ABRIDGED ADDENDA
CALIFORNIA TUMOR TISSUE REGISTRY
NINETY-THIRD SEMI-ANNUAL SLIDE SEMJJIIAR
ON
Ct!RRENT CONCEPTS IN UROLOGIC PATHOLOGY
MODERATOR: . DAVID G. BOS'IWICK. M.D. MAYO CLINIC ROCHESTER, MINNESOTA
CHAIRMAN:
JOZEF KOLLIN, M.D. DOCTORS' HOSPITAL OF LAKEWOOD LAKEWOOD, CALIFORNIA
DECEMBER 6, 1992 PARC FIFTY FIVE HOTEL SAI''i FRANCISCO, CALIFORNIA CURRENT CONCEPTS IN UROLOGIC PATHOLOGY DAVID G. BOSTWICK, M.D. MAYO CLINIC
CASE HISTORIES:
CASE NO. I- ACCESSION NO. 27146 Jo'>),de_
A 62 year-old male with an equivocal prostatic nodule and PSA of 3.5 ng/ml (monoclonal) underwent random needle biopsy. The focus shown in the photomicrograph was the only suspicious finding.
CASE NO.2 -ACCESSION NO. 27147
A 65 year-old male with clinical diagnosis of benign prostatic hyperplasia underwent transurethral resection (TURP). The focus shown in the photomicrograph was the only finding other than typical nodular hyperplasia.
CASE NO.3 - ACCESSION NO. 27174
A 61 year-old retired airline pilot was found to have a diffusely indurated prostate. Random needle biopsies revealed adenocarcinoma, and radical retropubic prostatectomy was perfonned.
~NO . 4- ACCESSION NO. 27148
A 66 year-old male underwent radical retropubic prostatectomy for clinical stage C adenocarcinoma (extra-prostatic extension without metastases). For three months prior to surgery, th.e patient received.therapeutic doses of anti-androgen medications (Zoludex and Lupron) in an effort io "doiVDstage" the tumor.
C2ASE NO. 5- ACCESSION NO. 27149
A 79 year-old male with a palpable prostatic mass on the right side underwent transrectal ultrasound-guided needle biopsy. The photomicrograph shows the only suspicious focus in one of two right-sided cores.
CASE NO. 6 - ACCESSION NO. 27164
A 76-year- A 60 year-old male underwent recurrent tronsurethral resection of the prostate in April l992. Since 1980, he has had recurrent gross hematuria with multiple resections for nodular hyperplasia and "phyUodes tumor• of the prostate. CASE NO 8 - ACCESSION NO, 27163 A 72 year-old male was found to have prostatic adenocarcinoma by needle biopsy and underwent radical retropubic prostatectomy. CASE NO.9- ACCESSION NO. 27168 A 54 year-old male presented with a !-year history of progressive urinary obstructive symptoms. In February, 1984, he underwent transurethral resection of the prostate with "tumor in the urethral canal," and the following month he underwent radical retropubic prostatectomy and staging pelvic lymphadenectomy. The fum.ily history was remarkable for a brother who bad been found to have a retroperitoneal sarcoma at age 42 (in 1917). CASE NO. 10- ACCESSION NQ. 27151 A 70 year-old retiml MiMesota postman undement tranSurethral resection of the prostate in September 1987 for clinical diagnosis of benign prostatic hyperplasia. In the week prior to surgecy, he was found to have chronic lymphocytic leukemia. Past history was remarkable for rheumatic fever necessitating 2 mitrnl valve replacementS (both in 1976) and left cerebral infarct with mild aphasia in !984. Fantily history is remarkable for a brother with prostatic adenocarcinoma. CASE NQ 11 - ACCESSION NO 27087 A 47 year-old male farmer presented in I 950 with a !-year ltistory of increasing fatigue and mild nocturia. He was noted to have a "rectal tumor," consisting of a firm, rubbery, non-tender mass anterior and to the left of the rectum and above and lateral to the prostate. On cystoscopy, the mass was noted to be exuavesicular, pushing the bladder anteriorly and to the right; the left ureteral orifice could not be visualized. Radiographs revealed a soft tissue mass in the left side oflhe pelvis. Laborotory testS of blood and urine were normal. A 14 x 6 x 6 em lobulated cystic mass was removed from ihe area of the left seminal vesicle. CASE NO. 12 - ACCESSIQNNQ. 27088 A 61 year-old male underwent tranSurethral resection of ihe prostate for nodular hyperplasia in 1987, and developed recurrent acute urinary retention post-operatively. Ul~ound and computed tomographic (CT) scan of the pelvis revealed an 8.5 em diameter mass posterior to the urinary bladder replacing the seminal vesicles. Serum PSA was normal, and two urine cytologies were benign. The patient was surgically explored with frozen section diagnosis, and then undenvent cystoprostatosemino vesiculectomy, bilateral pelvic lymphadenectomy, and segmental resection of the sigmoid colon. CASE NO. 13 ·ACCESSION NO. 27169 A 56 year- CASE NO. 14 ·ACCESSION NO. 27152 A 49 year- CASE NO. IS • ACCESSION NO 27131 A 47 year- CASE NO. 16 ·ACCESSION NO, 27173 A 72 year- CASE NO. 17 ·ACCESSION NO. 27175 A} A 54 year- CASE NO. 18 • ACCESSION NO. 27153 A 43 year- CASE NO. 19 • ACCESSION NQ. 27089 A 49 year- A 23 month-<31d male was chronic:illy ill and presented with a large left abdominal m:ISS. A 9.0 em cUameter rumor e~ CASE NQ. 21 ·ACCESSION NO. 27132 A 66 year - CASE NQ. 22 • ACCESSION NO. 27165 A 76 year- CASE NO 23 ·ACCESSION NQ. 27142 An otherwise healthy 72 year-old white male complained ofgross hematuria without clotting. He was placed on Bactrim, but hematuria persisted. Physical examination revealed a tender, palpable mass in the hypogastric area, and cystoscopy and cr scan showed a large mass in the dome of the bladder measuring about 5 x 10 em. The patient underwent radical cystectomy, and a 9 em inttacystic and 6 em c.' CASE NO. 24 • ACCESSION NO, 27154 An otherwise healthy 68 year-old white male was found to have a large mass in the left kidney, and underwent nephrectomy. (Case courteSY of Dr. Dean Lauer. Poner Memorial Hospital, Valpariso, lndiana.) CASE NO. 25 · ACCESSION NQ. 27142 An otherwise healthy 72 year - A 32 year~ld mal.e presented with acute onset of pain in the right loin and CVA region. Physical examinntion revealed right upper quadrant tenderness. and a mass was equivocably palpable to deep palpation. A right radical nephrectomy was performed in June 1992. The kidney was opened in surgery, where it was surrounded by lobulated soft, yellow perirenal adipose tissue. A large mass was apparent in the lower pole which when bivalved rewaled a large necrotic, hemorrhagic, well· circumscribed mass. It did not violate the renal capsule. (Case counesy of Dr. Jerree Suo h. Saddleback Memorial Medical Center, Long Beach, California.) CURRENT CONCEPTS IN UROLOGIC PATHOLOGY San Francisco, Califor nia Calif ornia Tumor T issue Registry Sunday, December 6, 1992 David G. Bostwick M.D. Senior Associate Consultant and Associate Pro fessor of Pathology Mayo Clinic and Mayo Medical School Rochester, MN. 55905 (507)-284-1 870 FAX: (507)-284- 1599 Bostwick -2- CURRENT CONCEPTS IN UROLOGIC PATHOLOGY CASE HISTORIES December 6, 1992 David G Bostwick M.D. Mayo Clinic 1. A 62 year-old male with an equivocal prostatic nodule and PSA of 3.5 ng/ml (monoclonal) underwent random needle biopsy. The focus shown in the photomicrograph was the only suspicious finding. 2. A 65 year-old male with a clinical diagnosis of benign prostatic hyperplasia underwent transurethral resection (TURP). The focu~ shown in the photomicrograph was the only finding other than typical nodular hyperplasia. 3. A 61 year-old retired airline pilot was found to have a diffusely indurated prostate. Random needle biopsy revealed adenocarcinoma, and radical retropubic prostatectomy was performed. 4. A 66 year-old male underwent radical retropubic prostatectomy for clinical stage C adenocarcinoma (extra-prostatic eX1ension without metastases). For 3 months prior to surgery. the patient received therapeutic doses of anti-androgen medications (Zoludex and Lupron) in an effort to "downstage• the tumor. 5. A 79 year-old male with a palpable prostatic mass on the righ t side underwent transrectal ultrasound-guided needle biopsy. The photomicrograph shows the only suspicious focus in one of two right- sided cores. 6. A 76 year-old male with a clinical diagnosis of benign prostatic hyperplasia underwent transurethral resection (TURP). The entire specimen was submitted in 16 blocks. and 11 showed the findings present on the submitted slide (case courtesy of Or. E.F. Schlenk, Marshalltown,t A). 7. A 60 year-old male underwent recurren t transurethral resection of the prostate in April, 1992. Since 1980, he has had recurrent gross hematuria with multiple resections for nodular hyperplasia and "phllyodes tu mor" of the prostate. 