SMALL CELL CARCINOMA OF PROSTATE: EFFECTIVENESS OF HORMONAL VERSUS CHEMOTHERAPY STEVEN R. MOORE, M.D YURI REINBERG, M.D. (:ANG ZHANG, M.D.
From the Aspen Medical Group, St. Paul. Medical Center, Minneapolis. Minnesota
and Veterans
Affairs
ABSTRACT-Small cell carcinoma of the prostate is rare and associated with a rapidly fatal course. Since 1977, 47 cases have been reported in the world literature with data from 3 additional cases presented herein. The purpose o.f our review was to determine the effectiveness of hormonal ver,sus chemotherapy. Thirty-four of the 50 cases have known clinical histories. Four patients xere not treated, and all were dead of their disease within an average of 2.7.5 months. Six patients were eliminated from our review because small cell carcinoma was discovered at autopsy. Another 5 cases were omitted because hormonal + chemotherapy had already been given for a previous diagnosis of adenocarcinoma, but no specific therapy was given once the small cell carcinoma developed. Of the remaining 19 cases, only 2 have survived. One is still alive forty-three months after hormonal treatment, and another is alive with disease six months after the initiation of hormonal therapy and chemotherapy. Five patients were given hormonal therapy only, and none of them responded. In 4 patients chemotherapy was given after hormonal therapy had failed, and they too died of their disease within a short period of time. However, an additional 8 patients were treated with immediate chemotherapy + hormonar’ therapy and had substantially longer clinical remissions. Therefore, although .small cell carcinoma is a uniformly fatal disease, immediate chemotherapy should be considered to promote better clinical remissions.
Small cell carcinomas of the prostate are rare anaplastic neoplasms that are almost uniformly fatal. These tumors often have unusual clinical presentations such as malignant hypercalcemia, I !‘.Cushing’s syndrome from ectopic corticotropin (ACTH),” 7 and the syndrome of inappropriate antidiuretic hormone (SIADH) .” Webster, Touchstone, and Suzuki” were the first to report an association between prostate carcinoma and ectopic ACTH. In their case, however, the primarv tumor was determined to be poorly differentiated adenocarcinoma of the prostate rather than small cell carcinoma. New-
mark, Dluhy, and Bennett’” have reported a similar association. However, it was not until 1977 that Wenk et a1.3 actually discovered the entity of small cell carcinoma originating from the prostate. Immunohistochemical staining revealed the prostate tumor to be the source of the ectopic ACTH. Since then, 47 cases’ 8 l’ 21 of small cell carcinoma of the prostate have been reported in the world literature witlh data from 3 additional cases presented herein. We specifically address the comparative effectiveness of hormonal therapy and chemotherapy in treating this unusual tumor.
Case Reports Case 1
large prostate tumor impinging on the bladder base. Due to the relentless progression of his malignancy, an orchiectomy was performed. Unfortunately, there was no clinical improvement. Intravenous therapy with cyclophosphamide (Cytoxan), doxorubicin hydrochloride (Adriamycin), and etoposide was recommended. Unfortunately, the patient never recovered sufficiently to tolerate chemotherapy, and he died of pneumonia and sepsis within weeks after the diagnosis was made. Autopsy findings were remarkable for extensive small cell carcinoma of the prostate with invasion into the vesical neck and posterior bladder wall. In addition to the bone lesions previously mentioned, he had micrometastases to the periaortic lymph nodes and liver. Scattered pericentral necrosis of the liver was also identified. Tissue sections of the lung showed no evidence of small cell carcinoma. PSA staining was positive for the adenocarcinema portion of the tumor but negative for the small cell component. Electron microscopic studies were performed for evidence of a neuroendocrine component. No neurosecretory granules were found. Staining for neuron-specific enolase was not done.
A sixty-five-year-old white man presented with pain in upper part of back and ribs. Physical examination revealed several painful trigger points along the left trapezius muscle and ribs. X-ray films showed multiple pathologic fractures along the anterolateral aspects of the left second, sixth, eighth, and ninth ribs as well as the right sixth and seventh ribs. An osteolytic lesion was identified on the right tenth rib. Chest x-ray film was otherwise unremarkable. Rectal examination revealed a rock-hard non-nodular prostate. Prostate-specific antigen (PSA) was 0.9 ng/mL (normal , 2 patients have survived.” One is still alive wit.hout disease forty-three months after initiation of diethylstilbestrol and megestrol acetate, and the other is alive with disease six months after treatment with both hormonal therap!~ and chemotherapy. The remaining 24 cases arc: ca.tegorized in Table II. Group 1 consisted of 8 patients with initial diagnosis of small cell carcinoma. The average time from diagnosis to local or systemic progression was only 5.4 months, and the average time to death was 10.4 months. Group 2 consisted of 3 patients with an initial diagnosis of adenocarcinema of the prostate in whom small cell carcinoma subsequently developed. Hormonal therapy was instituted at the time the small cell component was discovered. The average time to disease progression was 3.7 months, and the average time to death 6.2 months. The 7 patients in group 3 were already on hormonal therapy for adenocarcinoma of the prostate. The small cell tumor developed despite androgen ablation, and the onset of this event carried a very poor prognosis. The average survival was only 7.3 months. Finally, 6 patients in group 4 who had been treated with hormonal therapy for adenocarcinoma were actuall!, found to have small cell carcinoma at autops!-. Those in groups 1 and 2 seem to gi\pe the best indication of the effectiveness of hormonal therapy for small cell carcinoma. It .is in these 11 patients that hormonal theral)? was instituted at the time the small cell component was
No. of
Hormonal
Therapy
Diethylstilbestrol Orchiectomy and diethylstilbestrol Orchiectom) Diethylstilbestrol and Megace Orchiectomy and chlorotrianisene Leuprolide
Cases 9 9 5 1 1
(TACE)
1
TOTAI,
~~
26
adenoca.rcinoma mixed with small cell anaplastic carcinoma. Acid phosphatase and PSA levels were normal. The patient subsequently underwent a staging pelvic lymphadenectomy showing met,astatic small cell carcinoma. Obstructive symptoms worsened, and a transurethral prostatectomy was performed. Pathologic examination again revealed small cell carcinoma and staining of the tissue was strongly positive for neuron-specific enolase. Osseous metastases developed, and the patient’s condition rapidly deteriorated. He refused further treatment, and he died seven weeks later. An autopsy was not performed. Comment There are a total of 47 cases of small cell carcinoma of the prostate reported in the world literature along with 3 additional cases mentioned here. Histologically, these tumors met the criteria of small cell carcinoma as established by the World Health Organization. They contain uniform small malignant cells twice the diameter of nor:mal lymphocytes. The nuclei are pyknotic and round to oval in shape with evenl) TABLE II.
