Testicular Germ-Cell Tumors with Spermatic Cord Involvement: A Retrospective International Multi-Institutional Experience.

The 8th Edition of the American Joint Committee on Cancer (AJCC) Staging Manual designates discontinuous involvement of spermatic cord soft tissue by testicular germ cell tumors as a metastatic deposit. We conducted a retrospective international multi-institutional study to validate the current recommendations. Thirty-three (72%) nonseminomatous and 13 (28%) seminomatous testicular germ cell tumors were collected from 15 institutions in America, Europe, and Asia. Testicular tumor size ranged from 1.3 to 18.0 cm (mean: 6.1). Cases were classified as discontinuous involvement of spermatic cord soft tissue (n = 26), continuous cord involvement (n = 17), or cord lymphovascular invasion (n = 3). The mean follow-up was 39 months. Clinical stage for discontinuous involvement of spermatic cord soft-tissue patients was I (local disease) in 2/24 (8%), II (regional disease) in 6/24 (25%), and III (distant disease) in 16/24 (67%) cases; 16 (67%) patients presented with distant metastasis. Clinical stage for continuous cord involvement patients was I in 9/17 (53%), II in 4/17 (23%), and III in 4/17 (23%); 4 (23%) patients presented with distant metastasis. Disease progression was seen in 4 patients with discontinuous involvement of spermatic cord soft tissue and 5 with continuous cord-involvement (p = 0.699). When comparing discontinuous and continuous cord involvement, a significant difference was found in cord margin status (p = 0.044), spermatic cord tumor size (p = 0.016), lymph-node involvement (p = 0.037), distant metastasis (p = 0.010), individual clinical stage (p = 0.003), and nonadvanced vs. advanced disease (p = 0.003) at presentation. In multivariate analysis, after adjusting for age, histology, testicular tumor size, percent of embryonal carcinoma, lymphovascular invasion, and cord margin status, discontinuous involvement of spermatic cord soft tissue was significantly associated (p = 0.011) with advanced clinical stage at presentation. Our findings support the designation of metastatic disease for discontinuous involvement of spermatic cord soft tissue, as introduced by the 8th edition of the AJCC staging.

Prostate cancer: a presentation of clinicopathologic prognosticators among Filipino and American men at radical prostatectomy.

Lower incidence and mortality rates from prostate cancer (PCa) have been shown in Asian men in general compared to Westerners. This is the first study detailing the clinicopathologic features of resected prostate cancer in Filipino men living in the Philippines (PH). This study investigated the supposed "lower risk" Filipino and "higher risk" American PCa patients from the PH and the United States of America (USA), respectively. We examined 348 (176 from PH, 172 from USA) radical prostatectomy cases. The clinicopathologic features of both groups (age at time of diagnosis, preoperative prostate-specific antigen [pre-op PSA] level, Gleason score [GS], Grade groups [GG], margin involvement, extraprostatic extension [EPE], seminal vesicle invasion [SVI], and regional lymph node [RLN] metastasis) were compared. Six of seven prognosticators examined were more strongly associated with Filipinos than with Americans. Filipinos were older at diagnosis (PH: 64.32 ± 6.56 years vs USA: 58.98 ± 8.08 years) and had higher pre-op PSA levels (PH: 21.39 ± 46.40 ng ml-1 vs USA: 7.63 ± 9.19 ng ml-1). Filipino men had more advanced grade, GG 2 with minor pattern 5 (PH: 6.2% vs USA: 2.9%) and GG 5 (PH: 14.8% vs USA: 3.5%). Likewise, other adverse pathological features in margin positivity (PH: 52.3% vs USA: 23.8%), focal EPE (PH: 14.2% vs USA: 2.3%), and SVI (PH: 17.1% vs USA: 5.8%) were more commonly observed in Filipinos. This study reveals the prognostic disadvantage of Filipinos versus Americans and highlights an important difference of Filipinos from other studied Asian ethnicities that have repeatedly been shown to have lower-risk PCa. This study, the first on Filipino PCa patients with RP, suggests the need to modify Western-based risk stratification when employed in other countries like the PH.

Diagnostic approach in TFE3-rearranged renal cell carcinoma: a multi-institutional international survey.