8. A 72 year-old male was found to have prostatic adenocarcinoma by needle biopsy and underwent radical retropubic prostatectomy. 9. A 54 year-old male presented with a 1 year history of progressive urinary obstructive symptoms. In February, 1984, he underwent transurethral resection of the prostate with "tumor In the (urethral) canal," and the following month he underwent radical retropubic prostatectomy and staging pelvic lymphadenectomy. The family history was remarkable for a brother who had a retroperiton eal sarcoma at age 42 (In 1977). Bostwick -3- 10. A 70 year-old retired Minnesota postman underwent transurethral resection of the prostate in September 1987 for clinical diagnosis of benign prostatic hyperplasia. In the week prior to surgery, he was found to have chronic lymphocytic leukemia. Past history was remarkable for rheumatic fever necessitating 2 mitral valve replacements (both in 1976) and left cerebral infarct with mild aphasia in 1984. Family history was remarkable for a brother with prostatic adenocarcinoma. 11. A 47 year-old male farmer presented in 1950 with a one year history of increasing fatigue and mild nocturia. He was noted to have a •rectal tumor." consisting of a firm, rubbery nontender mass anterior and to the left of the rectum and above and lateral to the prostate. On cystoscopy, the mass was noted to be extravesicular, pushing the bladder anteriorly and to the right; the left ureteral orifice could not be visualized. Radiographs revealed a soft tissue mass In the left side of the pelvis. Laboratory test.s of blood and urine were normal. A 14 X 6 X 6 em lobulated cystic mass was removed from the area of the left seminal vesicle. 12. A 61 year-old mate underwent transurethral resection of the prostate for nodular hyperplasia in 1987, and developed recurrent acute urinary retention postoperatively. Ultrasound and computed tomographic (CT) scan of the pelvis revealed an 8.5 em. diameter mass posterior to the urinary bladder replacing the seminal vesicles. Serum PSA was normal, and 2 urine cytologies were benign. The patient was surgically explored with frozen section diagnosis, and then underwent cystoprostatosemino-vesiculectomy, bilateral pelvic lymphadenectomy, and segmental resection of the sigmoid colon. 13. A 56 year-old white male with an episode of gross painless hematuria underwent cystoscopy. A 1.5 em. diameter mass was resected from the bladder. 14. A 49 year-old male with longstanding urethral stricture underwent urethroplasty in 1967. In 1984, he developed a scrotal abscess at the base of the penis which was unresponsive to incision and drainage, antibiotics, 3 skin flap grafting attempts , and surgical debridement. By August. 1985, the non-healing ulcer extended along the entire ventral penile surface and extending io the anus exclusively limited to the midline of the perineum. It was markedly painful, inflamed, and exudative. Cultures revealed P. Aeruglnosa and Coagulase-negative Staphylococcus. CT scan of the pelvis showed no evidence of bone or lymph node involvement. Biopsy of th,e scrotum and perineum was undertaken. 15. A 47 year-old woman underwent cystectomy for a 5 em. diameter mass of the bladder. 16. A 72 year-old white male presented with symptoms of urinary obstruction. Cystoscopy showed prostatic nodular hyperplasia; the bladder appeared normal. Transurethral resection revealed undifferentiated carcinoma of the prostate in October 1991 involving 7 of 52 chips . Immunohistochemistry for prostate specific antigen (PSA) and prostatic acid phosphatase (PAP) was negative. The patient underwent pelvic exploration with biopsies; anterior pelvic exenteration was undertaken with ileal conduit urinary diversion. 17. A: A 54 year-old white female with a episode of gross painless hematuria underent cystoscopy. A 2 em. mass was resected from the right posterior wall. B: Similar history to A. Bostwick -4- 18. A 43 year-old white male underwent cystoprostatectomy for intractable cystitis. The section is representative of the entire bladder. 19. A 49 year-old woman underwent left nephrectomy for a 15 em. diameter mass in the upper pole. The tumor was pale brown-grey, partially necrotic, and focally penetrated the capsule with extension into the perirenal fat. 20. A 23 month-old male was chronically ill and presented with a large left abdominal mass. A 9 em. diameter tumor extended from the kidney, across the midline, and into the diaphragm. 21. A 66 year-old black female with recurrent cystitis presented with gross painless hematuria. Ultrasound and CT scan revealed a 3.5 em. diameter mass in the upper pole of the right kidney; angiogram revealed that the mass was hypovascular. The patient underwent nephrectomy (case courtesy of Dr. Jane-t Durham, Henry Ford Hospital, Detroit, Ml). 22. A 76 year-old male Minnesota surgeon with a long history of mild borderl ine diastolic hypertension presented in April of 1992 with a 6 week history of left upper abdominal pain, 3 weeks of postprandial nausea, and 5 pound weight loss over 6 months. The left kidney was noted to be replaced by a 1umor on CT scan, and the patient underwent nephrectomy. A 10 em. diameter solid partially-necrotic mass was noted predominately in the upper pole with capsular penetration and involving a renal hilar lymph node. Past history was remarkable for localized malignant melanoma of the right eye ( choroid) in December 1989 treated by enucleation and irradiation. The patient's father died of prostatic adenocarcinoma. 23. An otherwise-healthy 72 year-old wh ite male complained of gross hematuria withou t clotting. He was placed on Bactrim, but hematuria persisted. Physical examination revealed a tender palpable mass in the hypogastric area, and cystoscopy and CT scan showed a large mass in the dome of the bladder measuring about 5 X 10 em. The patient underNent radical cystectomy, and a 9 em intracystic and 6 em extracystic dumbell-shaped mass was noted arising near the urachus at the dome of the bladder (case courtesy of Drs. Charles McCammon and Mark Beck, Valley Clinical Laboratory Medical Group, Rancho Mirage, CA). 24. An otherwise-healthy 68 year-old white male was found to have a large mass in the left kidney, and underwent nephrectomy (case courtesy of Dr. Dean Lauer, Porter Memorial Hospital, Valpariso. IN). 25. An otherwise-healthy 72 year-old black male presented with a 2.5 year history of enlarging left scrotal mass. Physical examination revealed 2 large apparent spermatoceles and a painless! em . diameter solid mass in the upper pole. He underwent left radical orchiectomy in November 1991. The testis contained a fleshy circumscribed mass adjacent to the rete testis, as well as multiple minute foci of orange-yellow discoloration, most marked at the periphery without involving the tunica. Bostwick -7- CASE 1 HIGH GRADE PROSTATIC INTRAEPITHELIAL NEOPLASIA (PIN) Abstract Prostatic intraepithelial neoplasia (PIN) represents the putative precancerous end of the morphologic continuum of cellular proliferations with prostatic ducts, ductules, and acini. Two grades of PIN are identified (low grade and high grade), and high grade PIN is considered a precursor of invasive carcinoma. The continuum which culminates in high grade PIN and early invasive cancer is characterized by basal cell layer disruption, basement membrane disruption, progressive loss of markers of secretory differentiation, increasing nuclear and nucleolar abnormalities~ increasing proliferative potential, and increasing variation in DNA content (aneuploidy). Clinical studies suggest that PIN predates carcinoma by ten years or more, with low grade PIN first emerging in men in the third decade of life. The clinical importance of recognizing PIN is based on its strong association with carcinoma; its identification in biopsy specimens of the prostate warrants further search lor concurrent invasive carcinoma. Introduction Despite the potential importance of a premalignant phase in the natural history of human cancer, little attention has been given to th.e study of precursor lesions of malignancy in the prostate. Recently, two potential morphologic precursors of adeno.carcinoma has been identified , referred to prostatic intraepiihelial neoplasia (PIN) and atypical adonomatous hyperplasia (AAH). These lesions display some of the features of carcinoma, but PIN lacks stromal invasiveness and AAH lacks significant cytologic atypia. High grade PIN is commonly