REVIEW For reprint orders, please contact: [email protected]
Genitourinary small cell malignancies: prostate and bladder
Kashyap Shatagopam‡,1, Hristos Z Kaimakliotis*,‡,1, Liang Cheng2 & Michael O Koch1
ABSTRACT Small cell carcinoma is an aggressive malignancy often associated with dismal prognosis due to the presence of advanced disease. Small cell malignancies, initially described in the lung (small cell carcinoma of the lung), can occur in extrapulmonary sites, such as prostate (small cell carcinoma of the prostate) and bladder (small cell carcinoma of the bladder), with similar clinicopathologic outcomes. There has been a paradigm shift in the management of small cell carcinoma of the lung from initial surgical treatment to use of chemotherapy followed by local therapies. Such treatment modalities have been applied to small cell carcinoma of the prostate and the bladder, with promise in improving patient survival. Use of platinum-based combination chemotherapy followed by surgical resection and/or radiation offers the most benefit. Further investigation at the molecular level may offer targeted therapies earlier in the course of the disease. Small cell carcinoma was first described in 1926 by Barnard and the primary organ of involvement was the lung [1] . At this early time, small cell carcinoma of the lung was histologically described as a growth consisting of ‘small oval cells with scanty cytoplasm,’ and therefore this cancer is also referred to as ‘oat cell sarcoma’ [2] . Small cell carcinoma of the lung (SCCL) accounts for 15% of all pulmonary malignancies and is universally accepted to be an aggressive entity [3] . The bleak outlook of SCCL was known as early as the 1930s, when patients with SCCL were frequently found to have extra-pulmonary metastases [4] . Early approaches to treating SCCL involved surgical resection of the primary tumor, with or without localized radiotherapy of the chest. These methods were unsuccessful in curing disease, with a 5-year survival rate of only 1% for those who underwent surgical resection and a 5-year survival rate of 4% for those treated with radiation [5] . Retrospectively, it was noted that metastatic disease was often present at the time of diagnosis, a finding that eventually led to development of systemic interventions in the form of chemotherapy. Initial regimens consisted of single agents such as cyclophosphamide and by the early 1980s, combination chemotherapy regimens in conjunction with radiation therapy became the cornerstone of treatment for SCCL [6] . The transition from a local surgical management to a systemic approach with chemotherapy and local radiation increased median survival from 5 to 17 months in those with limited disease [6] . Over the last few decades, studies have shown that combination chemotherapy, utilizing a platinum-based agent in adjunct with etoposide, offers the most benefit and is currently the standard of care in management of patients with SCCL [3] .
KEYWORDS
• bladder cancer • chemotherapy • prostate cancer • radiotherapy • small cell carcinoma • surgery
Department of Urology, Indiana University School of Medicine, Simon Cancer Center, Indianapolis, IN 46202, USA Department of Pathology, Indiana University School of Medicine, Simon Cancer Center, Indianapolis, IN 46202, USA *Author for correspondence: Tel.: +1 203 530 0445; Fax: +1 317 278 0499; [email protected] ‡ Authors contributed equally 1 2
10.2217/FON.14.277 © 2015 Future Medicine Ltd
Future Oncol. (2015) 11(3), 479–488
part of
ISSN 1479-6694
479
Review Shatagopam, Kaimakliotis, Cheng & Koch Genitourinary small cell malignancies Small cell carcinoma, while most commonly found in the lungs, can occur in numerous extrapulmonary sites, including the head, neck, skin, esophagus, stomach, intestinal tract, breast, cervix, prostate and urinary bladder [1,7] . The emphasis of this paper will be to explore small cell malignancies of the genitourinary system, specifically focusing on small cell carcinoma of the prostate (SCCP) and small cell carcinoma of the bladder (SCCB). These comprise a class of cancers that are thought to be histologically and clinically similar to small cell carcinoma of the lung. All three of these types of small cell carcinomas fall under the category of neuroendocrine tumors [8] . Genitourinary small cell carcinomas have a particularly low incidence in the population and are rare variants that account for less than less than 2% of all primary cancers of the prostate and bladder [9,10] . Although uncommon, SCCP and SCCB are very aggressive and often have poor outcomes due to their rapidly progressing and systemic natures. Small case series of SCCP and SCCB have shown that while both of these genitourinary cancers have poor prognoses, small cell carcinoma of the prostate may have a worse prognosis and is associated with less favorable outcomes [7,11] . The scarcity of cases of SCCP and SCCB has limited our understanding of the biological progression of these diseases and thus prevented the ability to perform prospective studies. Over the years, management of SCCP and SCCB has largely been fashioned around the therapeutic regimens of their pulmonary counterpart. Systemic chemotherapy is considered to be the standard of care for SCCL, and in conjunction with surgery or radiation in a multimodality management approach is the main treatment algorithm used in attempting to address SCCP and SCCB. There are currently no universally accepted treatment methodologies for SCCP or SCCB, and most of the current guidelines have been fashioned around retrospective studies from single institutions, with only one prospective Phase II clinical trial in SCCB [12] . Small cell histopathology Small cell carcinomas are considered neuroendocrine tumors [8] . These tumors, which can occur in the lungs as well as numerous extrapulmonary sites, all exhibit the same morphology and are histologically identical [1,7–8] . Classic histologic findings in small cell carcinoma are
480
Future Oncol. (2015) 11(3)
sheets of round blue hyperchromatic cells that are slightly larger than lymphocytes with little cytoplasm and nuclei that are round, oval, or spindle-shaped [8–9,13] . The WHO has defined certain morphologic criteria for the diagnosis of small cell carcinoma of the lung, which are the same criteria currently used for the diagnosis for small cell carcinomas of the prostate and bladder [14–16] . The WHO describes SCCL as a proliferation of small cells that have “scant cytoplasm, ill-defined borders, finely granular salt and pepper chromatin, absent or inconspicuous nucleoli, frequent nuclear molding and a high mitotic count” [14] . In addition there are several markers that are used to confirm small cell pathology. Given their neuroendocrine origin, these tumors will stain positive for certain neural markers such as chromogranin, synaptophysin and neuron-specific enolase [16] . Small cell genitourinary malignancies have specific epithelial tumor markers that can also be stained. Some of these markers include cytokeratin 7, epithelial membrane antigen and CAM 5.2, and are found to be positive in a large percentage of cases of SCCP and SCCB [13,17] . Unique to SCCP is the expression of CD44, a cell-surface molecule that is positive in all SCCP tumors, while absent in small cell carcinomas that are not of prostatic origin [8] . Another specific finding in SCCP is the presence of fusion between the TMPRSS2 genes and ERG gene, which is an oncogene [18] . The TMPRSS2–ERG gene fusion product, believed to cause oncogenesis in SCCP, is not found in other small cell carcinomas such as SCCL and SCCB [18] . With regards to SCCB, it has been observed that the epithelial marker cytokeratin 20 was detected in 46–73% of cases compared with about 11% in SCCP [13,19] . The aforementioned histological descriptions and cellular markers highlight the high degree of similarity that is present across all classes of small cell carcinomas, while each subtype also maintains certain unique properties. Small cell carcinoma of the prostate ●●Pathogenesis
Adenocarcinoma of the prostate accounts for the vast majority of cancers of the prostate gland, with SCCP comprising less than 1–2% [1,15,20] . SCCP was first described by Wenk et al. in 1977, with patients usually presenting at an advanced stage, commonly with systemic findings of visceral metastases and lytic bone lesions [20–22] .