Treatment
of 24 patients
groupa l-4
No. of Group
Treatment
-_.__
1
2
3 3
Category
Initial diagnosis of SCC* of prostate: hormonal therapy given at time of diagnosis. Prior history of adenocarcinoma of prostate and subsequent SCC: hormonal therapy instituted at time SCC diagnosed Previous history of adenocarcinoma of prostate and subsequent SCC: hormonal therapy already instituted for adenocarcinoma Previous history of adenocarcinoma of prostate already on hormonal therapy: SCC discovered at autopsy
To~.AI. ____
Cases
Average l‘imr to (Mos.) Dis. Pro% Dtlath
8
5.4
It).3
:3
3.7
6.2
‘i
7.33
6 23
‘Sn~all~41 c.ilrcinorn;i
UROIXK’l
MAY 1093
1 \‘OI,UME SSXIN.
NUMBER 5
4 I-3
Clinical history of 21 patients
TABLE III.
Age (Yrs.)
No. of
Range
Treatment
Pts.
None Hormonal therapy alone Hormonal therapy plus delayed-onset chemotherapy Hormonal therapy with immediate chemotherapy Chemotherapy alone
4 5
(Avg. Age) 49-69 (62.25) 65-89 (73.2)
4 4 4
diagnosed. Combining the data from both groups, the average time from diagnosis to disease progression was 5.2 months and the average time to death 9.3 months. The 13 patients in groups 3 and 4 were eliminated from our review because no specific hormonal treatment was given at the time the small cell carcinoma was diagnosed. A summary of the clinical histories of the remaining 21 patients is given in Table III. Four patients received no treatment, and their average survival was only 2.75 months. Five patients received hormonal therapy alone. The average time to disease progression was only 6.1 months, and the average time to death 6.9 months, The remaining 12 patients had chemotherapy with or without hormonal therapy. In 4 patients, chemotherapy was given after horTABLE IV. Chemotherapy Adriamycin, Dacarbazine,
6 courses methotrexate,
5 fluorouracil,
??
Average Time to (Mos.) Death Dis. Prog. 1.0 6.1
2.75 6.9
61-71 (67.5)
1.25
4.0
61-72 (66.25) 30-73 (54.5)
7.25 9.0
12.25 12.25
monal therapy had failed. The average time to disease progression after chemotherapy was instituted was only 1.25 months, and time to death was 4.0 months. In another 4 patients, chemotherapy was given concomitantly with hormonal therapy. The average time to disease progression was increased to 7.25 months and to death 12.25 months. Another 4 patients received chemotherapy alone with the time to disease progression 9.0 months and the time to death 12.25 months. Statistical analysis by One way analysis of variance (ANOVA) was not significant for age (P 0.31) and only marginally significant for disease progression (P 0.08) and death (P 0.09). The chemotherapy regimens used are listed in Table IV Despite the increasing numbers of small cell carcinomas of the prostate being reported, the
Chemotherapy
regimens No. of Cases
Regimens
9 2 Unknown
1 course
Vinblastine, Adriamycin, cyclophosphamide Vinblastine, Adriamycin, cyclophosphamide (2 courses), followed by cyclophosphamide, Adriamycin, cis-platinum, followed by etoposide and cis-platinum Dacarbazine, methotrexate, 5 fluorouracil Vinblastine, Adriamycin, cyclophosphamide (1 course), followed by etoposide and cis-platinum Vinblastine, Adriamycin, methotrexate, followed by etoposide, cis-platinum Etoposide, cis-platinum 5 fluorouracil (2 courses), followed by vinblastine, Adriamycin, cyclophosphamide (2 courses), followed by vinblastine, Adriamycin, methotrexate Vinblastine, Adriamycin, cyclophosphamide (6 courses), followed by etoposide, cis-platinum (2 courses), followed by nitrogen mustard, procarbazine, methotrexate Cyclophosphamide, vincristine, Adriamycin, procarbazine Unknown
Survival (Mos.)