Transcription factor E3-rearranged renal cell carcinoma (TFE3-RCC) has heterogenous morphologic and immunohistochemical (IHC) features.131 pathologists with genitourinary expertise were invited in an online survey containing 23 questions assessing their experience on TFE3-RCC diagnostic work-up.Fifty (38%) participants completed the survey. 46 of 50 participants reported multiple patterns, most commonly papillary pattern (almost always 9/46, 19.5%; frequently 29/46, 63%). Large epithelioid cells with abundant cytoplasm were the most encountered cytologic feature, with either clear (almost always 10/50, 20%; frequently 34/50, 68%) or eosinophilic (almost always 4/49, 8%; frequently 28/49, 57%) cytology. Strong (3+) or diffuse (>75% of tumour cells) nuclear TFE3 IHC expression was considered diagnostic by 13/46 (28%) and 12/47 (26%) participants, respectively. Main TFE3 IHC issues were the low specificity (16/42, 38%), unreliable staining performance (15/42, 36%) and background staining (12/42, 29%). Most preferred IHC assays other than TFE3, cathepsin K and pancytokeratin were melan A (44/50, 88%), HMB45 (43/50, 86%), carbonic anhydrase IX (41/50, 82%) and CK7 (32/50, 64%). Cut-off for positive TFE3 fluorescent in situ hybridisation (FISH) was preferably 10% (9/50, 18%), although significant variation in cut-off values was present. 23/48 (48%) participants required TFE3 FISH testing to confirm TFE3-RCC regardless of the histomorphologic and IHC assessment. 28/50 (56%) participants would request additional molecular studies other than FISH assay in selected cases, whereas 3/50 participants use additional molecular cases in all cases when TFE3-RCC is in the differential.Optimal diagnostic approach on TFE3-RCC is impacted by IHC and/or FISH assay preferences as well as their conflicting interpretation methods.

Practice patterns related to prostate cancer grading: results of a 2019 Genitourinary Pathology Society clinician survey.

PURPOSE: To survey urologic clinicians regarding interpretation of and practice patterns in relation to emerging aspects of prostate cancer grading, including quantification of high-grade disease, cribriform/intraductal carcinoma, and impact of magnetic resonance imaging-targeted needle biopsy. MATERIALS AND METHODS: The Genitourinary Pathology Society distributed a survey to urology and urologic oncology-focused societies and hospital departments. Eight hundred and thirty four responses were collected and analyzed using descriptive statistics. RESULTS: Eighty percent of survey participants use quantity of Gleason pattern 4 on needle biopsy for clinical decisions, less frequently with higher Grade Groups. Fifty percent interpret "tertiary" grade as a minor/<5% component. Seventy percent of respondents would prefer per core grading as well as a global/overall score per set of biopsies, but 70% would consider highest Gleason score in any single core as the grade for management. Seventy five percent utilize Grade Group terminology in patient discussions. For 45%, cribriform pattern would affect management, while for 70% the presence of intraductal carcinoma would preclude active surveillance. CONCLUSION: This survey of practice patterns in relationship to prostate cancer grading highlights similarities and differences between contemporary pathology reporting and its clinical application. As utilization of Gleason pattern 4 quantification, minor tertiary pattern, cribriform/intraductal carcinoma, and the incorporation of magnetic resonance imaging-based strategies evolve, these findings may serve as a basis for more nuanced communication and guide research efforts involving pathologists and clinicians.

The 2019 Genitourinary Pathology Society (GUPS) White Paper on Contemporary Grading of Prostate Cancer.