future science group
Genitourinary small cell cancer SCCP can present either as a pure small cell primary lesion or a mixed histological form with components of adenocarcinoma. Pure SCCP may result in a decreased survival compared with the mixed histology pattern of SCCP, which contains both the typical histologic features of adenocarcinoma of the prostate and neuroendocrine cancer cell features [22] . Minimal or absent production of PSA and lack of androgen receptor expression are characteristic features of pure SCCP [15] . The lack of androgen receptor expression in SCCP adds to the difficulty in treating this cancer. Interestingly, patients with SCCP who have higher PSA levels prior to initiation of chemotherapy seem to have better outcomes after undergoing chemotherapy [22] . The higher levels of PSA in these patients may be attributed to the presence of a mixed tumor pattern with an adenocarcinoma element, which brings into question whether SCCP arises as a result of a de-differentiation pathway from pre-existing adenocarcinoma of the prostate and also whether the adenocarcinoma element in the mixed tumor directs the biological progression of this malignancy and thus confers a better prognosis. There have been several proposed theories over the years regarding the etiology of SCCP. The first theory suggests that SCCP originates from neuroendocrine cells [23] . SCCP is very similar in its clinical behavior and histopathologic morphology to small cell carcinoma of the lung (SCCL), which is considered to be a neuroendocrine tumor. Another theory suggests that SCCP results from the dedifferentiation of prostatic adenocarcinoma, as some tumor cells in SCCP stain for PSA [23] . This may establish presence of adenocarcinoma, although this finding parallels the observation that some cases of mixed SCCP arise in patients who previously received hormonal therapy for adenocarcinoma of the prostate [22] . Papandreou et al. state that of the patients in their study that have SCCP, 81% of them underwent androgen ablation therapy prior to the emergence of small cell carcinoma with neuroendocrine characteristics, supporting the theory that SCCP arises from adenocarcinoma of the prostate [22] . However, it is not known whether hormonal treatment is directly related to the emergence of the small cell phenotype [22] . The final theory that has been postulated states that stem cells are the immediate precursors of SCCP [23] . Given the rarity of this disease and lack of definitive evidence
future science group
Review
for these theories, further exploration is necessary. Perhaps as genetic signatures or fingerprints become better outlined, the nature of SCCP will be better understood. ●●Clinical presentation & diagnosis
Small cell carcinoma of the prostate affects males most commonly between 60 and 70 years of age [20] . Patients diagnosed with SCCP, unlike adenocarcinoma of the prostate, are usually asymptomatic but if present obstructive voiding symptoms are the most common [20] . Other symptoms that may be present include hematuria, hematochezia, abdominal and pelvic pain [20] . Paraneoplastic syndromes commonly accompany SCCP and include Cushing’s syndrome, hypercalcemia and excess production of antidiuretic hormone [20] . Neoplastic syndromes can also include elevated serum levels of peptides such as ACTH and PTH [20] . Digital rectal exam may reveal a normal, nodular or firm prostate; however, these examination findings are not specific to SCCP and may indicate adenocarcinoma of the prostate or benign prostatic hyperplasia [20] . If the examination is abnormal, further options include transrectal ultrasound of the prostate, which can be used to perform a needle biopsy [20] . Computed tomography (CT) or MRI can be used to identify the tumor and presence of metastatic disease [20,24] . Diagnosis of SCCP requires careful pathological evaluation of the tumor given the common occurrence of misdiagnosing SCCP for high Gleason grade poorly differentiated acinar adenocarcinoma due to similar microscopic appearances of both tumors [9,13,15,20] . SCCP is best diagnosed using the WHO criteria that are defined for small cell carcinoma of the lung [15] . Immunohistochemical staining for the markers mentioned previously can assist in the correct diagnosis of SCCP [13] . ●●Evolution of treatment
Chemotherapy
Once the systemic nature of the disease and the similarity to SCCL was appreciated, the earliest treatment protocol for SCCP was a combination chemotherapy regimen used for SCCL consisting of cyclophosphamide, doxorubicin and vincristine [25] . The single patient in this case study achieved remission, although the response was short lived [25] . In 1992 a retrospective study assessed the efficacy of various combination chemotherapy regimens in SCCP
www.futuremedicine.com
481
Review Shatagopam, Kaimakliotis, Cheng & Koch in the metastatic setting [26] . Regimens used included a combination of vincristine, doxorubicin and cyclophosphamide or etoposide and cisplatin, with or without doxorubicin. Again, development of these regimens was undertaken as they were considered to be effective in the treatment of small cell carcinoma of the lung. Of the 21 patients in this study, 62% exhibited a positive response to chemotherapy with a resulting median survival time of 9.4 months, thus indicating that SCCP has a high response rate to cytotoxic drugs and therefore early initiation of chemotherapy in these patients may increase overall survival time [26] . Based on these studies, and further developments in SCCL demonstrating a response rate to combination chemotherapy with etoposide and cisplatin, clinicians from MD Anderson explored this further in 2002 in a prospective trial by adding doxorubicin to the regimen of etoposide and cisplatin in an attempt to determine if this combination would result in complete remission in patients with SCCP [22] . A total of 61% of the patients in this study showed partial responses; however, overall survival did not improve compared with etoposide and cisplatin [22] . In addition, because the addition of doxorubicin resulted in severe toxicity and adverse side effects, it was concluded that adding doxorubicin does not improve patient outcomes [22] . The role of another chemotherapy regimen consisting of irinotecan and cisplatin has been investigated for SCCP after survival benefit was demonstrated previously in small cell carcinoma of the lung [27,28] . A Phase III trial in Japan demonstrated a survival benefit when using irinotecan/cisplatin compared with etoposide/cisplatin in the setting of metastatic SCCL [27] . A total of 154 four patients randomized to the two treatment groups, and the investigators were able to demonstrate a median overall survival of 12.8 months in the irinotecan/cisplatin cohort, compared with 9.4 months in the etoposide/cisplatin cohort (p = 0.002). This study suggested that irinotecan used in conjunct with a platinum-based agent may be an appealing management option for SCCL. However, a survival benefit was not demonstrated in randomized studies in the USA when comparing irinotecan to etoposide [29,30] . The difference in responses to these different agents could perhaps be attributed to variability in pharmacogenomics among the Japanese and American populations, and
482
Future Oncol. (2015) 11(3)
irinotecan has not gained widespread use in management of SCCL and etoposide remains the mainstay approach [29,30] . Application of irinotecan for SCCP has shown some promise in a study that involved the use of xenografts that were derived from human prostatic small cell carcinoma tumor tissue and transplanted into mice [28] . The mice were treated with either irinotecan alone or irinotecan in combination with cisplatin and there was a complete inhibition of xenograft growth when using irinotecan alone or in combination with cisplatin (p < 0.01). These results in mice models suggest that regimens consisting of irinotecan may be beneficial in the management of SCCP and further trials in humans will be needed to validate and expand on these results. Hormonal therapy
The role of hormonal therapy in the treatment of small cell carcinoma of the prostate is not well understood. Given the lack of androgen receptor expression in small cell carcinoma of the prostate, there is a common presumption that these cancers are refractory to androgen ablation therapy [15,24] . The utility of anti-androgen therapy in this population was assessed in a retrospective review from Mayo Clinic [31] . Outcomes of patients with SCCP treated over a 30-year-period were reviewed [31] . In total, 92% of these patients who had long-term follow-up died of this disease despite receiving anti-androgen therapy, consistent with current knowledge that tumor cells in SCCP lack androgen receptor expression and hence are refractory to hormonal therapy [15,31] . Furthermore, since SCCP may present as a mixed form with elements of adenocarcinoma, it would seem that anti- androgen therapy may be beneficial. However, this is still not well defined in the literature and the only conclusion is that hormonal therapy should not be used as a sole treatment modality for SCCP [24] . Surgery
The role of surgery in the management of SCCP is not yet well understood, as most cases present with metastatic disease and thus surgical resection of the primary tumor bestows little value. Symptomatic relief in patients with advanced SCCP can be achieved with transurethral resection of the prostate but this procedure is not curative [20] . The exact role of surgery versus radiation has not been well defined, although
future science group
Genitourinary small cell cancer there have been reports of patients with localized SCCP who underwent radical prostatectomy and were cured of the disease [20] . One study suggested that primary surgery, in the setting of no metastatic disease, was the only independent factor associated with longer survival [7] . However, surgery alone has not been demonstrated to be curative in advanced disease and clinical understaging, especially with micrometastatic involvement, is a limitation in guiding management. If surgical intervention is utilized in SCCP, it is currently accepted that neoadjuvant chemotherapy improves survival. Similarly, neoadjuvant chemotherapy should be used if radiation therapy is employed for local treatment [20] . Radiation
The use of radiation in the multimodal approach to treating small cell carcinoma of the prostate has yet to be clearly defined. In patients with limited or locally advanced disease, it seems that external beam radiation therapy administered concomitantly with platinum-based chemotherapy offers the best survival outcomes [20] . If administered in the adjuvant setting following prostatectomy, radiotherapy should be administered after chemotherapy [20,24] . There are no guidelines regarding the dose of radiation that should be administered due to the rarity of cases of SCCP, but it seems that a dose of between 45 and 55 Gy in a zone of radiation that includes the pelvic lymph nodes may prevent the possibility of local relapse [24] . With regard to SCCP in the metastatic setting, radiotherapy is mainly administered for palliative purposes to control local symptoms such as pain from bone metastases [20] . Small cell carcinoma of the bladder ●●Pathogenesis
The urinary bladder is another genitourinary organ with the propensity to develop small cell malignant differentiation, and similarly presents at advanced stages [17] . Conventional urothelial carcinoma is the most common type and accounts for 80% of cancers involving the bladder, and analogous to small cell carcinoma of the prostate a small cell component is one of the most important prognostic factors in bladder cancer [32,33] . Common sites of metastasis for SCCB include the liver, bone and abdominal cavity [34] . SCCB can present as a pure small cell form or mixed with components
future science group
Review
of adenocarcinoma, urothelial carcinoma, squamous cell carcinoma or other variants of urothelial cancer [17,19] . The first case of SCCB was described in 1981 by Cramer et al. [35] . Similar to SCCP, there are several hypotheses that have been proposed regarding the etiology of SCCB. One theory suggests SCCB arises as a result of transformation of neuroendocrine cells that are present within the transitional epithelium lining the bladder [17] . Another theory hypothesizes that SCCB arises from a cancerous stem cell that gives rise to multiple other cell types [17] . This is supported by the observation that SCCB has been found to occur along other primary bladder malignancies, such as urothelial carcinoma and adenocarcinoma of the bladder. A final theory is that SCCB potentially arises from a high-degree metaplasia of the cells within the transitional epithelium in the bladder [17] . Once again, there is no definitive evidence for these theories in the literature and further u nderstanding of this rare cancer is necessary. ●●Clinical presentation & diagnosis
Small cell carcinoma of the bladder predominantly affects males, with a male:female ratio of approximately 4:1, and usually presents in the sixth or seventh decade of life [17,19,36–37] . Similar to other urothelial malignancies, smoking is a risk factor and a majority of those diagnosed with SCCB have a history of smoking [16,37] . The most common presenting symptom in these individuals is hematuria, while dysuria, urinary urgency, urinary frequency and nocturia can also be seen [16–17,36–37] . Some patients may present with paraneoplastic syndromes, such as Cushing’s syndrome with ectopic production of ACTH [19] . Patients presenting with hematuria and suspected of having bladder cancer should undergo cystoscopic evaluation with transurethral resection of the bladder tumor to obtain a tissue sample, along with CT imaging for staging [16] . Microscopic analysis of the tissue sample, looking for the specific histology and morphology mentioned previously, is needed to make a definitive diagnosis of small cell carcinoma of the bladder [16–17,19] . Diagnostic criteria for SCCB are based on the WHO classification system mentioned earlier, and are identical to small cell carcinoma of the lung, with immunohistochemical staining for neural markers such as chromogranin, synaptophysin and neuron-specific enolase performed
www.futuremedicine.com
483
Review Shatagopam, Kaimakliotis, Cheng & Koch to confirm the diagnosis of SCCB [16–17,19] . ●●Evolution of treatment
Chemotherapy
Chemotherapy has largely been the choice of treatment for SCCB. One of the initial studies in patients with SCCB suggested that combination chemotherapy similar to that used for small cell carcinoma of the lung likely resulted in a prolonged survival [34] . A 1999 study reported the use of radiation in combination with chemotherapy in five patients with SCCB who were thought have localized disease [38] . Alternating cycles of chemotherapy and radiation, resulted in complete remission in all of the patients, with four alive free of disease at an interval ranging from 2 to 5 years [38] . The chemotherapy regimens used in this study were the same as those used for small cell carcinoma of the lung. One cycle consisted of etoposide and cisplatin, whereas the other cycle consisted of doxorubicin, cyclophosphamide and vincristine [38] . A second group published their results on the efficacy of chemotherapy given in combination with radiation that same year [39] . Ten patients, nine of whom had limited SCCB without metastasis, were treated with combination chemotherapy and radiation, with a 70% 2-year survival rate [39] . Five of these patients were disease free after 7 years, showing great promise for the incorporation of chemotherapy and radiation in improving outcomes for patients with SCCB [39] . In an isolated case report, the use of irinotecan in combination with etoposide and cisplatin for the management of nonmetastatic SCCB was noted to produce a complete pathological remission at time of cystectomy, with the patient being free of disease at 19 months following surgery [40] . Such isolated cases with new regimens may show promise for further improvement in the management of SCCB.