found in association with invasive cancer, and the high predictive value of this lesion suggests that further search for carcinoma be made in cases in which high grade PIN is found on biopsy; AAH is also found in association with carcinoma, but not as commonly as PIN. In 1991, an international consensus conference group sponsored by the American Cancer Society concluded that PIN was the most likely precursor of invasive carcinoma, and that AAH should be further investigated as a possible precursor. This report reviews the diagnostic criteria and clinical significance of PIN, including the evidence accumulated to date linking this histopathologic lesion with invasive cancer. Diagnostic Criteria for PIN Prostatic intraepithelial neoplasia (PIN) refers to th e putative precancerous (dysplastic) end of the morphologic continuum of cellular proliferations within Bostwick -8- prostatic ducts, ductules, and acini. I ·& The term PIN was endorsed by consensus at a 1989 international conference t·7 to replace other synonymous terms used in the literature, including intraductal dysplasia, s large acinar atypical hyperplasia, 9 atypical primary hyperplasia, to hyperplasia with malignant change,tt marked atypia,12 and duct-acinar dysplasia.t 3-ts This consensus group also agreed that PIN be divided into two grades (low grade and high grade) to replace the previous three grade system (PIN 1 is considered low grade, and PIN 2 and 3 are considered high grade).7 In low grade PIN, the cells within ducts and acini are heaped up, crowded, and irregularly spaced with marked variation in nuclear size (anisonucleosis) (Table 1). Elongate hyperchromatic nuclei and small nucleoli are also observed, but these are not usually prominent features. The diagnosis of PIN requires a combination of both cytologic and architectural features, and lesions displaying some but not all of these features are considered atypical but no ~ dysplastic. High grade PIN (formerly PIN 2 and 3) exhibits features similar to low grade PIN, although cell crowding and stratification are usually more pronounced, with less variability in nuclear size because the majority of nuclei are enlarged; the presence of prominent nucleoli, often numerous, is of greatest diagnostic utility. We have identified four patterns of high grade prostatic i ntraepithel ial neoplasia: tufting, micropapillary, cribiform, and fl at. ts PIN spreads through prostatic ducts in three different patterns, similar to prostatic carcinom a.s.t7 In the first pattern, neoplastic cells replace the normal luminal secretory epithelium, with preservation of the basal cell layer and basement membrane. Foci of high grade PIN are usually indistinguishable from ductal spread of carcinoma by routine light microscopy in our experience, although some authors claim that this distinction is possible.ta In the second pattern, there is direct invasion through the ductal or acinar wall , with disruption of · th~ basal cell layer and the basement membrane. In the third pattern, neoplastic cells invaginate between the basal cell layer and columnar secretory cell layer ("pagetoid spread"), a very uncommon finding. PIN and Cancer Occur Commonly in the Peripheral Zone The peripheral zone of the prostate, the area in which the majority of prostatic carcinomas occur (70%}, is alsc:> the most common location for PIN.t9 Cancer and PIN are frequently multlfocal in the peripheral zone, indicating a "field" effect similar to the multifocality of transitional cell carcinoma of the bladder. The transition zone and peri urethral area, the anatomic areas in which nodular hyperplasia occurs, account for about 20-25% of prostate cancers, and harbor foci of PIN in only 2% of cases.2o By contrast, atypical adenomatous hyperplasia (AAH) is found in up to 24% of transition zone specimens,20·22 . If AAH is not a precursor of carcinoma, then the infrequency of PIN in the Bostwick -9- transition zone could account for the infrequency of cancer originating in that area. The Basal Cell Layer and Basement Membrane Are Disrupted in High Grade PIN Increasing grades of PIN are associated with progressive disruption of the basal cell layer and basement membrane.2.2s-2s Basal cell-specific monoclonal antibodies directed against high molecular weight keratin (e.g., clone 34 8-E12) have been employed immunohistochemically to selectively label the prostatic basal cell layer.2 Tumor cells consistently failed to be decorated with this antibody, whereas normal prostatic epithelium was invariably stained, with a continuous intact circumferential basal cell layer observed in most instances. Basal cell layer disruption was present in 56% of cases of high grade PIN, and more commonly in glands adjacent to Invasive carcinoma than in distant glands. Also, the amount of disruption increased with increasing grades of PIN, w ith loss of more than one-third of the basal cell layer in 52% of loci of high grade PIN.2 Dysplasia Carcinoma Normal Vory Mild In Situ Microinvasive Lumenal (secre rory J Ce ll ~ayor 1~~~~~ Sasal Call Layer ;::i~ -~~~~~~~~~~~~~~~§~~~~§~ '~ ~".1:~/ Grade 1 Grade 2 Basement Membrane Prostatic lntraep•thallal Neoplasia Figure 1: Morphologic continuum from normal prostatic epithelium through increasing grades of PIN to early invasive carcinoma, according to the disease-continuum concept. Low grade PIN (grade 1) corresponds to very mild to mild dysplasia. High grade PIN (grades 2 and 3) correspond to moderate to seve re dysplasia and carcinoma in situ. The precursor state ends when malignant cells invade the stroma; this invasion occurs where the basal cell layer is disrupted and the basement membrane is fragmented. Notice that the dysplastic changes occur in the superficial (luminal) secretory cell layer, perhaps in response to lumenal carcinogens. Disruption of the basal cell layer and basement membrane accompany the architectural and cytologic leatures of high grade PIN, and appear to be necessary prerequisites for stromal invasion. Bostwick -I 0- The type IV collagen-immunoreactive basement membrane normally surrounding prostatic glands was focally attenuated or absent in 40% of cases of PIN .2·3 Preliminary data have shown increased expression of type IV collagenase in PIN and cancer:2S collagenase is a proteolytic enzyme which is thought to induce fragmentation of the basement membrane during invasion.27 Early invasive carcinoma occurs at sites of glandular out-pouching anc basal cell disruption.2.1s Although one author has referred to this as "transitive" gland change,ts we feel that "microinvasion" is the preferred terminology as it is i n other organs, avoiding introduction of a new and unnecessary term. A model of prostatic carcinogenesis has been proposed based on the morphologic continuum of PIN and the multi-step· theory of transformation.2 FREQUENCY OF PIN AND AAH IN AUTOPSY PROSTATES 100 en r::l 80 en u< rx.. 60 0 0:: (:;:! c:c 40 ::E ~ z 20 0 L..--- PIN AAH • CANCER [iJ BENIGN Figure 2: Frequency of PIN and MH in autopsy prostates. These data are from an autopsy series of 100 serially sectioned prostates with cancer and 100 prostates without cancer (McNeal and Bostwick, 1986). Note that the frequency of both of these putative premalignant lesions (PIN and AAH [atypical adenomatous hyperplasia) ) are significantly increased in prostates with cancer when compared with those not harboring cancer, although PIN is significantly more common. Bostwick -11· There is Increased Frequency, Severity, and Extent of PIN with Cancer The frequency of PIN in prostates with cancer was significantly increased when compared with prostates without cancer.s-9. 28-32 We observed PIN in 82% of step-sectioned prostates with cancer, but in only 43% of benign prostates from patients of similar age.s PIN was more extensive in amount in lower stage tumors, presumably due to ' overgrowth" or obliteration of PIN by larger high· stage tum ors.15.33 The severity of PIN in prostates with cancer was significantly increased when compared with prost~tes without cancer.s PIN and Cancer Increase with Patient Age In a study of 429 step-sectioned whole prostates. Kovi et al. found thatthe prevalence of PIN in prostates with cancer increased with age, pr_edating the onset of carcinoma by more than five years. 