Small Cell Carcinoma Of Prostate Research Articles

Abstract A28: N-Myc drives small cell neuroendocrine cancer initiated from human prostate basal cells

Abstract Human small cell prostate carcinoma (SCPC) represents up to 25% of lethal castration-resistant prostate cancer. Molecular characterization of a panel of SCPCs recently identified frequent genomic amplification of both MYCN and AURKA. The oncogenic function of N-Myc has been characterized in many cancer types but its role in the initiation of human SCPC has not been defined. To investigate the function of N-Myc in human prostate transformation, we utilized a tissue regeneration model of human prostate cancer. Human prostate basal epithelial cells were isolated from benign primary prostate tissue from four independent human donors, infected with lentiviruses expressing the oncogenes N-Myc and activated (myristoylated) AKT1, mixed with mouse urogenital sinus mesenchyme, and grafted subcutaneously in immunodeficient NOD-SCID-IL2Rγnull mice. Palpable tumors were appreciated within 2-3 months and histological evaluation revealed regions of mixed high-grade adenocarcinoma and small cell carcinoma. The small cell carcinoma histology showed typical findings of high nuclear-to-cytoplasmic ratio, nuclear molding, stippled chromatin, and frequent mitotic and apoptotic features. Immunohistochemical analysis demonstrated low to absent androgen receptor (AR) staining in both the adenocarcinoma and small cell carcinoma. Further, we found heterogeneous staining for neuroendocrine markers including neural cell adhesion molecule 1, chromogranin A, synaptophysin, thyroid transcription factor 1, and forkhead box A2 in the regions of small cell carcinoma in support of the histological diagnosis. To assess the androgen dependence of tumor growth, regenerated N-Myc and activated AKT1 tumors derived from the lentiviral infection of primary human prostate basal cells were passaged in either intact or castrate immunodeficient mice. Tumors were propagated both in the presence and absence of androgens and showed a small but progressive enrichment of the small cell carcinoma over the adenocarcinoma with successive passage in castrate hosts. Molecular profiling by RNA-Seq of three regenerated N-Myc and activated AKT1 tumors showed a significant resemblance to a subset of human SCPC clinical specimens. Further, the adenocarcinoma and small cell carcinoma components of each tumor were remarkably similar at the transcriptional level despite their differences in histological appearance. In conclusion, we have established a novel model of human small cell prostate cancer arising from benign human prostate basal cells. Overexpression of N-Myc and activated AKT1 in basal cells produces tumors that recapitulate the histology, immunophenotype, and transcriptional profile of human SCPC. These findings support a direct role for N-Myc in the neuroendocrine transformation of basal cells in the human prostate. Further studies are ongoing to elucidate the mechanisms by which N-Myc induces a neuroendocrine differentiation program in prostate cancer. Citation Format: John K. Lee, Bryan A. Smith, John W. Phillips, Jungwook Park, Tanya I. Stoyanova, Robert Baertsch, Artem Sokolov, Colleen Mathis, Donghui Cheng, Joshua M. Stuart, Jiaoti Huang, Owen N. Witte. N-Myc drives small cell neuroendocrine cancer initiated from human prostate basal cells. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr A28.

Cyclin D1 Loss Distinguishes Prostatic Small-Cell Carcinoma from Most Prostatic Adenocarcinomas.