cystectomy alone [41] . A total of 57% of patients undergoing neoadjuvant chemotherapy also had a pathologic downstaging of their disease [41] . Following up on this study, the same group from MD Anderson performed the first prospective study for SCCB and found their results to be consistent with prior retrospective studies [12] . This study consisted of 30 patients with any component SCCB, of whom 18 had localized SCCB without any metastases [12] . The chemotherapy regimen consisted of alternating cycles of etoposide with cisplatin, followed by ifosfamide and doxorubicin [12] . Patients who underwent four cycles of neoadjuvant chemotherapy followed by cystectomy were found to have a median overall survival of 58 months, with an even higher 5-year survival rate of 80% for patients with cT2N0M0 [12] . The results from these two studies demonstrate the importance of chemotherapy in the multimodal approach to treating small cell carcinoma of the bladder. Surgical intervention for management of SCCB, similar to its role in SCCP, appears to offer the most benefit if disease is limited. Surgical options for SCCB include transurethral resection of the bladder tumor, partial cystectomy and radical cystectomy. In 2005 a small study of 17 SCCB patients with limited disease suggested that because patients did not die due to local tumor progression, cystectomy may not be the treatment of choice [32] . However, a Mayo Clinic study of 44 patients with SCCB that same year concluded that if metastatic disease is absent, radical cystectomy should be performed with a 64% 5-year survival [36] . They also indicated that for patients with SCCB after cystectomy, adjuvant chemotherapy should be utilized. It is now believed that neoadjuvant chemotherapy followed by surgery is the optimal strategy, as seen by the ability to completely resect all tumor burden, pathological downstaging and improved survival observed with this approach [12,36,41] .
Surgery
It was not until 2004, when Siefker et al. further investigated the role of neoadjuvant chemotherapy followed by surgery in the treatment of SCCB [41] . In this small retrospective study, 25 patients were treated with initial cystectomy and 21 patients with neoadjuvant cisplatin and etoposide prior to cystectomy [41] . Combination therapy with cisplatin/etoposide produced a significantly improved 78% 5-year survival rate, compared with a 36% 5-year survival rate for
484
Future Oncol. (2015) 11(3)
Radiation
Radiation therapy can be considered for small cell carcinoma of the bladder if a bladdersparing approach is desired or comorbidities preclude extirpation. It appears that radiation is a reasonable option for loco-regional SCCB when given in a sequential manner following chemotherapy. In a study of 17 patients with limited disease, patients were treated with 56–70 Gy radiotherapy in conjunction with
future science group
Genitourinary small cell cancer platinum-based chemotherapy [42] . Median overall survival for these individuals was 32.5 months and the 5-year overall survival was 36% [17,42] . A similar study of 27 patients undergoing chemoradiation for limited disease SCCB, with radiotherapy doses ranging from 50 to 70 Gy, showed comparable results with a median overall survival of 26 months and 5-year overall survival of 22.2% [43] . It remains unclear if radiation provides a cumulative benefit to chemotherapy; nonetheless it has been used for management of loco-regional SCCB to achieve reasonable outcomes. The role of radiation in patients with extensive SCCB is also not clearly understood, although radiation has been used for patients with locally advanced or unresectable disease. One small case series involving 11 patients with limited or locally advanced SCCB showed that radiation delivered at a median dose of 59 Gy in combination with chemotherapy resulted in a 27% metastasis-free survival rate [44] . For patients with distant metastases to sites such as bone, the role of radiotherapy has not been well described and seems to be used mostly for symptomatic control [17] . Genitourinary small cell summary Based on the progression and evolution of management of small cell cancer of the lung, treatment algorithms have been replicated in the management of genitourinary small cell involvement. As noted in the studies highlighted above, it is clear that systemic therapy with cisplatin and etoposide is the backbone of treatment, although the optimal multimodality approach to management of small cell carcinomas of the genitourinary system has yet to be developed and will require further study. With regards to small cell carcinoma of the prostate and bladder, if amenable to extirpative surgery, it appears that neoadjuvant chemotherapy followed by surgery offers the most benefit in patients who have limited disease with no signs of metastasis. For limited disease SCCP, it has been noted that radical prostatectomy was curative in select cases, although wide acceptance of the systemic nature of the disease is now commonplace. In patients with extensive, locally advanced and/or metastatic SCCP, it would appear as though multimodality chemo-radiation therapy can improve outcomes. The role of radiation may be obviated in distant metastatic disease, although useful in extensive loco-regional disease. Similarly,
future science group
Review
for loco-regional SCCB, neoadjuvant chemotherapy followed by cystectomy has been observed to provide the most promising outcomes. However, in patients with advanced or initially unresectable disease, combination chemotherapy and radiation therapy should likely be the management, as surgery may not improve prognosis. Irrespective of slight differences in surgical management guidelines for these genitourinary malignancies, a common conclusion in most studies is that platinumbased combination chemotherapy is essential in the multimodal treatment approach, whether used as the primary mode of treatment or in the neoadjuvant/adjuvant setting. Conclusion Small cell carcinomas of the genitourinary system present a definite clinical challenge. Both SCCP and SCCB are very aggressive cancers with a poor prognosis despite advancements in the understanding of the disease from knowledge applied in other organ counterparts. The low incidence of these cancers has made it challenging to study their biological and clinical progression, making the development of standardized treatment regimens a difficult undertaking. Treatment modalities thus far for SCCP and SCCB have been based on those used for small cell carcinoma of the lung and it appears that multimodality therapies, consisting of cisplatin and etoposide chemotherapy as the cornerstone of systemic therapy, with radiotherapy or surgery as adjunct treatments are currently recommended for optimal outcomes. Diagnosing these cancers at earlier stages will allow prospective studies to be performed, but this may prove to be a challenging task. Furthermore, a better understanding of small cell cancer overall, its genitourinary involvement, molecular alterations and differentiation pathways is of outmost importance and will potentially allow for the development of personalized treatment algorithms and perhaps targeted therapies in the future. Future perspective Small cell carcinoma continues to have poor a prognosis due to the malignant nature of this disease and limited therapeutic options that are currently available. With regards to management of small cell genitourinary carcinoma, future directions can be modeled after advances in the treatment of small cell carcinoma of the
www.futuremedicine.com
485
Review Shatagopam, Kaimakliotis, Cheng & Koch lung. Several biological targets and molecular pathways are being studied for the management of SCCL. One such target is angiogenesis, a critical pathway for the progression of tumor development in SCCL [16,45] . This process has been targeted with inhibitors of VEGF such as bevacizumab and thalidomide, albeit without promising results [16,45] . Another target of interest was the Bcl-2 anti-apoptosis pathway that is thought be overexpressed in SCCL [45] . Bcl-2 antagonists have been used to target this pathway but have failed to show any meaningful response [45] . Several other pathways implicated in SCCL are being studied, including the sonic hedgehog pathway and DNA damage repair pathways [45] . The sonic hedgehog pathway is thought to play a role in tumorigenesis in SCCL, and inhibitors of this pathway are currently being studied [45] . It is also believed that inhibiting the DNA repair pathway may increase the cytotoxic nature of chemotherapeutic agents in SCCL by increasing sensitivity of the tumor to these agents [45] . Several inhibitors of this pathway are currently being studied. If these studies show promising
results in managing SCCL, it may be plausible to apply similar strategies to its genitourinary small cell carcinoma counterparts. Another area of study focusing specifically on SCCP centers on loss of retinoblastoma protein in 90% of cases [46] . Loss of this protein may represent an integral step in the development of SCCP and thus could prove to be a potential target. Further investigation of such molecular targets and pathways will be essential to the development of targeted therapies consisting of novel agents that may be used alone or in combination with other drugs that are already being applied for the treatment of small cell carcinomas. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
EXECUTIVE SUMMARY ●●
Small cell carcinomas of the genitourinary system, specifically bladder and prostate, are rare malignancies that present at advanced stages and have poor prognoses.
●●
Histologically, small cell carcinomas of the bladder and prostate are identical to small cell carcinoma of the lung (SCCL), all of which express neuroendocrine markers such as chromogranin, synaptophysin and neuron-specific enolase.
●●
Certain markers are specific to the individual small cell subtypes, with small cell carcinoma of the prostate expressing
CD44 and TMPRSS2–ERG gene fusion product and small cell carcinoma of the bladder expressing the epithelial marker cytokeratin 20. ●●
Given similarities, management of small cell genitourinary carcinomas has largely been modeled after their pulmonary counterpart, SCCL.
●●
Over the past few decades, there has been a paradigm shift in the management of SCCL from initial surgical resection to the use of systemic chemotherapy followed by locally-directed therapies.
●●
Platinum-based chemotherapy regimens are currently the mainstay of treatment for SCCL, and this has since been translated toward management of small cell carcinomas of the prostate and bladder.
●●
There are no well-defined treatment guidelines for genitourinary small cell cancers, and the role of surgery and
radiation is not well established; however, it seems that a multimodal approach with platinum-based combination chemotherapy leads to improved outcomes. ●●
Specific molecular pathways, such as the sonic hedgehog and DNA repair pathways, implicated in the tumorigenesis of SCCL are being investigated and may be shown to be relevant in the pathogenesis of small cell carcinoma of the prostate and the bladder.
●●
Diagnosing genitourinary small cell cancers at earlier stages, as well as investigating novel molecular targets and
differentiation pathways, may shed light on their aggressive nature and prove to be essential in the development of personalized treatment algorithms in the future.
486
Future Oncol. (2015) 11(3)
future science group
Genitourinary small cell cancer examined the effect of chemotherapy in the neoadjuvant setting. They reported a median overall survival of 58 months in patients with limited disease who receieved four cycles of platinum-based neoadjuvant chemotherapy.
References Papers of special note have been highlighted as: • of interest 1
Abbas F, Civantos F, Benedetto P, Soloway MS. Small cell carcinoma of the bladder and prostate. Urology 46(5), 617–630 (1995).
2
Barnard WG. The nature of the “oat-celled sarcoma” of the mediastinum. Pathol. Bacteriol. 29, 241–244 (1926).
3
Chan BA, Coward JI. Chemotherapy advances in small-cell lung cancer. J. Thorac. Dis. 5(Suppl. 5), S565–S578 (2013).
4
Karsner HT, Saphir O. Small cell carcinomas of the lung. Am. J. Pathol. 6(5), 553–562.553 (1930).
5
Fox W, Scadding JG. Medical Research Council comparative trial of surgery and radiotherapy for primary treatment of small-celled or oat-celled carcinoma of bronchus. Ten-year follow-up. Lancet 2(7820), 63–65 (1973).