CONTEXT.­: Controversies and uncertainty persist in prostate cancer grading. OBJECTIVE.­: To update grading recommendations. DATA SOURCES.­: Critical review of the literature along with pathology and clinician surveys. CONCLUSIONS.­: Percent Gleason pattern 4 (%GP4) is as follows: (1) report %GP4 in needle biopsy with Grade Groups (GrGp) 2 and 3, and in needle biopsy on other parts (jars) of lower grade in cases with at least 1 part showing Gleason score (GS) 4 + 4 = 8; and (2) report %GP4: less than 5% or less than 10% and 10% increments thereafter. Tertiary grade patterns are as follows: (1) replace "tertiary grade pattern" in radical prostatectomy (RP) with "minor tertiary pattern 5 (TP5)," and only use in RP with GrGp 2 or 3 with less than 5% Gleason pattern 5; and (2) minor TP5 is noted along with the GS, with the GrGp based on the GS. Global score and magnetic resonance imaging (MRI)-targeted biopsies are as follows: (1) when multiple undesignated cores are taken from a single MRI-targeted lesion, an overall grade for that lesion is given as if all the involved cores were one long core; and (2) if providing a global score, when different scores are found in the standard and the MRI-targeted biopsy, give a single global score (factoring both the systematic standard and the MRI-targeted positive cores). Grade Groups are as follows: (1) Grade Groups (GrGp) is the terminology adopted by major world organizations; and (2) retain GS 3 + 5 = 8 in GrGp 4. Cribriform carcinoma is as follows: (1) report the presence or absence of cribriform glands in biopsy and RP with Gleason pattern 4 carcinoma. Intraductal carcinoma (IDC-P) is as follows: (1) report IDC-P in biopsy and RP; (2) use criteria based on dense cribriform glands (>50% of the gland is composed of epithelium relative to luminal spaces) and/or solid nests and/or marked pleomorphism/necrosis; (3) it is not necessary to perform basal cell immunostains on biopsy and RP to identify IDC-P if the results would not change the overall (highest) GS/GrGp part per case; (4) do not include IDC-P in determining the final GS/GrGp on biopsy and/or RP; and (5) "atypical intraductal proliferation (AIP)" is preferred for an intraductal proliferation of prostatic secretory cells which shows a greater degree of architectural complexity and/or cytological atypia than typical high-grade prostatic intraepithelial neoplasia, yet falling short of the strict diagnostic threshold for IDC-P. Molecular testing is as follows: (1) Ki67 is not ready for routine clinical use; (2) additional studies of active surveillance cohorts are needed to establish the utility of PTEN in this setting; and (3) dedicated studies of RNA-based assays in active surveillance populations are needed to substantiate the utility of these expensive tests in this setting. Artificial intelligence and novel grading schema are as follows: (1) incorporating reactive stromal grade, percent GP4, minor tertiary GP5, and cribriform/intraductal carcinoma are not ready for adoption in current practice.

Spectrum of Cystic Epithelial Tumors of the Prostate: Most Cystadenocarcinomas Are Ductal Type With Intracystic Papillary Pattern.

Cystic epithelial tumors arising from the prostate are rare, and their full histologic spectrum has yet to be defined. Herein, we present 8 examples of prostatic cystic tumors including 1 giant multilocular cystadenoma and 7 cystadenocarcinomas. We divided the cystadenocarcinomas into "giant multilocular" cystadenocarcinoma (3) and "microscopic" cystadenocarcinoma (4) because of their differing clinical presentations with clinically apparent cystic masses in the former. The cystadenoma was an 11 cm multilocular cystic pelvic tumor in a 55-year-old man who presented with lower urinary tract symptoms. The cystadenoma was lined predominantly by benign acinar cells and had a distinct basal cell layer. No recurrence occurred 3 months after resection. The 3 patients with giant multilocular cystadenocarcinomas were 62 to 82 years old, had large pelvic cystic masses (up to 16 cm), and 2 presented with obstructive urinary and lower intestinal tract symptoms. One giant multilocular cystadenocarcinoma had a markedly high cystic fluid prostate-specific antigen at >80,000 ng/mL. All 3 giant multilocular cystadenocarcinomas were ductal adenocarcinoma with exuberant intracystic papillary formations. One tumor was associated with a high-grade noncystic conventional (acinar) adenocarcinoma (Gleason score 9 [ISUP grade group 5]). Follow-up on the 3 giant multilocular cystadenocarcinoma cases (7 to 21 mo) showed multiple metastases in 1 patient but was attributed to the high-grade conventional adenocarcinoma component. In addition, we described 4 examples of microscopic cystadenocarcinomas that were small (≤1 cm) solitary or multiple cystic tumors identified on pathologic examination of the prostate. In 3 of 4 microscopic cystadenocarcinomas the lining was ductal adenocarcinoma with occasional to exuberant papillae and appeared similar to the smaller cysts in the giant multilocular cystadenocarcinomas. One of the 4 microscopic cystadenocarcinomas had an acinar adenocarcinoma lining with occasional papillae and was associated with a conventional adenocarcinoma. Follow-up of the 4 patients with microscopic cystadenocarcinoma (1 to 14 mo) showed no evidence of disease. Review of literature highlighted similarities between the findings in our cases and previously published prostatic cystadenocarcinomas, including the markedly high cystic fluid prostate-specific antigen level in giant multilocular cystadenocarcinomas and the typical ductal adenocarcinoma morphology with intracystic papillary pattern. In conclusion, cystic epithelial tumors of the prostate exhibit unique clinicopathologic features. Cystadenocarcinomas, whether the clinically apparent giant multilocular form or the incidentally identified microscopic type, represent a rare underrecognized pattern of prostatic adenocarcinoma mostly within the histologic spectrum of the ductal variant.