9 A similar study by Sakr et aL in young men revealed the onset of PIN in men in their twenties and thirties (9% and 22% frequency, respectively), which preceded the onset of carcinoma by more than ten years.34 Most loci of PIN in young males were low grade, wi th increasing frequency of high grade PIN with advancing age. The prevalence of PIN was similar in blacks and whites. Lee et al. studied 256 ultrasound-guided biopsies of hypoechoic lesions of the prostate, and identified 103 cancers and 27 cases of PIN; the mean age of those with PIN (65 years) was signifi cantly lower than those with cancer (70 years), 35 PIN and Cancer are Phenotypically Similar There is progressive loss of markers of secretory differentiation w ith increasing grades of PIN, indicating progressive impairment of cell differentiation and regulatory control with advancing stages of prostatic carcinogenesis (Table 2).13-1 5,36-39 With rare exceptions, the expression of a wide variety of secretory proteins, cytoskeletal proteins, and glycoproteins are similar in PIN and invasive prostatic carcinoma, compared with normal prostatic epithelium. Nagle et al suggested th at changes in cytoskeletal proteins in PIN may affect transport of cell products, accounting lor the differences in secretory protein distribution.37 Recently, McNeal et aJ have shown that reduction of cytoplasmic differentiation markers during the pre-i nvasive phase may be fo llowed by abrupt re-expresslon at the site of microinvasvion.15 Bostwick - 12- ·sor------, 40 ...... ························· ...... /. / PIN/ CANCER 30 ...... ;...... : 20 ...... ,...... 10 .., ...... !...... 0~~~~~~~--~--~----~--~----~ !0- 19 2 0-29 30- 39 40-49 50-59 60-69 70 - 7.9 80 - 89 AGE (YEARS) Figure 3: Frequency of PIN and cancer with increasing age. There is a parallel increase in the frequency of PIN and cancer, according to serially-sectioned autopsy prostates, although PIN appears to predate cancer by more than i 0 years. ( Data on PIN from Sakr et al, i 991 and McNeal and Bostwick, 1986; data on cancer curve from Bostwick et al 1992). PIN and Cancer are Morphometrically Sim ilar Virtually all measures of nuclear abnormali ty by co mputer-based image an alysis revealed the similarity of PIN and cancer, in contrast with normal and hyperplastic epithelium (Table 3).40·44 These changes include nu clear area, DNA content, chromatin content and distribution, nuclear perimeter, nuclear diameter, and nuclear roundness. Also, most measures of nucleolar abnormali ty revealed the similarity of PIN and cancer, in contrast with normal ep ithelium.41.43.4S-4S Layfield and Goldstein fou nd that core and needle biopsies were more reliable than fine needle aspiration in separating, PIN from cancer based on a morphometric study of 50 "atypical" cases.49 These cumulative data indicate th at the morphologic continuum from PIN to cancer is characterized by progressive morphometric derangements of nuclei and nucleoli. PIN is Frequently Aneuploid Morphologic derangements of nuclei and nucleoli observed during prostatic carcinogenesis are accompanied by progressive transformation of the normal diploid DNA content to a nondiploid one, according to computer-based static Bostwick -13- image analysis of tissue sections_,, ,45.50-52 Montironi et al suggested that two successive phases occur; the first occurs in hyperplastic epithelium and I ow grade PIN, and is characterized by DNA duplication without nuclear division, resulting in euploidy (diploid (2N) or tetraploid {4N)); the second occurs only in high grade PIN and cancer, and results in emergence of aneuploid elements (triploid, hyperdiploid, hypotetraploid, and aneuploid) _4s Similar results were reported by Petein et al, who noted that the mean proliferative index and proportion of aneuploid cel.l nuclei in high grade PIN were similar to cancer, bu t differed significantly from hyperplastic epithelium and low grade PIN _41 Amin et al found an incidence of 32% aneuploidy In high grade PIN and 55% in carcinoma,so somewhat lower than the ·results of Crissman et aJ (57% and 62%, respectively)_S2 Weinberg and Weidner also noted concordance of DNA content in a small series of PIN and cancer, with the majority being diploid _5 1 A study of 67 cases evaluated by flow cytometry by O'Malley _et al revealed that aneuploidy was rare in PIN (1-8%) , and that there was significant discordance of results with cancer-53 The discrepancy in results between this flow cytometry study and the static image analysis studies of PIN may be due to sampling or other variations in methods- Animal Models of PIN Studies to date have not determined whether PIN remains stable, regresses, or progresses, although the implication is that these lesions can progress Evidence supporting this hypothesis of progression have been obtained in animal models. 5~-58 Leav et al reported Induction of prostatic hyperplasia, "dysplasia', and carcinoma in the Noble rat by administration of testosterone in 17 B estradioLS 4 This report suggests that dysplasia may progress to carcinoma and that long-term hormonal stimulation plays a significant role in the genesis of these lesions_ Recent work on the aging ACI/Seg rat reveals a high frequency of spontaneous development of prostatic carcinoma_ss-ss Histopathologic studies have found a sequential series of steps which culminate in grossly manifest prostatic cancer, indicating a multistep process_ Interestingly, substantial alteration of the testosterone: estrogen serum ratio with malignancy supports the promotive role of steroid hormones In carcinogenesis.ss The Lobund-Wistar rat has a 10% incidence of prostatic carcinoma with metastases when raised in a germ-free environment ss Recently, Pollard et al demonstrated prevention of the developm ent of primary and metastatic tumors in this rat model by feeding synthetic retinoids (N-[4-hydroxyphenyl) retinamide)_S9 Bostwick -14- Figure 4: Suggested diagnostic response to PIN and AAH. Clinical Evaluation and Significance of PIN The clinical importance of recognizing PIN is based on its strong association with prostatic carcinoma. Because PIN has a high predictive value as a marker for adenocarcinoma, its identification in biopsy specimens of the prostate warrants further search for concurrent invasive carcinoma . This is particularly true for hi.gh grade PIN; if these lesions are identified by the pathologist, close surveillance and follow-up appears to be indicated. In a series of 21 patients with PIN identified on prostate biopsy because of abnormal findings by digital rectal examination, 12 {57%) had carcinoma identified on second biopsy;so these results were confirmed in another study of 12 patients.s1 Carcinoma was observed in 39% of 104 follow-up aspiration biopsies of patients with an original diagnosis of PIN 3, according to Park et al, and an additional 35% had recurrent PIN. 52 Of 48 patients with clinical suspicion of cancer and negative aspiration biopsies, follow-up aspiration revealed PIN in 15 (31%) and invasive carcinoma in 8 {17%). In another study of PIN diagnosed by fine needle aspiration, 13 of 32 patients with high grade PIN developed cancer compared with 3 of 23 with low grade PIN; the patients were followed for 18 months with re-biopsy.s3 These data underscore the strong association of PIN and adenocarcinoma and indicate that vigorous diagnostic follow-up is needed. When PIN is encountered in prostatic specimens, all tissue should be embedded and made available for examination; serial sections · of.. suspicious foci may be useful. Basal cell-specific anti-keratin antibodies such as .3513-E12 (high molecular weight keratin) can be used to stain tissue sections lor the presence of basal cells. Unfortunately, needle biopsy specimens and cytologic specimens sometimes fail to show the suspicious focus on deeper levels, confounding the Bostwick -15- diagnostic dilemma. Biopsy remains the definitive method for detecting PIN and early invasive cancer, but non-invasive methods are being evaluated. By transrectal ultrasound, PIN has been reported as being hypoechoic, indistinguishable from carcinoma.35,64 Transrectal ultrasound--directed biopsy allows localization of the needle and tissue being sampled. Repeat biopsy has been suggested by some authors if the first attempt is unrevealing. Serum PSA levels may be elevated in patients with PIN, according to Brawer et a1,ss although these findings have not been confirmed. If all procedures fail to identify coexistent carcinoma, close