6
7
8
9
Morstyn G, Ihde DC, Lichter AS et al. Small cell lung cancer 1973–1983: early progress and recent obstacles. Int. J. Radiat. Oncol. Biol. Phys. 10(4), 515–539 (1984). Mackey JR, Au HJ, Hugh J, Venner P. Genitourinary small cell carcinoma: determination of clinical and therapeutic factors associated with survival. J. Urol. 159(5), 1624–1629 (1998). Mazzucchelli R, Morichetti D, Lopez-Beltran A et al. Neuroendocrine tumours of the urinary system and male genital organs: clinical significance. BJU Int. 103(11), 1464–1470 (2009). Wang W, Epstein JI. Small cell carcinoma of the prostate. A morphologic and immunohistochemical study of 95 cases. Am. J. Surg. Pathol. 32(1), 65–71 (2008).
11 Asmis TR, Reaume MN, Dahrouge S,
Malone S. Genitourinary small cell carcinoma: a retrospective review of treatment and survival patterns at The Ottawa Hospital Regional Cancer Center. BJU Int. 97(4), 711–715 (2006). 12 Siefker-Radtke AO, Kamat AM, Grossman
HB et al. Phase II clinical trial of neoadjuvant alternating doublet chemotherapy with ifosfamide/doxorubicin and etoposide/ cisplatin in small-cell urothelial cancer. J. Clin. Oncol. 27(16), 2592–2597 (2009). •
This prospective study consisting of patients with small cell carcinoma of the bladder
future science group
Treatment outcomes of small cell carcinoma of the prostate: a single-center study. Cancer 110(8), 1729–1737 (2007). •
Tavora F. Review of small cell carcinomas of the prostate. Prostate Cancer 2011, 543272 (2011). 14 Brambilla E, Travis WD, Colby TV, Corrin
Small cell (neuroendocrine) carcinoma of the prostate: etiology, diagnosis, prognosis, and therapeutic implications – a retrospective study of 30 patients from the rare cancer network. Am. J. Med. Sci. 336(6), 478–488 (2008).
carcinoma of the prostate: an immunohistochemical study. Am. J. Surg. Pathol. 30(6), 705–712 (2006). 16 Pant-Purohit M, Lopez-Beltran A, Montironi
•
R, MacLennan GT, Cheng L. Small cell carcinoma of the urinary bladder. Histol. Histopathol. 25(2), 217–221 (2010). 17 Thota S, Kistangari G, Daw H, Spiro T. A
clinical review of small-cell carcinoma of the urinary bladder. Clin. Genitourin. Cancer 11(2), 73–77 (2013). •
Outlines clinicopathologic characteristics and treatment guidelines for small cell carcinoma of the bladder by looking at various studies from major institutions.
Small-cell carcinoma of prostate. Transient complete remission with chemotherapy. Urology, 26(2), 182–184 (1985). 26 Amato RJ, Logothetis CJ, Hallinan R, Ro JY,
Sella A, Dexeus FH. Chemotherapy for small cell carcinoma of prostatic origin. J. Urol. 147(3 Pt 2), 935–937 (1992). 27 Noda K, Nishiwaki Y, Kawahara M et al.
Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N. Engl. J. Med. 346(2), 85–91 (2002).
19 Pan CX, Zhang H, Lara PN, Jr., Cheng L.
Small-cell carcinoma of the urinary bladder: diagnosis and management. Expert Rev. Anticancer Ther. 6(12), 1707–1713 (2006). 20 Palmgren JS, Karavadia SS, Wakefield MR.
Unusual and underappreciated: small cell carcinoma of the prostate. Semin. Oncol. 34(1), 22–29 (2007). •
Discusses small-cell carcinoma of the prostate and highlights clinical and histological characteristics of this malignancy, and discusses treatment options based on studies from major institutions.
21 Wenk RE, Bhagavan BS, Levy R, Miller D,
Weisburger W. Ectopic ACTH, prostatic oat cell carcinoma, and marked hypernatremia. Cancer 40(2), 773–778 (1977). 22 Papandreou CN, Daliani DD, Thall PF et al.
Results of a phase II study with doxorubicin, etoposide, and cisplatin in patients with fully characterized small-cell carcinoma of the prostate. J. Clin. Oncol. 20(14), 3072–3080 (2002).
Discusses characteristics that are unique to small cell carcinoma of the prostate, such as low PSA levels and lack of androgen receptor expression. They also summarize studies investigating SCCP and outcomes from major institutions.
25 Hindson DA, Knight LL, Ocker JM.
18 Guo CC, Dancer JY, Wang Y et al.
TMPRSS2–ERG gene fusion in small cell carcinoma of the prostate. Hum. Pathol. 42(1), 11–17 (2011).
Looked at 83 patients with metastatic and nonmetastatic small cell carcinoma (SCCP) of the prostate. They reported a statistically significant difference in disease specific survival between the two groups (17.7 months in nonmetastatic SCCP vs 12.5 months in metastatic SCCP).
24 Stein ME, Bernstein Z, Abacioglu U et al.
15 Yao JL, Madeb R, Bourne P et al. Small cell
10 Zhao X, Flynn EA. Small cell carcinoma of
the urinary bladder: a rare, aggressive neuroendocrine malignancy. Arch. Pathol. Lab. Med. 136(11), 1451–1459 (2012).
23 Spiess PE, Pettaway CA, Vakar-Lopez F et al.
13 Furtado P, Lima MV, Nogueira C, Franco M,
B, Shimosato Y. The new World Health Organization classification of lung tumours. Eur. Respir. J. 18(6), 1059–1068 (2001).
Review
•
Phase III trial that demonstrated a statistically significant survival benefit when using irinotecan/cisplatin compared with etoposide/cisplatin in the management of patients with metastatic small cell carcinoma of the lung.
28 Tung WL, Wang Y, Gout PW, Liu DM,
Gleave M, Wang Y. Use of irinotecan for treatment of small cell carcinoma of the prostate. Prostate 71(7), 675–681 (2011). 29 Hanna N, Bunn PA Jr, Langer C et al.
Randomized Phase III trial comparing irinotecan/cisplatin with etoposide/cisplatin in patients with previously untreated extensive-stage disease small-cell lung cancer. J. Clin. Oncol. 24(13), 2038–2043 (2006). 30 Lara PN Jr, Natale R, Crowley J et al. Phase
III trial of irinotecan/cisplatin compared with etoposide/cisplatin in extensive-stage small-cell lung cancer: clinical and
www.futuremedicine.com
487
Review Shatagopam, Kaimakliotis, Cheng & Koch pharmacogenomic results from SWOG S0124. J. Clin. Oncol. 27(15), 2530–2535 (2009). 31 Oesterling JE, Hauzeur CG, Farrow GM.
Small cell anaplastic carcinoma of the prostate: a clinical, pathological and immunohistological study of 27 patients. J. Urol. 147(3 Pt 2), 804–807 (1992). 32 Bex A, Nieuwenhuijzen JA, Kerst M et al.
Small cell carcinoma of bladder: a singlecenter prospective study of 25 cases treated in analogy to small cell lung cancer. Urology 65(2), 295–299 (2005). 33 Willis DL, Porten SP, Kamat AM. Should
histologic variants alter definitive treatment of bladder cancer? Curr. Opin. Urol. 23(5), 435–443 (2013). 34 Blomjous CE, Vos W, De Voogt HJ, Van der
Valk P, Meijer CJ. Small cell carcinoma of the urinary bladder. A clinicopathologic, morphometric, immunohistochemical, and ultrastructural study of 18 cases. Cancer 64(6), 1347–1357 (1989). 35 Cramer SF, Aikawa M, Cebelin M.
Neurosecretory granules in small cell invasive carcinoma of the urinary bladder. Cancer 47(4), 724–730 (1981). 36 Choong NW, Quevedo JF, Kaur JS. Small cell
carcinoma of the urinary bladder. The Mayo
488
Clinic experience. Cancer 103(6), 1172–1178 (2005). •
This retrospective study from the Mayo Clinic investigated 44 patients with small cell carcinoma of the bladder. They reported an overall median survival of 1.7 years and recommend that patients should undergo radical cystectomy when metastatic disease is absent.
37 Cheng L, Pan CX, Yang XJ et al. Small cell
carcinoma of the urinary bladder: a clinicopathologic analysis of 64 patients. Cancer 101(5), 957–962 (2004). 38 Bastus R, Caballero JM, Gonzalez G et al.
Small cell carcinoma of the urinary bladder treated with chemotherapy and radiotherapy: results in five cases. Eur. Urol 35(4), 323–326 (1999). 39 Lohrisch C, Murray N, Pickles T, Sullivan L.
Small cell carcinoma of the bladder: long term outcome with integrated chemoradiation. Cancer 86(11), 2346–2352 (1999). 40 Kawahara T, Nishiyama H, Yamamoto S,
Kamoto T, Ogawa O. Protocol consisting of cisplatin, etoposide and irinotecan induced complete pathological remission of primary small cell carcinoma of the bladder. Int. J. Urol. 13(9), 1251–1253 (2006).
