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Small cell carcinoma of the prostate
Mini-symposium: pathology of the prostate
Small cell carcinoma of the prostate
5b). The distinction of SCPC from high-grade prostate carcinoma (HGPC) is important because SCPC cannot be followed using typical prostatic carcinoma parameters such as serum prostate specific antigen (PSA) levels and requires a different treatment regimen.8–11 This review provides a summary of the clinical, histologic and immunohistochemical features of SCPC; diagnostic points for differentiating SCPC from HGPC; and a brief discussion of pathogenesis and possible future therapeutic targets for this disease.
Jorge L Yao Jiaoti Huang P Anthony di Sant’Agnese
Clinical features SCPC is a lethal disease with poor response to androgen blockade/hormone therapy (HT). Patients may present with the typical symptoms of prostatism (urinary obstruction, increased frequency), non-specific constitutional symptoms (weight loss) or a paraneoplastic syndrome. Unlike conventional prostatic carcinoma, SCPC patients usually have little or no elevation of serum PSA levels, although serum chromogranin and calcitonin levels may be increased.12–14 SCPC may also appear as a new phenotype in tumors progressing after prolonged HT.15 The pattern of metastasis in SCPC can be similar to conventional prostatic carcinoma with spread to regional lymph nodes and bone. SCPC also has a propensity for involving visceral organs, most commonly the brain and liver, a behavior not commonly seen in conventional prostatic adenocarcinoma.16–19 Therefore, patients with a history of prostatic carcinoma presenting with visceral metastasis should be suspected of having a SCPC component. It is important to distinguish this tumor from conventional prostatic carcinoma because SCPC is non-responsive to hormonal therapy. Although the conventional chemotherapy regimen used in SCLC (cisplatin and etoposide) increases survival time, it does not produce complete remission.11
Abstract Small cell carcinoma of the prostate is a rare diagnostic entity that can be mistaken for high-grade conventional prostate carcinoma. It is important to recognize this tumor because of its poor prognosis and different treatment regimen from conventional prostatic carcinoma. Small cell carcinoma of the prostate shares the same morphologic and immunohistochemical profile of small cell carcinoma of the lung and extra-pulmonary sites. The clinical, histological and immunohistochemical features of this tumor are summarized and its distinction from high-grade conventional prostate carcinoma is discussed. The current concepts on pathogenesis and possible therapeutic targets for this disease are briefly examined.
Keywords immunohistochemistry; neuroendocrine tumors; prostate; prostate carcinoma; small cell carcinoma
Introduction Small cell carcinoma (SCC) is an aggressive neuroendocrine tumor first described in the lung and subsequently identified in numerous extra-pulmonary sites including the prostate.1–3 The morphology and behavior of extra-pulmonary SCC mirrors that of small cell lung carcinoma (SCLC).2 The prostate is one of the most common sites of extra-pulmonary SCC; although small cell carcinoma of the prostate (SCPC) is rare and is estimated at 0.5–1% of de novo prostate cancers. Interestingly, in some patients who have had a conventional adenocarcinoma of the prostate, the disease will recur as a SCC after hormonal therapy.3–6 Overall, SCPC is a rare and aggressive form of prostate carcinoma characterized by an advanced stage at diagnosis, non-response to anti-androgen therapy and poor prognosis.7,8 The diagnosis of SCPC is complicated by some morphologic similarities to high-grade prostate carcinoma (Gleason grade pattern
Pathologic features Histologic features SCPC may be found in both the pure form and mixed with conventional prostatic carcinoma. Tumors classified as SCPC display the typical histologic features of SCC seen in the lung and other extra-pulmonary sites. The tumor is composed of small, round to spindle cells with scant cytoplasm, high nuclear/cytoplasmic ratio and ill-defined borders (Figure 1a). There are no obvious gland formation and the tumor cells are present as sheets or individual cells with very infiltrative edges. There is usually marked crush or smear artifact due to the fragile nature of the cells (Figure 1b). The nuclei are typical of neuroendocrine differentiation: hyperchromatic with finely granular chromatin (salt and pepper), nuclear molding and absent or inconspicuous nucleoli (Figure 1c). Mitotic activity is high and there are extensive areas of necrosis present (Figure 1d). The pure form of SCPC is less common than the combined or mixed form where SCPC is present along with a component of conventional prostate adenocarcinoma. Gleason grading does not apply to SCPC.20
Jorge L Yao MD is at the Genito-Urinary Pathology Section, Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York, USA. Jiaoti Huang MD PhD is at the Genito-Urinary Pathology Section, Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York, USA.
Immunohistochemical features Immunohistochemically, SCPC variably express neuroendocrine markers such as chromogranin A (Figure 2a), synaptophysin, bombesin, somatostatin and calcitonin.6,8,21 They also express
P Anthony di Sant’ Agnese MD is at the Genito-Urinary Pathology Section, Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York, USA.