surveillance and follow-up appear to be indicated. Follow-up is suggested at six month intervals for two ye"ars, and thereafter at twelve-month intervals for lif e.3 The pathologist must have an understanding of the criteria for separating PIN from benign and malignant mimics, and should report the presence, severity, and extent of these lesions. Because our understanding and recognition of PIN i s recent, some have suggested that only high grade PIN be reported to avoid diagnostic and therapeutic confusion, and this suggestion seems appropriate. Only through identification and reporting of premalignant lesions can further investigations be insured and pe riodic examinations undertaken. In difficult and borderline situations, the pathologist should communicate closely with the urologist and report as much information as possible. Most authors agree that the identification of premalignant lesions in the prostate should not influence or dictate therapeutic decisions. PIN also offers promise as an intermediate end-point in studies of chemoprevention of prostatic carcinoma. Recognizing the slow growth rate of prostate cancer and the considerable amount of time needed in animal and human studies for adequate follow-up, the non-invasive precursor lesion PIN would be a suitable intermediate histologic marker to indicate subsequent likelihood of cancer. References 1 . Bostwick DG. Prostatic lntraepithelial Neoplasia (PIN). Urology 1989 (Suppl); 34:16- 22. 2. Bostwick OG, Brawer MK. Prostatic Intra-Epithelial Neoplasi·a and Early Invasion in Prostate Cancer. Cancer 1987; 59:788-794. 3. Bostwick DG. The Pathology of Early Prostate Cancer. Ca-A Cancer Journal for Clinicians 1989: 39:376-393. 4. Bostwick DG. Premalignant Lesions of the Prostate. Sem Diag Pathol 1988; 5:240-253. Bostwick -16- 5. Bostwick DG, Srigley J. Premalignant Lesions. In: Bostwick DG (Ed). Pathology of the Prostate, Churchiii-Uvingstone, New York 1990; pp 37-59. 6. Boone CW. Kellolt G.l, Steele 'IJ. Histopathology ol \he Premalignant Process. Cancer Bul\ 1991; 43:481-484. 7. Drago JR, Mostofi FK, Lee F. Introductory Remarks and Workshop Summary. Urology 1989; 34(Suppl):2-3 8. McNeal JE, Bostwick DG. Intraductal Dysplasia: A Premalignant Lesion of the Prostate. Hum Pathol 1986; 17:64-71. 9. Kovi J, Mostofi FK, Heshmat MY, Enterline JP. Large Acinar Atypical Hyperplasia and Carcinoma of the Prostate. Cancer1988; 61:555-561. 10. Srigley JR. Small-Acinar Patterns in the Prostate Gland with Emphasis on Atypical Adenomatous Hyperplasia and Small-Acinar Carcinoma. Sem Diag Pathot 1988; 5:254-272. 11. Mostofi FK. Precancerous Lesions of the Prostate. In: Carter RL (Ed). Precancerous States. Oxford University Press, New York 1984; pp 304-316. 12. Miller A, Seljelid R. Cellular Atypia in the Prostate. Scand J. Urol Nephrol 1971; 5:17- 21. 13. McNeal JE; Alroy J, Leav I, Redwine EA, Freiha FS, Stamey TA. Immunohistochemical Evidence for Impaired Cell Differentiation in the Premalignant Phase of Prostate Cancinogenesis. Am J Clin Path 1988; 90:23-32. 1 4. McNeal JE, Leav I, Alroy J, Skutelsky E. Differential Lectin Staining of Central and Peripheral Zones of the Prostate and Alterations in Dysplasia. Am J Clin Pathol 1988; 89:41- 48. 15. McNeal JE, Villers A, Redwine EA. Freiha FS , Stamey TA. Microcarcinoma In the Prostate: Its Association with Duct-Acinar Dysplasia. Hum Pathol 1991; 22:644-652. 16. Amln MB, Dundore P, Schultz OS, Marsh W, Bostwick D. Architectural Spectrum of High Grade Prostatic lntraepithelial Neoplasia. Modern Pathol 1992; 5:50A (abstract). 17. Kovi J, Jackson MA, Heshmat MY. Ductal Spread in Prostatic Carcinoma. Cancer 1985; 56:1566-1573. 1 8. Becich MJ. In-Situ Spread (ISS) on Prostate Needle Biopsy (PNB) is Predictive of Invasive Adenocarcinoma. Modern Pathol 1992; 5:50A (abstract). 1 9. McNeal JE, Bostwick DG. Anatomy of the Prostate: Implications for Disease. tn: Bostwick DG (Ed). pathology of the prostate, Churchiii-Livingstone. New York 1990; pp 1-14. Bostwick -17- 20. Srigley J, Toth P, Hartwick RWJ. Atypical Histologic Patterns in Cases of Benign Prostatic Hyperplasia. Lab Invest 1989; 60 -90A (abstract). 21 . Bostwick DG, Cooner WH, Denis L, Jones GW, Scardino PT, Murphy GP. The Association of Benign Prostatic Hyperplasia (BPH) and Cancer of the Prostate. Cancer 1992 (July 1, Suppl). 22. Greene DR, Wheeler TM, Egawa S, et al. A Comparison of the Morphological Features of Cancer Arising in the Transition Zone and in the Peripheral Zone of the Prostate. J Ural 1991. 23. Schultz DS, Amin MB, Zarbo RJ. Type IV Collagen Basement Membrane Component of Prostatic lntraepithellal Neoplasia and Associated Carcinoma. Modern Pathol 1992; 5:59A (abstract). 24 . Barsky SH, Siegal GP, Jannona F, et at Loss of Basement Membrane Components by Invasive Tumors But Not by Their Benign Counterparts. Lab Invest 1983; 49:140-1 47 . • 25. Beckman WC Jr, Camps JL Jr, Weissman RM, et al. The Epithelial Origin of a Stromal Cell Population in Adenocarcinoma of the Rat Prostate. Am J Pathoi 1987; 128:555-5'65. 26. Boag AH, Young ID. Type IV Collagenase Expression in Prostatic Adenocarcinoma. Modern Pathol 1992; 5:51A (abstract). 27. D'Errico A, Garbisa S, Uona LA , Castronovo V, Statler-Stevenson WG , Grigioni WF. Augmentation 28. Kovi J, Mostoti FK. Atypical Hyperplasia of Prostate. Urology (Suppl)1989; 24:23-27. 29. Troncosco P, Babaian RJ , Ro JY, Grignon DJ, von Eschenbach AC, Ayala AC. Prostatic lntraepithelial Noeplasia and Invasive Prostatic Adenocarcinoma in Cystoprotatectomy Specimens. Urology (Suppl) 1989; 24:52-56. 30. Tsukamoto T, Kumamoto Y, Masumori N, Miyao N. Studies on Incidental Carcinoma of the Prostate. Nippon Hinyokika Gakkai Zasshi 1990; 81:1343-1350. 31. Sentinelli S, Rondanelli E. La Neoplasia lntraepiteliale Prostatica: Una Nuova Lesioe Displastica Della Prostata. Pathologica 1989; 81:127-137. 32. Kastendieck H, Helpap B. Prostatic •oysplasia/Atypical Hyperplasia". Urology (Suppl) 1989; 24:28-42. 33. Humphrey PA. Frazier HA, Paulson DF, Vollmer AT. Extent of Severe Dysplasia in the Prostate is Inversely Related to Pathologic Stage. Modern Pathol 1992; 5:54A (abstract). Bostwick -18- 34. Sakr WA, Haas GP, Cassin BJ, Pontes JE, Crissman JD. Prevalence of Prostatic Carcinoma in Young Males. An Autopsy Study of Age and Race Distribution. Modern Pat hoi 1992; 5:58 A. 35. Lee F, Torp-Pedersen ST, Carroll JT, Siders DB, Christensen-Day C, Mitchell AE. Use of Trans rectal Ultrasound and Prostate-Specific Antigen in Diagnosis of Prostatic In traepithellal Neoplasia. Urology (Suppl) 1989; 24:4-8. 36. Humphrey PA. Mucin in Severe Dysplasia in the Prostate. Surg Pathol 1991; 4:137-143. 37. Nagle RB, Brawer MK, Kittelson J, Clark V. Phenotypic Relationships of Prostatic lntraepithelial Neoplasia to Invasive Prostatic Carcinoma. Am J Pathol 191; 138:119-128. 38. Perlman EJ, Epstein Jl. Blood Grou.p Antigen Expression in Dysplasia and Adenocarcinoma of the Prostate. Am J Surg Pathol 1990; 14:810-818. 39. Doria M, Jin J, Wang H, Martinez R, Matthews J, Bostwick D. Glycoconjugate Expression in Hyperplastic, Dysplastic, and Malignant Prostatic Epithelium. Lab Invest 1991; 4:45A (abstract). 40. Montironi R, Braccischi A, Matera G, Scarpelli M, Pisani E. Quantitation of the Prostatic Intra-Epithelial Neoplasia. Ana)ysis of the Nuclear Size, Number and Location. Path Res Pract 1991; 187:307-314. 41 . Petein M, Michel P, Van Velthoven R, Pasteels J, Brawer MK, Davis JR, Nagle RB, Kiss R. Morpholonuclear Rel.ationship Between Prostatic lntraepithelial Neoplasia and Cancers as Ass·esed by Digital Cell Image Analysis. Am J Clin Pathol 1991; 96:628-634. 42. Sakr WA, Haas GP, Drozdowicz SM, Crissman JD. Nuclear DNA Content of Prostatic Carcinoma and lntraepithelial Neoplasia (PIN) in Young Males. An Image Analysis Study. Modern Pathol 1992; 5:58A (abstract). 43. Sarkar F, Sakr W, Drozdowicz S, Sreepathi P, Crissman J. Measurement of Cellular Proliferation in Human Prostate by AgNOR, PCNA, and SPF. Modern Pathol 1992; 5:59A (abstract). 44. Sesterhen lA, Becker RL, Avallone FA, Mostofi FK, Un TE, Davis CJ. Image Analysis of Nucleoli and Nucieolar Organizer Regions in Prostatic Hyperplasia, lntraepithelial Neoplasia, and Prostatic Carcinoma. J Urogen Pathol t 991; 1 :61-74. 45. Montironi R, Scarpelli M, Sisti S, Braccischi A, Gusella P, Pisani E, Alberti' R, Mariuzzi GM. Quantitative Analysis of Prostatic Intra-Epithelial Neoplasia on Tissue Sections. Analytical and Quantative Cytology and Histology 1990; 12:366-372. 