Small-cell neuroendocrine differentiation in prostatic carcinoma is an increasingly common resistance mechanism to potent androgen deprivation therapy (ADT), but can be difficult to identify morphologically. We investigated whether cyclin D1 and p16 expression can inform on Rb functional status and distinguish small-cell carcinoma from adenocarcinoma. We used gene expression data and immunohistochemistry to examine cyclin D1 and p16 levels in patient-derived xenografts (PDX), and prostatic small-cell carcinoma and adenocarcinoma specimens. Using PDX, we show proof-of-concept that a high ratio of p16 to cyclin D1 gene expression reflects underlying Rb functional loss and distinguishes morphologically identified small-cell carcinoma from prostatic adenocarcinoma in patient specimens (n = 13 and 9, respectively). At the protein level, cyclin D1, but not p16, was useful to distinguish small-cell carcinoma from adenocarcinoma. Overall, 88% (36/41) of small-cell carcinomas showed cyclin D1 loss by immunostaining compared with 2% (2/94) of Gleason score 7-10 primary adenocarcinomas at radical prostatectomy, 9% (4/44) of Gleason score 9-10 primary adenocarcinomas at needle biopsy, and 7% (8/115) of individual metastases from 39 patients at autopsy. Though rare adenocarcinomas showed cyclin D1 loss, many of these were associated with clinical features of small-cell carcinoma, and in a cohort of men treated with adjuvant ADT who developed metastasis, lower cyclin D1 gene expression was associated with more rapid onset of metastasis and death. Cyclin D1 loss identifies prostate tumors with small-cell differentiation and may identify a small subset of adenocarcinomas with poor prognosis. Clin Cancer Res; 21(24); 5619-29. ©2015 AACR.

Abstract 4208: The castrate resistant PC-3 cell line with neuroendocrine features is enriched in tumor initiating cells and is resistant to enzalutamide and abiraterone but sensitive to antimetabolites

Abstract BACKGROUND. Prostatic small cell carcinoma is increasing in frequency in patients resistant to all forms of androgen ablation. It is a high-grade malignant neoplasm with neuroendocrine features. There are no suitable cellular models to study this particular type of carcinoma. A recent study showed that the PC-3 cell line has neuroendocrine characteristics (1). This report prompted us to determine if this cell line is enriched in tumor initiating cells, and to use this cell line as a model to determine sensitivity to second generation anti androgen treatments and chemotherapeutic agents. METHODS. To determine the percentage of tumor initiating cells (TICs) marker expression comparing LNCaP with PC-3 cells, flow cytometry analysis was used. Functional assays such as migration, invasion, colony formation and sphere formation were used to determine metastatic potential. Secondary and tertiary spheroid assays were used to determine the self-renewal ability. The CellTiter 96® AQueous non-radioactive cell proliferation assay was used to identify response to hormone deprivation and chemotherapeutic drugs. RESULTS. The growth rate of PC-3 was similar to LNCaP cells while the TIC marker CD44 was only expressed on PC-3 cells. Both LNCaP and PC-3 cells expressed α2β1 with the highest expression detected in PC-3 cells. No expression of CD133 was detected in either of the cell lines. PC-3, as compared to LNCaP cells, displayed an increase in 5-minute collagen-I attachment, cell migration, invasion, colony formation and sphere formation in an anchorage-independent environment. PC-3 cells were capable of self-renewal in the secondary and tertiary spheroid assays and expressed neuroendocrine markers such as chromogranin A and EMT marker, Twist. PC-3 cells were able to also grow in androgen-deprived media, and as compared to LNCaP cells, demonstrated resistance to anti-androgen drugs that included enzalutamide and abiraterone and chemotherapy drugs such as doxorubicin and taxotere. Surprisingly, PC-3 cells were more sensitive to methotrexate than LNCaP or DU145 cells. PC3 cells had lower levels of MTAP (methylthioadenosine phosphorylase) and hence may be the reason for their sensitivity to denovo purine synthesis inhibitors such as methotrexate. CONCLUSIONS. The novel findings presented here provide evidence that castrate resistant PC-3 cells are CD44+/ α2β1+/CD24low/CD133_ and possess stem cell properties and may serve as a useful model to study the role of new treatments for prostate cancer with neuroendocrine features. Reference: 1) Prostate. 2011 Nov; 71(15): 1668-79; PC3 is a cell line characteristic of prostatic small cell carcinoma; Tai S, Sun Y, Squires JM, Zhang H, Oh WK, Liang CZ, Huang J Citation Format: Nitu Bansal, Lisa Wu, Nadine Johnson Farley, Philip Tedeschi, Joseph R. Bertino. The castrate resistant PC-3 cell line with neuroendocrine features is enriched in tumor initiating cells and is resistant to enzalutamide and abiraterone but sensitive to antimetabolites. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4208. doi:10.1158/1538-7445.AM2015-4208