Future Oncol. (2015) 11(3)
41 Siefker-Radtke AO, Dinney CP, Abrahams
NA et al. Evidence supporting preoperative chemotherapy for small cell carcinoma of the bladder: a retrospective review of the M. D. Anderson cancer experience. J. Urol. 172(2), 481–484 (2004). 42 Bex A, de Vries R, Pos F, Kerst M, Horenblas
S. Long-term survival after sequential chemoradiation for limited disease small cell carcinoma of the bladder. World J. Urol. 27(1), 101–106 (2009). 43 Meijer RP, Meinhardt W, van der Poel HG
et al. Local control rate and prognosis after sequential chemoradiation for small cell carcinoma of the bladder. Int. J. Urol. 20(8), 778–784 (2013). 44 Bryant CM, Dang LH, Stechmiller BK,
Gilbert SM, Morris CG, Zlotecki RA. Treatment of small cell carcinoma of the bladder with chemotherapy and radiation after transurethral resection of a bladder tumor. Am. J. Clin. Oncol. (2014). 45 Pillai RN, Owonikoko TK. Small cell lung
cancer: therapies and targets. Semin. Oncol. 41(1), 133–142 (2014). 46 Tan HL, Sood A, Rahimi HA et al. Rb loss is
characteristic of prostatic small cell neuroendocrine carcinoma. Clin. Cancer Res. 20(4), 890–903 (2014).
future science group
Genitourinary small cell malignancies: prostate and bladder
Kashyap Shatagopam‡,1, Hristos Z Kaimakliotis*,‡,1, Liang Cheng2 & Michael O Koch1
ABSTRACT Small cell carcinoma is an aggressive malignancy often associated with dismal prognosis due to the presence of advanced disease. Small cell malignancies, initially described in the lung (small cell carcinoma of the lung), can occur in extrapulmonary sites, such as prostate (small cell carcinoma of the prostate) and bladder (small cell carcinoma of the bladder), with similar clinicopathologic outcomes. There has been a paradigm shift in the management of small cell carcinoma of the lung from initial surgical treatment to use of chemotherapy followed by local therapies. Such treatment modalities have been applied to small cell carcinoma of the prostate and the bladder, with promise in improving patient survival. Use of platinum-based combination chemotherapy followed by surgical resection and/or radiation offers the most benefit. Further investigation at the molecular level may offer targeted therapies earlier in the course of the disease. Small cell carcinoma was first described in 1926 by Barnard and the primary organ of involvement was the lung [1] . At this early time, small cell carcinoma of the lung was histologically described as a growth consisting of ‘small oval cells with scanty cytoplasm,’ and therefore this cancer is also referred to as ‘oat cell sarcoma’ [2] . Small cell carcinoma of the lung (SCCL) accounts for 15% of all pulmonary malignancies and is universally accepted to be an aggressive entity [3] . The bleak outlook of SCCL was known as early as the 1930s, when patients with SCCL were frequently found to have extra-pulmonary metastases [4] . Early approaches to treating SCCL involved surgical resection of the primary tumor, with or without localized radiotherapy of the chest. These methods were unsuccessful in curing disease, with a 5-year survival rate of only 1% for those who underwent surgical resection and a 5-year survival rate of 4% for those treated with radiation [5] . Retrospectively, it was noted that metastatic disease was often present at the time of diagnosis, a finding that eventually led to development of systemic interventions in the form of chemotherapy. Initial regimens consisted of single agents such as cyclophosphamide and by the early 1980s, combination chemotherapy regimens in conjunction with radiation therapy became the cornerstone of treatment for SCCL [6] . The transition from a local surgical management to a systemic approach with chemotherapy and local radiation increased median survival from 5 to 17 months in those with limited disease [6] . Over the last few decades, studies have shown that combination chemotherapy, utilizing a platinum-based agent in adjunct with etoposide, offers the most benefit and is currently the standard of care in management of patients with SCCL [3] .
KEYWORDS
• bladder cancer • chemotherapy • prostate cancer • radiotherapy • small cell carcinoma • surgery
Department of Urology, Indiana University School of Medicine, Simon Cancer Center, Indianapolis, IN 46202, USA Department of Pathology, Indiana University School of Medicine, Simon Cancer Center, Indianapolis, IN 46202, USA *Author for correspondence: Tel.: +1 203 530 0445; Fax: +1 317 278 0499; [email protected] ‡ Authors contributed equally 1 2
10.2217/FON.14.277 © 2015 Future Medicine Ltd
Future Oncol. (2015) 11(3), 479–488
part of
ISSN 1479-6694
479
Review Shatagopam, Kaimakliotis, Cheng & Koch Genitourinary small cell malignancies Small cell carcinoma, while most commonly found in the lungs, can occur in numerous extrapulmonary sites, including the head, neck, skin, esophagus, stomach, intestinal tract, breast, cervix, prostate and urinary bladder [1,7] . The emphasis of this paper will be to explore small cell malignancies of the genitourinary system, specifically focusing on small cell carcinoma of the prostate (SCCP) and small cell carcinoma of the bladder (SCCB). These comprise a class of cancers that are thought to be histologically and clinically similar to small cell carcinoma of the lung. All three of these types of small cell carcinomas fall under the category of neuroendocrine tumors [8] . Genitourinary small cell carcinomas have a particularly low incidence in the population and are rare variants that account for less than less than 2% of all primary cancers of the prostate and bladder [9,10] . Although uncommon, SCCP and SCCB are very aggressive and often have poor outcomes due to their rapidly progressing and systemic natures. Small case series of SCCP and SCCB have shown that while both of these genitourinary cancers have poor prognoses, small cell carcinoma of the prostate may have a worse prognosis and is associated with less favorable outcomes [7,11] . The scarcity of cases of SCCP and SCCB has limited our understanding of the biological progression of these diseases and thus prevented the ability to perform prospective studies. Over the years, management of SCCP and SCCB has largely been fashioned around the therapeutic regimens of their pulmonary counterpart. Systemic chemotherapy is considered to be the standard of care for SCCL, and in conjunction with surgery or radiation in a multimodality management approach is the main treatment algorithm used in attempting to address SCCP and SCCB. There are currently no universally accepted treatment methodologies for SCCP or SCCB, and most of the current guidelines have been fashioned around retrospective studies from single institutions, with only one prospective Phase II clinical trial in SCCB [12] . Small cell histopathology Small cell carcinomas are considered neuroendocrine tumors [8] . These tumors, which can occur in the lungs as well as numerous extrapulmonary sites, all exhibit the same morphology and are histologically identical [1,7–8] . Classic histologic findings in small cell carcinoma are
480
Future Oncol. (2015) 11(3)
sheets of round blue hyperchromatic cells that are slightly larger than lymphocytes with little cytoplasm and nuclei that are round, oval, or spindle-shaped [8–9,13] . The WHO has defined certain morphologic criteria for the diagnosis of small cell carcinoma of the lung, which are the same criteria currently used for the diagnosis for small cell carcinomas of the prostate and bladder [14–16] . The WHO describes SCCL as a proliferation of small cells that have “scant cytoplasm, ill-defined borders, finely granular salt and pepper chromatin, absent or inconspicuous nucleoli, frequent nuclear molding and a high mitotic count” [14] . In addition there are several markers that are used to confirm small cell pathology. Given their neuroendocrine origin, these tumors will stain positive for certain neural markers such as chromogranin, synaptophysin and neuron-specific enolase [16] . Small cell genitourinary malignancies have specific epithelial tumor markers that can also be stained. Some of these markers include cytokeratin 7, epithelial membrane antigen and CAM 5.2, and are found to be positive in a large percentage of cases of SCCP and SCCB [13,17] . Unique to SCCP is the expression of CD44, a cell-surface molecule that is positive in all SCCP tumors, while absent in small cell carcinomas that are not of prostatic origin [8] . Another specific finding in SCCP is the presence of fusion between the TMPRSS2 genes and ERG gene, which is an oncogene [18] . The TMPRSS2–ERG gene fusion product, believed to cause oncogenesis in SCCP, is not found in other small cell carcinomas such as SCCL and SCCB [18] . With regards to SCCB, it has been observed that the epithelial marker cytokeratin 20 was detected in 46–73% of cases compared with about 11% in SCCP [13,19] . The aforementioned histological descriptions and cellular markers highlight the high degree of similarity that is present across all classes of small cell carcinomas, while each subtype also maintains certain unique properties. Small cell carcinoma of the prostate ●●Pathogenesis
Adenocarcinoma of the prostate accounts for the vast majority of cancers of the prostate gland, with SCCP comprising less than 1–2% [1,15,20] . SCCP was first described by Wenk et al. in 1977, with patients usually presenting at an advanced stage, commonly with systemic findings of visceral metastases and lytic bone lesions [20–22] .
