0022-5347/92/14 73-0804$03.00/0 THE JOURNAL OF UROLOGY Copyright© 1992 by AMERICAN UROLOGICAL ASSOCIATION, INC.
Vol. 147, 804-807, March 1992
Printed in U.S.A.
SMALL CELL ANAPLASTIC CARCINOMA OF THE PROSTATE: A CLINICAL, PATHOLOGICAL AND IMMUNOHISTOLOGICAL STUDY OF 27 PATIENTS JOSEPH E. OESTERLING,* CLAUDE G. HAUZEUR
AND
GEORGE M. FARROW
From the Departments of Urology and Pathology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota
ABSTRACT
~sause -smaU-ceU a-naplastic~aI'cinoma-0f the -pr--0state is-anuncom.monlumor, it_has_remained a poorly defined entity. To elucidate further the clinical, pathological and immunohistochemical characteristics of this cancer the 27 patients who presented to the Mayo Clinic from 1960 to 1990 were reviewed. Of these patients 18 (67%) presented with pure small cell anaplastic carcinoma, and 9 (33%) were diagnosed with small cell anaplastic carcinoma and adenocarcinoma of the prostate. Twenty-six patients (96%) had either stage C or D disease at the time of diagnosis. Two patients presented with a paraneoplastic syndrome, including 1 man with inappropriate antidiuretic hormone secretion and 1 who suffered from thyroxine intoxication. Of 24 men with long-term followup 22 (92%) died of small cell anaplastic carcinoma of the prostate despite antiandrogen therapy and the remaining 2 are alive with active, progressive disease. The median survival time following diagnosis was 17.1 months (range 2 to 90 months). All tumors with tissue available for immunohistochemical staining reacted positive for neuronspecific enolase, indicating that small cell anaplastic carcinoma of the prostate is most likely a neuroendocrine neoplasm. No tumor stained positive for either prostatic acid phosphatase or prostate specific antigen. Pathologically, small cell anaplastic carcinoma of the prostate appears to be similar to oat cell carcinoma of the lung. This series of 27 patients emphasizes that small cell anaplastic carcinoma of the prostate is highly malignant, is frequently of advanced stage at presentation, responds poorly to antiandrogen therapy and has a poor prognosis. KEY WORDS:
prostatic neoplasms; carcinoma, oat cell; adenocarcinoma; pathology; histology
In 1926 Barnard described the first small cell anaplastic carcinoma and noted it to be of pulmonary origin. 1 Since then this tumor, also known as oat cell carcinoma, has been described to arise in numerous extrapulmonary sites, including the kidney, ureter, bladder and prostate. 2 Extrapulmonary neoplasms possess the same light microscopic, immunocytochemical and ultrastructural characteristics as small cell anaplastic carcinoma of the lung, including the presence of neurosecretory granules in the cytoplasm. Also, like the pulmonary counterpart, oat cell carcinoma of other origins has a high malignant potential and is capable of ectopic hormonal production. 3• 6 Small cell anaplastic carcinoma of the prostate is a rare tumor, representing less than 1% of all prostatic neoplasms. As a result, there are few reports in the literature that describe the salient features and appropriate management of this cancer. We report on the clinical characteristics, management and long-term followup of 27 patients with small cell anaplastic carcinoma of the prostate who were treated at the Mayo Clinic during a 30-year period. MATERIALS AND METHODS
Clinical evaluation. Between January 1960 and January 1990, 27 patients with small cell anaplastic carcinoma of the prostate were managed at this institution. The medical charts of all patients were examined to obtain data on the clinical signs and symptoms at the time of presentation, acid phosphatase and prostate specific antigen (PSA), treatment, histological evaluation of the specimen, time to local recurrence, time to occurrence of distant metastases and survival after treatment. The serum acid phosphatase level was determined according to the technique of Kind and King, which has a reference range of 3 Accepted for publication September 13, 1991. *Requests for reprints: Department of Urology, Mayo Clinic, 200 First St., S.W., Rochester, Minnesota, 55905.