Integrative molecular profiling of routine clinical prostate cancer specimens

Comprehensive molecular profiling led to the recognition of multiple prostate cancer (PCa) molecular subtypes and driving alterations, but translating these findings to clinical practice is challenging. We developed a formalin-fixed paraffin-embedded (FFPE) tissue compatible integrative assay for PCa molecular subtyping and interrogation of relevant genetic/transcriptomic alterations (MiPC). We applied MiPC, which combines capture-based next generation sequencing and quantitative reverse transcription PCR (qRT-PCR), to 53 FFPE PCa specimens representing cases not well represented in frozen tissue cohorts, including 8 paired primary tumor and lymph node metastases. Results were validated using multiplexed PCR based NGS and Sanger sequencing. We identified known and novel potential driving, somatic mutations and copy number alterations, including a novel BRAF T599_V600insHT mutation and CYP11B2 amplification in a patient treated with ketoconazole (a potent CYP11B2 inhibitor). qRT-PCR integration enabled comprehensive molecular subtyping and provided complementary information, such as androgen receptor (AR) target gene module assessment in advanced cases and SPINK1 over-expression. MiPC identified highly concordant profiles for all 8 tumor/lymph node metastasis pairs, consistent with limited heterogeneity amongst driving events. MiPC and exome sequencing were performed on separately isolated conventional acinar PCa and prostatic small cell carcinoma (SCC) components from the same FFPE resection specimen to enable direct comparison of histologically distinct components. While both components showed TMPRSS2:ERG fusions, the SCC component exclusively harbored complete TP53 inactivation (frameshift variant and copy loss) and two CREBBP mutations. Our results demonstrate the feasibility of integrative profiling of routine PCa specimens, which may have utility for understanding disease biology and enabling personalized medicine applications.

Cytotoxic and anti-angiogenic effects of lanostane triterpenoids from Ganoderma lucidum

Two new lanostane triterpenes, 3α,12β,15α-triacetoxy-5α-lanosta-7,9(11),24-trien-26-oic acid (1) and 5α-lanosta-8,24-diene-26,27-dihydroxy-3,7-dione (2), together with sixteen known compounds (3–18) were isolated from the fruiting bodies of the Vietnamese mushroom Ganoderma lucidum. Their chemical structures were determined by extensive spectroscopic (IR, HR-EI-MS, 1D and 2D NMR) analyses. Potential cytotoxic activities of these compounds were evaluated against human non-small cell lung adenocarcinoma (A549), breast adenocarcinoma (MCF-7), and prostatic small cell carcinoma (PC-3). Among the compounds, 3α,12β,15α-triacetoxy-5α-lanosta-7,9(11),24-trien-26-oic acid (1) showed significant cytotoxic activity against PC-3 cells with an IC50 of 11.5μM. In studies of anti-angiogenesis activity, ganoderic acid F (17) was found to have the most potent inhibitory effect on the formation of capillary-like structures of human umbilical vein endothelial cells.

Distinct genetic alterations in small cell carcinoma from different anatomic sites.

Small cell carcinoma (SmCC) is a distinct clinicopathological entity first described in the lung. It represents approximately 15% of all bronchogenic carcinoma. Extrapulmonary small cell carcinoma (EPSmCC) morphologically indistinguishable from small cell lung cancer (SCLC) was first reported in 1930. Since its first description, EPSmCC has been reported in virtually all anatomical sites, including: gynecologic organs (ovary and cervix); genitourinary organs (urinary bladder and prostate); the gastrointestinal tract (esophagus); skin (Merkel cell carcinoma) and head and neck region. Regardless of the anatomic sites, all SmCCs have similar, if not identical, histo-pathology features and immunohistochemical profile. SmCC is one of the most aggressive malignancies. The molecular mechanisms underlying its development and progression remain poorly understood. Herein, we reviewed the literature in SmCC in respect to its site of occurrence, clinical features, immunohistochemical characteristics. SmCCs have heterogeneous molecular mutations. Dinstinct genetic alterations associated with SmCC from different body sites were reviewed. Some genetic alterations such as RB1, TP53 are commonly seen in different origins of SmCC. Other genes with site specificity were also summarized, such as bladder SmCC with TERT promoter mutations; prostate SmCC with ERG translocations; ovarian SmCC with SMARCA4 mutations; Merkel cell carcinoma (skin) and cervical SmCC with Merkel cell polyomavirus (MCV or MCPyV) and human papillomavirus (HPV). Further studies are needed to employ a genetically oriented approach for the diagnosis and therapy of SmCC.