1 1
5
1
11
1
1
14 12
1
9
3
1 1 2
15 8 24iAWD * 6
‘Alive with disease
414
UROLOGY
/) MAY 1992
!
VOLUhlE
XXSIM, NUMBER
5
choice of therapy remains a debatable issue. Some authors have suggested these tumors behave in a similar fashion to adenocarcinoma.‘Y However, given the rather dismal response of small cell carcinomas to hormonal therapy, it appears that their biologic behavior deviates significantl?, from adenocarcinomas. In addition. most patients with advanced disease had normal serum acid phosphatase and/or PSA levels. The cellular origins of small cell tumors have been the subject of extensive histologic and histochemical investigation.7 l4 Is 1y~2’~22Initially, these were thought to be ancestors of the neural crest line, but experiments with chicken and quail embryos have prompted the theory of a totipotential stem cell line as being the origin of the neoplasm.“” Azzopardi and Evans,15 as well as several others2’1.22 have identified the presence of endocrineiparacrine cells in both normal and malignant prostatic tissues. Using both argyrophil and argentaffin stain, Kazzazz4 found silver positive cells in 16 percent of prostate tumors. Capella and associates in 198122 detected ararophil (Grimelius) cells in 32.S percent of prostatic carcinomas. It is estimated that carcinomas with extensive neuroendocrine differentiation account for about 10 percent of all pros,tatic malignancies.2s Some case reports have implied that the development of small cell carcinoma may have involved a shift in cell populations and an alteration of differentiation processes within the tumor. Schron, Gipson, and Mendelsohr?’ recently reported on 3 patients who initially presented with adenocarcinoma and small cell carcinoma subsequently developed during the course of disease progression. Each of the 3 cases had obvious progression of the tumor despite hormonal therapy. In 1 case, there were clear transition zones histologically between adenocarcinoma and small cell. GhandurMnaymlneh, Satterfield, and Blocks reported a similar finding which would suggest that both small cell carcinoma and adenocarcinoma components have a common cell of origin. With the relatively high percentage of prostate cancers harboring neuroendocrine cells. it is possible that the emergence of hormonal resistance ma! be due to an overgrowth of this small cell component. Neuroendocrine cells within prostate tumors lack androgen receptors.5 Further clinical research is warranted to see if hormonall>rresistant tumors represent an alteration of differentiation along neuroendocrine lines.
1’1~01.0(.1-
“\li\Y 1092.
\‘OI,UIlE
SSNIS.
Y‘lMREH
r,
With the advent of increasingly sensitive silver-staining techniques and immlnnocvtochemistry, we will likely see an increase in-the number of small cell prostate cancers being reported. Several early case reports have identified an association of ectopic AC’I’H syndrome with adenocarcinoma of the prostate. However, it was not until 1977 that Wenk et al.” were able to identify the cell of origin as small cell carcinoma of the prostate and not adenocarcinema. It is possible that the lack of availability of sophisticated silver-staining and immunocytochemical techniques mistakenly classified prior tumors as poorly differentiated adenocarcinomas instead of small cell carcinomas. In Cases 1 and 3 of our report, i-t was necessary to do immunoperoxidase stains for PSA and neuron-specific enolase to make a definitive diagnosis. With these improved histochemical methods, it would be interesting to see if hormonally resistant prostatic adenocarcinomas actually represent a dedifferentiation along neuroendocrine cell lines similar to small cell carcinoma. The emergence of new chemotherapy regimens holds some promise for the treatment of small cell carcinoma. Even though this tumor is almost uniformly fatal, it would appear from our data that the immediate institution of chemotherapy provides a better chance at longer clinical remissions. Hindson, Knight, and Ocker’” reported a case of a sixty-one-year-old man near death from an extremely aggressive small cell carcinoma of the prostate who had an excellent six-month remission with chemotherapy. Four patients in our review were given chemotherapy only after hormonal therapy had failed, and the response was poor. The average delay in instituting chemotherap!, \vas three months. However, in 8 patients who received immediate chemotherapy, substantially longer clinical remissions were noted. The excellent clinical remission response of bronchogenic small cell carcinomas26 to various chemotherapeutic regimens suggests the need for further research with small cell prostate tumors. Candidates with a suspicious small cell carcinoma of the prostate include those with a history of adenocarcinoma that does not respond to hormonal therapy. In addition. the presentation of hypercalcemia should alert the clinician to the possibility of a neuroendocrine prostate tumor. Our first patient presented with malignant hypercalcemia requiring aggressive treatment with mithramycin. Mahade\?a cd al.’