future science group
Genitourinary small cell cancer SCCP can present either as a pure small cell primary lesion or a mixed histological form with components of adenocarcinoma. Pure SCCP may result in a decreased survival compared with the mixed histology pattern of SCCP, which contains both the typical histologic features of adenocarcinoma of the prostate and neuroendocrine cancer cell features [22] . Minimal or absent production of PSA and lack of androgen receptor expression are characteristic features of pure SCCP [15] . The lack of androgen receptor expression in SCCP adds to the difficulty in treating this cancer. Interestingly, patients with SCCP who have higher PSA levels prior to initiation of chemotherapy seem to have better outcomes after undergoing chemotherapy [22] . The higher levels of PSA in these patients may be attributed to the presence of a mixed tumor pattern with an adenocarcinoma element, which brings into question whether SCCP arises as a result of a de-differentiation pathway from pre-existing adenocarcinoma of the prostate and also whether the adenocarcinoma element in the mixed tumor directs the biological progression of this malignancy and thus confers a better prognosis. There have been several proposed theories over the years regarding the etiology of SCCP. The first theory suggests that SCCP originates from neuroendocrine cells [23] . SCCP is very similar in its clinical behavior and histopathologic morphology to small cell carcinoma of the lung (SCCL), which is considered to be a neuroendocrine tumor. Another theory suggests that SCCP results from the dedifferentiation of prostatic adenocarcinoma, as some tumor cells in SCCP stain for PSA [23] . This may establish presence of adenocarcinoma, although this finding parallels the observation that some cases of mixed SCCP arise in patients who previously received hormonal therapy for adenocarcinoma of the prostate [22] . Papandreou et al. state that of the patients in their study that have SCCP, 81% of them underwent androgen ablation therapy prior to the emergence of small cell carcinoma with neuroendocrine characteristics, supporting the theory that SCCP arises from adenocarcinoma of the prostate [22] . However, it is not known whether hormonal treatment is directly related to the emergence of the small cell phenotype [22] . The final theory that has been postulated states that stem cells are the immediate precursors of SCCP [23] . Given the rarity of this disease and lack of definitive evidence
future science group
Review
for these theories, further exploration is necessary. Perhaps as genetic signatures or fingerprints become better outlined, the nature of SCCP will be better understood. ●●Clinical presentation & diagnosis
Small cell carcinoma of the prostate affects males most commonly between 60 and 70 years of age [20] . Patients diagnosed with SCCP, unlike adenocarcinoma of the prostate, are usually asymptomatic but if present obstructive voiding symptoms are the most common [20] . Other symptoms that may be present include hematuria, hematochezia, abdominal and pelvic pain [20] . Paraneoplastic syndromes commonly accompany SCCP and include Cushing’s syndrome, hypercalcemia and excess production of antidiuretic hormone [20] . Neoplastic syndromes can also include elevated serum levels of peptides such as ACTH and PTH [20] . Digital rectal exam may reveal a normal, nodular or firm prostate; however, these examination findings are not specific to SCCP and may indicate adenocarcinoma of the prostate or benign prostatic hyperplasia [20] . If the examination is abnormal, further options include transrectal ultrasound of the prostate, which can be used to perform a needle biopsy [20] . Computed tomography (CT) or MRI can be used to identify the tumor and presence of metastatic disease [20,24] . Diagnosis of SCCP requires careful pathological evaluation of the tumor given the common occurrence of misdiagnosing SCCP for high Gleason grade poorly differentiated acinar adenocarcinoma due to similar microscopic appearances of both tumors [9,13,15,20] . SCCP is best diagnosed using the WHO criteria that are defined for small cell carcinoma of the lung [15] . Immunohistochemical staining for the markers mentioned previously can assist in the correct diagnosis of SCCP [13] . ●●Evolution of treatment
Chemotherapy
Once the systemic nature of the disease and the similarity to SCCL was appreciated, the earliest treatment protocol for SCCP was a combination chemotherapy regimen used for SCCL consisting of cyclophosphamide, doxorubicin and vincristine [25] . The single patient in this case study achieved remission, although the response was short lived [25] . In 1992 a retrospective study assessed the efficacy of various combination chemotherapy regimens in SCCP
www.futuremedicine.com
481
Review Shatagopam, Kaimakliotis, Cheng & Koch in the metastatic setting [26] . Regimens used included a combination of vincristine, doxorubicin and cyclophosphamide or etoposide and cisplatin, with or without doxorubicin. Again, development of these regimens was undertaken as they were considered to be effective in the treatment of small cell carcinoma of the lung. Of the 21 patients in this study, 62% exhibited a positive response to chemotherapy with a resulting median survival time of 9.4 months, thus indicating that SCCP has a high response rate to cytotoxic drugs and therefore early initiation of chemotherapy in these patients may increase overall survival time [26] . Based on these studies, and further developments in SCCL demonstrating a response rate to combination chemotherapy with etoposide and cisplatin, clinicians from MD Anderson explored this further in 2002 in a prospective trial by adding doxorubicin to the regimen of etoposide and cisplatin in an attempt to determine if this combination would result in complete remission in patients with SCCP [22] . A total of 61% of the patients in this study showed partial responses; however, overall survival did not improve compared with etoposide and cisplatin [22] . In addition, because the addition of doxorubicin resulted in severe toxicity and adverse side effects, it was concluded that adding doxorubicin does not improve patient outcomes [22] . The role of another chemotherapy regimen consisting of irinotecan and cisplatin has been investigated for SCCP after survival benefit was demonstrated previously in small cell carcinoma of the lung [27,28] . A Phase III trial in Japan demonstrated a survival benefit when using irinotecan/cisplatin compared with etoposide/cisplatin in the setting of metastatic SCCL [27] . A total of 154 four patients randomized to the two treatment groups, and the investigators were able to demonstrate a median overall survival of 12.8 months in the irinotecan/cisplatin cohort, compared with 9.4 months in the etoposide/cisplatin cohort (p = 0.002). This study suggested that irinotecan used in conjunct with a platinum-based agent may be an appealing management option for SCCL. However, a survival benefit was not demonstrated in randomized studies in the USA when comparing irinotecan to etoposide [29,30] . The difference in responses to these different agents could perhaps be attributed to variability in pharmacogenomics among the Japanese and American populations, and
482
Future Oncol. (2015) 11(3)
irinotecan has not gained widespread use in management of SCCL and etoposide remains the mainstay approach [29,30] . Application of irinotecan for SCCP has shown some promise in a study that involved the use of xenografts that were derived from human prostatic small cell carcinoma tumor tissue and transplanted into mice [28] . The mice were treated with either irinotecan alone or irinotecan in combination with cisplatin and there was a complete inhibition of xenograft growth when using irinotecan alone or in combination with cisplatin (p < 0.01). These results in mice models suggest that regimens consisting of irinotecan may be beneficial in the management of SCCP and further trials in humans will be needed to validate and expand on these results. Hormonal therapy
The role of hormonal therapy in the treatment of small cell carcinoma of the prostate is not well understood. Given the lack of androgen receptor expression in small cell carcinoma of the prostate, there is a common presumption that these cancers are refractory to androgen ablation therapy [15,24] . The utility of anti-androgen therapy in this population was assessed in a retrospective review from Mayo Clinic [31] . Outcomes of patients with SCCP treated over a 30-year-period were reviewed [31] . In total, 92% of these patients who had long-term follow-up died of this disease despite receiving anti-androgen therapy, consistent with current knowledge that tumor cells in SCCP lack androgen receptor expression and hence are refractory to hormonal therapy [15,31] . Furthermore, since SCCP may present as a mixed form with elements of adenocarcinoma, it would seem that anti- androgen therapy may be beneficial. However, this is still not well defined in the literature and the only conclusion is that hormonal therapy should not be used as a sole treatment modality for SCCP [24] . Surgery
The role of surgery in the management of SCCP is not yet well understood, as most cases present with metastatic disease and thus surgical resection of the primary tumor bestows little value. Symptomatic relief in patients with advanced SCCP can be achieved with transurethral resection of the prostate but this procedure is not curative [20] . The exact role of surgery versus radiation has not been well defined, although
future science group
Genitourinary small cell cancer there have been reports of patients with localized SCCP who underwent radical prostatectomy and were cured of the disease [20] . One study suggested that primary surgery, in the setting of no metastatic disease, was the only independent factor associated with longer survival [7] . However, surgery alone has not been demonstrated to be curative in advanced disease and clinical understaging, especially with micrometastatic involvement, is a limitation in guiding management. If surgical intervention is utilized in SCCP, it is currently accepted that neoadjuvant chemotherapy improves survival. Similarly, neoadjuvant chemotherapy should be used if radiation therapy is employed for local treatment [20] . Radiation
The use of radiation in the multimodal approach to treating small cell carcinoma of the prostate has yet to be clearly defined. In patients with limited or locally advanced disease, it seems that external beam radiation therapy administered concomitantly with platinum-based chemotherapy offers the best survival outcomes [20] . If administered in the adjuvant setting following prostatectomy, radiotherapy should be administered after chemotherapy [20,24] . There are no guidelines regarding the dose of radiation that should be administered due to the rarity of cases of SCCP, but it seems that a dose of between 45 and 55 Gy in a zone of radiation that includes the pelvic lymph nodes may prevent the possibility of local relapse [24] . With regard to SCCP in the metastatic setting, radiotherapy is mainly administered for palliative purposes to control local symptoms such as pain from bone metastases [20] . Small cell carcinoma of the bladder ●●Pathogenesis
The urinary bladder is another genitourinary organ with the propensity to develop small cell malignant differentiation, and similarly presents at advanced stages [17] . Conventional urothelial carcinoma is the most common type and accounts for 80% of cancers involving the bladder, and analogous to small cell carcinoma of the prostate a small cell component is one of the most important prognostic factors in bladder cancer [32,33] . Common sites of metastasis for SCCB include the liver, bone and abdominal cavity [34] . SCCB can present as a pure small cell form or mixed with components
future science group
Review
of adenocarcinoma, urothelial carcinoma, squamous cell carcinoma or other variants of urothelial cancer [17,19] . The first case of SCCB was described in 1981 by Cramer et al. [35] . Similar to SCCP, there are several hypotheses that have been proposed regarding the etiology of SCCB. One theory suggests SCCB arises as a result of transformation of neuroendocrine cells that are present within the transitional epithelium lining the bladder [17] . Another theory hypothesizes that SCCB arises from a cancerous stem cell that gives rise to multiple other cell types [17] . This is supported by the observation that SCCB has been found to occur along other primary bladder malignancies, such as urothelial carcinoma and adenocarcinoma of the bladder. A final theory is that SCCB potentially arises from a high-degree metaplasia of the cells within the transitional epithelium in the bladder [17] . Once again, there is no definitive evidence for these theories in the literature and further u nderstanding of this rare cancer is necessary. ●●Clinical presentation & diagnosis
Small cell carcinoma of the bladder predominantly affects males, with a male:female ratio of approximately 4:1, and usually presents in the sixth or seventh decade of life [17,19,36–37] . Similar to other urothelial malignancies, smoking is a risk factor and a majority of those diagnosed with SCCB have a history of smoking [16,37] . The most common presenting symptom in these individuals is hematuria, while dysuria, urinary urgency, urinary frequency and nocturia can also be seen [16–17,36–37] . Some patients may present with paraneoplastic syndromes, such as Cushing’s syndrome with ectopic production of ACTH [19] . Patients presenting with hematuria and suspected of having bladder cancer should undergo cystoscopic evaluation with transurethral resection of the bladder tumor to obtain a tissue sample, along with CT imaging for staging [16] . Microscopic analysis of the tissue sample, looking for the specific histology and morphology mentioned previously, is needed to make a definitive diagnosis of small cell carcinoma of the bladder [16–17,19] . Diagnostic criteria for SCCB are based on the WHO classification system mentioned earlier, and are identical to small cell carcinoma of the lung, with immunohistochemical staining for neural markers such as chromogranin, synaptophysin and neuron-specific enolase performed
www.futuremedicine.com
483
Review Shatagopam, Kaimakliotis, Cheng & Koch to confirm the diagnosis of SCCB [16–17,19] . ●●Evolution of treatment
Chemotherapy
Chemotherapy has largely been the choice of treatment for SCCB. One of the initial studies in patients with SCCB suggested that combination chemotherapy similar to that used for small cell carcinoma of the lung likely resulted in a prolonged survival [34] . A 1999 study reported the use of radiation in combination with chemotherapy in five patients with SCCB who were thought have localized disease [38] . Alternating cycles of chemotherapy and radiation, resulted in complete remission in all of the patients, with four alive free of disease at an interval ranging from 2 to 5 years [38] . The chemotherapy regimens used in this study were the same as those used for small cell carcinoma of the lung. One cycle consisted of etoposide and cisplatin, whereas the other cycle consisted of doxorubicin, cyclophosphamide and vincristine [38] . A second group published their results on the efficacy of chemotherapy given in combination with radiation that same year [39] . Ten patients, nine of whom had limited SCCB without metastasis, were treated with combination chemotherapy and radiation, with a 70% 2-year survival rate [39] . Five of these patients were disease free after 7 years, showing great promise for the incorporation of chemotherapy and radiation in improving outcomes for patients with SCCB [39] . In an isolated case report, the use of irinotecan in combination with etoposide and cisplatin for the management of nonmetastatic SCCB was noted to produce a complete pathological remission at time of cystectomy, with the patient being free of disease at 19 months following surgery [40] . Such isolated cases with new regimens may show promise for further improvement in the management of SCCB.