Small cell carcinoma of prostate presenting with Cushing′s syndrome

Small cell carcinoma of prostate (SCPCa) was initially described by Wenk et al. in 1977. SCPCa is a very rare cancer that accounts for only 0.5-2% of all prostate carcinomas. Although, this pathology is usually accompanied with prostate adenocarcinomas, there are a few hypotheses about the origin of SCPCa. Poorly differentiated acinar adenocarcinoma must be distinguished from SCPCa in histopathological examination. These patients may present with different paraneoplastic syndromes. Early diagnosis is very important because of the aggressive tumor behavior. Here, we report a patient who presented with Cushing syndrome and thereafter diagnosed with SCPCa.

Overlap of CD44 expression between prostatic small cell carcinoma and acinar adenocarcinoma.

Small cell carcinoma (SmCC) of the prostate is a rare and aggressive histologic subtype of the prostate cancer. It can sometimes mimic acinar adenocarcinoma with a high Gleason score (GS). A previous study showed that immunohistochemical staining for CD44 could help in the differential diagnosis of these 2 entities. In this study, we used 2 tissue microarrays including 63 cases of prostate cancer (18 pure SmCC, 37 pure acinar adenocarcinoma, and 8 mixed acinar adenocarcinoma and SmCC) to validate the value of CD44. When analyzed as a continuous variable, CD44 positivity was significantly higher in acinar adenocarcinoma with GS 8 than GS 9 to 10 (P = .027). However, the difference of CD44 expression between SmCC and acinar adenocarcinoma was insignificant. The current study fails to confirm the value of CD44 in differential diagnosis between prostatic SmCC and acinar adenocarcinoma.

Best Practices Recommendations in the Application of Immunohistochemistry in the Prostate

The following are the International Society of Urological Pathology (ISUP) recommendations for the use of immunohistochemistry (IHC) in prostate specimens. Either high-molecular weight cytokeratin (34βE12 or CK5/6 or others) or p63 or a combination of the 2 with AMACR either in a double or triple cocktail is recommended for the workup of small foci of atypical glands suspicious for adenocarcinoma of the prostate (PCa). ERG is optional as it is present in only 40% to 50% of prostate cancers and also positive in high-grade prostatic intraepithelial neoplasia. In the setting of obvious carcinoma or benign glands, there is no justification to do basal cell stains and AMACR. If there is a Gleason score of 3+4=7 or a higher-grade cancer on at least 1 part, the workup of other parts with an atypical focus suspicious for Gleason score 3+3=6 cancer is not recommended. In the setting of Gleason score 4+3 or 4+4=8 cancer on at least 1 part, the extent of high-grade cancer could affect clinical treatment such that workup of other atypical possible high-grade cancer foci is justified. In the setting of Gleason score 4+3 or higher-grade cancer on at least 1 part, given that intraductal carcinoma in the vast majority of cases is considered extension of high-grade cancer into prostatic ducts and acini, it is not recommended in the setting of definitive invasive high-grade cancer that workup of additional cribriform lesions be pursued. In the setting of Gleason score 3+3 on at least 1 part, the number of positive cores and/or their location could possibly affect subsequent therapy in terms of suitability for active surveillance or focal therapy, such that unless one knows with certainty that it would not affect therapy, it is justified to perform an IHC workup of additional atypical foci. In the differential diagnosis of high-grade PCa versus urothelial carcinoma (UC), the primary option is to use prostate-specific antigen (PSA) as a first test to identify PCa and GATA3 to identify UC. If GATA3 is not available, then HMWCK and p63 can be used. If the tumor is PSA positive with intense staining and HMWCK and p63 negative, the findings are diagnostic of PCa. If the tumor is equivocal/weak/negative for PSA and negative/focal for p63 and HMWCK, then one needs to perform staining for P501S, NKX3.1, and GATA3. Some experts also include PAP in this second round of staining. If the tumor is negative for PSA and diffusely strongly positive for p63 and HMWCK, the findings are diagnostic of UC. If the tumor is negative for PSA and moderately to strongly positive for GATA3, it is diagnostic of UC. Laboratories should be encouraged to use GATA3 for UC and add P501S and NKX3.1 as prostate markers in addition to PSA, p63, and HMWCK. If GATA3, p501S, and NKX3.1 are not available in equivocal cases, the case should be sent out for consultation to laboratories with these antibodies. The article also covers the use of IHC in: (1) high-grade PCa versus bladder adenocarcinoma; (2) prostatic small cell carcinoma versus high-grade PCa; (3) metastatic carcinoma of unknown primary: rule out PCa; (4) nonspecific granulomatous prostatitis/xanthoma versus high-grade PCa; (5) adult prostate sarcoma versus sarcomatoid PCa; (6) colorectal adenocarcinoma versus high-grade PCa; and (7) prognostic IHC markers.