to 7 IU/1. 7 The serum PSA concentration was determined by the Tandem-R PSA monoclonal immunoradiometric assay with a normal range of 0.0 to 4.0 ng./ml. 8 Pathological evaluation. All pathological specimens were reviewed by 1 pathologist (G. M. F.) to confirm the original diagnosis of small cell anaplastic carcinoma of the prostate. Tissue specimens were available in all cases: 22 specimens (81 %) were obtained at the Mayo Clinic and 5 (19%) were sent from other institutions for evaluation. All tissue specimens were evaluated according to the Gleason histological grading system. 9 Because of the markedly anaplastic nature of small cell anaplastic carcinoma and the lack of adenocarcinomatous differentiation, no Gleason grade could be assigned to these tumors. For those patients with concomitant adenocarcinoma of the prostate a Gleason grade was assigned for that element. From the original paraffin blocks in which sufficient tumor tissue was available (9 patients who underwent transurethral resection of the prostate) microscopic slide sections were prepared, and immunohistological stains were performed using the immunoperoxidase technique for PSA, prostatic acid phosphatase (PAP) and neuron-specific enolase, a marker for neurosecretory cytoplasmic granules. 10 An avidin biotin peroxidase complex method was used for all 3 antigens. For the 9 patients in whom paraffin embedded transurethrally resected prostatic tissue was available flow cytometry also was performed using cells obtained from 3 paraffin sections, 50 µm. in thickness. Nuclear suspensions were prepared from deparaffinized tissue sections using the method of Hedley et al. 11 The isolated nuclei were stained with propidium iodide via the method of Vindel?v et al. 12 Cellular deoxyribonucleic acid (DNA) content was measured on a Becton Dickinson cell analyzer with a mercury vapor light source and histograms for 20,000 nuclei on each specimen were recorded. Criteria for classification of prostatic cellular histograms were established
804
SMALL CELL ANAPLASTIC CARCINOMA OF PROSTATE
previously by a study of 60 specimens of human benign pros tatic hyperplasia. 13 RESULTS
Clinical findings. The 27 patients with small cell anaplastic carcinoma of the prostate ranged in age from 48 to 87 years (median age 72 years). In 18 patients (67%) pure small cell anaplastic carcinoma of the prostate was diagnosed without evidence of concomitant adenocarcinoma. Of these 18 men 12 (67%) had clinical stage C cancer and 6 (33%) had stage D2 disease. Five men (19%) presented with a mixed pattern of small cell anaplastic carcinoma and adenocarcinoma of the prostate at the time of initial diagnosis and 4 patients (14%) had an ordinary adenocarcinoma of the prostate that was diagnosed 36, 48, 52 and 99 months before the diagnosis of small cell anaplastic carcinoma was established. Of note is the fact that these 4 adenocarcinomas were of low grade (Gleason grades 2 and 3). Of the 9 men with mixed small cell anaplastic carcinoma and adenocarcinoma 4 (44 %) had clinical stage C cancer and 5 (56%) had metastatic disease (stage D2). Serum acid phosphatase levels were available in 26 patients (96%) and serum PSA concentration was obtained in 3 men. The mean acid phosphatase value was 8.1 IU/1. with a range of 0.7 to 24 IU/1. The PSA values for the 3 patients were 0.2, 1.7 and 20.3 ng./ml. The value of 20.3 ng./ml. was from a patient with adenocarcinoma and small cell anaplastic carcinoma of the prostate. With respect to the survival data, 3 patients were excluded after being lost to followup at 2, 4 and 18 months after treatment. Of the 24 remaining patients 22 (92%) died of small cell anaplastic carcinoma of the prostate, including 1 who died of thyrotoxicosis secondary to tumor secretion of thyroxine (serum thyroxine level 14.2 µg./dl., reference range 5.0 to 11.0). Clinically, there was no evidence of primary thyroid disease and at postmortem examination the thyroid gland was entirely normal. Another patient had inappropriate secretion of antidiuretic hormone (serum antidiuretic hormone level 5.3 pg./ ml., reference range less than 1.5) with no definite diagnosis of a pituitary abnormality. The median survival time following the diagnosis of small cell anaplastic carcinoma of the prostate was 17.1 months (range 2 to 90 months) for the 18 patients with pure small cell anaplastic carcinoma of the prostate. For the 9 men with small cell anaplastic carcinoma and adenocarcinoma of the prostate the median survival time was 22.6 months (range 16 to 45 months). For all 24 patients with longterm followup the median survival time was 17.5 months (range 2 to 90 months). There was no statistically significant difference between the survival of patients with pure small cell anaplastic carcinoma of the prostate, and men with adenocarcinoma and small cell anaplastic carcinoma. Only 2 of the 24 evaluable patients are alive but both have clinical evidence of progressive disease 15 and 34 months after diagnosis. Frequently, distant metastases were present at the time of diagnosis or occurred rapidly after instituting therapy for the small cell anaplastic carcinoma. The most frequent metastatic site in this series was the skeleton (16 patients), followed by the liver (7) and lung (4). At postmortem examination 3 patients had pelvic lymph node involvement, 2 had brain metastasis and 1 had a metastatic lesion involving the pericardium. In 2 of the patients with skeletal metastases the lesion involving the bone was noted to be lytic, which is unusual for prostatic carcinoma. Pathological and immunohistochemical findings. Based on the available pathological specimens, the cases were classified according to whether they were pure small cell anaplastic carcinoma or whether there was small cell anaplastic carcinoma and adenocarcinoma. Among the 27 cases 18 (67%) were pure small cell anaplastic carcinomas, and 9 (33%) showed varying degrees of mixture with adenocarcinoma. The pure small cell anaplastic carcinomas were composed of relatively uniform small cells,
805
