P rare and, therefore, their histopathologic

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1 PROSTATIC ADENOCARCINOMA OF DUCTAL ORIGIN VOLKER E. DUBE, MD,+ GEORGE M. FARROW, AND LAURENCE F. GREENE, MD+ MD+ Clinical and histopathologic features of prostatic ductal adenocarcinomas have been incompletely described. A review of 4,286 cases of prostatic adenocarcinoma (1950 through 1970) at the Mayo Clinic showed 55 cases in which lesions were of a distinctive ductal type. Eight of the 55 lesions originated from periurethral primary prostatic ducts and had exuberant papillary folds. Cystoscopic examination revealed a polypoid and villous or an infiltrative urethral component. The 5-year survival rate (42.8%) was similar to that for the usual acinic adenocarcinomas. Carcinomas originating from secondary ducts had a multicentric origin and papillary, comedo-like, and cribriform-papillary histopathologic features. The overall 5-year survival rate was 24.2%. Palliative hormone therapy appeared to be less effective in prolonging life in these patients as compared to patients with acinic carcinomas. Bone metastases were osteoblastic, and serum acid phosphatase activities were elevated if metastases were present. ROSTATIC DUCTAL ADENOCARCINOMAS ARE P rare and, therefore, their histopathologic and clinical features have not been described in detail. Over the years, a sufficient number of such cases have accumulated at the Mayo Clinic to allow a meaningful description of these features and of survival data. out diastase digestion, mucicarmine stains, and histochemical study of acid and alkaline phosphatase and aminopeptidase activity in fresh tissue from a primary duct carcinoma. The histories of patients with mixed acinic and ductal adenocarcinoma also were reviewed. MATERIALS AND METHODS We reviewed sections of 4,286 consecutive adenocarcinomas of the prostate accumulated, from January 1950 through December 1970, at the Mayo Clinic. The cases were divided into three groups: group 1, ordinary acinic adenocarcinomas; group 2, pure ductal adenocarcinornas; and group 3, mixed acinic and ductal adenocarcinomas. Pure ductal adenocarcinomas (group 2) were selected for detailed clinical appraisal and further histologic study. In addition to the original sections, sections stained with hematoxylin and eosin also were prepared from tissue that had been preserved in formalin. In selected cases, tissue was submitted for special staining, which included periodic acid-schiff stain (PAS) with and with- Read at the meeting of the American Society of Clinical Pathologists, San Francisco, Calif., October 13-21, St. Joseph Mercy Hospital, Mason City, Iowa. t Mayo Clinic and Mayo Foundation, Rochester, Minn. Received for publication March 15, RESULTS From the total of 4,286 cases, 55, or l.s.%, were adenocarcinomas of purely ductal type (group 2). An additional 207 cases from group 3 showed an acinic type of neoplasm and foci of ductal adenocarcinoma. Therefore, the neoplasm was observed in 6.3% of all cases of prostatic cancer. Because of a characteristic localization within the prostate in relation to the ducts, and because of distinctive histopathologic features, prostatic ductal adenocarcinomas could be divided into two main groups: 1. adenocarcinoma of the primary prostatic ducts, and 2. adenocarcinoma of the secondary prostatic ducts. 402 HISTOPATHOLOGIC FINDINGS Adenocarcinoma of the primary prostatic ducts: Eight patients showed distinctive histopathologic features that we considered characteristic of primary duct carcinomas. The neoplasms were noted within large central peri-

2 No. 2 PROSTATIC DUCTAL ADENOCARCINOMA Dube et al. 403 urethral prostatic ductal spaces (Fig. 1). These spaces were identified by a distinct basement membrane and a concentric fine peripheral fibrous stroma. In some sections the columnar lining of the duct merged with the pseudostratified transitional epithelium of the adjacent urethra, and papillary tumor nodules projected freely into the lumen (Fig. 2). The tumors were composed of exuberant papillary fronds supported by complex, branching fibroconnective tissue cores, usually lined by a single layer of tall columnar epithelium. The epithelial cells had elongated, even nuclei in a basal position and ample apical cytoplasm. The cytoplasm was pale eosinophilic, but pro- duction of mucus generally was not observed. A positive reaction to PAS was obtained before but not after diastase digestion, and mucicarmine stains also were negative. In some neoplasms, epithelial cells were piled up and multilayered. In these the nuclei revealed more pleomorphism and hyperchromatism (Fig. 3). In one case, tumor cells examined histochemically for enzyme activity revealed a strongly positive cytoplasmic reaction for acid phosphatase and negative alkaline phosphatase and aminopeptidase reactions. The neoplasms were graded 1 to 4 according to the degree of dedifferentiation (with grade 1 being the least and grade 4 the high- FIG. 1. Adenocarcinoma of primary ducts. The papillary neoplasm is within the prostatic ducts directly ra:ig the urethral mucosa (H and E, x80). Fic. 2. Adenocarcinoma of primary ducts. The polypoid neoplasm is composed of exuberant branching papillary folds (H and E. ~80).