Characterization of the genomic architecture and mutational spectrum of a small cell prostate carcinoma.

We present the use of a series of laboratory, analytical and interpretation methods to investigate personalized cancer care for a case of small cell prostate carcinoma (SCPC), a rare and aggressive tumor with poor prognosis, for which the underlying genomic architecture and mutational spectrum has not been well characterized. We performed both SNP genotyping and exome sequencing of a Virchow node metastasis from a patient with SCPC. A variety of methods were used to analyze and interpret the tumor genome for copy number variation, loss of heterozygosity (LOH), somatic mosaicism and mutations in genes from known cancer pathways. The combination of genotyping and exome sequencing approaches provided more information than either technique alone. The results showed widespread evidence of copy number changes involving most chromosomes including the possible loss of both alleles of CDKN1B (p27/Kip1). LOH was observed for the regions encompassing the tumor suppressors TP53, RB1, and CHD1. Predicted damaging somatic mutations were observed in the retained TP53 and RB1 alleles. Mutations in other genes that may be functionally relevant were noted, especially the recently reported high confidence cancer drivers FOXA1 and CCAR1. The disruption of multiple cancer drivers underscores why SCPC may be such a difficult cancer to manage.

Neuroendocrine prostate cancer: subtypes, biology, and clinical outcomes.

Neuroendocrine prostate cancer (NEPC) encompasses various clinical contexts, ranging from the de novo presentation of small cell prostatic carcinoma to a treatment-emergent transformed phenotype that arises from typical adenocarcinoma of the prostate. The development of resistance to potent androgen receptor signaling inhibition may be associated with the emergence of aggressive phenotype, advanced castration-resistant NEPC. Clinically, small cell prostate cancer and NEPC are often manifested by the presence of visceral or large soft tissue metastatic disease, a disproportionately low serum prostate-specific antigen level relative to the overall burden of disease, and a limited response to targeting of the androgen signaling axis. These tumors are often characterized by loss of androgen receptor expression, loss of retinoblastoma tumor suppressor copy number or expression, amplification of Aurora kinase A and N-Myc, and activation of the PI3K pathway. However, a consensus phenotype-genotype definition of NEPC has yet to emerge, and molecularly based biomarkers are needed to expand on traditional morphologic and immunohistochemical markers of NEPC to fully define the spectrum of this aggressive, androgen receptor-independent disease. Emerging studies implicate a shared clonal origin with prostatic adenocarcinoma in many cases, with the adaptive emergence of unique cellular programming and gene expression profiles. Ongoing clinical studies are focused on developing novel targeted therapeutic approaches for this high-risk, lethal subset of disease, to improve on the limited durations of response often observed with traditional platinum-based chemotherapy.

Increased androgen receptor gene copy number is associated with TMPRSS2-ERG rearrangement in prostatic small cell carcinoma.