46. Deschenes J, Weidner N. Nucleolar Organizer Regions (NOR) in Hyperplastic and Neoplastic Prostate Disease. Am J Surg Pathol 1990; 14:1 148-1155. 4 7. Helpap B. Observations on the Number, Size and Location of Nucleoli in Hyperplastic and Bostwick -19· Neoplastic Prostatic Disease. Histopathology 1988; 13:203-211. 48·. Min KW, Jin J-K, Blank J, Hemstreet G. AgNOR in the Human Prostatic Gland. Am J Clin Path 1990; 95:508. 4 9. Layfield L.J , Goldstein NS. Morphometric Analysis of Berderline Atypia in Prostatic Aspiration Biopsy Specimen. Anal Quant Cytol Histol 1991 ; 13:288-292. 50. Amin MB, Schultz OS , Zarbo RJ. Kubus J, Shaheen C. Computerized Static DNA Ploidy Analysis of Prostatic lntraepithelial Neoplasia. Modern Pathol 1991; 4:43A (abstract). 51 . Weinberg OS, Weidner N. The Relationship Between Prostatic lntraepithelial Neoplasia (PIN) and Invasive Prostatic Carcinoma St_udied by Static DNA Cytometry. Modern Pathol 1991; 4:53A (abstract). 52. Crissman JD, Sakr WA, Pontes JE. DNA Quantitation in PIN and Invasive Carcinoma of the Prostate. Modern Pathol 1992; 5:51 A (abstract). ' 53. O'Malley F, Grignon 0, Keeney M, Kerkvliet N, McLean C. DNA Flow Cytometric Studies of Prostatic lntraepithelial Neoplasia. Modern Pathol 1991; 4:50A (abstract). 54. Leav I, Ho SM. Ofner P, et al: Biochemical Alterations in Sex Hormone-Induced Hyperplasia and Dysplasia of the Dorsolateral Prostates of Noble Rats. J Natl Cancer lnst 1988; 80:1045-1053. 55. Pollard M. Spontaneous Prostate Adenocarcinoma in Aged Germ-free Wistar Rats. J Nafl Cancer lnst 1973; 51:1235. 56. Isaacs JT. The Aging ACI/Seg Versus Male Copenhagen Rat as a Model System for the Study of Prostatic Carcinogenesis. Cancer Res 1984; 44:1. 57. Ward JM, Reznick G, Stinson SF, Lattuada CP, Longfellow DG, Camerson TP. Histogenesis and Morphology of a Naturally Occurring Prostatic Carcinoma in the ACI/Seg HAP BR Rat. Lab Invest 1980; 43:51.7. 58. Shain SA, McCullough B, Nutchuck M, Boesel RW. Prostate Carcinogenesis in the AXC Rat. Oncology 1977; 34:114. 59. Pollard M. Luckert PH, Sporn MB. Prevention of Primary Prostate Cancer in Lobund Wistar Rats by N-(4-Hydroxyphenyl) retinamide1. Cancer Research 1991; 51 :3610-3611. 60. Brawer MK, Bigler SA, Sohlberg OE, Nagle RB, Lange PH. Significance of Prostatic lntraepitheliai ·Neoplasia on Prostate Needle Biopsy. Urology 1991; 38:103·107. 61 . Weinstein MH, Epstein Jl. Significance of High Grade Prostatic lntraepithelial Neoplasia (PIN) on Needle Biopsy. Modern Pathol 1992; 5:60A (abs.tract). Bostwick -20- 62. Park C, Galang C, Johennig P, et al. Follow-up Aspiration Biopsies for Dysplasia of the Prostate. Lab Invest 1989; 60:70A (abstract). 63. Markham CW. Prostatic lntraepithelial Noeplasia: Detection and Correlation with Invasive Cancer in Fine•Needle Biopsy. Urology (Suppl) 1989; 24:57-61 . 64. Shinohara K, Scardino PT, Carter SSC, Wheeler TM. Pathologic Basis of the Sonographic Appearance of the Normal and Malginant Prostate. Urologic Clinics of North America 1989; 16:675-691 0 65. Brawer MK, Lange PH. Prostate-specific Antigen and Premalignant Change: Implications for Early Detection. CA-A Cancer Journal 1989; 39:361-375. Bostwick -21 PROST AT!C INTRAEPfTHatAL NeOPlASIA {PIN): DIAGNOSTIC CRITERJA '-""'Gr... ,... l Ep.lhelial cell crOW'dlng aoo Similar lo bw 9tldo PIN; moi'G Slrltlllc:ation. wllh lrre~uJa.r crowd~no and sttatifO(ion; $1)001'<;1 . 4 pattems: luttlng, m•etooapiDary. cribriform. and tla1._ Entargfd, with ma~ size Enlal9ed: some slze al'd ""'PP varta1lon varia tion cn:mmatjn Normal lnaeased dlnll1y and ~ Raraty promlntnl OC:c:a.sionaUy to frequently latgt and prominonl, ~imilat ro Invasive carcinoma: $0metimtt multiple Intact M.ry ShOw some di$tUpeion ~ BASeJMMMBANE IR IIC: i May show $0mO disruption FREO!Jt:J'IICY OF ARCHITECTURAL PATTERNS OF HIGH GRADE PROSTATIC INTRAEPITHEUAL NEOPLASIA (PIN) Tufting Micropapillary Cribrifor m Rat Number of Cases with Each pattern crota! - 60 cases! 52 51 19 17 % of Cases wjth Each Pattern • 86.6% 85% 31.6% 28.3% Number of Eje!ds wjth Each pauem Total 332 555 100 35 Mean per case 5.53 9.25 1.67 0.58 Range per case 0-27 0-38 0-54'. 0-9 Standard Deviation per case 5.89 10.47 7.08 1.42 % of Fields/Case wjth Each Paltem Mean (Total • 100%) 32.5% 54.3% 9.8% 3.4% Range (0-1 00%) (0-100o/o) (0-100%) (0 -37.5%) Standard Deviation 30.2 31 .9 21.2 6.6 Median 33.0 55.5 0 0 ' These values are underestimates of the true frequency because many fields had more than 1 pattern present; the data were recorded as predominant pattern per field. . ..The range was 0-9 except for a single case with 54 of 57 fields of cribriform pattern of high grade PIN. Bostwick -22- ASSOCIATED HISTOLOGIC FEATURES OF HIGH GRADE PROSTATIC INTRAEPITHEUAL NEOPLASIA (PIN) # Cases (%) with # Fields of PIN(%) Mean # Fields Range of# each Feature with each Feature of PIN per Fields of PIN 1 !Total • 60 Cases) (Total • 1022 Fields) Positive Case Positive Case s 36 {60%) 88 (9%) 2.4 1-7 cular Bars 13 (22) 22 (2) 1.7 1-6 an• Bridges 18 {30) 27 (3) •1.5 1-5 I Gland Involvement 49 {82) 149 {1 5) 3.0 1-11 olnvasion 14 (23) 23 (2} 1.6 1-4 e Cystic Gland Involvement 6 (1 0} 15 (2) 2.5 1-5 ular Hyperplasia Involvement 3 {5} 3 {1} 1.0 1 I Cytoplasmic Blebs 60 (100%) 835 {82) 13.9 1-43 asmic Pigment 18 {30} 51 {5} 2.8 1-5 Cytoplasm 9 (15) 16 (2) 1.8 1·5 ocalclflcatlons 5 (8) 8 (1) 1.6 1-3 lnaceous Secrections 37 (62%) 147 (14) 4.0 1·17 raAmylacea 33 {55) 149 {15) 4.5 1·21 led Cells of PIN 24 (42) 73 {7) 3.0 1-13 alloids 2 (3) 2 (1) 1.0 1 Bostwick -23· CASE 2 ATYPICAL ADENOMATOUS HYPERPLASIA (AAH) (The following Is exc erpted f rom ATYPICAL ADENOMATOUS HYPERPLASIA (AAH) OF THE PROSTATE: Morphologic Criteria for It s Distinction from Well-Different iated Carcinoma, David G. Bostwick,John Srigley, David Grignon, John Maksem, Peter Humphrey. Theodorus H. yan dar Kwast, Oebashish Bose. Jay Harrison, Roben H. Young .. submitted) ABSTRACT Atypical adenomatous hyperplasia (AAH, or adenosis) is a localized proliferation of small glands within the prostate that may be mistaken I or carcinoma. To determine the diagnostic criteria for separating AAH from carcinoma, seven observers independently evaluated 54 selected lesions from 44 transurethral resection specimens. Three patterns of glandular proliferation were observed, all arising in association with nodular hyperplas i~: ·low-grade AAH (38 ·toci), high-grade AAH (8), and well-differentiated carcinoma (8). lnterobserver concordance was 80.7%. Of 24 architectural and cytologic features evaluated, the following were useful in separating low-grade AAH , high-grade AAH, and cancer: variation in nuclear size (14%, 22%, and 25%, respectively), mean nucleolar diameter (0.69 1-1m. 1.43 1-1m. and 1.78 IJ.m, respectively), largest nucleolar diameter (mean, 1.66 IJ.m, 2.71 J.Lm, and 2.81 1-1m. respectively), percentage of nucleoli greater than 1 1-1m in diameter (17 .6%, 58.1 %, and 77.5%, res pectively), crystalloids within suspicious glands (16%, 13%, and 75%, re spectively), luminal basophilic mucinous secretions, infiltrative borders , discontinuity of the basal cell layer in AAH (compared with complete absence in carcinoma; shown with basal cell-specific anti-keratin monoclonal antibody 34BE12 immunostaining), and intact basement membrane in AAH (compared with discontinuity in carcin oma; shown with type IV collagen immunostaining). Features that could not reliably separate- AAH from carcinoma included lesion shape, circumscription, multifocality, average gland size, variation in gland size and shape, nuclear shape, chromatin pattern, and amount and tinctorial quality of cytoplasm. Although the biologic signiiicance of AAH is uncertain, its light microscopic appearance and immunophenotype allow it to be distinguished from carcinoma in most cases. INTRODUCTION Small glandular proliferations in the prostate form a morphologic continuum ranging from benign proliferations with minimal architectural and cytologic atypia to those in which the degree of atypia is such that they are easily recognized as well differentiated adenocarcinoma. The proliferations are distinguished easily at widely spaced points of the spectrum; however, no abrupt changes are apparent along the continuum. Lesions with a degree of atypia that Bostwick -24- raises the possibility of carcinoma have recently been the subject of much interest. Despite this, criteria for their clear separation from cancer are not firmly established. Brawn noted that there were "no absolute histologic criteria to separate these two entities•, 1 and some of his photomicrographs of severe . adenosis were subsequently interpreted by others as carcinoma.2·4 Another author'ss photomicrographs of well-differentiated carcinoma were considered by one reviewer as •suspicious by all perhaps, certain by few".s Murphy wondered "if interlobular acinar carcinoma can be recognized at all". 