Paul B. Gaudin

The 2005 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma.

Five years after the last prostatic carcinoma grading consensus conference of the International Society of Urological Pathology (ISUP), accrual of new data and modification of clinical practice require an update of current pathologic grading guidelines. This manuscript summarizes the proceedings of the ISUP consensus meeting for grading of prostatic carcinoma held in September 2019, in Nice, France. Topics brought to consensus included the following: (1) approaches to reporting of Gleason patterns 4 and 5 quantities, and minor/tertiary patterns, (2) an agreement to report the presence of invasive cribriform carcinoma, (3) an agreement to incorporate intraductal carcinoma into grading, and (4) individual versus aggregate grading of systematic and multiparametric magnetic resonance imaging-targeted biopsies. Finally, developments in the field of artificial intelligence in the grading of prostatic carcinoma and future research perspectives were discussed.

Comparison of the 5-year outcome and morbidity of three-dimensional conformal radiotherapy versus transperineal permanent iodine-125 implantation for early-stage prostatic cancer.

PURPOSE: To compare the prostate-specific antigen (PSA) relapse-free survival outcome and incidence of late toxicity for patients with early-stage prostate cancer treated at a single institution with either three-dimensional conformal radiotherapy (3D-CRT) or transperineal permanent implantation (TPI) with iodine-125 seeds. MATERIALS AND METHODS: Patients with favorable-risk prostate cancer, defined as a pretreatment PSA of less than or equal to 10.0 ng/mL, Gleason score of 6 or lower, and stage less than or equal to T2b, were selected for this analysis. Between 1989 and 1996, 137 such patients were treated with 3D-CRT and 145 with TPI. The median ages of the 3D-CRT and TPI groups were 68 years and 64 years, respectively. The median dose of 3D-CRT was 70.2 Gy, and the median implant dose was 150 Gy. Prostate-specific antigen relapse was defined according to the American Society of Therapeutic Radiation Oncology Consensus Statement, and toxicity was graded according to the Radiation Therapy Oncology Group ...

Renal oncocytoma: a clinicopathologic study of 70 cases.

We reviewed 954 primary nonurothelial epithelial renal neoplasms with primary resection at Memorial Sloan-Kettering Cancer Center between the years 1980 and 1995 and classified 70 cases (7%) as renal oncocytomas. The study population was composed of 39 men and 31 women, and the mean age was 65 years (range 25 to 86 years). Fifty-six patients (80%) were asymptomatic at presentation, six (4%) had flank pain, six (4%) presented with a mass, and two (3%) had hematuria. Sixty-one were treated with total or radical nephrectomy, nine with partial nephrectomy. The right kidney was involved in 35 cases (50%), the left kidney in 32 (46%). Three cases (4%) were bilateral. Sixty-one cases (87%) were unifocal, nine (13%) multifocal. All the tumors were well circumscribed but unencapsulated. Forty-five (64%) were described as brown or red, whereas the remainder were variously described as tan to yellow. Central fibrosis or scar was described in 23 cases (33%), and gross areas of hemorrhage or cystic changes in 14 (20%). The mean size was 5.2 cm and median 5.0 cm (range 1.5 cm to 14 cm). Histologically, the tumors were characterized by a mixture of architectural patterns: compact cellular nests and acini embedded in a hyalinized, hypocellular stroma were present in 62 cases (89%), a solid nested architecture in 47 cases (67%), and a variable tubular component in 50 cases (71%). Small papillae, pseudopapillae, and intratubular epithelial tufts were seen in 19 cases (27%). Cytologically, the neoplasms also showed a mixture of cell types, the most common being the classic oncocyte, which consisted of round or polygonal cells with moderate to abundant granular, eosinophilic cytoplasm, and small round nuclei with evenly dispersed granular chromatin. Small basophilic nucleoli were visible in many of these cells in all cases. Thirty-one cases (44%) had a variable number of oncocytic cells with pyknotic nuclei and 20 (30%) contained clusters of small cells with a high nuclear/cytoplasmic ratio and dense hyperchromatic nuclei (so-called oncoblasts). Foci of tubules with clear cells embedded in a hyalinized stroma were present in six cases (9%). Cellular atypia was evident in 42 cases (60%) and was marked in 21 (30%). Eleven cases (16%) exhibited mitotic activity, albeit low. No case had atypical mitoses or necrosis. Twenty-two cases (31%) had areas of calcification within the hyalinized stroma, 12 (17%) had calcospherites, and three (4%) had osseous and myeloid metaplasia. Vascular invasion was present in three cases (4%), and invasion of perinephric fat in 14 (20%). One patient presented with liver metastasis. Fourteen cases (20%) were pT1, 42 (60%) pT2, and 14 (20%) pT3. After a mean follow-up of 58 months (range 1 to 181), 62 patients (89%) were alive with no evidence of tumor, six (9%) had died of other causes, one was alive with stable metastatic disease in the liver 58 months after diagnosis, and one died with metastatic disease to bone and liver. We conclude that renal oncocytomas have a varied morphologic appearance and their pathologic diagnosis should be based on a constellation of architectural and cytologic features. The overwhelming majority of cases behave in a benign fashion, although in rare instances they can metastasize. The presence of atypical morphologic features do not alter the excellent prognosis associated with oncocytomas and do not predict an aggressive clinical course.