Small cell carcinoma of the prostate (PSCC) is a highly aggressive malignancy that often develops in patients previously treated with hormonal therapy for metastatic prostatic acinar adenocarcinoma. The TMPRSS2-ERG gene rearrangement is highly specific for prostate cancer and shared by PSCC; however, the role of androgen receptor (AR) gene alterations and interaction with TMPRSS2-ERG rearrangement are incompletely understood in PSCC. Sixty-one cases of PSCC were examined for AR gene copy number and TMPRSS2-ERG rearrangement by fluorescence in situ hybridization (FISH) and AR protein expression by immunohistochemistry. Of 61 cases of PSCC, 51% (31/61) demonstrated increased AR gene copy number (FISH+), 54% (33/61) were positive for TMPRSS2-ERG gene fusion, and 38% (23/61) showed AR protein expression. Of the 31 AR FISH+ cases, 23 also showed TMPRSS2-ERG gene fusion, and 16 expressed AR protein. Of the 33 cases with TMPRSS2-ERG fusion, 28 were AR FISH+ or expressed AR protein. Statistically significant correlations were observed between AR gene copy number or AR protein expression and TMPRSS2-ERG gene fusion (P = 0.001 and P = 0.03, respectively). In summary, high AR gene copy number emerges during the development of PSCC, often in association with TMPRSS2-ERG rearrangement. This potential mechanism warrants further study. Improvement will come from understanding the biology of the disease and integrating new therapies into the treatment of this rare and aggressive tumor.

GATA3 expression in small cell carcinoma of bladder and prostate and its potential role in determining primary tumor origin.

GATA3 is a sensitive marker for urothelial carcinoma. We here evaluate, for the first time, GATA3 expression in small cell carcinoma of bladder and prostate and assess its utility in the differential diagnosis with small cell carcinoma of lung primary. Archival tissues from 60 small cell carcinomas (12 bladder, 15 lung, and 33 prostate primary cases) were used to build 2 tissue microarrays. We also assessed whole slide sections from 10 additional primary small cell carcinomas of bladder. GATA3 nuclear expression was evaluated using standard immunohistochemistry. Intensity (weak, moderate, and strong) and extent of expression were assessed in each tissue microarray spot. Extent positivity was categorized as focal (1%-25%), multifocal (>25%), and diffuse (>75%). Nuclear GATA3 expression was encountered in 7 bladder (7/22, 32%) and 2 lung (2/15, 13%) small cell carcinomas. All 33 primary prostate small cell carcinomas were negative. Among bladder tumors, strong and diffuse (>75%) GATA3 labeling was seen in 3 cases (3/22, 14%); focal positivity was observed in the 4 remaining cases (4/22, 18%). Both positive lung cases had only focal positivity. Our study is the first to reveal GATA3 expression in the small subset of lung small cell carcinoma that should be taken into consideration in assigning site of origin in advanced small cell carcinoma cases. Our novel finding of GATA3 positivity in one-third of bladder small cell carcinoma is of potential value in differentiating small cell carcinomas of prostate origin from those of bladder origin.

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.

Rb Loss Is Characteristic of Prostatic Small Cell Neuroendocrine Carcinoma

Small cell neuroendocrine carcinoma of the prostate is likely to become increasingly common with recent advances in pharmacologic androgen suppression. Thus, developing molecular markers of small cell differentiation in prostate cancer will be important to guide the diagnosis and therapy of this aggressive tumor. We examined the status of RB1, TP53, and PTEN in prostatic small cell and acinar carcinomas via immunohistochemistry (IHC), copy-number alteration analysis, and sequencing of formalin-fixed paraffin-embedded specimens. We found retinoblastoma (Rb) protein loss in 90% of small cell carcinoma cases (26 of 29) with RB1 allelic loss in 85% of cases (11 of 13). Of acinar tumors occurring concurrently with prostatic small cell carcinoma, 43% (3 of 7) showed Rb protein loss. In contrast, only 7% of primary high-grade acinar carcinomas (10 of 150), 11% of primary acinar carcinomas with neuroendocrine differentiation (4 of 35), and 15% of metastatic castrate-resistant acinar carcinomas (2 of 13) showed Rb protein loss. Loss of PTEN protein was seen in 63% of small cell carcinomas (17 of 27), with 38% (5 of 13) showing allelic loss. By IHC, accumulation of p53 was observed in 56% of small cell carcinomas (14 of 25), with 60% of cases (6 of 10) showing TP53 mutation. Loss of RB1 by deletion is a common event in prostatic small cell carcinoma and can be detected by a validated IHC assay. As Rb protein loss rarely occurs in high-grade acinar tumors, these data suggest that Rb loss is a critical event in the development of small cell carcinomas and may be a useful diagnostic and potential therapeutic target.

