Oleksandr N. Kryvenko

Do adenocarcinomas of the prostate with gleason score (GS)≤6 have the potential to metastasize to lymph nodes?

Although rare, there are cases within reported series of men with Gleason score (GS)⩽6 on radical prostatectomies that show pelvic lymph node (LN) metastases. However, there are no studies on whether pelvic LN metastases occur in tumors with GS⩽6 using the International Society of Urological Pathology (ISUP) updated GS system. We performed a search of the radical prostatectomy databases at 4 large academic centers for cases of GS⩽6. Only prostatectomies submitted and embedded in entirety with pelvic LN dissections were included. A combined total of 14,123 cases were identified, of which 22 cases had a positive LN. Histopathologic review of 19 cases (3 cases unavailable for review) showed higher grade than originally reported by the pathologists in all cases. Of the 17 pre-ISUP reviewed cases, 2 were upgraded to 4+3=7 with both cribriform and poorly formed glands. One case was upgraded to 4+3=7 with tertiary pattern 5 displaying cribriform glands, poorly formed glands, and cords of single cells. Eleven cases were upgraded to 3+4=7 with glomeruloid structures and small to large cribriform glands (1 of these also had features of ductal adenocarcinoma). Two cases had tertiary pattern 4 with small cribriform glands. One case had a prominent colloid component that would currently be graded as 4+5=9 because of large cribriform glands and solid sheets of cells within the mucin. Of the 2 post-ISUP cases, 1 demonstrated tertiary pattern 4, and the other showed GS 3+4=7 with irregular cribriform glands. Undergrading is the primary reason for LN positivity with GS⩽6, which has decreased significantly since the adoption of the ISUP grading system in 2005. Of over 14,000 totally embedded radical prostatectomies from multiple institutions, there was not a single case of a GS⩽6 tumor with LN metastases. In contrast to prevailing assumptions, GS⩽6 tumors do not appear to metastasize to LNs. Rather, Gleason pattern 4 or 5, as better defined by the current ISUP updated grading system, is required for metastatic disease.

Small cell carcinoma of the prostate

Pure small-cell carcinoma (SCC) of the prostate is a rare entity and one of the most aggressive malignancies of the prostate. Histologically, prostatic SCCs of the prostate are part of a spectrum of anaplastic tumours of the prostate and are similar to SCCs of the lungs. In most cases, SCC of the prostate is associated with conventional prostatic adenocarcinoma. Both components of these mixed tumours frequently share molecular alterations such as ERG gene rearrangements or AURKA and MYCN amplifications, suggesting a common clonal origin. The clinical behaviour of small-cell prostate carcinomas is characterized by extensive local disease, visceral disease, and low PSA levels despite large metastatic burden. Commonly, the emergence of the SCC occurs in patients with high-grade adenocarcinoma who are often treated with androgen deprivation treatment (ADT). However, SCCs do not usually benefit from ADT. A biopsy of accessible lesions is strongly recommended to identify those with SCC pathological features, as management is undoubtedly affected by this finding. Chemotherapy is the standard approach for treating patients with either localized or advanced prostatic SCC. Despite the emergence of more-aggressive treatment modalities, the prognosis of men with prostatic SCC remains dismal.

Pathological examination of radical prostatectomy specimens in men with very low risk disease at biopsy reveals distinct zonal distribution of cancer in black American men

PURPOSE Of men with very low risk prostate cancer at biopsy recent evidence shows that black American men are at greater risk for adverse oncologic outcomes after radical prostatectomy. We studied radical prostatectomy specimens from black and white men at very low risk to determine whether there are systematic pathological differences. MATERIALS AND METHODS Radical prostatectomy specimens were evaluated in men with National Comprehensive Cancer Network® (NCCN) very low risk prostate cancer. At diagnosis all men underwent extended biopsy sampling (10 or more cores) and were treated in the modern Gleason grade era. We analyzed tumor volume, grade and location in 87 black and 89 white men. For each specimen the dominant nodule was defined as the largest tumor with the highest grade. RESULTS Compared to white men, black men were more likely to have significant prostate cancer (61% vs 29%), Gleason 7 or greater (37% vs 11%, each p <0.001) and a volume of greater than 0.5 cm(3) (45% vs 21%, p = 0.001). Dominant nodules in black men were larger (median 0.28 vs 0.13 cm(3), p = 0.002) and more often anterior (51% vs 29%, p = 0.003). In men who underwent pathological upgrading the dominant nodule was also more frequently anterior in black than in white men (59% vs 0%, p = 0.001). CONCLUSIONS Black men with very low risk prostate cancer at diagnosis have a significantly higher prevalence of anterior cancer foci that are of higher grade and larger volume. Enhanced imaging or anterior zone sampling may detect these significant anterior tumors, improving the outcome in black men considering active surveillance.