115
in 1986 reported a series of 8 patients with prostate carcinoma and hypercalcemia. Two of the 8 cases had carcinoid features and another 4 had anaplastic small cell carcinoma of the prostate. Patients presenting with SIADH or ectopic ACTH syndrome also should be highly suspect for small cell carcinoma. In conclusion, it appears that small cell carcinoma is a hormonally resistant tumor. However, most patients in our review presented with a mixture of both adenocarcinoma and small cell components. In such cases we advocate the use of immediate chemotherapy along with hormonal therapy to hopefully promote longer clinical remissions. With the development of improved histochemical techniques, we will likely see an increase in the reported frequency of this tumor. Neuroendocrine components existing within prostate malignancies may eventually account for the emergence of hormoneresistance typically seen in prostate tumors. Further research is needed to find effective treatments for this fatal disease. Aspen Medical Group 1020 W. Bandana Boulevard St. Paul, Minnesota 55108 (DR. MOORE) ACKNOWLEDGMENT. To Michael Perament, M.D., Carl Smith, M.D., Douglas Johnson, M.D., and MS Denise Tenney for providing the case histories. References 1. Mahadevia I’S, et al: Ilypercalcemia in prostatic carcinoma, report of 8 cases, Arch Intern Med 143: 1339 (1986). 2. Barkin J. Crassweller PO, Roncari DAK, and Onrot J: Hypercalcemia associated with cancer of prostate without any metastases, Urology 24: 368 (1984). 3. Wenk RE, et al: Ectopic ACTH, prostatic oat cell carcinoma. and marked hypernatremia, Cancer 40: 773 (1977). 4. Vuitch MF, and Mendelsohn G: Relationship of ectopic ACTH production tumor differentiation: a morphologic and immunohistochemical study of prostatic carcinoma with Gushing’s syndrome, Cancer 47: 296 (1981). 5. Ghali V’S, and Garcia RI,: Prostatic adenocarcinoma with carcinoidal features producing adrenocorticotropic syndrome, immunohistochemical study and review of the literature, Cancer 54: 1043 (1984). 6. Carey RM, et al: Ectopic secretion of corticotropic releasing
416
factor as a cause of Gushing’s syndrome, N Engl J Med 311: 13 (1984). 7. Jelbart ME, et al: Ectopic hormone production by a prostatic small cell carcinoma xenograft line, Mel Cell Endocrinol 55: 167 (1988). 8. Ghandur-Mnaymneh I,, Satterfield S, and Block NL: Small cell carcinoma of the prostate gland with inappropriate antidiuretic hormone secretion: morphological, immunohistochemical and clinical expressions, J Ural 135: 1263 (1986). 9. Webster GD Jr, Touchstone JC, and Suzuki M: Adrenocortical hyperplasia occurring with me&static carcinoma of the prostate: report of a case exhibiting increased urinary aldosterone and glucocorticoid excretion, J Clin Endocrinol Metab 19: 967 (1959). 10. Newmark SR, Dluhy RG, and Bennett AH: Ectopic adrenocorticotropin syndrome with prostatic carcinoma, Urology 2: 666 (1973). of the prostate, a clini11. Tetu B, et al: Small cell carcinoma copathologic study of 20 cases, Cancer 59: 1803 (1987). 12. Bleichner JC, Chun B, and Klappenbach RS: Pure small cell carcinoma of the prostate with fatal liver metastasis, Arch Path01 Lab Med 110: 1041 (1986). 13. Manson AL, Terhune D, and MacDonald G: Small cell carcinoma of the prostate, Urology 33: 78 (1989). 14. van Haaften-Day C, et al: Xenografted small cell undifferentiated cancer of prostate: possible common origin with prostatic adenocarcinoma, Prostate 11: 271 (1971). 15. Azzopardi JG, and Evans DJ: Argentaffin cells in prostatic carcinoma: differentiation from lipofuchcin and melanin in prostatic epithelium, J Path01 104: 247 (1971). 16. Fer MF, Levenson RM, and Cohen MH: Extrapulmonary small cell carcinoma, in Greco FA, Oldham RK, and Bunn PA (Eds): Small Cell Lung Cancer, New York, Grune and Stratton, 1981, pp 301-325. 17. Richardson RL, and Weiland LH: Undifferentiated small cell carcinoma in extrapulmonary sites, Semin Oncol 9: 484 (1982). 18. Hindson DA, Knight LL, and Ocker JM: Small cell carcinoma of prostate, transient complete remission with chemotherapy, Urology 26: 182 (1985). 19. Pittman S, et al: Flow cytometric and karyotypic analysis of a primary small cell carcinoma of the prostate: a xenografted cell line, Cancer Genet Cytogenet 26: 165 (1987). 20. Turbat-Herrara EA, et al: Neuroendocrine differentiation in prostatic carcinomas, Arch Path01 Lab Med 112: 1100 (1988). 21. Schron DS, Gipson T, and Mendelsohn G: The histogenesis of small cell carcinoma of the prostate, an immunohistochemical study, Cancer 53: 2478 (1984). 22. Capella C, et al: The endocrine component of prostatic carcinomas, mixed adenocarcinoma-carcinoid tumours and nontumour prostate. Histochemical and ultrastructural identification of the endocrine cells, Histopathology 5: 175 (1981). 23. LeDouarin N, and Teillet MA: The migration of neural crest cells to the wall of the digestive tract in avian embryo, J Embryo1 Exp Morph01 30: 31 (1973). 24. Kazzaz BA: Argentaffin and argyrophil cells in the prostate, J Pathol 112: 189 (1974). 25. di Sant’Agnese A: Neuroendocrine differentiation and prostatic carcinoma, the concept comes of age, Arch Pathol Lab Med 112: 1097 (1988). 26. Cohen MH, and Matthews MJ: Small cell bronchogenic carcinoma: a distinct clinicopathologic entity, Semin Oncol5: 234 (1978).