Clinicopathological study of prostatic biopsies.

Prostatism is a common malady in the geriatric age group. Benign prostatic hyperplasia and Carcinoma of the prostate are increasingly frequent with advancing age. The aim of the present study is to study the spectrum of prostatic lesions among the biopsies received in a rural hospital. One hundred and six cases of prostatic biopsies received in the Department of Pathology, Rajah Muthiah Medical College and Hospital - Annamalai University were included in the present study. There were 44 needle biopsies and 62 TURP specimens. All the specimens were fixed in 10% neutral buffered formalin and 5μ sections were stained with Hematoxylin and Eosin stain (H & E stain). Relevant clinical data including age, the presenting complaints and S.PSA values in suspected cases of carcinoma prostate were recorded. Among the 106 biopsies received, 79 (74.52%) cases were of Benign prostatic hyperplasia, two cases (1.89%) were Prostatic intraepithelial neoplasia and 25 cases (23.58%) were Carcinoma of Prostate. Prostatitis was the most common associated lesion in cases of benign prostatic hyperplasia presenting in 25.31% patients. Among the Carcinoma patients, 20 cases (80%) were of Adenocarcinoma of prostate and 5 cases (20%) were Small cell carcinoma of prostate. Both Benign prostatic hyperplasia and Carcinoma prostate were common in the seventh decade. Most common clinical presentation was difficulty in micturition. Most common histological type of Carcinoma prostate was Adenocarcinoma. Serum PSA estimation was done in 49 cases of prostate biopsies. Elevations of serum PSA levels were noted in both BPH and Carcinoma prostate patients.Eight cases of BPH, had serum PSA values in the range of 0-4ng/ml. Six cases of Carcinoma prostate ,had serum PSA values in the range of >80 ng/ml. Benign prostatic hyperplasia is the most commonly encountered prostatic lesion. Although, investigations like transrectal ultrasonogram and serum PSA estimation aids in diagnosis, a definitive diagnosis of benign and malignant lesions of prostate can be made by histopathological study of prostatic biopsies.

Small cell carcinoma of the urinary bladder and prostate: Cytological analyses of four cases with emphasis on the usefulness of cytological examination

The occurrence of small cell carcinoma in the urinary bladder and prostate is rare. Only a few reports on the cytological features of small cell carcinoma of the urinary bladder in the urine specimen have been documented and, moreover, the urinary cytological features of prostate small cell carcinoma have been rarely reported. In this study, we analyzed the cytological features of four cases of small cell carcinoma of the urinary bladder and prostate, and discussed the usefulness of cytological examination of urine specimen for this type of tumor. This study included two urinary bladder and two prostate small cell carcinoma cases. Analyses of the cytological features of these cases revealed the following: i) the background was mostly inflammatory and necrotic material was also occasionally observed; ii) numerous tumor cells were present in two cases, whereas only a few neoplastic cells were observed in the remaining cases; iii) the neoplastic cells were small in size, had scant cytoplasm and a high nuclear/cytoplasmic ratio, and were arranged in small clusters or occasionally as single cells; iv) the tumor cell clusters showed prominent nuclear moldings; and v) the nuclei of the neoplastic cells were round to oval in shape with finely granular chromatin containing inconspicuous nucleoli. The cytological features of small cell carcinoma in the urine specimen are characteristic. Therefore, careful observation of the urine specimen may lead to a correct diagnosis of small cell carcinoma of the urinary bladder and, moreover, cytodiagnosis of prostate small cell carcinoma may also be possible.