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Typical H&E features of SCPC: a small, round cells with scant cytoplasm, high nuclear-cytoplasmic ratio and ill-defined borders. b Marked crush or smear artifact present. c Hyperchromatic nuclei with finely granular chromatin, nuclear molding and absent or inconspicuous nucleoli. d Prominent areas of necrosis are present. H&E stain, a 200× original magnification, b-d 400× original magnification. Figure 1
immunohistochemical panel of markers. Yao et al.8 recommend a panel consisting of TTF-1, CD56 and chromogranin-A as the most helpful in classifying borderline cases. Lymphoma, although occurring in only 0.09% of prostate neoplasia,23 is another difficult differential diagnosis for SCPC. Certain lymphomas may share some of the features of SCPC: small cells with low nuclear/cytoplasmic ratio, smear/crush artifact and areas of necrosis. However, nuclear characteristics are different in lymphoma (prominent nucleoli, irregular nuclear countours, heterochromatin) and SCPC (finely granular chromatin and inconspicuous nucleoli). Difficult cases can be resolved by immunohistochemical staining for cytokeratin and lymphocytic markers. Metastatic SCC from other sites is difficult to distinguish from SCPC on both morphology and immunohistochemistry.24,25 Expression of organ-specific markers (lung surfactant protein, PSA, PAP) may be helpful, if present, but clinical correlation would be the best arbiter. Direct extension from SCC of the urinary bladder is even more difficult in advanced cases since the clinical manifestation of both tumors is similar. The distinction of the primary site may not be of great clinical significance since treatment for SCC of all sites is similar.
markers common to SCC in other sites, such as: TTF-1, CD56 and perinuclear dot-like staining with cytokeratin, such as CAM 5.2 (Figure 2b–d). The expression of markers characteristic of the prostate (PSA, prostate specific acid phosphatase (PAP), androgen receptor) is seen in a minority of SCPC, albeit mostly in a focal manner.8,21,22 This is comparable to the expression of lung surfactant protein in SCLC and estrogen/progesterone receptors in SCC of the breast. Basal cell markers (p63, EAB903) are also expressed in SCPC. There is no single marker that is consistently expressed in SCPC and for diagnostic purposes, a panel of several markers for neuroendocrine differentiation and SCC is necessary in borderline cases that show overlapping features of SCPC and HGPC. Differential diagnosis The differential diagnosis of SCPC includes HGPC, lymphoma and metastatic SCC. Tumors classified as HGPC have a solid pattern of growth or individual cells with comedonecrosis but no glandular formation. These features may mimic SCPC but the distinction of SCPC from HGPC is usually facilitated by adherence to strict histologic criteria for SCC, especially nuclear features. Some cases may be more difficult and require the judicious application of an
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Immunohistochemical features of SCPC: Tumor cells of SCPC stain positive for a chromogranin A, b TTF-1, c CD56, and d CAM5.2 (perinuclear dot-like pattern). Immunohistochemical stains, 400× original magnification. Figure 2
lines of molecular phenotypic differentiation with a predominance of the neuroendocrine phenotype.31 Poorly differentiated neuroendocrine carcinoma (either small or large cell) appears to be a common feature of several transgenic mouse models of prostate cancer, particularly in those animals that have been castrated.32–35 Although, SCPC cell lines and xenograft/allograft prostate cancer models of SCC have been developed,36–39 no definite conclusion has been reached whether SCPC arises from new subclones of malignant pluripotential stem cells or from transdifferentiation of epithelial tumor cells. Randolph et al.40 reported a single case of SCC phenotype within high-grade prostatic intraepithelial neoplasia, which supports the transdifferentiation hypothesis. However, further investigation into the molecular mechanism of neuroendocrine differentiation is needed to further understand the pathogenesis of this interesting tumor. Some novel tumor markers (c-Kit, Bcl-2 and EGFR) that have been used in targeted therapy are expressed in SCLC and SCPC. Recent clinical studies in the use of targeted therapy in SCLC and other extrapulmonary SCC point towards a promising outlook in treatment of these types of tumor.41–44 Additional studies and trials of these and other targeted therapies may be successful in altering the currently bleak outlook for patients with this disease.
Recent advances SCPC, like SCLC, is considered an unresectable disease in most cases and represents an extreme example of androgen-independent prostate carcinoma. The decreased or absent expression of androgen receptor in these tumors most probably explains the lack of response to HT.8 The presence of SCPC in patients with recurrent prostate carcinoma after prolonged androgen ablation therapy may be interpreted as evidence that SCPC is the result of a very successful attempt of tumor cells to escape androgen deprivation by differentiation into an androgen-independent phenotype. Prostatic neuroendocrine cells are terminally differentiated cells that are able, under certain neoplastic conditions, to increase in numbers as a result of differentiation from the proliferative/amplifying cell compartment.26 There is evidence that malignant epithelial tumors may either contain, or arise from, stem cells that through ongoing molecular/morphologic phenotypic differentiation mimic normal differentiation pathways, albeit in caricature.27–29 There is also evidence to suggest that carcinomas originate from differentiated cell types with transdifferentiation of one malignant cell type to another as well as occurrence of dedifferentiation.30 SCCs, as a general group and SCPC in particular, tend to show multiple