consisting mainly of a nucleus. These nuclei measured from 6 to 12 µ. (the size of a small to intermediate lymphocyte), and were densely chromatic and often slightly elongated (oat cell configuration). No architectural arrangement, such as gland formation, was evident except for the occasional rosette-like structures observed in some patients. The tumor cells were usually arranged in poorly defined sheets and exhibited exten sive infiltration into adjacent tissue structures (see figure). Among the 9 patients in whom immunohistochemical studies were performed the same cell component in 8 exhibited strong cytoplasmic immunoreactivity for neuron-specific enolase, a marker for neurosecretory activity (see table). The 1 specimen that did not react for neuron-specific enolase suffered from a marked degree of thermally induced artifact produced by the transurethral resection of the prostate. Although electron microscopy could not be performed on material available from any of the patients, neurosecretory activity is represented in small cell anaplastic carcinoma ultrastructurally by dense core granules. Among the 9 patients with mixed small cell anaplastic carcinoma, the adenocarcinomatous component was Gleason grade 4 in 3 men, grade 3 in 2 and grade 2 in 4. It is notable that the grade of the adenocarcinoma tended to be lower (Gleason grades 2 and 3) in patients in whom adenocarcinoma preceded the small cell anaplastic carcinoma and higher (Gleason grades 3 and 4) in those with concomitant cancers. In no patient was there immunoreactivity for neuron-specific enolase in the adenocarcinomatous component; however, these areas showed marked reactivity for PSA and PAP (see table). Satisfactory ploidy studies were performed by flow cytometry in 8 of 9 patients who had transurethral resection specimens available. In 1 patient the histogram was not of sufficient quality to allow for reliable interpretation. These results are also summarized in detail in the table. Treatment. The 27 patients included in this review were managed with different therapies, including antiandrogen therapy (bilateral orchiectomy and/or diethylstilbestrol), a combination of radiotherapy and chemotherapy or a combination of all 3 treatments. Antiandrogen treatment alone was used in 10 patients (38%), 13 (48%) underwent combined antiandrogen and radiation therapy, and 2 (7%) were treated with combined antiandrogen therapy, radiotherapy and chemotherapy. In 2 patients (7%) radical cystoprostatectomy was done at the time of initial diagnosis because it was believed that there was extension of the tumor into the bladder neck and trigone without involvement of other adjacent tissues (see figure). The chemotherapy regimens used in the management of these pa-
Small cell anaplastic carcinoma infiltrating muscular wall of adjacent bladder. H & E, reduced from X160.
806
OESTERLING, HAUZEUR AND FARROW
Immunostaining and DNA ploidy of transurethral resection specimens Neuron-Specific Enolase
Pt. No.
Histological Classification
DNAPloidy
1
Small cell anaplastic Ca, adenoca. Gleason 4 Small cell anaplastic Ca Small cell anaplastic Ca Small cell anaplastic Ca Small cell anaplastic Ca, adenoca. Gleason 3 Small cell anaplastic Ca Small cell anaplastic Ca, few elements adenoca. Gleason 2 Small cell anaplastic Ca, adenoca. Gleason 4 Small cell anaplastic Ca
Diploid
1+
Tetraploid Aneuploid Diploid
3+ 3+ 3+ 2+
Aneuploid Tetraploid
3+ 3+
5
7 17 18 21 23 24
Aneuploid
DISCUSSION
Small cell anaplastic carcinoma of the prostate is a unique neoplasm most likely of neuroendocrine derivation. 14- 18 The most common presenting features include large size, dissemination at time of diagnosis and a poor prognosis. Although small cell anaplastic carcinomas of the prostate rarely express PSA or PAP, they have been found to stain positive for a variety of other substances, including neuron-specific enolase, adrenocorticotropic hormone, somatostatin, parathormone, calcitonin, glucagon, bombezine, chromatogranin and carcinoembryogenic antigen. 19 In all of our cases small cell anaplastic carcinoma available for immunostaining expressed neuronspecific enolase strongly but none stained positive for either PSA or PAP. These results are similar to the findings of Ghandur-Mnaymneh5 and Ro et al. 20 In both studies the small cell anaplastic carcinomas did not stain for prostatic specific markers; only the neuroendocrine markers were expressed. di Sant' Agnese studied 53 acinar adenocarcinomas of the prostate using the argyrophilic stain and immunostains for various neuroendocrine markers. 21 He found that 25 tumors (47%) showed neuroendocrine differentiation, suggesting that some adenocarcinoma cells may coexpress PAP and PSA as well as neuron-specific enolase. 21 Although this finding has been observed most frequently in well differentiated tumors, it may also occur in poorly differentiated cancers. 5 • 20 , 22• 23 In our series 1 Gleason grade 4 adenocarcinoma stained positive for neuron-specific enolase (patient 24, see table). A form of glycolytic enzyme enolase has been found to be produced by a variety of cell types including tumors exhibiting neuroendocrine differentiation. Although the commercially available antibody for histochemical use has been termed neuron-specific enolase, it is now known that a variety of tissue types other than neuronal cells can exhibit reactivity to this antibody. In the context of small cell anaplastic neoplasms, any tumor with neuroectodermal differentiation, including such neoplasms as neuroblastomas, can exhibit immunoreactivity. A positive reactivity is generally accepted as evidence of neuroendocrine differentiation and corresponds to the finding of cytoplasmic "dense core" or neurosecretory granules. With respect to the serum markers, acid phosphatase was measured in 26 patients (96%) at the time of diagnosis and PSA was determined in 3 (11%). The serum acid phosphatase concentration was elevated above the reference range in 11 of 27 patients (41%), and all patients with small cell anaplastic carcinoma and adenocarcinoma had an elevated acid phosphatase level. PSA was elevated above the normal range in 2 patients; 1 had adenocarcinoma and small cell anaplastic carcinoma (serum PSA level 20.3 ng./ml.), and 1 had pure small cell anaplastic carcinoma (serum PSA level 11.7 ng./ml.). The latter patient had a markedly enlarged prostate by digital rectal
PSA
2+
2+
2+
2+
3+
3+
1+
1+
2+ 1+
• Aneuploid -- 27 --* Specimen suffered from extensive thermally induced artifact produced by the transurethral resection of the prostate. tients included cyclophosphamide, doxorubicin, etoposide and vincristine.