3 404 CANCER August 1973 Vol. 92 FIG. 9. Adenocarcinoma of primary ducts. This papillary frond is covered by a multilayered epithelium. The nuclei show moderate pleomorphism (H and E, ~160). est) as follows: grade I-one case, grade 2-five cases, and grade %two cases; none was judged grade 4. In six cases, invasion of the adjacent periductal stroma and prostatic tissue was noted, and, in four cases, focal extension into the secondary prostatic ducts had occurred. The small areas in which secondary ducts were involved revealed merging of histopathologic features with those of secondary duct type. Adenocarcinoma of the secondary prostatic ducts: Forty-seven of the adenocarcinomas were designated as this type. One typical feature of the neoplasm was multicentric involvement, characterized by areas in which the growth was confined within intermediate and small ducts. Neoplastic cells lining these ducts varied from single to multilayered and usually had small papillary projections. Many of the lumina were filled with eosinophilic debris, which imparted a comedo-like appearance (Fig. 4A). The component cells had large nuclei and abundant cytoplasm resembling apocrine change (Fig. 4B). In other cases, cellular outfoldings bridged the lumen and created a aibriform-papillary growth pattern (Fig. 5A). An exclusively papillary pattern was observed in other areas (Fig. 5B). The cells lining the papillae were generally tall and columnar, and they exhibited ample eosinophilic, sometimes clear, cytoplasm. Many of the neoplasms were undifferentiated and had large pleomorphic hyperchromatic nuclei. Invasion of the prostatic tissue was noted in every instance. On the basis of differentiation, 2 of the 47 adenocarcinomas were judged grade 1, 18 grade 2,21 grade 3, and 6 grade 4. CLINICAL ASPECTS Age distribution: The ages of the total group of 55 patients ranged from 41 to 81 years, the average age being 68.8 years. Of the eight patients having primary duct adenocarcinomas, five were in the seventh decade and one each in the fifth, sixth, and ninth decades. Of the 47 patients having secondary duct adenocarcinomas, 10 were in the sixth, 25 in the seventh, 10 in the eighth, and 2 in the ninth decades. No significant difference of the age distribution was observed between primary and secondary duct carcinomas. Symptoms: Obstruction in the lower urinary tract accounted for the presenting symptoms in most patients. Seven of the 8 patients with primary duct adenocarcinomas complained of progressive obstructive symptoms, as did 44 of the 47 with secondary duct adenocarcinomas. Gross hematuria was noted by 10 patients and other less frequent symptoms were dysuria, low back pain, perineal pain, and impotence (2 patients). Two patients were asymptomatic. The duration of symptoms to the time of definitive diagnosis ranged from 1 week to 9 years with an average of 24.8 months in the patients with secondary duct involvement. Symptoms in patients with primary duct lesions were notably shorter in duration, ranging from 3 to 30 months with an average of 11.1 months.