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and discussion of a therapeutic strategy. Am J Clin Oncol 1997; 20(4): 376–80. 14 Sim SJ, Glassman AB, Ro JY, Lee JJ, Logothetis CJ, Liu FJ. Serum calcitonin in small cell carcinoma of the prostate. Ann Clin Lab Sci 1996; 26(6): 487–95. 15 Tanaka M, Suzuki Y, Takaoka K, et al. Progression of prostate cancer to neuroendocrine cell tumor. Int J Urol 2001; 8(8): 431–6. (discussion 437). 16 Aygun C. Small cell carcinoma of the prostate: a case report and review of the literature. Md Med J 1997; 46(7): 353–6. 17 Venkatesh PK, Motwani B, Sherman N, et al. Metastatic pure smallcell carcinoma of prostate. Am J Med Sci 2004; 328(5): 286–9. 18 Erasmus CE, Verhagen WI, Wauters CA, van Lindert EJ. Brain metastasis from prostate small cell carcinoma: not to be neglected. Can J Neurol Sci 2002; 29(4): 375–7. 19 Matschke J, Erbersdobler A. Extensive cerebral metastases from neuroendocrine carcinoma of the prostate. Virchows Arch 2004; 444(2): 202–3. 20 Epstein JI, Allsbrook Jr WC, Amin MB, Egevad LL. The 2005 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma. Am J Surg Pathol 2005; 29(9): 1228–42. 21 Ro JY, Tetu B, Ayala AG, Ordonez NG. Small cell carcinoma of the prostate. II. Immunohistochemical and electron microscopic studies of 18 cases. Cancer 1987; 59(5): 977–82. 22 Okada H, Gotoh A, Ogawa T, Arakawa S, Ohbayashi C, Kamidono S. Two cases of small cell carcinoma of the prostate. Scand J Urol Nephrol 1996; 30(6): 503–8. 23 Bostwick DG, Iczkowski KA, Amin MB, Discigil G, Osborne B. Malignant lymphoma involving the prostate: report of 62 cases. Cancer 1998; 83(4): 732–8. 24 Cheuk W, Kwan MY, Suster S, Chan JK. Immunostaining for thyroid transcription factor 1 and cytokeratin 20 aids the distinction of small cell carcinoma from Merkel cell carcinoma, but not pulmonary from extrapulmonary small cell carcinomas. Arch Pathol Lab Med 2001; 125(2): 228–31. 25 Kaufmann O, Dietel M. Expression of thyroid transcription factor-1 in pulmonary and extrapulmonary small cell carcinomas and other neuroendocrine carcinomas of various primary sites. Histopathology 2000; 36(5): 415–20. 26 Huang J, Yao JL, di Sant’Agnese PA. Neuroendocrine differentiation in prostate cancer. In: Kirby R, Partin A, Feneley M, Parsons JK, eds. Prostate cancer: principles and practice, 1st edn. Abdington: Taylor and Francis Medical Books, 2006, p. 143–50. 27 Huss WJ, Gray DR, Werdin ES, Funkhouser Jr WK, Smith GJ. Evidence of pluripotent human prostate stem cells in a human prostate primary xenograft model. Prostate 2004; 60(2): 77–90. 28 Pardal R, Clarke MF, Morrison SJ. Applying the principles of stem-cell biology to cancer. Nat Rev Cancer 2003; 3(12): 895–902. 29 Smalley M, Ashworth A. Stem cells and breast cancer: A field in transit. Nat Rev Cancer 2003; 3(11): 832–44. 30 Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature 2001; 414(6859): 105–11. 31 Clegg N, Ferguson C, True LD, et al. Molecular characterization of prostatic small-cell neuroendocrine carcinoma. Prostate 2003; 55(1): 55–64. 32 Kaplan-Lefko PJ, Chen TM, Ittmann MM, et al. Pathobiology of autochthonous prostate cancer in a pre-clinical transgenic mouse model. Prostate 2003; 55(3): 219–37.
Summary SCPC is a rare type of prostate cancer with a poor prognosis. The tumor usually presents at an advanced stage and is not amenable to therapy used for conventional prostatic carcinoma. The tumor may occur in pure form or mixed with conventional prostatic adenocarcinoma, especially after HT. Combination chemotherapy using agents for SCLC can prolong life but does not cure patients with SCPC. The histologic morphology of SCPC is identical to SCC in other sites: small cells with high nuclear/cytoplasmic ratio, marked crush or smear artifact, hyperchromatic nuclei with finely granular chromatin, nuclear molding and tumor necrosis. The tumor cells express typical neuroendocrine markers (chromogranin-A), along with SCC markers (TTF-1, CD56). Distinction of this entity from HGPC is important because of prognostic and therapeutic implications. The use of therapy targeted to novel tumor markers (C-kit, BCL-2) warrant future investigation. ◆