PAP
examination. In addition, the diagnosis of small cell anaplastic carcinoma was established by needle biopsy, and it may be that concomitant adenocarcinoma existed elsewhere in the prostate gland but it was not identified. In this study the median overall survival from the time of diagnosis of small cell anaplastic carcinoma of the prostate was 17.5 months, which is similar to the survival time reported by others. 22• 24 The 2-year overall survival for patients with clinical stage C disease at the time of diagnosis was 21.4% (3 of 14 patients), which is markedly lower than the 80% 2-year survival rate for patients with stage C adenocarcinoma of the prostate. 23 This poor prognosis of small cell anaplastic carcinoma of the prostate emphasizes the need for early recognition and appropriate therapeutic intervention. Dauge and Delmas found the degree of aggressive behavior to be in direct proportion to the extent of neuroendocrine differentiation. 25 There is evidence to suggest that the neuroendocrine component of small cell anaplastic carcinoma may be resistant to antiandrogen therapy. 20 Van Haaften-Day et al examined small cell anaplastic carcinoma of the prostate that was resistant to antiandrogen therapy and found the cancer cells to be devoid of androgen and estrogen receptors, which may be an explanation why these tumors are unresponsive to antiandrogen therapy. 23 Thus, if a successful outcome is to be achieved in patients with locally advanced or metastatic small cell anaplastic carcinoma of the prostate, chemotherapy will most likely be an integral part of the management plan. Indeed, transient remissions have been observed for some patients with small cell anaplastic carcinoma of the prostate who have received a combined surgical, radiation therapy and chemotherapy approach. 26• 27 REFERENCES
1. Barnard, W. G.: The nature of the oat-celled sarcoma of medias-
tinum. J. Path. Bacteriol.; 29: 241, 1926. 2. Oesterling, J. E., Brendler, C. B., Burgers, J. K., Marshall, F. F. and Epstein, J. I.: Advanced small cell carcinoma of the bladder. Successful treatment with combined radical cystoprostatectomy and adjuvant methotrexate, vinblastine, doxorubicin, and cisplatin chemotherapy. Cancer, 65: 1928, 1990. 3. Partanen, S. and Asikainen, U.: Oat cell carcinoma of the urinary bladder with ectopic adrenocorticotropic hormone production. Hum. Path., 16: 313, 1985. 4. Carey, R. M., Varma, S. K., Drake, C. R., Jr., Thorner, M. 0., Kovacs, K., Rivier, J. and Vale, W.: Ectopic secretion of corticotropin-releasing factor as a cause of Cushing's syndrome. A clinical, morphologic, and biochemical study. New Engl. J. Med., 311: 13, 1984. 5. Ghandur-Mnaymneh, L., Satterfield, S. and Block, N. L.: Small cell carcinoma of the prostate gland with inappropriate antidiuretic hormone secretion: morphological, immunohistochemical and clinical expressions. J. Urol., 135: 1263, 1986. 6. Wenk, R. E., Bhagavan, B. S., Levy, R., Miller, D. and Weisburger, W.: Ectopic ATCH, prostatic oat cell carcinoma, and marked hypernatremia. Cancer, 40: 773, 1977. 7. Kind, P. R. N. and King, E. J.: Estimation of plasma phosphatase
SMALL CELL ANAPLASTIC CARCINOMA OF PROSTATE by determination of hydrolysed phenol with amino-antipyrine, J, Clin, Path,, 7: 322, 1954, 8, Oesterling, J, K: Prostate specific antigen: a critical assessment of
9,
10.
lL
12,
13,
the most useful tumor marker for adenocarcinoma of the prostate, J, UroL, 145: 907, 199L Gleason, D. F,: Classification of prostatic carcinomas, Cancer Chemother. Rep,, 50: 125, 1966, Marangos, P, J, and Schmechel, D, K: Neuron specific enolase, a clinically useful marker for neurons and neuroendocrine cells, Ann, Rev, Neurosci,, 10: 269, 1987, Hedley, D, W,, Friedlander, M L,, Taylor, L W,, Rugg, C, A, and Musgrove, K A,: Method for analysis of cellular DNA content of paraffin-embedded pathological material using flow cytometry, J, Histochem, Cytochem,, 31: 1333, 1983, Vindel0v, L L, Christensen, L J, and Nissen, N. L: A detergenttrypsin method for the preparation of nuclei for flow cytometric DNA analysis, Cytometry, 3: 323, 1983, Winkler, H. Z,, Rainwater, L M,, Myers, R P,, Farrow, G, M,, Therneau, T. M,, Zincke, H. and Lieber, M, M,: Stage Dl prostatic adenocarcinoma: significance of nuclear DNA ploidy patterns studied by flow cytometry, Mayo Clin, Proc,, 63: 103,
1988, 14, Kazzaz, B. A,: Argentaffin and argyrophil cells in the prostate, J, Path,, 112: 189, 1974, 15, Azzopardi, J, G, and Evans, D. J.: Argentaffin cells in prostatic
carcinoma: differentiation from lipofuscin and melanin in prostatic epithelium, J, Path,, 104: 247, 197L 16, Skrabanek, P, and Powell, D.: Unifying concept of non-pituitary ATCH-secreting tumors: evidence of common origin of neuralcrest tumors, carcinoids, and oat-cell carcinomas, Cancer, 42: 1263, 1978, 17, Pearse, AG, Kand Takor, T, T.: Neuroendocrine embryology and the APUD concept, Clin. Endocr., suppL, 5: 229, 1976,
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18, Almagro, U. A,, Tieu, T. M,, Remeniuk, K, Kueck, R and Strumpf,
19,
20,
2L
22,
23,
24,
25,
26,
27.