Biopsy Criteria for Determining Appropriateness for Active Surveillance in the Modern Era

OBJECTIVE To evaluate algorithms to predict insignificant prostate cancer at radical prostatectomy (RP). METHODS Five hundred and fifty men (410 Caucasian, 100 African American [AA], and 40 others) with prostate-specific antigen (PSA) level <10 ng/dL, T1c, 12-core biopsy, and biopsy Gleason score 3 + 3 = 6 were categorized into training and validation sets. Six biopsy algorithms were tested for predicting insignificant (0.5 cm(3), organ confined, and Gleason score ≤6) cancer at RP. Cancers incorrectly predicted to be insignificant were ranked into 4 groups of increasing aggressiveness. RESULTS Original (Gleason score ≤6, PSA density ≤0.15, ≤2 positive cores, and maximum core involvement ≤50%) and modified Epstein criteria (Gleason score ≤6, PSA density ≤0.15, ≤2 positive cores, and unilateral cancer) had the highest negative predictive values-correct classification of insignificant cancer. Among cancers predicted to be insignificant in Caucasians, 29.9% cases using the original and 27% cases using the modified Epstein criteria had significant cancer at RP. However, more adverse findings at RP were misclassified as insignificant in only 3.5% and 2.2% of cases using the original and modified Epstein criteria, respectively. Of cancers predicted insignificant in AA men, 54.1% cases using the original and 51.6% cases using the modified Epstein criteria were misclassified as insignificant. Dominant anterior tumors were seen in 117 Caucasian (28.5%) and 44 AA men (44%). CONCLUSION The Epstein criteria maintain their accuracy in the modern era with extended biopsy sampling. The negative predictive values are lower in AA men, in part due to higher frequency of anterior tumors, where multiparametric magnetic resonance imaging should be recommended in AAs considering surveillance.

Anastomosing hemangioma of the genitourinary system: eight cases in the kidney and ovary with immunohistochemical and ultrastructural analysis.

We describe 3 ovarian and 5 renal anastomosing hemangiomas. One manifested with polycythemia, others were incidental; none recurred. The mean patient age was 58 years. Three hemangiomas developed in end-stage renal disease. Tumors were well-demarcated, mahogany brown, spongy lesions measuring 0.1 to 5 cm. Tortuous large vessels fed and drained tightly packed anastomosing sinusoidal capillary channels. Four hemangiomas exhibited lobular architecture, central edema/hyalinization, and intravascular growth. Five cases had thrombosis, hemorrhage, and hemosiderin. One ovarian tumor induced stromal luteinization. Three tumors had foci of extramedullary hematopoiesis (one associated with polycythemia). Six cases demonstrated eosinophilic intracytoplasmic globules. Three cases included hobnail endothelial cells. Atypia was minimal and mitoses were absent in all cases. We find this vascular neoplasm unique for the genitourinary system. Despite selected features mimicking angiosarcoma, our data support its benign nature. The current study expands the gross and radiographic appearance, clinical aspects, and ultrastructure, with the first report of the lesion occurring in the ovary.