4 No. 2 PROSTATIC DUCTAL ADENOCARCINOMA - Dube et al. 405 FIG. 4A. Adenocarcinoma of secondary ducts. Comedo pattern. The epithelium forms small intraluminal pro'ections. The lumina contain debris. (H and E, x64). FIG. 4B. Columnar cells with ample clear cytoplasm. (H and E, X200). Rectal findings: Findings on prostatic digital rectal examination were recorded for each case and tabulated according to whether the examining physician judged the prostatic lesion to be benign or malignant and, if malignant, whether there was a localized nodule or diffuse infiltration (Table 1). Of the 47 patients with secondary duct adenocarcinomas, only 4 had prostatic lesions that were regarded as benign, while 4 of the 8 patients with primary duct adenocarcinoma were judged to have essentially normal prostates. Cystoscopic findings: Such findings were recorded in 41 of the 47 cases of secondary duct adenocarcinoma. Findings suggestive of infiltration of the prostatic urethra by a malignant lesion were reported in 28 cases and polypoid or villous intra-urethral projections in 3; lesions in the prostate were judged benign in 10 cases. In the seven cases of primary duct adenocarcinoma in which cystoscopic findings were reported, villous or polypoid tumors extending into the urethra were noted in five and infiltrative obstructive malignant lesions in two. None was judged benign. Acid phosphatase: Serum acid phosphatase determinations were done initially in 52 of 55 cases. Generally, serum acid phosphatase

5 406 CANCER August 1975 Vol. 32 FIG. 5A. Tumor showing intraductal cribriform-papillary growth. (H and E, ~100). FIG. 5B. Adenocarcinoma of secondary ducts. Section of tumor showing exclusively papillary pattern (H and E, ~100). activity was elevated if metastasis was present. Of the 28 patients with primary and secondary duct carcinoma in whom metastasis had been demonstrated in bones and lungs, 21 had in- TABLE 1. Prostatic Digital Examination Adenocarcinoma Of primary Of secondary Impression ducts ducts Malignancy suspected Diffuse 3 34 Localized 1 9 Malignancy not suspected 4 4 creased serum acid phosphatase activities averaging three times the upper normal values. Only 7 of the 28 patients had normal values for serum acid phosphatase. The highest value occurred in a recent patient who had 242 IU with a 66% tartrate inhibition (normal value, <7.9 IU and <20% inhibition). In six patients with elevated acid phosphatase values in whom tartrate inhibition was performed, the values for inhibition were 9%, 12%, 15%, 55%, 66%. and 71%. There was no difference in the degree of elevation of acid phosphatase in patients with primary duct carcinoma and those with secondary duct carcinoma.

6 ~ ~ ~~~~ ~ No. 2 PROSTATIC DUCTAL ADENOCARCINOMA * Dube et al. 407 TABLE 2. Primary Duct Adenocarcinoma. Survival Data Present initially Metastasis None initially Average Average survival 5-year survival 5-year Treatment No. patients (mo.) survivors No. patients (rno.) survivors Estrogen therapy 1 9 o/ 1 3* 80 2 /3 No estrogen therapy / /1 TOTAL / /4 * Two also had orchiectomy. TREATMENT AND COURSE Primary duct adenocarcinoma (eight cases): Each patient had transurethral resection, and two patients required subsequent resections for recurrent obstruction. None of the patients underwent radical prostatectomy. One patient was also explored suprapubically but was found inoperable because of extensive metastasis to the pelvic lymph nodes. Table 2 relates survival to the presence or absence of initial metastasis and to hormone therapy. Metastasis was discovered in four of the eight patients on initial examination: three had osteoblastic spinal metastasis, and the aforementioned patient had metastasis to the pelvic lymph nodes. None of these patients survived for 5 years. One patient with initial metastasis is still alive at the time of this writing 6 weeks after diagnosis. Of the four patients free of detectable metastasis, three survived for 5 years (75%). The overall 5-year survival rate was 42.8% and correlated closely with the histologic grade of the malignancy. Six of the total group of seven patients died from metastasis. Two patients with initial metastatic carcinoma and one patient without initial metastasis had no hormone therapy. Secondary duct adenocarcinoma (47 cases): Forty of the 47 patients had transurethral resection of the prostate. One patient had conservative suprapubic prostatectomy; another patient underwent prostatectomy incidental to total cystectomy for cancer of the bladder. The other five patients had radical prostatectomy. Of the 47 patients in this group, 33 