Sarcomas and related proliferative lesions of specialized prostatic stroma : A clinicopathologic study of 22 cases

Sarcomas and related proliferative lesions of the specialized prostatic stroma have been the subject of case reports and, thus, have not been well characterized. We reviewed the clinicopathologic features of 22 cases and studied the immunohistochemical profile of 9. Patient age ranged from 25 to 86 years; mean age was 54 years, and peak incidence was in the 6th and 7th decades. The most common clinical presentation was urinary retention, then abnormal results of digital rectal examination, hematuria or hematospermia, and a palpable rectal mass. The cases were grouped into two categories: prostatic stromal proliferation of uncertain malignant potential (PSPUMP, 18 cases) and prostatic stromal sarcoma (PSS, 4 cases) based on the degree of stromal cellularity and the presence of mitotic figures, necrosis, and stromal overgrowth. Four histologic patterns of PSPUMP were identified: (1) hypercellular stroma with scattered cytologically atypical cells associated with benign glands, (2) hypercellular stroma with minimal cytological atypia associated with benign glands, (3) hypercellular stroma with or without cytologically atypical cells, associated with benign glands in a leaflike growth pattern that resembled phyllodes tumors of the mammary gland, and (4) hypercellular stroma without cytologically atypical stromal cells and without glands. Prostatic stromal sarcoma showed greater cellularity, mitoses, necrosis, and stromal overgrowth than PSPUMP and consisted either of stromal elements with benign glands in a pattern that resembled malignant phyllodes tumors of the mammary gland (3 cases) or of purely stromal elements (1 case). Positive immunohistochemical reactions were noted using vimentin in 9 of 9 cases, CD34 in 8 of 8, HHF-35 in 2 of 8, smooth muscle actin in 3 of 9, desmin in 4 of 8, S-100 protein in 0 of 9, estrogen receptor in 1 of 7, and progesterone receptor in 6 of 7. None of the cases classified as PSS were positive for HHF-35, smooth muscle actin, or desmin. Of the 13 patients classified as having PSPUMP who did not undergo definitive local therapy at the time of diagnosis, recurrent signs or symptoms were seen in six (46%), necessitating additional therapy. Distant metastases to lung and bone developed in one patient classified as having PSS. Clinical and pathologic findings in this patient suggested a progression from PSPUMP to PSS. We conclude that sarcomas and related proliferative lesions of the specialized prostatic stroma encompass a spectrum of histologic features and may be grouped into two clinicopathologic categories: PSPUMP and PSS. Based on their distinctive histologic appearance and immunohistochemical profile, PSPUMP and PSS can be differentiated from other mesenchymal lesions of the prostate.