Atypical diagnosis in prostate needle biopsies from a developing country (Philippines): The essential role of a urological pathologist.

PURPOSE: Borderline prostatic lesions, with insufficient histomorphologic features, to be definitely diagnosed as prostatic adenocarcinoma (PCa) are often signed out as "atypical glands suspicious for carcinoma" or atypical small acinar proliferation (ASAP). These findings that eventually warrant either immunohistochemical (IHC) studies or a repeat biopsy, prove to be more burdensome to patients in developing countries (such as the Philippines), where health care is not as progressive nor is it an utmost priority. At the same time, in countries like the Philippines, there is a shortage of urological pathologists. METHODS: In this study, we compared the transrectal ultrasound-guided prostate (TRUS) biopsies signed out by general surgical pathologists in St. Luke's Medical Center Quezon City from 2008-2010, and the TRUS Biopsies primarily signed out by a urologic pathologist in both St. Luke's Medical Center Quezon City and Global City from July 2013 to July 2014, and from September 2013 to July 2014, respectively. RESULTS: From 2008 to 2010, 30.6% (129 of 421) of the cases were signed out as atypical. Of these, 79 underwent IHC staining, 21 (26.6%) of which were eventually signed out as PCa. Compared to those signed out in 2013 to 2014 by our genitourinary pathologist, only 16.6% (39 of 235) of the cases were signed out as atypical. Of these, 16 underwent IHC staining, with 15 (93%) of them being definitively diagnosed as PCa. Among the 21 cases wherein a repeat biopsy was recommended, only three followed and two of these had findings of PCa on repeat biopsy. Looking at our 16.6% rate of atypicals and subtracting those that were eventually established as PCa after IHCs, our atypicals would be down to 10% (24/235) in 2013-2014 compared to 25.7% (108/421) in 2008-2010. CONCLUSIONS: These results highlight the critical role a specialist has in the field of urological pathology, especially in developing countries. It is in the diagnosis of PCa in needle biopsies that a urological pathologist impacts the use of an atypical diagnosis, by ensuring its judicious use. This ultimately benefits the patients, by lessening unwarranted expenses through the decreased dependence on IHC staining and if necessary, a repeat biopsy.

Variant of prostatic adenocarcinoma with Paneth cell-like neuroendocrine differentiation readily misdiagnosed as Gleason pattern 5.

This study focused on 11 cases of prostatic adenocarcinoma with Paneth cell-like change, which had sparse to no Paneth cell-like granules; grading the tumor conventionally would have resulted in assigning a Gleason pattern 5 for the primary or secondary pattern. Ten cases were entirely composed of the Paneth cell-like component. Architectural patterns included the following: nest and cord-like architecture (n = 4; 36.4%), nests only (n = 6; 54.5%), and cords only (n = 1; 9.1%). All 11 cases had amphophilic cytoplasm. Among the 11 cases, 7 had rare granules, 1 had 10% of the cells with granules, and 3 had no granules. Within the Paneth cell-like feature component, rare nucleolar prominence was seen in only 4 (36.4%) of 11 cases. Eight cases were diffusely positive for chromogranin and synaptophysin, 2 for chromogranin only, and 1 for synaptophysin only. In the 3 cases where performed, Ki-67 showed a very low rate of less than 5%. The keys to recognizing these cases are as follows: (1) nests and cords in a small focus, (2) deeply amphophilic cytoplasm with careful search in most cases revealing rare Paneth cell-like eosinophilic granules, (3) indistinct nucleoli, and (4) immunohistochemical staining for neuroendocrine markers. Based on follow-up from prior studies and the current work, these tumors appear to have a favorable prognosis. The importance of recognizing this variant of adenocarcinoma with Paneth cell-like differentiation is that if these tumors were graded conventionally, 9 of the 11 cases would have been assigned a misleading Gleason score of 5 + 5 = 10 or 5 + 4 = 9.

Histologic features of pseudohyperplastic perineural invasion in prostatic adenocarcinoma: a mimicker of benign hyperplastic glands and high-grade prostatic intraepithelial neoplasia.