References 1 Wenk RE, Bhagavan BS, Levy R, Miller D, Weisburger W. Ectopic ACTH, prostatic oat cell carcinoma, and marked hypernatremia. Cancer 1977; 40(2): 773–8. 2 Haider K, Shahid RK, Finch D, et al. Extrapulmonary small cell cancer: a Canadian province’s experience. Cancer 2006; 107(9): 2262–9. 3 Abbas F, Civantos F, Benedetto P, Soloway MS. Small cell carcinoma of the bladder and prostate. Urology 1995; 46(5): 617–30. 4 Tetu B, Ro JY, Ayala AG, Johnson DE, Logothetis CJ, Ordonez NG. Small cell carcinoma of the prostate. Part I. A clinicopathologic study of 20 cases. Cancer 1987; 59(10): 1803–9. 5 Oesterling JE, Hauzeur CG, Farrow GM. Small cell anaplastic carcinoma of the prostate: a clinical, pathological and immunohistological study of 27 patients. J Urol 1992; 147(3 Pt 2): 804–7. 6 Helpap B, Kollermann J. Undifferentiated carcinoma of the prostate with small cell features: immunohistochemical subtyping and reflections on histogenesis. Virchows Arch 1999; 434(5): 385–91. 7 Christopher ME, Seftel AD, Sorenson K, Resnick MI. Small cell carcinoma of the genitourinary tract: an immunohistochemical, electron microscopic and clinicopathological study. J Urol 1991; 146(2): 382–8. 8 Yao JL, Madeb R, Bourne P, et al. Small cell carcinoma of the prostate: an immunohistochemical study. Am J Surg Pathol 2006; 30(6): 705–12. 9 Moore SR, Reinberg Y, Zhang G. Small cell carcinoma of prostate: effectiveness of hormonal versus chemotherapy. Urology 1992; 39(5): 411–6. 10 Steineck G, Reuter V, Kelly WK, Frank R, Schwartz L, Scher HI. Cytotoxic treatment of aggressive prostate tumors with or without neuroendocrine elements. Acta Oncol 2002; 41(7–8): 668–74. 11 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 2002; 20(14): 3072–80. 12 Yashi M, Terauchi F, Nukui A, et al. Small-cell neuroendocrine carcinoma as a variant form of prostate cancer recurrence: a case report and short literature review. Urol Oncol 2006; 24(4): 313–7. 13 Rubenstein JH, Katin MJ, Mangano MM, et al. Small cell anaplastic carcinoma of the prostate: seven new cases, review of the literature,
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Further reading Huang J, Yao JL, di Sant’Agnese PA. Neuroendocrine dfferentiation in prostate cancer. In: Kirby R, Partin A, Feneley M, Kellogg Parsons J, eds. Prostate cancer: principles and practice, Abdington, UK: Taylor and Francis Medical Books, 2006, p. 143–50. 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 2002; 20: 3072–80. Yao JL, Madeb R, Bourne P, et al. Small cell carcinoma of the prostate: an immunohistochemical study. Am J Surg Pathol 2006; 30: 705–12.
33 Kasper S, Smith Jr JA. Genetically modified mice and their use in developing therapeutic strategies for prostate cancer. J Urol 2004; 172(1): 12–9. 34 Masumori N, Thomas TZ, Chaurand P, et al. A probasin-large T antigen transgenic mouse line develops prostate adenocarcinoma and neuroendocrine carcinoma with metastatic potential. Cancer Res 2001; 61(5): 2239–49. 35 van Bokhoven A, Varella-Garcia M, Korch C, et al. Molecular characterization of human prostate carcinoma cell lines. Prostate 2003; 57(3): 205–25. 36 Okada H, Shirakawa T, Miyake H, et al. Establishment of a prostatic small-cell carcinoma cell line (SO-MI). Prostate 2003; 56(3): 231–8. 37 Kim CJ, Kushima R, Okada Y, Seto A. Establishment and characterization of a prostatic small-cell carcinoma cell line (PSK-1) derived from a patient with Klinefelter syndrome. Prostate 2000; 42(4): 287–94. 38 Pinthus JH, Waks T, Schindler DG, et al. WISH-PC2: a unique xenograft model of human prostatic small cell carcinoma. Cancer Res 2000; 60(23): 6563–7. 39 True LD, Buhler K, Quinn J, et al. A neuroendocrine/small cell prostate carcinoma xenograft-LuCaP 49. Am J Pathol 2002; 161(2): 705–15. 40 Randolph TL, Amin MB, Ro JY, Ayala AG. Histologic variants of adenocarcinoma and other carcinomas of prostate: pathologic criteria and clinical significance. Mod Pathol 1997; 10(6): 612–29. 41 Kurt E, Sezgin C, Evrensel T, et al. Therapy, outcome and analysis of c-kit expression in patients with extrapulmonary small cell carcinoma. Int J Clin Pract 2005; 59(5): 537–43. 42 Lonardo F, Pass HI, Lucas DR. Immunohistochemistry frequently detects c-Kit expression in pulmonary small cell carcinoma and may help select clinical subsets for a novel form of chemotherapy. Appl Immunohistochem Mol Morphol 2003; 11(1): 51–5. 43 Micke P, Basrai M, Faldum A, et al. Characterization of c-kit expression in small cell lung cancer: prognostic and therapeutic implications. Clin Cancer Res 2003; 9(1): 188–94. 44 Pan CX, Yang XJ, Lopez-Beltran A, et al. c-kit expression in small cell carcinoma of the urinary bladder: prognostic and therapeutic implications. Mod Pathol 2004.
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Practice points • Diagnosis of SCPC should be based on morphologic features • The correct diagnosis of SCPC is essential for the patient to receive appropriate treatment • SCPC often occurs as a component of a mixed tumor containing conventional prostatic adenocarcinoma • Immunohistochemical stains for SCPC should be interpreted with care and used only for confirmation of borderline cases • SCPC can be positive for AR, PSA, PSAP and P504s • Suggested panel: TTF-1, chromogranin-A, and CD56
Research directions • Use of novel therapeutic agents in SCPC • Use of neuroendocrine serum biomarkers in diagnosing and/ or following patients with SCPC • Role of androgen blockade/HT in pathogenesis of SCPC • Molecular mechanisms in neuroendocrine differentiation of prostate cancer
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Small cell carcinoma of the prostate
5b). The distinction of SCPC from high-grade prostate carcinoma (HGPC) is important because SCPC cannot be followed using typical prostatic carcinoma parameters such as serum prostate specific antigen (PSA) levels and requires a different treatment regimen.8–11 This review provides a summary of the clinical, histologic and immunohistochemical features of SCPC; diagnostic points for differentiating SCPC from HGPC; and a brief discussion of pathogenesis and possible future therapeutic targets for this disease.