Immunophenotype of High-Grade Prostatic Adenocarcinoma and Urothelial Carcinoma

Morphologic features alone can usually be used to distinguish prostatic adenocarcinoma and urothelial carcinoma of the urinary bladder. Poorly differentiated tumors, however, can occasionally have features of both neoplasms, making determination of site of origin difficult. No study has provided a panel of antibodies to assist in the distinction of these two tumors. For this study, 73 examples of moderately and poorly differentiated prostatic adenocarcinoma and 46 examples of high-grade urothelial carcinoma were obtained from radical resection specimens. Immunohistochemical studies were performed using the following panel of antibodies: cytokeratin (CK) 7, CK 20, 34βE12, Leu M1, carcinoembryonic antigen (CEA)m, CEAp, p53, Leu 7, prostate-specific acid phosphatase (PSAP), prostate-specific antigen (PSA), and B72.3. Mucicarmine was also performed. Intermediate and high-grade prostatic carcinoma were compared and then high-grade prostatic carcinoma was compared with high-grade urothelial carcinoma. PSA and PSAP each stained 94% of prostatic adenocarcinomas, but no urothelial carcinomas. Leu 7 stained 94% of prostate and 17% of urothelial carcinomas. Over half of the urothelial carcinomas showed positivity for 34βE12 (65%), as did two cases of prostatic carcinoma (6%). Eighty-three percent of urothelial carcinomas and 12% of prostatic adenocarcinomas stained with CK 7. Forty-one percent of urothelial carcinomas and 12% of prostatic carcinomas were reactive for CEAm, and p53 stained 33% and 3% of urothelial and prostatic adenocarcinomas, respectively. No significant difference was seen in the expression of CEAp, CK 20, B72.3, Leu M1, or mucicarmine between prostate and urothelial carcinoma. We propose a panel of six antibodies to assist in the distinction of high-grade prostatic adenocarcinoma from high grade urothelial carcinoma: PSA, PSAP, 34βE12, Leu 7, CK 7, and p53. The first three antibodies should be used initially; if results are negative, the remaining antibodies may be employed.

Metastatic renal cell carcinoma neovasculature expresses prostate-specific membrane antigen

OBJECTIVESnTo determine whether the tumor-associated neovasculature of metastatic prostate and metastatic conventional (clear cell) renal carcinoma express prostate-specific membrane antigen (PSMA). PSMA is a type II integral membrane glycoprotein highly expressed in prostate cancer cells and also recently discovered to be expressed in the neovasculature of non-prostatic primary malignancies.nnnMETHODSnWe examined metastatic prostate carcinoma (22 patients) and metastatic conventional (clear cell) renal carcinoma (20 patients) in various anatomic sites, including bone, lymph nodes, liver, lung, and soft tissue. Using the biotin-streptavidin method, we performed immunohistochemical reactions with the anti-PSMA monoclonal antibodies (mAbs) 7E11 and PM2J004.5 and with the anti-endothelial cell mAb CD34.nnnRESULTSnMetastatic conventional (clear cell) renal carcinoma consistently expressed PSMA. The PM2J004.5 mAb was positive in 20 of 20 specimens, and the 7E11 mAb was positive in 15 of 20. The anti-PSMA immunoreactions with the neovasculature were confirmed by similar staining by the anti-CD34 mAb (20 of 20). Although the metastatic prostatic cancer cells expressed PSMA in all the specimens, only 2 of 22 had neovasculature PSMA expression.nnnCONCLUSIONSnAs in primary prostatic adenocarcinomas, the neovasculature of metastatic prostate cancer, regardless of site, rarely express PSMA. The neovascular endothelial cells of metastatic clear cell renal carcinoma, however, express PSMA. This expression may make PSMA an effective target for mAb-based antineovasculature therapy in metastatic renal carcinoma.