Gleason Score 7 Adenocarcinoma of the Prostate With Lymph Node Metastases: Analysis of 184 Radical Prostatectomy Specimens

CONTEXT Prostate cancer (PC) with lymph node metastases (LN(+)) is relatively rare, whereas it is relatively common in disease with a Gleason score (GS) 8 to 10 and virtually never seen in PC with GS 6 or less. It is most variable in GS 7 PC. OBJECTIVE To determine clinicopathologic features associated with GS 7 PC with LN(+) compared with a control group without lymph node metastases (LN(-)). DESIGN We analyzed 184 GS 7 radical prostatectomies with LN(+) and the same number of LN(-) Gleason-matched controls. The LN(+) cases were GS 3 + 4 = 7 (n = 64; 34.8%), GS 4 + 3 = 7 (n = 66; 35.9%), GS 3 + 4 = 7 with tertiary 5 (n = 10; 5.4%), and GS 4 + 3 = 7 with tertiary 5 (n = 44; 23.9%). RESULTS The LN(+) cases demonstrated higher average values in preoperative prostate-specific antigen (12.2 versus 8.1 ng/mL), percentage of positive biopsy cores (59.1% versus 42.9%), prostate weight (54.4 versus 49.4 g), number of LNs submitted (12.7 versus 9.4), incidence of nonfocal extraprostatic extension (82.6% versus 63.6%), tumor volume (28.9% versus 14.8%), frequency of lymphovascular invasion (78.3% versus 38.6%), intraductal spread of carcinoma (42.4% versus 20.7%), incidence of satellite tumor foci (16.4% versus 4.3%), incidence of pT3b disease (49.5% versus 14.7%), and lymphovascular invasion in the seminal vesicles (52% versus 30%). There were differences in GS 4 patterns and cytology between LN(+) and LN(-) cases, with the former having higher volumes of cribriform and poorly formed patterns, larger nuclei and nucleoli, and more-frequent macronucleoli. All P ≤ .05. CONCLUSION Gleason score 7 PC with LN(+) has features highlighting a more-aggressive phenotype. These features can be assessed as prognostic markers in GS 7 disease on biopsy (eg, GS 4 pattern, intraductal spread, cytology) or at radical prostatectomies (all variables), even in men without LN dissection or LN(-) disease.

Inflammation and preneoplastic lesions in benign prostate as risk factors for prostate cancer

Benign changes ranging from atrophy and inflammation to high-grade prostatic intraepithelial neoplasia (HGPIN) are common findings on prostate core needle biopsies. Although atrophy and inflammation may be precursors of prostate cancer, only HGPIN is currently recommended to be included in surgical pathology reports. To determine whether these benign findings increase prostate cancer risk, we conducted a case–control study nested within a historical cohort of 6692 men with a benign prostate specimen collected between 1990 and 2002. The analytic sample included 574 case–control pairs comprised of cases diagnosed with prostate cancer a minimum of 1 year after cohort entry and controls matched to cases on date and age at cohort entry, race, and type of specimen. The initial benign specimen was reviewed for presence of HGPIN, atrophy (simple, lobular, and partial) and inflammation (glandular and/or stromal). HGPIN significantly increased risk for prostate cancer (odds ratio (OR)=2.00; 95% confidence interval (CI)=1.25–3.20). Inflammation within the stromal compartment was associated with decreased risk (OR=0.66; CI=0.52–0.84), and diffuse stromal inflammation of severe grade had the strongest inverse association with risk (OR=0.21; CI=0.07–0.62). In a model adjusted for prostate-specific antigen (PSA) level at cohort entry and inflammation, simple atrophy was associated with a 33% increased prostate cancer risk that was marginally significant (P=0.03). Clinicians should consider patterns and extent of inflammation when managing high-risk patients with negative biopsy results. Identifying benign inflammatory processes that underlie high PSA levels would help to reduce the number of unnecessary repeated prostate biopsies.