cystectomy alone [41] . A total of 57% of patients undergoing neoadjuvant chemotherapy also had a pathologic downstaging of their disease [41] . Following up on this study, the same group from MD Anderson performed the first prospective study for SCCB and found their results to be consistent with prior retrospective studies [12] . This study consisted of 30 patients with any component SCCB, of whom 18 had localized SCCB without any metastases [12] . The chemotherapy regimen consisted of alternating cycles of etoposide with cisplatin, followed by ifosfamide and doxorubicin [12] . Patients who underwent four cycles of neoadjuvant chemotherapy followed by cystectomy were found to have a median overall survival of 58 months, with an even higher 5-year survival rate of 80% for patients with cT2N0M0 [12] . The results from these two studies demonstrate the importance of chemotherapy in the multimodal approach to treating small cell carcinoma of the bladder. Surgical intervention for management of SCCB, similar to its role in SCCP, appears to offer the most benefit if disease is limited. Surgical options for SCCB include transurethral resection of the bladder tumor, partial cystectomy and radical cystectomy. In 2005 a small study of 17 SCCB patients with limited disease suggested that because patients did not die due to local tumor progression, cystectomy may not be the treatment of choice [32] . However, a Mayo Clinic study of 44 patients with SCCB that same year concluded that if metastatic disease is absent, radical cystectomy should be performed with a 64% 5-year survival [36] . They also indicated that for patients with SCCB after cystectomy, adjuvant chemotherapy should be utilized. It is now believed that neoadjuvant chemotherapy followed by surgery is the optimal strategy, as seen by the ability to completely resect all tumor burden, pathological downstaging and improved survival observed with this approach [12,36,41] .
Surgery
It was not until 2004, when Siefker et al. further investigated the role of neoadjuvant chemotherapy followed by surgery in the treatment of SCCB [41] . In this small retrospective study, 25 patients were treated with initial cystectomy and 21 patients with neoadjuvant cisplatin and etoposide prior to cystectomy [41] . Combination therapy with cisplatin/etoposide produced a significantly improved 78% 5-year survival rate, compared with a 36% 5-year survival rate for
484
Future Oncol. (2015) 11(3)
Radiation
Radiation therapy can be considered for small cell carcinoma of the bladder if a bladdersparing approach is desired or comorbidities preclude extirpation. It appears that radiation is a reasonable option for loco-regional SCCB when given in a sequential manner following chemotherapy. In a study of 17 patients with limited disease, patients were treated with 56–70 Gy radiotherapy in conjunction with
future science group
Genitourinary small cell cancer platinum-based chemotherapy [42] . Median overall survival for these individuals was 32.5 months and the 5-year overall survival was 36% [17,42] . A similar study of 27 patients undergoing chemoradiation for limited disease SCCB, with radiotherapy doses ranging from 50 to 70 Gy, showed comparable results with a median overall survival of 26 months and 5-year overall survival of 22.2% [43] . It remains unclear if radiation provides a cumulative benefit to chemotherapy; nonetheless it has been used for management of loco-regional SCCB to achieve reasonable outcomes. The role of radiation in patients with extensive SCCB is also not clearly understood, although radiation has been used for patients with locally advanced or unresectable disease. One small case series involving 11 patients with limited or locally advanced SCCB showed that radiation delivered at a median dose of 59 Gy in combination with chemotherapy resulted in a 27% metastasis-free survival rate [44] . For patients with distant metastases to sites such as bone, the role of radiotherapy has not been well described and seems to be used mostly for symptomatic control [17] . Genitourinary small cell summary Based on the progression and evolution of management of small cell cancer of the lung, treatment algorithms have been replicated in the management of genitourinary small cell involvement. As noted in the studies highlighted above, it is clear that systemic therapy with cisplatin and etoposide is the backbone of treatment, although the optimal multimodality approach to management of small cell carcinomas of the genitourinary system has yet to be developed and will require further study. With regards to small cell carcinoma of the prostate and bladder, if amenable to extirpative surgery, it appears that neoadjuvant chemotherapy followed by surgery offers the most benefit in patients who have limited disease with no signs of metastasis. For limited disease SCCP, it has been noted that radical prostatectomy was curative in select cases, although wide acceptance of the systemic nature of the disease is now commonplace. In patients with extensive, locally advanced and/or metastatic SCCP, it would appear as though multimodality chemo-radiation therapy can improve outcomes. The role of radiation may be obviated in distant metastatic disease, although useful in extensive loco-regional disease. Similarly,
future science group
Review
for loco-regional SCCB, neoadjuvant chemotherapy followed by cystectomy has been observed to provide the most promising outcomes. However, in patients with advanced or initially unresectable disease, combination chemotherapy and radiation therapy should likely be the management, as surgery may not improve prognosis. Irrespective of slight differences in surgical management guidelines for these genitourinary malignancies, a common conclusion in most studies is that platinumbased combination chemotherapy is essential in the multimodal treatment approach, whether used as the primary mode of treatment or in the neoadjuvant/adjuvant setting. Conclusion Small cell carcinomas of the genitourinary system present a definite clinical challenge. Both SCCP and SCCB are very aggressive cancers with a poor prognosis despite advancements in the understanding of the disease from knowledge applied in other organ counterparts. The low incidence of these cancers has made it challenging to study their biological and clinical progression, making the development of standardized treatment regimens a difficult undertaking. Treatment modalities thus far for SCCP and SCCB have been based on those used for small cell carcinoma of the lung and it appears that multimodality therapies, consisting of cisplatin and etoposide chemotherapy as the cornerstone of systemic therapy, with radiotherapy or surgery as adjunct treatments are currently recommended for optimal outcomes. Diagnosing these cancers at earlier stages will allow prospective studies to be performed, but this may prove to be a challenging task. Furthermore, a better understanding of small cell cancer overall, its genitourinary involvement, molecular alterations and differentiation pathways is of outmost importance and will potentially allow for the development of personalized treatment algorithms and perhaps targeted therapies in the future. Future perspective Small cell carcinoma continues to have poor a prognosis due to the malignant nature of this disease and limited therapeutic options that are currently available. With regards to management of small cell genitourinary carcinoma, future directions can be modeled after advances in the treatment of small cell carcinoma of the
www.futuremedicine.com
485
Review Shatagopam, Kaimakliotis, Cheng & Koch lung. Several biological targets and molecular pathways are being studied for the management of SCCL. One such target is angiogenesis, a critical pathway for the progression of tumor development in SCCL [16,45] . This process has been targeted with inhibitors of VEGF such as bevacizumab and thalidomide, albeit without promising results [16,45] . Another target of interest was the Bcl-2 anti-apoptosis pathway that is thought be overexpressed in SCCL [45] . Bcl-2 antagonists have been used to target this pathway but have failed to show any meaningful response [45] . Several other pathways implicated in SCCL are being studied, including the sonic hedgehog pathway and DNA damage repair pathways [45] . The sonic hedgehog pathway is thought to play a role in tumorigenesis in SCCL, and inhibitors of this pathway are currently being studied [45] . It is also believed that inhibiting the DNA repair pathway may increase the cytotoxic nature of chemotherapeutic agents in SCCL by increasing sensitivity of the tumor to these agents [45] . Several inhibitors of this pathway are currently being studied. If these studies show promising
results in managing SCCL, it may be plausible to apply similar strategies to its genitourinary small cell carcinoma counterparts. Another area of study focusing specifically on SCCP centers on loss of retinoblastoma protein in 90% of cases [46] . Loss of this protein may represent an integral step in the development of SCCP and thus could prove to be a potential target. Further investigation of such molecular targets and pathways will be essential to the development of targeted therapies consisting of novel agents that may be used alone or in combination with other drugs that are already being applied for the treatment of small cell carcinomas. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
EXECUTIVE SUMMARY ●●
Small cell carcinomas of the genitourinary system, specifically bladder and prostate, are rare malignancies that present at advanced stages and have poor prognoses.
●●
Histologically, small cell carcinomas of the bladder and prostate are identical to small cell carcinoma of the lung (SCCL), all of which express neuroendocrine markers such as chromogranin, synaptophysin and neuron-specific enolase.
●●
Certain markers are specific to the individual small cell subtypes, with small cell carcinoma of the prostate expressing
CD44 and TMPRSS2–ERG gene fusion product and small cell carcinoma of the bladder expressing the epithelial marker cytokeratin 20. ●●
Given similarities, management of small cell genitourinary carcinomas has largely been modeled after their pulmonary counterpart, SCCL.
●●
Over the past few decades, there has been a paradigm shift in the management of SCCL from initial surgical resection to the use of systemic chemotherapy followed by locally-directed therapies.
●●
Platinum-based chemotherapy regimens are currently the mainstay of treatment for SCCL, and this has since been translated toward management of small cell carcinomas of the prostate and bladder.
●●
There are no well-defined treatment guidelines for genitourinary small cell cancers, and the role of surgery and
radiation is not well established; however, it seems that a multimodal approach with platinum-based combination chemotherapy leads to improved outcomes. ●●
Specific molecular pathways, such as the sonic hedgehog and DNA repair pathways, implicated in the tumorigenesis of SCCL are being investigated and may be shown to be relevant in the pathogenesis of small cell carcinoma of the prostate and the bladder.
●●
Diagnosing genitourinary small cell cancers at earlier stages, as well as investigating novel molecular targets and
differentiation pathways, may shed light on their aggressive nature and prove to be essential in the development of personalized treatment algorithms in the future.
486
Future Oncol. (2015) 11(3)
future science group
Genitourinary small cell cancer examined the effect of chemotherapy in the neoadjuvant setting. They reported a median overall survival of 58 months in patients with limited disease who receieved four cycles of platinum-based neoadjuvant chemotherapy.
References Papers of special note have been highlighted as: • of interest 1
Abbas F, Civantos F, Benedetto P, Soloway MS. Small cell carcinoma of the bladder and prostate. Urology 46(5), 617–630 (1995).
2
Barnard WG. The nature of the “oat-celled sarcoma” of the mediastinum. Pathol. Bacteriol. 29, 241–244 (1926).
3
Chan BA, Coward JI. Chemotherapy advances in small-cell lung cancer. J. Thorac. Dis. 5(Suppl. 5), S565–S578 (2013).
4
Karsner HT, Saphir O. Small cell carcinomas of the lung. Am. J. Pathol. 6(5), 553–562.553 (1930).
5
Fox W, Scadding JG. Medical Research Council comparative trial of surgery and radiotherapy for primary treatment of small-celled or oat-celled carcinoma of bronchus. Ten-year follow-up. Lancet 2(7820), 63–65 (1973).