Comparison of anti-prostate-specific membrane antigen antibodies and other immunomarkers in metastatic prostate carcinoma

OBJECTIVESnTo compare the immunohistochemical properties of the 7E11 anti-prostate-specific membrane antigen (anti-PSMA) monoclonal antibody (mAb) with the recently developed anti-PSMA mAb, PM2J004.5, and with other common immunomarkers in metastatic prostate cancer. PSMA is a type II integral membrane glycoprotein highly expressed in prostate cancer cells. The mAb 7E11 is currently used in the radioisotopic evaluation of prostate cancer, and its immunohistochemical properties have been examined in primary prostate cancer specimens.nnnMETHODSnWe examined 23 formalin-fixed, paraffin-embedded, metastatic prostate carcinoma specimens from various anatomic sites, including bone, lymph node, liver, lung, and soft tissue. Using the biotin-streptavidin method, we performed immunohistochemical reactions with the anti-PSMA mAbs 7E11 and PM2J004.5 and with antibodies to prostate-specific antigen and prostatic acid phosphatase. The immunoreactions were scored by pathologists unaware of the clinical and pathologic data according to a staining intensity scale and the percentage of cells stained.nnnRESULTSnAll four mAbs consistently stained the metastatic prostate cancer specimens. In 2 (8.7%) of 23 cases, however, the prostate-specific antigen immunoreaction was negative but the anti-PSMA mAbs had positive staining. Although 7E11 and PM2J004.5 had a similar staining intensity and percentage of cells stained for most specimens, in 3 (13%) of 23 specimens, 7E11 had less intense staining. None of the specimens were negative for all four antibodies.nnnCONCLUSIONSnAnti-PSMA mAbs consistently immunoreacted with metastatic prostate cancer specimens and were positive in instances when prostate-specific antigen staining was negative. The anti-PSMA mAbs demonstrated similar staining patterns; however, in select cases, the PM2J004.5 mAb did show more intense staining. The anti-PSMA mAbs 7E11 and PM2J004.5 are useful in the pathologic evaluation of paraffin-embedded metastatic prostate cancer specimens.

Histopathologic effects of three-dimensional conformal external beam radiation therapy on benign and malignant prostate tissues.

We reviewed 137 prostate sextant needle biopsies from 137 patients obtained at a median of 35.7 months after three-dimensional conformal external beam radiation therapy (3DCRT). Thirty-one patients (23%) received 3 months of androgen deprivation therapy (ADT) before 3DCRT. We also retrospectively reviewed and assigned a combined Gleason score to the pre-3DCRT needle biopsies (97 patients) or transurethral resection of the prostate gland (1 patient). High-molecular-weight cytokeratin (34betaE12) and prostate-specific antigen (PSA) immunohistochemistry was performed in select cases. After 3DCRT, histopathologic changes in benign prostate gland consisted of glandular atrophy, cytologic atypia, and basal cell prominence. The benign glands showed intensely positive reactions with antibodies to high-molecular-weight cytokeratin (34betaE12) and negative to weakly positive reactions to PSA. Paneth cell-like change was seen in 44 (32%) of the biopsies, mucinous metaplasia in 29 (21%), luminal blue-tinged mucinous secretions in 14 (10%), and squamous metaplasia in 8 (6%). The changes in benign prostate tissues were similar between patients treated with ADT and 3DCRT and those treated with 3DCRT alone. After 3DCRT, we recognized two histologic patterns of prostate cancer: (1) prostate cancer showing radiation therapy (RT)-related changes characterized by PSA-positive/34betaE12-negative poorly formed glands or individual cells with abundant clear to finely granular cytoplasm, and (2) prostate cancer showing no apparent RT effect. High-grade prostatic intraepithelial neoplasia (PIN) was seen in 12 post-3DCRT biopsies (8.8%). The use of neoadjuvant ADT had a significant impact on the results of post-RT biopsy. Of the 31 patients treated with neoadjuvant ADT and 3DCRT, 3 (10%) had post-3DCRT biopsies showing prostate cancer without RT effect compared to 44 of 106 men (41%) treated with 3DCRT alone (p = 0.004). Compared to the Gleason score pre-RT, the Gleason score of cancers showing no RT effect was the same in 25 patients (71%), +/-1 point in 8 patients (23%), and +2 points in 2 patients (6%). The mean combined Gleason score post-RT was slightly, although significantly, higher than that pre-RT (7.29 +/- 0.71 versus 7.00 +/- 0.59, p = 0.01). Serum PSA at the time of post-3DCRT biopsy correlated with biopsy results. Prostate cancer without therapy effect was seen in only one of 43 patients (2%) with a serum PSA level < or = 1 ng/ml compared to 46 of 94 patients (49%) with a PSA level > 1 ng/ml (p = 0.0001). After 3DCRT, benign prostate glands show profound histopathologic changes and may be confused with prostate cancer. The effects of 3DCRT on prostate cancer are variable, with some cases showing profound therapy-related changes and others showing no apparent therapy effect.