Perineural invasion (PNI) seen in prostatic adenocarcinoma (PCa) on biopsy has both diagnostic and prognostic implications. On biopsy, PNI is 1 of the 4 pathognomonic features of PCa; it is associated with an increased risk for extraprostatic extension, and its finding can affect therapy. From January 1, 2013 to June 30, 2013, 3120 cases of PCa were seen by the Genitourinary Pathology Consultation Service at the Johns Hopkins Hospital. Of these, 418 (13.4%) had PNI. During this interval, we prospectively identified an unusual pattern of PNI, which we have termed "pseudohyperplastic PNI," which was defined by a "gland-within-gland" morphology, wherein the centrally located gland was wrapped around a nerve. Pseudohyperplastic PNI was found in 9 (2.1%) cases, with an additional 3 cores from 2 patients biopsied at our institution with this finding also included. Of the 12 cores with pseudohyperplastic PNI, the Gleason scores were 6 in 11 cores and 4+3=7 in the remaining core. In 6 cases, the only focus of PNI in the entire case was pseudohyperplastic. In 7 of the 12 foci, the central gland wrapping around the nerve appeared to "float" unattached within the surrounding gland closely resembling a benign hyperplastic gland or high-grade prostatic intraepithelial neoplasia (HGPIN). In the remaining 5 foci, the central PNI was focally attached to the outer gland. In 11 of 12 foci, there was no to mild cytologic atypia. One focus of pseudohyperplastic PNI had prominent nucleoli in a large gland with tufting architecture and foamy cytoplasm. Of the 9 consult cases, pseudohyperplastic PNI was missed in 5, and in all 5 cases PNI was initially not diagnosed in the entire case. In 2 of these cases with missed pseudohyperplastic PNI, PCa was not diagnosed at the outside institution. In 1 of the cases biopsied at our institution, pseudohyperplastic PNI was misdiagnosed as HGPIN. In addition to the morphology of cancer appearing to float within a surrounding gland, other features that contribute to the difficulty of recognizing the focus as cancer are: (1) lack of adjacent cancer in about one half of the foci; (2) larger glands than typical cancer surrounding the PNI in a minority of cases; (3) tufting of the gland surrounding the PNI in a few cases; (4) atrophic or foamy gland features in some cases; and (5) lack of prominent cytologic atypia in most cases. Although this pattern of PNI that mimics either a benign hyperplastic gland or HGPIN is uncommon, accurately recognizing it as carcinoma can have both diagnostic and prognostic implications.

GATA3 expression in paragangliomas: a pitfall potentially leading to misdiagnosis of urothelial carcinoma.

GATA3 is a zinc-finger transcription factor, which is expressed in various normal and neoplastic tissues. Amongst tumors, it labels urothelial carcinoma, collecting duct carcinoma of the kidney, breast carcinoma, lymphoma and, uncommonly, endometrial carcinoma. Few studies have investigated its positivity in various neoplasms that may mimic urothelial neoplasms. In this study, we evaluated GATA3 expression in urinary bladder paragangliomas, which may closely mimic urothelial carcinomas. We retrieved 12 cases of paragangliomas from the urinary bladder and 20 cases of paragangliomas from non-urologic sites using the Hopkins Pathology Data Base system. GATA3 was positive in 10 of the 12 (83%) urinary bladder paragangliomas studied on routine slide sections. Most (6/12) of the staining was diffusely strong (3+) staining, whereas the rest (4/12) that were positive showed mixed intensities (strong 3+ to moderate 2+). The 20 paragangliomas from other sites were constructed into tissue microarrays, wherein three cores from each tumor were taken. Fifteen out of 20 (75%) paragangliomas outside of the bladder were positive for GATA3 staining. Moderate (2+) or strong (3+) staining was seen in 13/20 (65%) of extravesical paragangliomas, ranging from 5 to 100% of the cell labeling (mean 59%, median 60%). In the remaining 7/20 (35%) cases, only weak (2/7) or negative (5/7) immunoreactivity for GATA3 was seen. An additional 15 cases of metastatic paraganglioma from various primary sites were retrieved with 12 of 15 (80%) metastatic paragangliomas staining positively for GATA3. Overall, for paragangliomas, regardless of site, 78.7% were positive for GATA3. Recognition of this finding will aid pathologists in preventing a misdiagnosis of a urothelial tumor based on GATA3 expression, which is critical given the differences in treatment, follow-up and prognosis between bladder paragangliomas and urothelial carcinoma.