7 Additional problems associated with AAH concern the extent to which it has, or has not, premalignant features. Circumstantial evidence supports the validity of AAH as a precursor lesion or marker tor prostatic adenocarcinoma.1.B·12 However, follow-up studies are needed to demonstrate the natural history of these lesions and to determine optimal patient management. Such studies require standardized terminology and criteria for grading these l ~slons. It is apparent from previous reports that such standardization does not exist. To define strict morphologic criteria for distinguishing AAH from well differentiated carcinoma, seven pathologists independently evaluated various light microscopic features in 54 lesions from 44 transurethral resection specimens. Immunohistochemical stains directed at the prostatic basal cell layer (basal cell-specific anti-keratin monoclonal antibody 3413E12) and basement membrane (anti-type IV collagen) were compared with the light microscopic findings. Our results suggest that the com bination of architectural, nuclear, nucleolar, and immunohistochemical features allows identification of two grades of AAH (low grade and high grade) that can be separated accurately from adenocarcinoma in most cases. DISCUSSION Atypical adenomatous hyperplasia varies in incidence from 19.6% (transurethral resection specimens)1B to 24% (autopsy series in 20 to 40 year old men). 19 It can be found throughout the prostate but is usually observed near the apex and in the transition zone and periurethral area.1s.19 Our results indicate that AAH is distinguished from well-differentiated carcinoma by the following: (1) inconspicuous nucleoli, (2) infrequent crystalloids; (3) lack of basophilic mucin, and (4) fragmented basal cell layer as seen with basal cell-specific anti-keratin antibodies (Table 3). Despite the utility of these features, the absolute distinction between AAH and carcinoma is still problematic in some cases, particularly In those with high grade AAH (see below). We found that all measures of nucleolar size all owed separation of AAH from adenocarcinoma, including mean nucleolar diameter, largest nucleolar diameter, Bostwick -25- and percentage of nucleoli greater than 1 JJ-m in diameter. The level of interobserver concordance (80.7%) was higher than expected, considering that the participating pathologists did not discuss diagnostic criteria before undertaking the study: afterward_, all agreed that nucleolar size was the single most useful feature. Such concordance is probably due to widespread acceptance of Gleason's criterion of nucleolar diameter greater than 1 J.l.m for separating well-differentiated cancer (Gleason primary grades 1 and 2) from other proliferative lesions.3 It is interesting to note that micrometer-based measurements of nucleolar size were available to only one of the pathologists (D.G.B.), and none used morphometry in reaching a final opinion, relying instead oo individual (subjective) evaluation and experience. Concordance of individual pathologists with group diagnoses ranged from 71.6% to 87.5%. Nucleoli, or chromocenters, are found in virtually all cells but are not usually considered "prominent" or enlarged in the prostatic epithelium until they measure gre'ater than 1.0 to 1.5 j.J.m in greatest dimension in routine formalin fixed sections. The prognostic significance and diagnostic usefulness of nucleolar area and size in prostatic carcinoma have been demonstrated by various methods, including scanning electron microscopy22 and computerized image analysis.23-25 Tannenbaum et al.22 found that nucleolar diameter was a powerful discriminant of cancer when compared with benign prostatic epithelium. Hoda and Reed24 showed that nucleoli in AAH were intermediate in size between nodular hyperplasia and well-differentiated adenocarcinoma and that only cancer had two or more nucleoli in an individual cell. Similarly, Ke leman el a1.2s found that nucleolar prominence separated AAH from carcinoma; however, they considered a nucleolus prominent when the diameter was 3 (lm or greater, considerably larger than that observed by Socking et al.26 (1.88 J.Lm), Gleason3 (1 J.J.m), Tannenbaum et al (2.4 JJ-m2 surface area ),22 Deschenes and Weidner1o (AAH, 0.79 J,Lm; Gleason grades 2 and 3 cancer, 1.60 IJ.m), Montironi et al.,23 and us. Conversely, Layfield and Goldstein27 failed to find any nucleoli >1.8 Jlm in diameter in benign or low-grade malignant fine needle aspirates. Interestingly, Keleman et aJ.2S also found no significant difference in nucleolar diameter be.tween AAH and normal and hyperplastic epithelium. Various other morphologic features were not useful in distinguishing AAH from adenocarcinoma, including lesion shape, circumscription, multi focal ity, average gland size, variation in gland size antd shape, chromatin pattern, and the amount and tinctorial quality of the cytoplasm. Immunohistochemistry is also valuable in the diagnosis of AAH. Our study showed that the basal cell layer is characteristically discon~inuous and fragmented in both grades of AAH, a feature that can be demonstrated immunohistochemically to separate AAH from carcinoma; these results agree with those of others.13-14.28-31 The basal ce ll layer of the prostate is absent in Bostwick -26- cancer but intact although occasionally fragmented in prostatic intraepithelial neoplasia, a useful diagnostic feature that can be demonstrated immunohistochemically in routine formalin-fixed sections with basal cell specific anti-keratin (high molecular weight keratin antibodies (34BE12]}.14.32 The type IV collagen-immunoreactive basement membrane aa appeared to be normal in AAH and decreased in carcinoma, although this was a difficult feature to evaluate due to the intense stromal and vascular smooth muscle immunoreactivity. Other phenotypic markers also may be of value in separating AAH from carcinoma, such as acid mucin stains;3t.34-3S however, acid mucin is not specific for malignancy.34 There is no standard terminology for the small glandular proliferations of the prostate that we refer to as "AAH", and consensus may be difficult to reach until more Is known of their prognostic significance. We recommend this term but recognize that there is a morphologic spectrum encompassing low,-g rade and high- grade lesions. We think that the term "adenosis", if used at all, should be limit ed to obviously benign lesions with little or no nucleolomegaly. The greatest difficulty in distinguishing AAH from carcinoma is with lesions containing nucleoli intermediate in size between benign and malignant.3 To accommodate th is borderline group, we recommend separating AAH into low-grade (clearly beni gn) and high-grade (possibly benign, but having some features of carcinoma) lesions. We found that three grades of AAH 1 were cumbersome and unnecessary. Importantly, our high grade AAH category, despite showing enlarged nucleoli, maintained a fragmented basal cell layer on keratin immunostaining similar to that noted with low grade AAH. Furthermore , this group of cases caused considerable discordance among observers. In view of the uncertainty of the nature of high grade AAH, some pathologists may prefer a more non-committal term such as "atypical small acinar proliferation, not further classified," to categorize these lesions. Histologic mimics of AAH include simple lobular atrophy, postatrophic hyperplasia, sclerosing atrophy, basal cell hyperplasia,20-21 atypical basal ce II hyperplasia, 21 and metaplastic changes associated with radiation, infarction, and prostatitis. Many of these mimics can display architectural and cytologic atypia, including nucleolomegaly; thus, caution is warranted in interpretation of scant specimens, cauterized or distorted specimens, and specimens submitted with incomplete patient history. Atypical