Jorge L Yao Jiaoti Huang P Anthony di Sant’Agnese
Clinical features SCPC is a lethal disease with poor response to androgen blockade/hormone therapy (HT). Patients may present with the typical symptoms of prostatism (urinary obstruction, increased frequency), non-specific constitutional symptoms (weight loss) or a paraneoplastic syndrome. Unlike conventional prostatic carcinoma, SCPC patients usually have little or no elevation of serum PSA levels, although serum chromogranin and calcitonin levels may be increased.12–14 SCPC may also appear as a new phenotype in tumors progressing after prolonged HT.15 The pattern of metastasis in SCPC can be similar to conventional prostatic carcinoma with spread to regional lymph nodes and bone. SCPC also has a propensity for involving visceral organs, most commonly the brain and liver, a behavior not commonly seen in conventional prostatic adenocarcinoma.16–19 Therefore, patients with a history of prostatic carcinoma presenting with visceral metastasis should be suspected of having a SCPC component. It is important to distinguish this tumor from conventional prostatic carcinoma because SCPC is non-responsive to hormonal therapy. Although the conventional chemotherapy regimen used in SCLC (cisplatin and etoposide) increases survival time, it does not produce complete remission.11
Abstract Small cell carcinoma of the prostate is a rare diagnostic entity that can be mistaken for high-grade conventional prostate carcinoma. It is important to recognize this tumor because of its poor prognosis and different treatment regimen from conventional prostatic carcinoma. Small cell carcinoma of the prostate shares the same morphologic and immunohistochemical profile of small cell carcinoma of the lung and extra-pulmonary sites. The clinical, histological and immunohistochemical features of this tumor are summarized and its distinction from high-grade conventional prostate carcinoma is discussed. The current concepts on pathogenesis and possible therapeutic targets for this disease are briefly examined.
Keywords immunohistochemistry; neuroendocrine tumors; prostate; prostate carcinoma; small cell carcinoma
Introduction Small cell carcinoma (SCC) is an aggressive neuroendocrine tumor first described in the lung and subsequently identified in numerous extra-pulmonary sites including the prostate.1–3 The morphology and behavior of extra-pulmonary SCC mirrors that of small cell lung carcinoma (SCLC).2 The prostate is one of the most common sites of extra-pulmonary SCC; although small cell carcinoma of the prostate (SCPC) is rare and is estimated at 0.5–1% of de novo prostate cancers. Interestingly, in some patients who have had a conventional adenocarcinoma of the prostate, the disease will recur as a SCC after hormonal therapy.3–6 Overall, SCPC is a rare and aggressive form of prostate carcinoma characterized by an advanced stage at diagnosis, non-response to anti-androgen therapy and poor prognosis.7,8 The diagnosis of SCPC is complicated by some morphologic similarities to high-grade prostate carcinoma (Gleason grade pattern
Pathologic features Histologic features SCPC may be found in both the pure form and mixed with conventional prostatic carcinoma. Tumors classified as SCPC display the typical histologic features of SCC seen in the lung and other extra-pulmonary sites. The tumor is composed of small, round to spindle cells with scant cytoplasm, high nuclear/cytoplasmic ratio and ill-defined borders (Figure 1a). There are no obvious gland formation and the tumor cells are present as sheets or individual cells with very infiltrative edges. There is usually marked crush or smear artifact due to the fragile nature of the cells (Figure 1b). The nuclei are typical of neuroendocrine differentiation: hyperchromatic with finely granular chromatin (salt and pepper), nuclear molding and absent or inconspicuous nucleoli (Figure 1c). Mitotic activity is high and there are extensive areas of necrosis present (Figure 1d). The pure form of SCPC is less common than the combined or mixed form where SCPC is present along with a component of conventional prostate adenocarcinoma. Gleason grading does not apply to SCPC.20
Jorge L Yao MD is at the Genito-Urinary Pathology Section, Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York, USA. Jiaoti Huang MD PhD is at the Genito-Urinary Pathology Section, Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York, USA.
Immunohistochemical features Immunohistochemically, SCPC variably express neuroendocrine markers such as chromogranin A (Figure 2a), synaptophysin, bombesin, somatostatin and calcitonin.6,8,21 They also express
P Anthony di Sant’ Agnese MD is at the Genito-Urinary Pathology Section, Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York, USA.