K: Argyrophilic, 'carcinoid-like' prostatic carcinoma, An immunocytochemical study, Arch, Path, Lab. Med,, 110: 916, 1986, Rojas-Corona, R R, Chen, L Z, and Mahadevia, P, S,: Prostate carcinoma with endocrine features, A report of a neoplasm containing multiple immunoreactive hormonal substances. Amer, J, Clin, Path,, 88: 759, 1987, Ro, J, Y,, Tetu, R, Ayala, A, G, and Ordonez, N, G,: Small cell carcinoma of the prostate, Part IL Immunohistochemical and electron microscopic studies of 18 cases, Cancer, 59: 977, 1987, di Sant' Agnese, P, A,: Neuroendocrine differentiation and prostatic carcinoma, The concept 'comes of age! Arch, Path, Lab. Med., 112: 1097, 1988, Turbat-Herrera, KA,, Herrera, G, A,, Gore, L, Lott, R L, Grizzle, W, K and Bonnin, J, M,: Neuroendocrine differentiation in prostatic carcinomas, A retrospective autopsy study, Arch, Path, Lab. Med,, 112: 1100, 1988, van Haaften-Day, C., Raghavan, D,, Russell, P., Wills, K J,, Gregory, P,, Tilley, W, and Horsfall, D, J,: Xenografted small cell undifferentiated cancer of prostate: possible common origin with prostatic adenocarcinoma, Prostate, 11: 271, 1987, Schron, D, S,, Gipson, T, and Mendelsohn, G,: The histogenesis of small cell carcinoma of the prostate, An immunohistochemical study, Cancer, 53: 2478, 1984, Dauge, M, C, and Delmas, V.: A.P,UD, type endocrine tumour of the prostate, Incidence and prognosis in association with adenocarcinoma, Prog, Clin, BioL Res,, 243A: 529, 1987, Hindson, D, A, Knight, L L and Ocker, J. M,: Small-cell carcinoma of prostate, Transient complete remission with chemotherapy, Urology, 26: 182, 1985, Tetu, R, Ro, J, Y, Ayala, A, G,, Johnson, D, K, Logothetis, C, J, and Ordonez, N. G,: Small cell carcinoma of the prostate, Part L A clinicopathologic study of 20 cases, Cancer, 59: 1803, 1987,
Vol. 147, 804-807, March 1992
Printed in U.S.A.
SMALL CELL ANAPLASTIC CARCINOMA OF THE PROSTATE: A CLINICAL, PATHOLOGICAL AND IMMUNOHISTOLOGICAL STUDY OF 27 PATIENTS JOSEPH E. OESTERLING,* CLAUDE G. HAUZEUR
AND
GEORGE M. FARROW
From the Departments of Urology and Pathology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota
ABSTRACT
~sause -smaU-ceU a-naplastic~aI'cinoma-0f the -pr--0state is-anuncom.monlumor, it_has_remained a poorly defined entity. To elucidate further the clinical, pathological and immunohistochemical characteristics of this cancer the 27 patients who presented to the Mayo Clinic from 1960 to 1990 were reviewed. Of these patients 18 (67%) presented with pure small cell anaplastic carcinoma, and 9 (33%) were diagnosed with small cell anaplastic carcinoma and adenocarcinoma of the prostate. Twenty-six patients (96%) had either stage C or D disease at the time of diagnosis. Two patients presented with a paraneoplastic syndrome, including 1 man with inappropriate antidiuretic hormone secretion and 1 who suffered from thyroxine intoxication. Of 24 men with long-term followup 22 (92%) died of small cell anaplastic carcinoma of the prostate despite antiandrogen therapy and the remaining 2 are alive with active, progressive disease. The median survival time following diagnosis was 17.1 months (range 2 to 90 months). All tumors with tissue available for immunohistochemical staining reacted positive for neuronspecific enolase, indicating that small cell anaplastic carcinoma of the prostate is most likely a neuroendocrine neoplasm. No tumor stained positive for either prostatic acid phosphatase or prostate specific antigen. Pathologically, small cell anaplastic carcinoma of the prostate appears to be similar to oat cell carcinoma of the lung. This series of 27 patients emphasizes that small cell anaplastic carcinoma of the prostate is highly malignant, is frequently of advanced stage at presentation, responds poorly to antiandrogen therapy and has a poor prognosis. KEY WORDS:
prostatic neoplasms; carcinoma, oat cell; adenocarcinoma; pathology; histology
In 1926 Barnard described the first small cell anaplastic carcinoma and noted it to be of pulmonary origin. 1 Since then this tumor, also known as oat cell carcinoma, has been described to arise in numerous extrapulmonary sites, including the kidney, ureter, bladder and prostate. 2 Extrapulmonary neoplasms possess the same light microscopic, immunocytochemical and ultrastructural characteristics as small cell anaplastic carcinoma of the lung, including the presence of neurosecretory granules in the cytoplasm. Also, like the pulmonary counterpart, oat cell carcinoma of other origins has a high malignant potential and is capable of ectopic hormonal production. 3• 6 Small cell anaplastic carcinoma of the prostate is a rare tumor, representing less than 1% of all prostatic neoplasms. As a result, there are few reports in the literature that describe the salient features and appropriate management of this cancer. We report on the clinical characteristics, management and long-term followup of 27 patients with small cell anaplastic carcinoma of the prostate who were treated at the Mayo Clinic during a 30-year period. MATERIALS AND METHODS