Rare Expression of High-molecular-weight Cytokeratin in Adenocarcinoma of the Prostate Gland: A Study of 100 Cases of Metastatic and Locally Advanced Prostate Cancer

Immunohistochemistry with antibodies for high-molecular-weight cytokeratin labels basal cells and is used as an ancillary study in diagnosing prostate carcinoma, which reportedly lacks expression of high-molecular-weight cytokeratin. A recent report questioned the specificity of this marker, describing immunopositivity for high-molecular-weight cytokeratin in a small series of metastatic prostate cancer. We have also noted rare cases of prostate lesions on biopsy with typical histological features of adenocarcinoma showing immunopositivity for high-molecular-weight cytokeratin, either in tumor cells or in patchy cells with the morphology of basal cells. In some of these cases, it was difficult to distinguish cancer from out-pouching of high-grade prostatic intraepithelial neoplasia. To investigate whether prostate cancer cells express high-molecular-weight cytokeratin, we studied 100 cases of metastatic prostate carcinoma and 10 cases of prostate cancer invading the seminal vesicles from surgical specimens. Metastatic sites included regional lymph nodes (n = 67), bone (n = 19), and miscellaneous (n = 14). Cases with any positivity for high-molecular-weight cytokeratin antibody (34betaE12) were verified as being of prostatic origin with immunohistochemistry for prostate-specific antigen and prostate-specific acid phosphatase. Only four cases were detected positive for high-molecular-weight cytokeratin. In two cases (one metastasis, one seminal vesicle invasion) there was weakly diffuse positivity above background level. Two metastases in lymph nodes showed scattered strong staining of clusters of tumor cells, which represented <0.2% of tumor cells in the metastatic deposits. These positive cells did not have the morphology of basal cells. We conclude that prostate cancer, even high grade, only rarely expresses high-molecular-weight cytokeratin. This marker remains a very useful adjunct in the diagnosis of prostate cancer.

Florid vascular proliferation associated with neural and neuroendocrine neoplasms: a diagnostic clue and potential pitfall

We report the light microscopic and immunohistochemical features of vascular proliferations associated with 26 extracranial neural and neuroendocrine neoplasms including esthesioneuroblastoma, neuroblastoma/ganglioneuroblastoma, the primitive neural component of immature teratoma, mediastinal teratoma, primitive neuroectodermal tumor, intra-abdominal desmoplastic small cell tumor, Merkel cell carcinoma of the skin, and thyroid medullary carcinoma. These vascular proliferations were similar to those associated with high-grade glial neoplasms and were characterized by tufts of vessels with a glomeruloid configuration or by long cords of vessels. Immunohistochemical evaluation documented the presence of endothelial cells, perithelial cells, and basement membrane components within the foci of proliferating vessels. We propose that these vascular proliferations represent a characteristic feature of the neuroendocrine/neural neoplastic phenotype and that they possibly arise as the result of angiogenic factors produced by the neoplastic cells. The presence of these distinctive vascular lesions in the stroma of a poorly differentiated neoplasm should alert the pathologist to the possibility of the neoplasm being of a neural or neuroendocrine nature.