6
7
8
9
Morstyn G, Ihde DC, Lichter AS et al. Small cell lung cancer 1973–1983: early progress and recent obstacles. Int. J. Radiat. Oncol. Biol. Phys. 10(4), 515–539 (1984). Mackey JR, Au HJ, Hugh J, Venner P. Genitourinary small cell carcinoma: determination of clinical and therapeutic factors associated with survival. J. Urol. 159(5), 1624–1629 (1998). Mazzucchelli R, Morichetti D, Lopez-Beltran A et al. Neuroendocrine tumours of the urinary system and male genital organs: clinical significance. BJU Int. 103(11), 1464–1470 (2009). Wang W, Epstein JI. Small cell carcinoma of the prostate. A morphologic and immunohistochemical study of 95 cases. Am. J. Surg. Pathol. 32(1), 65–71 (2008).
11 Asmis TR, Reaume MN, Dahrouge S,
Malone S. Genitourinary small cell carcinoma: a retrospective review of treatment and survival patterns at The Ottawa Hospital Regional Cancer Center. BJU Int. 97(4), 711–715 (2006). 12 Siefker-Radtke AO, Kamat AM, Grossman
HB et al. Phase II clinical trial of neoadjuvant alternating doublet chemotherapy with ifosfamide/doxorubicin and etoposide/ cisplatin in small-cell urothelial cancer. J. Clin. Oncol. 27(16), 2592–2597 (2009). •
This prospective study consisting of patients with small cell carcinoma of the bladder
future science group
Treatment outcomes of small cell carcinoma of the prostate: a single-center study. Cancer 110(8), 1729–1737 (2007). •
Tavora F. Review of small cell carcinomas of the prostate. Prostate Cancer 2011, 543272 (2011). 14 Brambilla E, Travis WD, Colby TV, Corrin
Small cell (neuroendocrine) carcinoma of the prostate: etiology, diagnosis, prognosis, and therapeutic implications – a retrospective study of 30 patients from the rare cancer network. Am. J. Med. Sci. 336(6), 478–488 (2008).
carcinoma of the prostate: an immunohistochemical study. Am. J. Surg. Pathol. 30(6), 705–712 (2006). 16 Pant-Purohit M, Lopez-Beltran A, Montironi
•
R, MacLennan GT, Cheng L. Small cell carcinoma of the urinary bladder. Histol. Histopathol. 25(2), 217–221 (2010). 17 Thota S, Kistangari G, Daw H, Spiro T. A
clinical review of small-cell carcinoma of the urinary bladder. Clin. Genitourin. Cancer 11(2), 73–77 (2013). •
Outlines clinicopathologic characteristics and treatment guidelines for small cell carcinoma of the bladder by looking at various studies from major institutions.
Small-cell carcinoma of prostate. Transient complete remission with chemotherapy. Urology, 26(2), 182–184 (1985). 26 Amato RJ, Logothetis CJ, Hallinan R, Ro JY,
Sella A, Dexeus FH. Chemotherapy for small cell carcinoma of prostatic origin. J. Urol. 147(3 Pt 2), 935–937 (1992). 27 Noda K, Nishiwaki Y, Kawahara M et al.
Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N. Engl. J. Med. 346(2), 85–91 (2002).
19 Pan CX, Zhang H, Lara PN, Jr., Cheng L.
Small-cell carcinoma of the urinary bladder: diagnosis and management. Expert Rev. Anticancer Ther. 6(12), 1707–1713 (2006). 20 Palmgren JS, Karavadia SS, Wakefield MR.
Unusual and underappreciated: small cell carcinoma of the prostate. Semin. Oncol. 34(1), 22–29 (2007). •
Discusses small-cell carcinoma of the prostate and highlights clinical and histological characteristics of this malignancy, and discusses treatment options based on studies from major institutions.
21 Wenk RE, Bhagavan BS, Levy R, Miller D,
Weisburger W. Ectopic ACTH, prostatic oat cell carcinoma, and marked hypernatremia. Cancer 40(2), 773–778 (1977). 22 Papandreou CN, Daliani DD, Thall PF et al.
Results of a phase II study with doxorubicin, etoposide, and cisplatin in patients with fully characterized small-cell carcinoma of the prostate. J. Clin. Oncol. 20(14), 3072–3080 (2002).
Discusses characteristics that are unique to small cell carcinoma of the prostate, such as low PSA levels and lack of androgen receptor expression. They also summarize studies investigating SCCP and outcomes from major institutions.
25 Hindson DA, Knight LL, Ocker JM.
18 Guo CC, Dancer JY, Wang Y et al.
TMPRSS2–ERG gene fusion in small cell carcinoma of the prostate. Hum. Pathol. 42(1), 11–17 (2011).
Looked at 83 patients with metastatic and nonmetastatic small cell carcinoma (SCCP) of the prostate. They reported a statistically significant difference in disease specific survival between the two groups (17.7 months in nonmetastatic SCCP vs 12.5 months in metastatic SCCP).
24 Stein ME, Bernstein Z, Abacioglu U et al.
15 Yao JL, Madeb R, Bourne P et al. Small cell
10 Zhao X, Flynn EA. Small cell carcinoma of
the urinary bladder: a rare, aggressive neuroendocrine malignancy. Arch. Pathol. Lab. Med. 136(11), 1451–1459 (2012).
23 Spiess PE, Pettaway CA, Vakar-Lopez F et al.
13 Furtado P, Lima MV, Nogueira C, Franco M,
B, Shimosato Y. The new World Health Organization classification of lung tumours. Eur. Respir. J. 18(6), 1059–1068 (2001).
Review
•
Phase III trial that demonstrated a statistically significant survival benefit when using irinotecan/cisplatin compared with etoposide/cisplatin in the management of patients with metastatic small cell carcinoma of the lung.
28 Tung WL, Wang Y, Gout PW, Liu DM,
Gleave M, Wang Y. Use of irinotecan for treatment of small cell carcinoma of the prostate. Prostate 71(7), 675–681 (2011). 29 Hanna N, Bunn PA Jr, Langer C et al.
Randomized Phase III trial comparing irinotecan/cisplatin with etoposide/cisplatin in patients with previously untreated extensive-stage disease small-cell lung cancer. J. Clin. Oncol. 24(13), 2038–2043 (2006). 30 Lara PN Jr, Natale R, Crowley J et al. Phase
III trial of irinotecan/cisplatin compared with etoposide/cisplatin in extensive-stage small-cell lung cancer: clinical and
www.futuremedicine.com
487
Review Shatagopam, Kaimakliotis, Cheng & Koch pharmacogenomic results from SWOG S0124. J. Clin. Oncol. 27(15), 2530–2535 (2009). 31 Oesterling JE, Hauzeur CG, Farrow GM.
Small cell anaplastic carcinoma of the prostate: a clinical, pathological and immunohistological study of 27 patients. J. Urol. 147(3 Pt 2), 804–807 (1992). 32 Bex A, Nieuwenhuijzen JA, Kerst M et al.
Small cell carcinoma of bladder: a singlecenter prospective study of 25 cases treated in analogy to small cell lung cancer. Urology 65(2), 295–299 (2005). 33 Willis DL, Porten SP, Kamat AM. Should
histologic variants alter definitive treatment of bladder cancer? Curr. Opin. Urol. 23(5), 435–443 (2013). 34 Blomjous CE, Vos W, De Voogt HJ, Van der
Valk P, Meijer CJ. Small cell carcinoma of the urinary bladder. A clinicopathologic, morphometric, immunohistochemical, and ultrastructural study of 18 cases. Cancer 64(6), 1347–1357 (1989). 35 Cramer SF, Aikawa M, Cebelin M.
Neurosecretory granules in small cell invasive carcinoma of the urinary bladder. Cancer 47(4), 724–730 (1981). 36 Choong NW, Quevedo JF, Kaur JS. Small cell
carcinoma of the urinary bladder. The Mayo
488
Clinic experience. Cancer 103(6), 1172–1178 (2005). •
This retrospective study from the Mayo Clinic investigated 44 patients with small cell carcinoma of the bladder. They reported an overall median survival of 1.7 years and recommend that patients should undergo radical cystectomy when metastatic disease is absent.
37 Cheng L, Pan CX, Yang XJ et al. Small cell
carcinoma of the urinary bladder: a clinicopathologic analysis of 64 patients. Cancer 101(5), 957–962 (2004). 38 Bastus R, Caballero JM, Gonzalez G et al.
Small cell carcinoma of the urinary bladder treated with chemotherapy and radiotherapy: results in five cases. Eur. Urol 35(4), 323–326 (1999). 39 Lohrisch C, Murray N, Pickles T, Sullivan L.
Small cell carcinoma of the bladder: long term outcome with integrated chemoradiation. Cancer 86(11), 2346–2352 (1999). 40 Kawahara T, Nishiyama H, Yamamoto S,
Kamoto T, Ogawa O. Protocol consisting of cisplatin, etoposide and irinotecan induced complete pathological remission of primary small cell carcinoma of the bladder. Int. J. Urol. 13(9), 1251–1253 (2006).
Future Oncol. (2015) 11(3)
41 Siefker-Radtke AO, Dinney CP, Abrahams
NA et al. Evidence supporting preoperative chemotherapy for small cell carcinoma of the bladder: a retrospective review of the M. D. Anderson cancer experience. J. Urol. 172(2), 481–484 (2004). 42 Bex A, de Vries R, Pos F, Kerst M, Horenblas
S. Long-term survival after sequential chemoradiation for limited disease small cell carcinoma of the bladder. World J. Urol. 27(1), 101–106 (2009). 43 Meijer RP, Meinhardt W, van der Poel HG
et al. Local control rate and prognosis after sequential chemoradiation for small cell carcinoma of the bladder. Int. J. Urol. 20(8), 778–784 (2013). 44 Bryant CM, Dang LH, Stechmiller BK,
Gilbert SM, Morris CG, Zlotecki RA. Treatment of small cell carcinoma of the bladder with chemotherapy and radiation after transurethral resection of a bladder tumor. Am. J. Clin. Oncol. (2014). 45 Pillai RN, Owonikoko TK. Small cell lung
cancer: therapies and targets. Semin. Oncol. 41(1), 133–142 (2014). 46 Tan HL, Sood A, Rahimi HA et al. Rb loss is
characteristic of prostatic small cell neuroendocrine carcinoma. Clin. Cancer Res. 20(4), 890–903 (2014).
future science group