Clinical evaluation. Between January 1960 and January 1990, 27 patients with small cell anaplastic carcinoma of the prostate were managed at this institution. The medical charts of all patients were examined to obtain data on the clinical signs and symptoms at the time of presentation, acid phosphatase and prostate specific antigen (PSA), treatment, histological evaluation of the specimen, time to local recurrence, time to occurrence of distant metastases and survival after treatment. The serum acid phosphatase level was determined according to the technique of Kind and King, which has a reference range of 3 Accepted for publication September 13, 1991. *Requests for reprints: Department of Urology, Mayo Clinic, 200 First St., S.W., Rochester, Minnesota, 55905.
to 7 IU/1. 7 The serum PSA concentration was determined by the Tandem-R PSA monoclonal immunoradiometric assay with a normal range of 0.0 to 4.0 ng./ml. 8 Pathological evaluation. All pathological specimens were reviewed by 1 pathologist (G. M. F.) to confirm the original diagnosis of small cell anaplastic carcinoma of the prostate. Tissue specimens were available in all cases: 22 specimens (81 %) were obtained at the Mayo Clinic and 5 (19%) were sent from other institutions for evaluation. All tissue specimens were evaluated according to the Gleason histological grading system. 9 Because of the markedly anaplastic nature of small cell anaplastic carcinoma and the lack of adenocarcinomatous differentiation, no Gleason grade could be assigned to these tumors. For those patients with concomitant adenocarcinoma of the prostate a Gleason grade was assigned for that element. From the original paraffin blocks in which sufficient tumor tissue was available (9 patients who underwent transurethral resection of the prostate) microscopic slide sections were prepared, and immunohistological stains were performed using the immunoperoxidase technique for PSA, prostatic acid phosphatase (PAP) and neuron-specific enolase, a marker for neurosecretory cytoplasmic granules. 10 An avidin biotin peroxidase complex method was used for all 3 antigens. For the 9 patients in whom paraffin embedded transurethrally resected prostatic tissue was available flow cytometry also was performed using cells obtained from 3 paraffin sections, 50 µm. in thickness. Nuclear suspensions were prepared from deparaffinized tissue sections using the method of Hedley et al. 11 The isolated nuclei were stained with propidium iodide via the method of Vindel?v et al. 12 Cellular deoxyribonucleic acid (DNA) content was measured on a Becton Dickinson cell analyzer with a mercury vapor light source and histograms for 20,000 nuclei on each specimen were recorded. Criteria for classification of prostatic cellular histograms were established
804
SMALL CELL ANAPLASTIC CARCINOMA OF PROSTATE
previously by a study of 60 specimens of human benign pros tatic hyperplasia. 13 RESULTS
Clinical findings. The 27 patients with small cell anaplastic carcinoma of the prostate ranged in age from 48 to 87 years (median age 72 years). In 18 patients (67%) pure small cell anaplastic carcinoma of the prostate was diagnosed without evidence of concomitant adenocarcinoma. Of these 18 men 12 (67%) had clinical stage C cancer and 6 (33%) had stage D2 disease. Five men (19%) presented with a mixed pattern of small cell anaplastic carcinoma and adenocarcinoma of the prostate at the time of initial diagnosis and 4 patients (14%) had an ordinary adenocarcinoma of the prostate that was diagnosed 36, 48, 52 and 99 months before the diagnosis of small cell anaplastic carcinoma was established. Of note is the fact that these 4 adenocarcinomas were of low grade (Gleason grades 2 and 3). Of the 9 men with mixed small cell anaplastic carcinoma and adenocarcinoma 4 (44 %) had clinical stage C cancer and 5 (56%) had metastatic disease (stage D2). Serum acid phosphatase levels were available in 26 patients (96%) and serum PSA concentration was obtained in 3 men. The mean acid phosphatase value was 8.1 IU/1. with a range of 0.7 to 24 IU/1. The PSA values for the 3 patients were 0.2, 1.7 and 20.3 ng./ml. The value of 20.3 ng./ml. was from a patient with adenocarcinoma and small cell anaplastic carcinoma of the prostate. With respect to the survival data, 3 patients were excluded after being lost to followup at 2, 4 and 18 months after treatment. Of the 24 remaining patients 22 (92%) died of small cell anaplastic carcinoma of the prostate, including 1 who died of thyrotoxicosis secondary to tumor secretion of thyroxine (serum thyroxine level 14.2 µg./dl., reference range 5.0 to 11.0). Clinically, there was no evidence of primary thyroid disease and at postmortem examination the thyroid gland was entirely normal. Another patient had inappropriate secretion of antidiuretic hormone (serum antidiuretic hormone level 5.3 pg./ ml., reference range less than 1.5) with no definite diagnosis of a pituitary abnormality. The median survival time following the diagnosis of small cell anaplastic carcinoma of the prostate was 17.1 months (range 2 to 90 months) for the 18 patients with pure small cell anaplastic carcinoma of the prostate. For the 9 men with small cell anaplastic carcinoma and adenocarcinoma of the prostate the median survival time was 22.6 months (range 16 to 45 months). For all 24 patients with longterm followup the median survival time was 17.5 months (range 2 to 90 months). There was no statistically significant difference between the survival of patients with pure small cell anaplastic carcinoma of the prostate, and men with adenocarcinoma and small cell anaplastic carcinoma. Only 2 of the 24 evaluable patients are alive but both have clinical evidence of progressive disease 15 and 34 months after diagnosis. Frequently, distant metastases were present at the time of diagnosis or occurred rapidly after instituting therapy for the small cell anaplastic carcinoma. The most frequent metastatic site in this series was the skeleton (16 patients), followed by the liver (7) and lung (4). At postmortem examination 3 patients had pelvic lymph node involvement, 2 had brain metastasis and 1 had a metastatic lesion involving the pericardium. In 2 of the patients with skeletal metastases the lesion involving the bone was noted to be lytic, which is unusual for prostatic carcinoma. Pathological and immunohistochemical findings. Based on the available pathological specimens, the cases were classified according to whether they were pure small cell anaplastic carcinoma or whether there was small cell anaplastic carcinoma and adenocarcinoma. Among the 27 cases 18 (67%) were pure small cell anaplastic carcinomas, and 9 (33%) showed varying degrees of mixture with adenocarcinoma. The pure small cell anaplastic carcinomas were composed of relatively uniform small cells,
805
consisting mainly of a nucleus. These nuclei measured from 6 to 12 µ. (the size of a small to intermediate lymphocyte), and were densely chromatic and often slightly elongated (oat cell configuration). No architectural arrangement, such as gland formation, was evident except for the occasional rosette-like structures observed in some patients. The tumor cells were usually arranged in poorly defined sheets and exhibited exten sive infiltration into adjacent tissue structures (see figure). Among the 9 patients in whom immunohistochemical studies were performed the same cell component in 8 exhibited strong cytoplasmic immunoreactivity for neuron-specific enolase, a marker for neurosecretory activity (see table). The 1 specimen that did not react for neuron-specific enolase suffered from a marked degree of thermally induced artifact produced by the transurethral resection of the prostate. Although electron microscopy could not be performed on material available from any of the patients, neurosecretory activity is represented in small cell anaplastic carcinoma ultrastructurally by dense core granules. Among the 9 patients with mixed small cell anaplastic carcinoma, the adenocarcinomatous component was Gleason grade 4 in 3 men, grade 3 in 2 and grade 2 in 4. It is notable that the grade of the adenocarcinoma tended to be lower (Gleason grades 2 and 3) in patients in whom adenocarcinoma preceded the small cell anaplastic carcinoma and higher (Gleason grades 3 and 4) in those with concomitant cancers. In no patient was there immunoreactivity for neuron-specific enolase in the adenocarcinomatous component; however, these areas showed marked reactivity for PSA and PAP (see table). Satisfactory ploidy studies were performed by flow cytometry in 8 of 9 patients who had transurethral resection specimens available. In 1 patient the histogram was not of sufficient quality to allow for reliable interpretation. These results are also summarized in detail in the table. Treatment. The 27 patients included in this review were managed with different therapies, including antiandrogen therapy (bilateral orchiectomy and/or diethylstilbestrol), a combination of radiotherapy and chemotherapy or a combination of all 3 treatments. Antiandrogen treatment alone was used in 10 patients (38%), 13 (48%) underwent combined antiandrogen and radiation therapy, and 2 (7%) were treated with combined antiandrogen therapy, radiotherapy and chemotherapy. In 2 patients (7%) radical cystoprostatectomy was done at the time of initial diagnosis because it was believed that there was extension of the tumor into the bladder neck and trigone without involvement of other adjacent tissues (see figure). The chemotherapy regimens used in the management of these pa-
Small cell anaplastic carcinoma infiltrating muscular wall of adjacent bladder. H & E, reduced from X160.
806
OESTERLING, HAUZEUR AND FARROW
Immunostaining and DNA ploidy of transurethral resection specimens Neuron-Specific Enolase
Pt. No.