had a 5-year follow-up and had been treated by conservative surgery, i.e., transurethral resection of the prostate. Of these 33 patients, 32 were treated with regular oral doses of estrogens and 20 also underwent bilateral orchiectomy. Survival data on the cases are tabulated in Table 3. The overall survival rate for this group was 24.20/,, and this correlated well with both the histopathologic grade of malignancy and the presence or absence of distant metastasis. Nine patients had metastasis on initial examination and none lived 5 years. For the 24 patients without detectable initial metastasis, the 5-year survival rate was 33.3%, and the average length of survival was 53.2 months. Only 1 of these 24 patients survived beyond 10 years and died in the 12th year from generalized metastasis. Of the total group of 33 patients, 24 ultimately died from metastasis; 1 died from recurrent obstruction of the lower urinary tract, 1 with massive hematuria, and 1 from incidental disease. In six patients, the cause of death is unknown. Five of the 47 patients were treated by radical prostatectomy (1 perineal and 4 retropubic); at the time of this study, 2 of these 5 are alive without evidence of tumor at 1 year and 10 years 6 months, respectively. None of the TABLE 3. Secondary Duct Adenocarcinoma. Survival Data by Presence of Initial Metastases and Grade of Malignancy Metastasis Grade of cancer Present None initially initially Total Case/survivors 1/1 4/13 3/13 0/ /24 8/33 (33.3%) (24.2%)

7 408 CANCER August 1973 VOl. 52 other three patients survived beyond 5 years. Two died of metastatic and recurrent disease and one of unrelated causes. The remaining 9 of the 47 patients, with a follow-up period of less than 5 years, are living at the time of this report, but 5 have evidence of distant metastasis. Mixed acinic and ductal carcinoma: Fiveyear follow-up was possible in 138 of the 207 patients. Twenty-five of these 138 patients had distant metastasis when first seen and were treated by transurethral resection and hormonal control. Twenty per cent survived 5 years. Of 113 patients without initial metastasis, 92 were treated conservatively and 21 had either undergone radical prostatectomy or had received no hormonal control. The 5-year survival rate for the 92 patients was 47.8y0. The overall 5-year survival rate for the 138 patients was 45.6y0. DISCUSSION Foot et a1.,6 in 1950, proposed a logical classification for prostatic carcinomas that provided for ductal type adenocarcinomas; recently Bates1 expanded the classification. However, only two cases similar to our secondary duct carcinomas have been reported thus far.2~7 To the best of our knowledge, the eight cases of primary duct adenocarcinomas encountered at this clinic and one recently encountered elsewhere by one of us (V.E.D.)3 are the only cases of this type of prostatic carcinomas that have been published. Review of a sufficient number of cases that have accumulated over the years in our files indicates that primary and secondary duct adenocarcinomas have distinctive histopathologic and clinical features that justify inclusion into a classification of prostatic carcinomas as separate entities. Furthermore, the need for recognition of primary duct prostatic adenocarcinomas as a distinct group is pointed out by the diagnostic confusion that has often attended pathologists' encounter with this neoplasm. The majority of adenocarcinomas of the prostate appear to arise from peripheral tubulo-alveolar secretory units within the posterior and posterolateral lobes.9 These neoplasms generally have a small glandular or acinic ~tructure.~~~jl Neoplasms of the primary ducts would be situated predominantly in a periurethral location, and those of the secondary ducts, more centrally than the usual prostatic carcinoma. Although most of our material came from transurethral resections, this expected localization was borne out by our study. In many of the sections, the papillary primary duct tumor growth was noted next to the transitional cell lining of the immediate periurethral ducts or the urethra. The secondary duct carcinomas also had a high incidence of involvement of the more central regions of the prostate. On account of their central location within the prostate, obstructive symptoms were observed in 94y0 of all ductal carcinomas as compared to obstruction observed in 80% of patients with the usual acinic carcinoma? All patients with primary duct carcinoma were suspected of having malignancy on cystoscopic examination, on account of the periurethral location of the neoplasm within the middle lobe. Most patients