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Typical H&E features of SCPC: a small, round cells with scant cytoplasm, high nuclear-cytoplasmic ratio and ill-defined borders. b Marked crush or smear artifact present. c Hyperchromatic nuclei with finely granular chromatin, nuclear molding and absent or inconspicuous nucleoli. d Prominent areas of necrosis are present. H&E stain, a 200× original magnification, b-d 400× original magnification. Figure 1
immunohistochemical panel of markers. Yao et al.8 recommend a panel consisting of TTF-1, CD56 and chromogranin-A as the most helpful in classifying borderline cases. Lymphoma, although occurring in only 0.09% of prostate neoplasia,23 is another difficult differential diagnosis for SCPC. Certain lymphomas may share some of the features of SCPC: small cells with low nuclear/cytoplasmic ratio, smear/crush artifact and areas of necrosis. However, nuclear characteristics are different in lymphoma (prominent nucleoli, irregular nuclear countours, heterochromatin) and SCPC (finely granular chromatin and inconspicuous nucleoli). Difficult cases can be resolved by immunohistochemical staining for cytokeratin and lymphocytic markers. Metastatic SCC from other sites is difficult to distinguish from SCPC on both morphology and immunohistochemistry.24,25 Expression of organ-specific markers (lung surfactant protein, PSA, PAP) may be helpful, if present, but clinical correlation would be the best arbiter. Direct extension from SCC of the urinary bladder is even more difficult in advanced cases since the clinical manifestation of both tumors is similar. The distinction of the primary site may not be of great clinical significance since treatment for SCC of all sites is similar.
markers common to SCC in other sites, such as: TTF-1, CD56 and perinuclear dot-like staining with cytokeratin, such as CAM 5.2 (Figure 2b–d). The expression of markers characteristic of the prostate (PSA, prostate specific acid phosphatase (PAP), androgen receptor) is seen in a minority of SCPC, albeit mostly in a focal manner.8,21,22 This is comparable to the expression of lung surfactant protein in SCLC and estrogen/progesterone receptors in SCC of the breast. Basal cell markers (p63, EAB903) are also expressed in SCPC. There is no single marker that is consistently expressed in SCPC and for diagnostic purposes, a panel of several markers for neuroendocrine differentiation and SCC is necessary in borderline cases that show overlapping features of SCPC and HGPC. Differential diagnosis The differential diagnosis of SCPC includes HGPC, lymphoma and metastatic SCC. Tumors classified as HGPC have a solid pattern of growth or individual cells with comedonecrosis but no glandular formation. These features may mimic SCPC but the distinction of SCPC from HGPC is usually facilitated by adherence to strict histologic criteria for SCC, especially nuclear features. Some cases may be more difficult and require the judicious application of an
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Mini-symposium: pathology of the prostate
Immunohistochemical features of SCPC: Tumor cells of SCPC stain positive for a chromogranin A, b TTF-1, c CD56, and d CAM5.2 (perinuclear dot-like pattern). Immunohistochemical stains, 400× original magnification. Figure 2
lines of molecular phenotypic differentiation with a predominance of the neuroendocrine phenotype.31 Poorly differentiated neuroendocrine carcinoma (either small or large cell) appears to be a common feature of several transgenic mouse models of prostate cancer, particularly in those animals that have been castrated.32–35 Although, SCPC cell lines and xenograft/allograft prostate cancer models of SCC have been developed,36–39 no definite conclusion has been reached whether SCPC arises from new subclones of malignant pluripotential stem cells or from transdifferentiation of epithelial tumor cells. Randolph et al.40 reported a single case of SCC phenotype within high-grade prostatic intraepithelial neoplasia, which supports the transdifferentiation hypothesis. However, further investigation into the molecular mechanism of neuroendocrine differentiation is needed to further understand the pathogenesis of this interesting tumor. Some novel tumor markers (c-Kit, Bcl-2 and EGFR) that have been used in targeted therapy are expressed in SCLC and SCPC. Recent clinical studies in the use of targeted therapy in SCLC and other extrapulmonary SCC point towards a promising outlook in treatment of these types of tumor.41–44 Additional studies and trials of these and other targeted therapies may be successful in altering the currently bleak outlook for patients with this disease.