Histological Classification
DNAPloidy
1
Small cell anaplastic Ca, adenoca. Gleason 4 Small cell anaplastic Ca Small cell anaplastic Ca Small cell anaplastic Ca Small cell anaplastic Ca, adenoca. Gleason 3 Small cell anaplastic Ca Small cell anaplastic Ca, few elements adenoca. Gleason 2 Small cell anaplastic Ca, adenoca. Gleason 4 Small cell anaplastic Ca
Diploid
1+
Tetraploid Aneuploid Diploid
3+ 3+ 3+ 2+
Aneuploid Tetraploid
3+ 3+
5
7 17 18 21 23 24
Aneuploid
DISCUSSION
Small cell anaplastic carcinoma of the prostate is a unique neoplasm most likely of neuroendocrine derivation. 14- 18 The most common presenting features include large size, dissemination at time of diagnosis and a poor prognosis. Although small cell anaplastic carcinomas of the prostate rarely express PSA or PAP, they have been found to stain positive for a variety of other substances, including neuron-specific enolase, adrenocorticotropic hormone, somatostatin, parathormone, calcitonin, glucagon, bombezine, chromatogranin and carcinoembryogenic antigen. 19 In all of our cases small cell anaplastic carcinoma available for immunostaining expressed neuronspecific enolase strongly but none stained positive for either PSA or PAP. These results are similar to the findings of Ghandur-Mnaymneh5 and Ro et al. 20 In both studies the small cell anaplastic carcinomas did not stain for prostatic specific markers; only the neuroendocrine markers were expressed. di Sant' Agnese studied 53 acinar adenocarcinomas of the prostate using the argyrophilic stain and immunostains for various neuroendocrine markers. 21 He found that 25 tumors (47%) showed neuroendocrine differentiation, suggesting that some adenocarcinoma cells may coexpress PAP and PSA as well as neuron-specific enolase. 21 Although this finding has been observed most frequently in well differentiated tumors, it may also occur in poorly differentiated cancers. 5 • 20 , 22• 23 In our series 1 Gleason grade 4 adenocarcinoma stained positive for neuron-specific enolase (patient 24, see table). A form of glycolytic enzyme enolase has been found to be produced by a variety of cell types including tumors exhibiting neuroendocrine differentiation. Although the commercially available antibody for histochemical use has been termed neuron-specific enolase, it is now known that a variety of tissue types other than neuronal cells can exhibit reactivity to this antibody. In the context of small cell anaplastic neoplasms, any tumor with neuroectodermal differentiation, including such neoplasms as neuroblastomas, can exhibit immunoreactivity. A positive reactivity is generally accepted as evidence of neuroendocrine differentiation and corresponds to the finding of cytoplasmic "dense core" or neurosecretory granules. With respect to the serum markers, acid phosphatase was measured in 26 patients (96%) at the time of diagnosis and PSA was determined in 3 (11%). The serum acid phosphatase concentration was elevated above the reference range in 11 of 27 patients (41%), and all patients with small cell anaplastic carcinoma and adenocarcinoma had an elevated acid phosphatase level. PSA was elevated above the normal range in 2 patients; 1 had adenocarcinoma and small cell anaplastic carcinoma (serum PSA level 20.3 ng./ml.), and 1 had pure small cell anaplastic carcinoma (serum PSA level 11.7 ng./ml.). The latter patient had a markedly enlarged prostate by digital rectal
PSA
2+
2+
2+
2+
3+
3+
1+
1+
2+ 1+
• Aneuploid -- 27 --* Specimen suffered from extensive thermally induced artifact produced by the transurethral resection of the prostate. tients included cyclophosphamide, doxorubicin, etoposide and vincristine.
PAP
examination. In addition, the diagnosis of small cell anaplastic carcinoma was established by needle biopsy, and it may be that concomitant adenocarcinoma existed elsewhere in the prostate gland but it was not identified. In this study the median overall survival from the time of diagnosis of small cell anaplastic carcinoma of the prostate was 17.5 months, which is similar to the survival time reported by others. 22• 24 The 2-year overall survival for patients with clinical stage C disease at the time of diagnosis was 21.4% (3 of 14 patients), which is markedly lower than the 80% 2-year survival rate for patients with stage C adenocarcinoma of the prostate. 23 This poor prognosis of small cell anaplastic carcinoma of the prostate emphasizes the need for early recognition and appropriate therapeutic intervention. Dauge and Delmas found the degree of aggressive behavior to be in direct proportion to the extent of neuroendocrine differentiation. 25 There is evidence to suggest that the neuroendocrine component of small cell anaplastic carcinoma may be resistant to antiandrogen therapy. 20 Van Haaften-Day et al examined small cell anaplastic carcinoma of the prostate that was resistant to antiandrogen therapy and found the cancer cells to be devoid of androgen and estrogen receptors, which may be an explanation why these tumors are unresponsive to antiandrogen therapy. 23 Thus, if a successful outcome is to be achieved in patients with locally advanced or metastatic small cell anaplastic carcinoma of the prostate, chemotherapy will most likely be an integral part of the management plan. Indeed, transient remissions have been observed for some patients with small cell anaplastic carcinoma of the prostate who have received a combined surgical, radiation therapy and chemotherapy approach. 26• 27 REFERENCES
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