UROLOGY
/ MAY 1992
/ VOLUME
XXXIX, NUMBER
5
From the Aspen Medical Group, St. Paul. Medical Center, Minneapolis. Minnesota
and Veterans
Affairs
ABSTRACT-Small cell carcinoma of the prostate is rare and associated with a rapidly fatal course. Since 1977, 47 cases have been reported in the world literature with data from 3 additional cases presented herein. The purpose o.f our review was to determine the effectiveness of hormonal ver,sus chemotherapy. Thirty-four of the 50 cases have known clinical histories. Four patients xere not treated, and all were dead of their disease within an average of 2.7.5 months. Six patients were eliminated from our review because small cell carcinoma was discovered at autopsy. Another 5 cases were omitted because hormonal + chemotherapy had already been given for a previous diagnosis of adenocarcinoma, but no specific therapy was given once the small cell carcinoma developed. Of the remaining 19 cases, only 2 have survived. One is still alive forty-three months after hormonal treatment, and another is alive with disease six months after the initiation of hormonal therapy and chemotherapy. Five patients were given hormonal therapy only, and none of them responded. In 4 patients chemotherapy was given after hormonal therapy had failed, and they too died of their disease within a short period of time. However, an additional 8 patients were treated with immediate chemotherapy + hormonar’ therapy and had substantially longer clinical remissions. Therefore, although .small cell carcinoma is a uniformly fatal disease, immediate chemotherapy should be considered to promote better clinical remissions.
Small cell carcinomas of the prostate are rare anaplastic neoplasms that are almost uniformly fatal. These tumors often have unusual clinical presentations such as malignant hypercalcemia, I !‘.Cushing’s syndrome from ectopic corticotropin (ACTH),” 7 and the syndrome of inappropriate antidiuretic hormone (SIADH) .” Webster, Touchstone, and Suzuki” were the first to report an association between prostate carcinoma and ectopic ACTH. In their case, however, the primarv tumor was determined to be poorly differentiated adenocarcinoma of the prostate rather than small cell carcinoma. New-
mark, Dluhy, and Bennett’” have reported a similar association. However, it was not until 1977 that Wenk et a1.3 actually discovered the entity of small cell carcinoma originating from the prostate. Immunohistochemical staining revealed the prostate tumor to be the source of the ectopic ACTH. Since then, 47 cases’ 8 l’ 21 of small cell carcinoma of the prostate have been reported in the world literature witlh data from 3 additional cases presented herein. We specifically address the comparative effectiveness of hormonal therapy and chemotherapy in treating this unusual tumor.
Case Reports Case 1
large prostate tumor impinging on the bladder base. Due to the relentless progression of his malignancy, an orchiectomy was performed. Unfortunately, there was no clinical improvement. Intravenous therapy with cyclophosphamide (Cytoxan), doxorubicin hydrochloride (Adriamycin), and etoposide was recommended. Unfortunately, the patient never recovered sufficiently to tolerate chemotherapy, and he died of pneumonia and sepsis within weeks after the diagnosis was made. Autopsy findings were remarkable for extensive small cell carcinoma of the prostate with invasion into the vesical neck and posterior bladder wall. In addition to the bone lesions previously mentioned, he had micrometastases to the periaortic lymph nodes and liver. Scattered pericentral necrosis of the liver was also identified. Tissue sections of the lung showed no evidence of small cell carcinoma. PSA staining was positive for the adenocarcinema portion of the tumor but negative for the small cell component. Electron microscopic studies were performed for evidence of a neuroendocrine component. No neurosecretory granules were found. Staining for neuron-specific enolase was not done.
A sixty-five-year-old white man presented with pain in upper part of back and ribs. Physical examination revealed several painful trigger points along the left trapezius muscle and ribs. X-ray films showed multiple pathologic fractures along the anterolateral aspects of the left second, sixth, eighth, and ninth ribs as well as the right sixth and seventh ribs. An osteolytic lesion was identified on the right tenth rib. Chest x-ray film was otherwise unremarkable. Rectal examination revealed a rock-hard non-nodular prostate. Prostate-specific antigen (PSA) was 0.9 ng/mL (normal , 2 patients have survived.” One is still alive wit.hout disease forty-three months after initiation of diethylstilbestrol and megestrol acetate, and the other is alive with disease six months after treatment with both hormonal therap!~ and chemotherapy. The remaining 24 cases arc: ca.tegorized in Table II. Group 1 consisted of 8 patients with initial diagnosis of small cell carcinoma. The average time from diagnosis to local or systemic progression was only 5.4 months, and the average time to death was 10.4 months. Group 2 consisted of 3 patients with an initial diagnosis of adenocarcinema of the prostate in whom small cell carcinoma subsequently developed. Hormonal therapy was instituted at the time the small cell component was discovered. The average time to disease progression was 3.7 months, and the average time to death 6.2 months. The 7 patients in group 3 were already on hormonal therapy for adenocarcinoma of the prostate. The small cell tumor developed despite androgen ablation, and the onset of this event carried a very poor prognosis. The average survival was only 7.3 months. Finally, 6 patients in group 4 who had been treated with hormonal therapy for adenocarcinoma were actuall!, found to have small cell carcinoma at autops!-. Those in groups 1 and 2 seem to gi\pe the best indication of the effectiveness of hormonal therapy for small cell carcinoma. It .is in these 11 patients that hormonal theral)? was instituted at the time the small cell component was
No. of
Hormonal
Therapy
Diethylstilbestrol Orchiectomy and diethylstilbestrol Orchiectom) Diethylstilbestrol and Megace Orchiectomy and chlorotrianisene Leuprolide
Cases 9 9 5 1 1
(TACE)
1
TOTAI,
~~
26
adenoca.rcinoma mixed with small cell anaplastic carcinoma. Acid phosphatase and PSA levels were normal. The patient subsequently underwent a staging pelvic lymphadenectomy showing met,astatic small cell carcinoma. Obstructive symptoms worsened, and a transurethral prostatectomy was performed. Pathologic examination again revealed small cell carcinoma and staining of the tissue was strongly positive for neuron-specific enolase. Osseous metastases developed, and the patient’s condition rapidly deteriorated. He refused further treatment, and he died seven weeks later. An autopsy was not performed. Comment There are a total of 47 cases of small cell carcinoma of the prostate reported in the world literature along with 3 additional cases mentioned here. Histologically, these tumors met the criteria of small cell carcinoma as established by the World Health Organization. They contain uniform small malignant cells twice the diameter of nor:mal lymphocytes. The nuclei are pyknotic and round to oval in shape with evenl) TABLE II.