Recent advances SCPC, like SCLC, is considered an unresectable disease in most cases and represents an extreme example of androgen-independent prostate carcinoma. The decreased or absent expression of androgen receptor in these tumors most probably explains the lack of response to HT.8 The presence of SCPC in patients with recurrent prostate carcinoma after prolonged androgen ablation therapy may be interpreted as evidence that SCPC is the result of a very successful attempt of tumor cells to escape androgen deprivation by differentiation into an androgen-independent phenotype. Prostatic neuroendocrine cells are terminally differentiated cells that are able, under certain neoplastic conditions, to increase in numbers as a result of differentiation from the proliferative/amplifying cell compartment.26 There is evidence that malignant epithelial tumors may either contain, or arise from, stem cells that through ongoing molecular/morphologic phenotypic differentiation mimic normal differentiation pathways, albeit in caricature.27–29 There is also evidence to suggest that carcinomas originate from differentiated cell types with transdifferentiation of one malignant cell type to another as well as occurrence of dedifferentiation.30 SCCs, as a general group and SCPC in particular, tend to show multiple
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Mini-symposium: pathology of the prostate
and discussion of a therapeutic strategy. Am J Clin Oncol 1997; 20(4): 376–80. 14 Sim SJ, Glassman AB, Ro JY, Lee JJ, Logothetis CJ, Liu FJ. Serum calcitonin in small cell carcinoma of the prostate. Ann Clin Lab Sci 1996; 26(6): 487–95. 15 Tanaka M, Suzuki Y, Takaoka K, et al. Progression of prostate cancer to neuroendocrine cell tumor. Int J Urol 2001; 8(8): 431–6. (discussion 437). 16 Aygun C. Small cell carcinoma of the prostate: a case report and review of the literature. Md Med J 1997; 46(7): 353–6. 17 Venkatesh PK, Motwani B, Sherman N, et al. Metastatic pure smallcell carcinoma of prostate. Am J Med Sci 2004; 328(5): 286–9. 18 Erasmus CE, Verhagen WI, Wauters CA, van Lindert EJ. Brain metastasis from prostate small cell carcinoma: not to be neglected. Can J Neurol Sci 2002; 29(4): 375–7. 19 Matschke J, Erbersdobler A. Extensive cerebral metastases from neuroendocrine carcinoma of the prostate. Virchows Arch 2004; 444(2): 202–3. 20 Epstein JI, Allsbrook Jr WC, Amin MB, Egevad LL. The 2005 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma. Am J Surg Pathol 2005; 29(9): 1228–42. 21 Ro JY, Tetu B, Ayala AG, Ordonez NG. Small cell carcinoma of the prostate. II. Immunohistochemical and electron microscopic studies of 18 cases. Cancer 1987; 59(5): 977–82. 22 Okada H, Gotoh A, Ogawa T, Arakawa S, Ohbayashi C, Kamidono S. Two cases of small cell carcinoma of the prostate. Scand J Urol Nephrol 1996; 30(6): 503–8. 23 Bostwick DG, Iczkowski KA, Amin MB, Discigil G, Osborne B. Malignant lymphoma involving the prostate: report of 62 cases. Cancer 1998; 83(4): 732–8. 24 Cheuk W, Kwan MY, Suster S, Chan JK. Immunostaining for thyroid transcription factor 1 and cytokeratin 20 aids the distinction of small cell carcinoma from Merkel cell carcinoma, but not pulmonary from extrapulmonary small cell carcinomas. Arch Pathol Lab Med 2001; 125(2): 228–31. 25 Kaufmann O, Dietel M. Expression of thyroid transcription factor-1 in pulmonary and extrapulmonary small cell carcinomas and other neuroendocrine carcinomas of various primary sites. Histopathology 2000; 36(5): 415–20. 26 Huang J, Yao JL, di Sant’Agnese PA. Neuroendocrine differentiation in prostate cancer. In: Kirby R, Partin A, Feneley M, Parsons JK, eds. Prostate cancer: principles and practice, 1st edn. Abdington: Taylor and Francis Medical Books, 2006, p. 143–50. 27 Huss WJ, Gray DR, Werdin ES, Funkhouser Jr WK, Smith GJ. Evidence of pluripotent human prostate stem cells in a human prostate primary xenograft model. Prostate 2004; 60(2): 77–90. 28 Pardal R, Clarke MF, Morrison SJ. Applying the principles of stem-cell biology to cancer. Nat Rev Cancer 2003; 3(12): 895–902. 29 Smalley M, Ashworth A. Stem cells and breast cancer: A field in transit. Nat Rev Cancer 2003; 3(11): 832–44. 30 Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature 2001; 414(6859): 105–11. 31 Clegg N, Ferguson C, True LD, et al. Molecular characterization of prostatic small-cell neuroendocrine carcinoma. Prostate 2003; 55(1): 55–64. 32 Kaplan-Lefko PJ, Chen TM, Ittmann MM, et al. Pathobiology of autochthonous prostate cancer in a pre-clinical transgenic mouse model. Prostate 2003; 55(3): 219–37.
Summary SCPC is a rare type of prostate cancer with a poor prognosis. The tumor usually presents at an advanced stage and is not amenable to therapy used for conventional prostatic carcinoma. The tumor may occur in pure form or mixed with conventional prostatic adenocarcinoma, especially after HT. Combination chemotherapy using agents for SCLC can prolong life but does not cure patients with SCPC. The histologic morphology of SCPC is identical to SCC in other sites: small cells with high nuclear/cytoplasmic ratio, marked crush or smear artifact, hyperchromatic nuclei with finely granular chromatin, nuclear molding and tumor necrosis. The tumor cells express typical neuroendocrine markers (chromogranin-A), along with SCC markers (TTF-1, CD56). Distinction of this entity from HGPC is important because of prognostic and therapeutic implications. The use of therapy targeted to novel tumor markers (C-kit, BCL-2) warrant future investigation. ◆