Frequent TMPRSS2-ERG rearrangement in prostatic small cell carcinoma detected by fluorescence in situ hybridization: the superiority of fluorescence in situ hybridization over ERG immunohistochemistry

Small cell carcinoma of the prostate is both morphologically and immunohistochemically similar to small cell carcinoma of other organs such as the urinary bladder or lung. TMPRSS2-ERG gene fusion appears to be a highly specific alteration in prostatic carcinoma that is frequently shared by small cell carcinoma. In adenocarcinoma, immunohistochemistry for the ERG protein product has been reported to correlate well with the presence of the gene fusion, although in prostatic small cell carcinoma, this relationship is not completely understood. We evaluated 54 cases of small cell carcinoma of the prostate and compared TMPRSS2-ERG gene fusion status by fluorescence in situ hybridization (FISH) to immunohistochemical staining with antibody to ERG. Of 54 cases of prostatic small cell carcinoma, 26 (48%) were positive for TMPRSS2-ERG gene fusion by FISH and 12 (22%) showed overexpression of ERG protein by immunohistochemistry. Of the 26 cases positive by FISH, 11 were also positive for ERG protein by immunohistochemistry. One tumor was positive by immunohistochemistry but negative by FISH. Urinary bladder small cell carcinoma (n = 25) showed negative results by both methods; however, 2 of 14 small cell carcinomas of other organs (lung, head, and neck) showed positive immunohistochemistry but negative FISH. Positive staining for ERG by immunohistochemistry is present in a subset of prostatic small cell carcinomas and correlates with the presence of TMPRSS2-ERG gene fusion. Therefore, it may be useful in confirming prostatic origin when molecular testing is not accessible. However, sensitivity and specificity of ERG immunohistochemistry in small cell carcinoma are decreased compared to FISH.

Platinum-Based Chemotherapy for Variant Castrate-Resistant Prostate Cancer

Clinical features characteristic of small-cell prostate carcinoma (SCPC), "anaplastic," often emerge during the progression of prostate cancer. We sought to determine the efficacy of platinum-based chemotherapy in patients meeting at least one of seven prospectively defined "anaplastic" clinical criteria, including exclusive visceral or predominantly lytic bone metastases, bulky tumor masses, low prostate-specific antigen levels relative to tumor burden, or short response to androgen deprivation therapy. A 120-patient phase II trial of first-line carboplatin and docetaxel (CD) and second-line etoposide and cisplatin (EP) was designed to provide reliable clinical response estimates under a Bayesian probability model with early stopping rules in place for futility and toxicity. Seventy-four of 113 (65.4%) and 24 of 71 (33.8%) were progression free after four cycles of CD and EP, respectively. Median overall survival (OS) was 16 months [95% confidence interval (CI), 13.6-19.0 months]. Of the seven "anaplastic" criteria, bulky tumor mass was significantly associated with poor outcome. Lactic acid dehydrogenase strongly predicted for OS and rapid progression. Serum carcinoembryonic antigen (CEA) concentration strongly predicted OS but not rapid progression. Neuroendocrine markers did not predict outcome or response to therapy. Our findings support the hypothesis that patients with "anaplastic" prostate cancer are a recognizable subset characterized by a high response rate of short duration to platinum-containing chemotherapies, similar to SCPC. Our results suggest that CEA is useful for selecting therapy in men with castration-resistant prostate cancer and consolidative therapies to bulky high-grade tumor masses should be considered in this patient population.

Clinical impact of 18F-fluorodeoxyglucose positron emission tomography/computed tomography in the evaluation of small cell carcinoma of the prostate

Small cell carcinoma of prostate (PSCC) is an uncommon and aggressive type of prostate malignancy with limited data on the use of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) in the clinical management of this rare entity. In this report, clinical and imaging findings of a patient with PSCC are presented. We aimed to discuss the role of PET/CT in the evaluation of PSCC in combination with histopathological characteristics of tumor and emphasize the importance of PET/CT in the clinical management of PSCC.