Treatment
of 24 patients
groupa l-4
No. of Group
Treatment
-_.__
1
2
3 3
Category
Initial diagnosis of SCC* of prostate: hormonal therapy given at time of diagnosis. Prior history of adenocarcinoma of prostate and subsequent SCC: hormonal therapy instituted at time SCC diagnosed Previous history of adenocarcinoma of prostate and subsequent SCC: hormonal therapy already instituted for adenocarcinoma Previous history of adenocarcinoma of prostate already on hormonal therapy: SCC discovered at autopsy
To~.AI. ____
Cases
Average l‘imr to (Mos.) Dis. Pro% Dtlath
8
5.4
It).3
:3
3.7
6.2
‘i
7.33
6 23
‘Sn~all~41 c.ilrcinorn;i
UROIXK’l
MAY 1093
1 \‘OI,UME SSXIN.
NUMBER 5
4 I-3
Clinical history of 21 patients
TABLE III.
Age (Yrs.)
No. of
Range
Treatment
Pts.
None Hormonal therapy alone Hormonal therapy plus delayed-onset chemotherapy Hormonal therapy with immediate chemotherapy Chemotherapy alone
4 5
(Avg. Age) 49-69 (62.25) 65-89 (73.2)
4 4 4
diagnosed. Combining the data from both groups, the average time from diagnosis to disease progression was 5.2 months and the average time to death 9.3 months. The 13 patients in groups 3 and 4 were eliminated from our review because no specific hormonal treatment was given at the time the small cell carcinoma was diagnosed. A summary of the clinical histories of the remaining 21 patients is given in Table III. Four patients received no treatment, and their average survival was only 2.75 months. Five patients received hormonal therapy alone. The average time to disease progression was only 6.1 months, and the average time to death 6.9 months, The remaining 12 patients had chemotherapy with or without hormonal therapy. In 4 patients, chemotherapy was given after horTABLE IV. Chemotherapy Adriamycin, Dacarbazine,
6 courses methotrexate,
5 fluorouracil,
??
Average Time to (Mos.) Death Dis. Prog. 1.0 6.1
2.75 6.9
61-71 (67.5)
1.25
4.0
61-72 (66.25) 30-73 (54.5)
7.25 9.0
12.25 12.25
monal therapy had failed. The average time to disease progression after chemotherapy was instituted was only 1.25 months, and time to death was 4.0 months. In another 4 patients, chemotherapy was given concomitantly with hormonal therapy. The average time to disease progression was increased to 7.25 months and to death 12.25 months. Another 4 patients received chemotherapy alone with the time to disease progression 9.0 months and the time to death 12.25 months. Statistical analysis by One way analysis of variance (ANOVA) was not significant for age (P 0.31) and only marginally significant for disease progression (P 0.08) and death (P 0.09). The chemotherapy regimens used are listed in Table IV Despite the increasing numbers of small cell carcinomas of the prostate being reported, the
Chemotherapy
regimens No. of Cases
Regimens
9 2 Unknown
1 course
Vinblastine, Adriamycin, cyclophosphamide Vinblastine, Adriamycin, cyclophosphamide (2 courses), followed by cyclophosphamide, Adriamycin, cis-platinum, followed by etoposide and cis-platinum Dacarbazine, methotrexate, 5 fluorouracil Vinblastine, Adriamycin, cyclophosphamide (1 course), followed by etoposide and cis-platinum Vinblastine, Adriamycin, methotrexate, followed by etoposide, cis-platinum Etoposide, cis-platinum 5 fluorouracil (2 courses), followed by vinblastine, Adriamycin, cyclophosphamide (2 courses), followed by vinblastine, Adriamycin, methotrexate Vinblastine, Adriamycin, cyclophosphamide (6 courses), followed by etoposide, cis-platinum (2 courses), followed by nitrogen mustard, procarbazine, methotrexate Cyclophosphamide, vincristine, Adriamycin, procarbazine Unknown
Survival (Mos.)