References 1 Wenk RE, Bhagavan BS, Levy R, Miller D, Weisburger W. Ectopic ACTH, prostatic oat cell carcinoma, and marked hypernatremia. Cancer 1977; 40(2): 773–8. 2 Haider K, Shahid RK, Finch D, et al. Extrapulmonary small cell cancer: a Canadian province’s experience. Cancer 2006; 107(9): 2262–9. 3 Abbas F, Civantos F, Benedetto P, Soloway MS. Small cell carcinoma of the bladder and prostate. Urology 1995; 46(5): 617–30. 4 Tetu B, Ro JY, Ayala AG, Johnson DE, Logothetis CJ, Ordonez NG. Small cell carcinoma of the prostate. Part I. A clinicopathologic study of 20 cases. Cancer 1987; 59(10): 1803–9. 5 Oesterling JE, Hauzeur CG, Farrow GM. Small cell anaplastic carcinoma of the prostate: a clinical, pathological and immunohistological study of 27 patients. J Urol 1992; 147(3 Pt 2): 804–7. 6 Helpap B, Kollermann J. Undifferentiated carcinoma of the prostate with small cell features: immunohistochemical subtyping and reflections on histogenesis. Virchows Arch 1999; 434(5): 385–91. 7 Christopher ME, Seftel AD, Sorenson K, Resnick MI. Small cell carcinoma of the genitourinary tract: an immunohistochemical, electron microscopic and clinicopathological study. J Urol 1991; 146(2): 382–8. 8 Yao JL, Madeb R, Bourne P, et al. Small cell carcinoma of the prostate: an immunohistochemical study. Am J Surg Pathol 2006; 30(6): 705–12. 9 Moore SR, Reinberg Y, Zhang G. Small cell carcinoma of prostate: effectiveness of hormonal versus chemotherapy. Urology 1992; 39(5): 411–6. 10 Steineck G, Reuter V, Kelly WK, Frank R, Schwartz L, Scher HI. Cytotoxic treatment of aggressive prostate tumors with or without neuroendocrine elements. Acta Oncol 2002; 41(7–8): 668–74. 11 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 2002; 20(14): 3072–80. 12 Yashi M, Terauchi F, Nukui A, et al. Small-cell neuroendocrine carcinoma as a variant form of prostate cancer recurrence: a case report and short literature review. Urol Oncol 2006; 24(4): 313–7. 13 Rubenstein JH, Katin MJ, Mangano MM, et al. Small cell anaplastic carcinoma of the prostate: seven new cases, review of the literature,
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Further reading Huang J, Yao JL, di Sant’Agnese PA. Neuroendocrine dfferentiation in prostate cancer. In: Kirby R, Partin A, Feneley M, Kellogg Parsons J, eds. Prostate cancer: principles and practice, Abdington, UK: Taylor and Francis Medical Books, 2006, p. 143–50. 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 2002; 20: 3072–80. Yao JL, Madeb R, Bourne P, et al. Small cell carcinoma of the prostate: an immunohistochemical study. Am J Surg Pathol 2006; 30: 705–12.
33 Kasper S, Smith Jr JA. Genetically modified mice and their use in developing therapeutic strategies for prostate cancer. J Urol 2004; 172(1): 12–9. 34 Masumori N, Thomas TZ, Chaurand P, et al. A probasin-large T antigen transgenic mouse line develops prostate adenocarcinoma and neuroendocrine carcinoma with metastatic potential. Cancer Res 2001; 61(5): 2239–49. 35 van Bokhoven A, Varella-Garcia M, Korch C, et al. Molecular characterization of human prostate carcinoma cell lines. Prostate 2003; 57(3): 205–25. 36 Okada H, Shirakawa T, Miyake H, et al. Establishment of a prostatic small-cell carcinoma cell line (SO-MI). Prostate 2003; 56(3): 231–8. 37 Kim CJ, Kushima R, Okada Y, Seto A. Establishment and characterization of a prostatic small-cell carcinoma cell line (PSK-1) derived from a patient with Klinefelter syndrome. Prostate 2000; 42(4): 287–94. 38 Pinthus JH, Waks T, Schindler DG, et al. WISH-PC2: a unique xenograft model of human prostatic small cell carcinoma. Cancer Res 2000; 60(23): 6563–7. 39 True LD, Buhler K, Quinn J, et al. A neuroendocrine/small cell prostate carcinoma xenograft-LuCaP 49. Am J Pathol 2002; 161(2): 705–15. 40 Randolph TL, Amin MB, Ro JY, Ayala AG. Histologic variants of adenocarcinoma and other carcinomas of prostate: pathologic criteria and clinical significance. Mod Pathol 1997; 10(6): 612–29. 41 Kurt E, Sezgin C, Evrensel T, et al. Therapy, outcome and analysis of c-kit expression in patients with extrapulmonary small cell carcinoma. Int J Clin Pract 2005; 59(5): 537–43. 42 Lonardo F, Pass HI, Lucas DR. Immunohistochemistry frequently detects c-Kit expression in pulmonary small cell carcinoma and may help select clinical subsets for a novel form of chemotherapy. Appl Immunohistochem Mol Morphol 2003; 11(1): 51–5. 43 Micke P, Basrai M, Faldum A, et al. Characterization of c-kit expression in small cell lung cancer: prognostic and therapeutic implications. Clin Cancer Res 2003; 9(1): 188–94. 44 Pan CX, Yang XJ, Lopez-Beltran A, et al. c-kit expression in small cell carcinoma of the urinary bladder: prognostic and therapeutic implications. Mod Pathol 2004.
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Practice points • Diagnosis of SCPC should be based on morphologic features • The correct diagnosis of SCPC is essential for the patient to receive appropriate treatment • SCPC often occurs as a component of a mixed tumor containing conventional prostatic adenocarcinoma • Immunohistochemical stains for SCPC should be interpreted with care and used only for confirmation of borderline cases • SCPC can be positive for AR, PSA, PSAP and P504s • Suggested panel: TTF-1, chromogranin-A, and CD56
Research directions • Use of novel therapeutic agents in SCPC • Use of neuroendocrine serum biomarkers in diagnosing and/ or following patients with SCPC • Role of androgen blockade/HT in pathogenesis of SCPC • Molecular mechanisms in neuroendocrine differentiation of prostate cancer
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