Diagnostic Approach to Eosinophilic Renal Neoplasms

CONTEXT Eosinophilic renal neoplasms include a spectrum of solid and papillary tumors ranging from indolent benign oncocytoma to highly aggressive malignancies. Recognition of the correct nature of the tumor, especially in biopsy specimens, is paramount for patient management. OBJECTIVE To review the diagnostic approach to eosinophilic renal neoplasms with light microscopy and ancillary techniques. DATA SOURCES Review of the published literature and personal experience. CONCLUSIONS The following tumors are in the differential diagnosis of oncocytic renal cell neoplasm: oncocytoma, chromophobe renal cell carcinoma (RCC), hybrid tumor, tubulocystic carcinoma, papillary RCC, clear cell RCC with predominant eosinophilic cell morphology, follicular thyroid-like RCC, hereditary leiomyomatosis-associated RCC, acquired cystic disease-associated RCC, rhabdoid RCC, microphthalmia transcription factor translocation RCC, epithelioid angiomyolipoma, and unclassified RCC. In low-grade nonpapillary eosinophilic neoplasms, distinction between oncocytoma and low-grade RCC mostly rests on histomorphology; however, cytokeratin 7 immunostain may be helpful. In high-grade nonpapillary lesions, there is more of a role for ancillary techniques, including immunohistochemistry for cytokeratin 7, CA9, CD10, racemase, HMB45, and Melan-A. In papillary eosinophilic neoplasms, it is important to distinguish sporadic type 2 papillary RCC from microphthalmia transcription factor translocation and hereditary leiomyomatosis-associated RCC. Histologic and cytologic features along with immunohistochemistry and fluorescence in situ hybridization tests for TFE3 (Xp11.2) and TFEB [t(6;11)] are reliable confirmatory tests. Eosinophilic epithelial neoplasms with architecture, cytology, and/or immunoprofile not qualifying for either of the established types of RCC should be classified as unclassified eosinophilic RCC and arbitrarily assigned a grade (low or high).

Changes in prostate cancer grading: Including a new patient-centric grading system.

The first structured approach to grade prostate cancer based on the underlying histological architecture was developed by Donald Gleason who in 1966 proposed a morphologic classification of prostate cancer and in 1974 demonstrated its clinical significance based on prostate cancer‐specific death. Contemporarily referred to as the Gleason grading system, it has gained worldwide recognition allowing a more individualized approach to patients with prostate cancer. In 2005, the International Society of Urologic Pathology (ISUP) made the first revisions to the grading system. Subsequently, based on the new discoveries in pathologic and clinical aspects of prostate cancer, as well as the changing nature of the prostate cancer in part due to a robust screening, there was a need for experts to re‐visit the approach to grade prostate cancer. In November 2014, the ISUP experts and clinical leaders in prostate cancer from 17 countries conducted a consensus conference in Chicago, IL, USA. The consensus conference defined various grade patterns and proposed the adoption of a new grading system of prostate cancer. Herein, we describe the background and rationale for the changes and provide guidelines to their clinical implementation. Prostate 76:427–433, 2016.

Low-grade clear cell renal cell carcinoma mimicking hemangioma of the kidney: a series of 4 cases.

CONTEXT Clear cell renal cell carcinoma (CCRCC) has a rich, sinusoid-like vascularity frequently used as a diagnostic criterion. CCRCC with predominantly vascular architecture has not been described. OBJECTIVE To describe 4 unusual CCRCC cases, primarily presenting with hemangioma-like morphologic pattern. DESIGN Clinicopathologic and selected immunohistochemical analysis of 4 cases of CCRCC mimicking hemangioma. RESULTS Cases were seen in 1 woman and 3 men (average age, 48.8 years; range, 40-66 years). Grossly, tumors were red-brown (3 of 4) with scant bright-yellow foci in 1. The average tumor size was 4 cm (range, 2.5-5.5 cm). Microscopically, all were composed of varying proportions of a rich, arborizing, sinusoid-like vasculature with focal hobnail appearance of endothelial cells. Entrapment of renal tubules between blood vessels was seen at the periphery of the tumors. This morphology was reminiscent of anastomosing hemangioma. Isolated tumor cells resembling lymphocytes with clear halos were sparsely interspersed between vessels. Cytokeratin immunostain confirmed the diagnosis of CCRCC. CONCLUSION Extensive sampling and immunohistochemical workup of what is deemed to be a benign vascular neoplasm of the kidney is needed to rule out the presence of individual carcinoma cells or small viable carcinoma cell clusters.