1 1
5
1
11
1
1
14 12
1
9
3
1 1 2
15 8 24iAWD * 6
‘Alive with disease
414
UROLOGY
/) MAY 1992
!
VOLUhlE
XXSIM, NUMBER
5
choice of therapy remains a debatable issue. Some authors have suggested these tumors behave in a similar fashion to adenocarcinoma.‘Y However, given the rather dismal response of small cell carcinomas to hormonal therapy, it appears that their biologic behavior deviates significantl?, from adenocarcinomas. In addition. most patients with advanced disease had normal serum acid phosphatase and/or PSA levels. The cellular origins of small cell tumors have been the subject of extensive histologic and histochemical investigation.7 l4 Is 1y~2’~22Initially, these were thought to be ancestors of the neural crest line, but experiments with chicken and quail embryos have prompted the theory of a totipotential stem cell line as being the origin of the neoplasm.“” Azzopardi and Evans,15 as well as several others2’1.22 have identified the presence of endocrineiparacrine cells in both normal and malignant prostatic tissues. Using both argyrophil and argentaffin stain, Kazzazz4 found silver positive cells in 16 percent of prostate tumors. Capella and associates in 198122 detected ararophil (Grimelius) cells in 32.S percent of prostatic carcinomas. It is estimated that carcinomas with extensive neuroendocrine differentiation account for about 10 percent of all pros,tatic malignancies.2s Some case reports have implied that the development of small cell carcinoma may have involved a shift in cell populations and an alteration of differentiation processes within the tumor. Schron, Gipson, and Mendelsohr?’ recently reported on 3 patients who initially presented with adenocarcinoma and small cell carcinoma subsequently developed during the course of disease progression. Each of the 3 cases had obvious progression of the tumor despite hormonal therapy. In 1 case, there were clear transition zones histologically between adenocarcinoma and small cell. GhandurMnaymlneh, Satterfield, and Blocks reported a similar finding which would suggest that both small cell carcinoma and adenocarcinoma components have a common cell of origin. With the relatively high percentage of prostate cancers harboring neuroendocrine cells. it is possible that the emergence of hormonal resistance ma! be due to an overgrowth of this small cell component. Neuroendocrine cells within prostate tumors lack androgen receptors.5 Further clinical research is warranted to see if hormonall>rresistant tumors represent an alteration of differentiation along neuroendocrine lines.
1’1~01.0(.1-
“\li\Y 1092.
\‘OI,UIlE
SSNIS.
Y‘lMREH
r,
With the advent of increasingly sensitive silver-staining techniques and immlnnocvtochemistry, we will likely see an increase in-the number of small cell prostate cancers being reported. Several early case reports have identified an association of ectopic AC’I’H syndrome with adenocarcinoma of the prostate. However, it was not until 1977 that Wenk et al.” were able to identify the cell of origin as small cell carcinoma of the prostate and not adenocarcinema. It is possible that the lack of availability of sophisticated silver-staining and immunocytochemical techniques mistakenly classified prior tumors as poorly differentiated adenocarcinomas instead of small cell carcinomas. In Cases 1 and 3 of our report, i-t was necessary to do immunoperoxidase stains for PSA and neuron-specific enolase to make a definitive diagnosis. With these improved histochemical methods, it would be interesting to see if hormonally resistant prostatic adenocarcinomas actually represent a dedifferentiation along neuroendocrine cell lines similar to small cell carcinoma. The emergence of new chemotherapy regimens holds some promise for the treatment of small cell carcinoma. Even though this tumor is almost uniformly fatal, it would appear from our data that the immediate institution of chemotherapy provides a better chance at longer clinical remissions. Hindson, Knight, and Ocker’” reported a case of a sixty-one-year-old man near death from an extremely aggressive small cell carcinoma of the prostate who had an excellent six-month remission with chemotherapy. Four patients in our review were given chemotherapy only after hormonal therapy had failed, and the response was poor. The average delay in instituting chemotherap!, \vas three months. However, in 8 patients who received immediate chemotherapy, substantially longer clinical remissions were noted. The excellent clinical remission response of bronchogenic small cell carcinomas26 to various chemotherapeutic regimens suggests the need for further research with small cell prostate tumors. Candidates with a suspicious small cell carcinoma of the prostate include those with a history of adenocarcinoma that does not respond to hormonal therapy. In addition. the presentation of hypercalcemia should alert the clinician to the possibility of a neuroendocrine prostate tumor. Our first patient presented with malignant hypercalcemia requiring aggressive treatment with mithramycin. Mahade\?a cd al.’