with secondary duct carcinoma were suspected of having malignancy on rectal examination, probably because of a somewhat more peripheral location. Our cases of primary duct carcinoma should be differentiated from the endometrial carcinoma of the uterus masculinus reported by Melicow and Tannenbaum.lo It appears that the tumor described by these authors has more glandular features as compared to the papillary pattern observed in primary duct carcinomas. The endometrial type of carcinomas said to originate from the uterus masculinus did not reveal osteoblastic metastasis or elevations of serum acid phosphatase activities as seen in the primary duct adenocarcinomas. The prostatic origin of our primary duct adenocarcinomas is further supported by histochemical examination showing positive acid phosphatase and negative aminopeptidase reactions similar to the reactions described as typical for ordinary acinic prostatic carcinomas.sj5 Reported 5-year survival figures for all patients with prostatic carcinomas treated by conservative surgery and hormone therapy ranged from 32.5% to 39.2y0.4v1*J4 The 5-year survival for patients treated by transurethral resection without orchiectomy or estrogens ranged from 9.1?1, to 27y It was our general impression that life was not prolonged by palliative hormone therapy in patients with secondary duct adenocarcinoma to the same extent as has been reported for all patients with prosta tic adenocarcinoma. However, we cannot conclude that the lower survival rate for patients with secondary duct carcinoma (24.2Y0) is significantly different from that re-

8 No. 2 PROSTATIC DUCTAL ADENOCARCINOMA Dube et al. 409 ported for patients with acinic carcinoma treated by hormones, because of the large variation of the estimate for the relatively small number of patients with secondary duct carcinoma. Whether hormone therapy exerts a palliative effect in secondary duct adenocarcinoma and prolongs life can be determined precisely only by adequately controlled studies. The 5-year survival rate (42.8%) for patients with prostatic primary duct adenocarcinomas was similar to that of patients with acinic carcinomas. The small number of pa- tients involved precludes valid conclusions, but it is notable that among the cases matched as to whether or not metastasis was present on initial examination, hormonal control had no apparent effect on survival. The presence of areas of a ductal type carcinoma in an ordinary acinic carcinoma did not change the prognosis, since survival for this group with mixed tumors was similar to that for patients with acinic carcinoma. Prostatic ductal adenocarcinoma should be considered separately in further studies evaluating the palliative benefit of hormone therapy. REFERENCES 1. Bates, H. R., Jr.: Histogenesis of prostatic carcinomas. Va. Med. Mon. 97: , Belter, L. F., and Dobson, A. I., Jr.: Papillomatosis and papillary adenocarcinoma of prostatic ducts: A case report. J. Urol. 104: , Dube, V. E., Joyce, G. T., and Kennedy, E.: Papillary primary duct adenocarcinoma of the prostate. J. Urol. 107: Emmett, J. L., Greene, L. F., and Papantoniou, A.: Endocrine therapy in carcinoma of the rostate gland: 10-year survival studies. J. Urol , Flocks, R. H.: Clinical cancer of the prostate: A study of 4,000 cases. JAMA 193: , Foot, N. C.. Humphreys, G. A., and Coats, E. C.: Carcinoma of the prostate: A review of 162 cases with a pathologic classification. N.Y. Stale J. Med , Kahler, J. E.: Carcinoma of the prostate gland: A pathologic study. J. Urol. 41: , Kirchheim, D., Gyorkey, F., Brandes. D.. and Scott, W. W.: Histochemistry of the normal, hyperplastic, and neoplastic human prostate gland. Invest. Urol. 1:403421, Kirchheim, D., Niles, N. R., Frankus, E., and Hodges, C. V.: Correlative histochemical and histological studies on thirty radical prostatectomy specimens. Cancer 19: , Melicow, M. M., and Tannenbaum, M.: Endometrial carcinoma of uterus masculinus (prostatic utricle): Report of 6 cases. J. Urol. 106: , Moore, R. A.: The morphology of small prostatic carcinoma. J. Urol. 33: , Nesbit, R. M., and Baum, W. C.: Endocrine control of prostatic carcinoma: Clinical and statistical survey of 1,818 cases. JAMA 143: , Nesbit, R. M., and Plumb, R. T.: Prostatic carcinoma: a follow-up on 795 patients treated prior to the endocrine era and a con~parison of survival rates between these and patients treated by endocrine therapy. Surgery , Pool. T. L., and Thompson, G. J.: Conservative treatment of carcinoma of the prostate. JAMA 160: , Rubin. P.: Comment: The penultimate in cancer diagnosis-enzymology. JAMA 209: , 1969.