were sometimes observed. On immunostaining, AE1/AE3 cytokeratin and glypican 3 provided the most intense and diffuse reactivity for solid yolk sac tumor, whereas α-fetoprotein was negative in 38%. CD117 stained 59%, whereas only rare cells in 1 case (3%) were weakly reactive for podoplanin; OCT3/4 was uniformly negative. We conclude that solid yolk sac tumor can generally be recognized by careful morphologic evaluation, especially its association with other yolk sac tumor patterns, the presence of intercellular band-like deposits of basement membrane, occasional microcysts, nuclear pleomorphism, intracellular hyaline globules, and usual absence of lymphocytes. In difficult cases a concise immunohistochemical panel consisting of AE1/AE3, glypican 3, and OCT3/4 distinguishes solid yolk sac tumor from other neoplasms. α-fetoprotein stains are commonly negative or weak and focal in solid yolk sac tumor and cannot be solely relied on for diagnosis. Common CD117 positivity in solid pattern yolk sac tumors makes it an unreliable discriminator between yolk sac tumor and seminoma.

    View details for DOI 10.1097/PAS.0b013e31823c510b

    View details for Web of Science ID 000301038200005

    View details for PubMedID 22261704