115
in 1986 reported a series of 8 patients with prostate carcinoma and hypercalcemia. Two of the 8 cases had carcinoid features and another 4 had anaplastic small cell carcinoma of the prostate. Patients presenting with SIADH or ectopic ACTH syndrome also should be highly suspect for small cell carcinoma. In conclusion, it appears that small cell carcinoma is a hormonally resistant tumor. However, most patients in our review presented with a mixture of both adenocarcinoma and small cell components. In such cases we advocate the use of immediate chemotherapy along with hormonal therapy to hopefully promote longer clinical remissions. With the development of improved histochemical techniques, we will likely see an increase in the reported frequency of this tumor. Neuroendocrine components existing within prostate malignancies may eventually account for the emergence of hormoneresistance typically seen in prostate tumors. Further research is needed to find effective treatments for this fatal disease. Aspen Medical Group 1020 W. Bandana Boulevard St. Paul, Minnesota 55108 (DR. MOORE) ACKNOWLEDGMENT. To Michael Perament, M.D., Carl Smith, M.D., Douglas Johnson, M.D., and MS Denise Tenney for providing the case histories. References 1. Mahadevia I’S, et al: Ilypercalcemia in prostatic carcinoma, report of 8 cases, Arch Intern Med 143: 1339 (1986). 2. Barkin J. Crassweller PO, Roncari DAK, and Onrot J: Hypercalcemia associated with cancer of prostate without any metastases, Urology 24: 368 (1984). 3. Wenk RE, et al: Ectopic ACTH, prostatic oat cell carcinoma. and marked hypernatremia, Cancer 40: 773 (1977). 4. Vuitch MF, and Mendelsohn G: Relationship of ectopic ACTH production tumor differentiation: a morphologic and immunohistochemical study of prostatic carcinoma with Gushing’s syndrome, Cancer 47: 296 (1981). 5. Ghali V’S, and Garcia RI,: Prostatic adenocarcinoma with carcinoidal features producing adrenocorticotropic syndrome, immunohistochemical study and review of the literature, Cancer 54: 1043 (1984). 6. Carey RM, et al: Ectopic secretion of corticotropic releasing
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factor as a cause of Gushing’s syndrome, N Engl J Med 311: 13 (1984). 7. Jelbart ME, et al: Ectopic hormone production by a prostatic small cell carcinoma xenograft line, Mel Cell Endocrinol 55: 167 (1988). 8. Ghandur-Mnaymneh I,, Satterfield S, and Block NL: Small cell carcinoma of the prostate gland with inappropriate antidiuretic hormone secretion: morphological, immunohistochemical and clinical expressions, J Ural 135: 1263 (1986). 9. Webster GD Jr, Touchstone JC, and Suzuki M: Adrenocortical hyperplasia occurring with me&static carcinoma of the prostate: report of a case exhibiting increased urinary aldosterone and glucocorticoid excretion, J Clin Endocrinol Metab 19: 967 (1959). 10. Newmark SR, Dluhy RG, and Bennett AH: Ectopic adrenocorticotropin syndrome with prostatic carcinoma, Urology 2: 666 (1973). of the prostate, a clini11. Tetu B, et al: Small cell carcinoma copathologic study of 20 cases, Cancer 59: 1803 (1987). 12. Bleichner JC, Chun B, and Klappenbach RS: Pure small cell carcinoma of the prostate with fatal liver metastasis, Arch Path01 Lab Med 110: 1041 (1986). 13. Manson AL, Terhune D, and MacDonald G: Small cell carcinoma of the prostate, Urology 33: 78 (1989). 14. van Haaften-Day C, et al: Xenografted small cell undifferentiated cancer of prostate: possible common origin with prostatic adenocarcinoma, Prostate 11: 271 (1971). 15. Azzopardi JG, and Evans DJ: Argentaffin cells in prostatic carcinoma: differentiation from lipofuchcin and melanin in prostatic epithelium, J Path01 104: 247 (1971). 16. Fer MF, Levenson RM, and Cohen MH: Extrapulmonary small cell carcinoma, in Greco FA, Oldham RK, and Bunn PA (Eds): Small Cell Lung Cancer, New York, Grune and Stratton, 1981, pp 301-325. 17. Richardson RL, and Weiland LH: Undifferentiated small cell carcinoma in extrapulmonary sites, Semin Oncol 9: 484 (1982). 18. Hindson DA, Knight LL, and Ocker JM: Small cell carcinoma of prostate, transient complete remission with chemotherapy, Urology 26: 182 (1985). 19. Pittman S, et al: Flow cytometric and karyotypic analysis of a primary small cell carcinoma of the prostate: a xenografted cell line, Cancer Genet Cytogenet 26: 165 (1987). 20. Turbat-Herrara EA, et al: Neuroendocrine differentiation in prostatic carcinomas, Arch Path01 Lab Med 112: 1100 (1988). 21. Schron DS, Gipson T, and Mendelsohn G: The histogenesis of small cell carcinoma of the prostate, an immunohistochemical study, Cancer 53: 2478 (1984). 22. Capella C, et al: The endocrine component of prostatic carcinomas, mixed adenocarcinoma-carcinoid tumours and nontumour prostate. Histochemical and ultrastructural identification of the endocrine cells, Histopathology 5: 175 (1981). 23. LeDouarin N, and Teillet MA: The migration of neural crest cells to the wall of the digestive tract in avian embryo, J Embryo1 Exp Morph01 30: 31 (1973). 24. Kazzaz BA: Argentaffin and argyrophil cells in the prostate, J Pathol 112: 189 (1974). 25. di Sant’Agnese A: Neuroendocrine differentiation and prostatic carcinoma, the concept comes of age, Arch Pathol Lab Med 112: 1097 (1988). 26. Cohen MH, and Matthews MJ: Small cell bronchogenic carcinoma: a distinct clinicopathologic entity, Semin Oncol5: 234 (1978).
UROLOGY
/ MAY 1992
/ VOLUME
XXXIX, NUMBER
5