adenomatous hyperplasia may be uncommonly associated wi th sclerosis, but further study is needed to determ ine the relationship of this lesion to sclerosing adenosis,a0-31 ,36-42 Sclerosing adenosis differs from AAH by a striking myoepithelial metaplasia of the basal cell compartment as well as an exuberant stroma composed of fibroblasts and loose ground substance. The basal cells in this condition show positivity for S-1 00 protein and muscle specific Bostwick -27- actin and demonstrate thin filament collections and dense bodies on electron microscopy.20,30·31,42 This immunophenotype is unusual in the prostate, because normal prostatic basal cells do not demonstrate myoepithelial differentiation consequently, most authors believe that sclerosing adenosis is a fo rm of meta pi asia. 20,31 ,36·38,42·43 AAH should also be distinguished from lobular atrophy and post-atrophic hyperplasia. Both of these lesions tend to have a low power lobular organization. Simple atrophy consists of shrunken glands which demonstrate strong basal cell specific keratin positivity. Post-atrophic hyperplasia may cause difficulties since proliferating luminal cells with small amounts of clear cytoplasm may be seen in an atrophic background. These cells may demonstrate some degree of cytologic atypia and luminal mucin · may be identified. In general, strong basal cell-specific keratin staining is maintained, in contrast to AAH where a fragmented pattern is usually seen. , Three significant unanswered questions remain. First, does high-grade AAH represent underdiagnosed adenocarcinoma? Six of the 8 cases considered high· grade AAH in our study created considerable diagnostic discord among the participants. Critics could reasonably argue that the lack of concordance for this lesion in our study indicates that it is not a distinct entity but merely a reflection of our uncertainty; also, the criteria for distinguishing the two grades of AAH may be difficult to apply in practice. We agree that there are valid issues that require further study, although we currently believe that high-grade AAH is a useful diagnostic category for those lesions with features intermediate between low-grade AAH and well-differentiated carcinoma as described. Our study has attempted to define the diagnostic criteria along this morphologic continuum to allow for valid comparisons among different observers. Second, does Gleason primary grade 1 adenocarcinoma represent overdiagnosed adenocarcinoma? These lesions, like high-grade AAH, are uncommon. Most would agree that Gleason primary grade 2 adenocarcinoma (infiltrating glands} Is malignant, but what is the true biologic potential of the uniform circumscribed proliferation of Gleason primary grade 1 adenocarcinoma? Presently, we consider these to be malignant, following the suggestions of Gleason and others.3 Third, is AAH a precursor of adenocarcinoma? AAH has been proposed as a premalignant lesion of the prostate because of the following: increased incidence in association with carcinoma (15% in 100 prostates without carcinoma at autopsy, and S1% in 100 prostates with cancer at autopsy), 1 ,a,19 .44,45 topographic relationship with small-acinar carcinoma, a. 12 age peak incidence that proceeds that of carcinoma,s increasing AgNOR count,10· 11 increased nuclear area and diameter,46 and a proliferative cell index that is similar to that of small-acinar carcinoma but significantly higher than that of Bostwick -28- normal and hyperplastic prostatic epithelium.47 Brawn showed that cancer developed in 7 of 108 patients with adenosis (6.5%) within 5 to 15 years, compared with 84 of 2,263 patients with hyperplasia (3.7%), although no "absolute" criteria were identified to separate his cases of severe adenosis from carcinoma. I Conversely, some authors claim that the link between cancer and AAH is an epiphenomenon and that the data are insufficient to conclude that AAH is a premalignant lesion. I S It has also been suggested that AAH may be related to the subset of cancers that arise in the transition zone in association with benign prostatic hyperplasia .4B Although the biologic significance of AAH is uncertain, its light microscopic appearance and immunophenotype allow it to be separated from carcinoma. When AAH is encountered in prostatic specimens, we believe that all tissue should be embedded and made available for examination; serial sections of suspicious foci may be useful. Unfortunately, needle biopsy speci{Tiens and cy1ologic specimens frequently fail to show the suspicious focus on deeper levels, confounding the diagnostic dilemma. The identification of low-grade or high-grade AAH shoul d not influence or dictate therapeutic decisions; however, the clinical importance of th ese lesions is not understood, and close surveillance and follow-up appear to be indicated, particularly for high-grade AAH.46 REFERENCES 1 . Brawn PN. Adenosis of the Prostate: A Dysplastic Lesion that Can Be Confused with Prc~tate Adenocarcinoma. Cancer 1982; 49:826-833. 2. Bostwick OG, Srigley J. Premalignant Lesions. In: Bostwick OG (Ed). Pathology of the Prostate, Churchiii-Livingstone, New York 1990; pp 37·59. 3. Gleason OF. Atypical Hyperplasia, Benign Hyperplasia, and Well-Differentiated Adenocarcinoma of the Prostate. Am J Surg Pathol 1985; 9:53-67. 4 . Bonnett BM, Epstein Jl. A Case Showing Sclerosing Adenosis and an Unusual Form of Basal Cell Hyperplasia of the Prostate. Am J Surg Palhol 1989; 13:866-872. 5. Epstein Jl. Prostate Biopsy Interpretation. Raven Press, NY 1989, p 99-112. 6. Rosen S. Prostatic Biopsy Interpretation (book review) Am J Surg Pathol 1991 ; 15:203. 7. Murphy WM. Urological Pathology. W. B. Saunders Company, Philadelphia, PA 1989. p 184. 8. Kovi J. Microscopic Differential Diagnosis of Small Acinar Adenocarcinoma of Prostate. Pathol Annu 1985; 20:1 57·179. Bosrwick -29· 9. Helpap B. Observations on the Number, Size, and Localization of Nucleoli in Hyperplastic and Neoplastic Prostatic Disease. Histopathol 1988; 13:203·21 1. 1 o. Deschenes JH, Weidner Noel. Nucleolar Organizer Regions (NOR) in Hyperplastic and Neoplastic Prostate Disease. Am J Surg Pathol1990; 14:1148·1155. 11. Ghazizadeh M, Sasaki Y, Oguro T, Aihara K. Silver Staining of Nucleolar Organizer Regions in Prostatic Lesions. Histopathol 1991; 19:369-372. 12. McNeal JE. Origin and Development of Carcinoma of the Prostate. Cancer 1969; 28:24· 34. 13. Brawer MK, Peehl OM , Stamey TA, eostwick DG. Keratin Immunoreactivity in Benign and Neoplastic Human Prostate. Cancer Res 1985; 45:3665·3669. 1 4. Bostwick DG, Brawer MK. Prostatic lntraepithelial Neoplasia and Early Invasion in Prostate Cancer. Cancer 1987; 59:788. 15. Havenith MG, Arends JW, Simon R, Volovics A, Wiggers T, Bosman FT. Type IV Collagen Immunoreactivity in Colorectal Cancer. Cancer 1988; 62:2207·2211. 16. Hochberg Y, Tamhane AC. Multiple Comparjsoo Procedures, John Wiley, NY (1987), pp 76·77. 17. Gleason OF. Histologic Grading of Prostatic Carcinoma. In: Bostwick DG (Ed). Pa!holooy of lhe Prostate, Curchiii-Livlngstone, New York 1990; pp 83·93. 18. Srigley J, Toth P, Hartwick RWJ. Atypical Histologic Patterns in Cases of Benign Prostatic Hyperplasia. Lab Invest 1989; 60:90A. 19. Brawn PN, Speights VO, Conlin JU, Bayardo RJ, Kuhl DL Atypical Hyperplasia in Prostates of 20 to 40 Year Old Men. J Clin Pathol 1989; 42:383·386. 20. Grignon OJ, Ro JY, Ordonez NG, Ayala AG, Cleary KR. Basal Cell Hyperplasia. Adenoid Basal Cell Tumor, and Adenoid Cystic Carcinoma of the Prostate Gland: An Immunohistochemical Study. Human Pathol 1988; 19:1425·1 433. 21 . Devaraj LT , Bostwick DG. Atypical Basal Cell Hyperplasia of the Prostate: lmmunophenotypic Profile and Proposed Classification of Basal Cell Proliferations. Am J Surg Pathol (in press). 22. Tannenbaum M, Tannenbaum S, DeSanctis PN, Olsson CA. Prognostic Significance of Nucleolar Surface Area in Prostate Cancer. Urol 1982; 19:546-551. 23. Montironi R, Scarpelli M, Sisti S, Braccischi A, Gusella P, Pisani E, Alberti R, Mariuzzi GM. Quantitative Analysis of Prostatic lntraepithelial Neoplasia on Tissue Sections. Anal Quant Cytol Histol 1990; 12:366·372. Bosrwick -30- 24. Hoda SA, Reed RJ. Morphologic Characteristics of Nucleoli in the Differential Diagnosi.s of Well-Differentiated Prostatic Adenocarcinoma. Am J Clin Pathol 1991; 95:271 (abstract). 25. Kelemen PR, Buschmann RJ, Weisz-Carrington P. Nucleolar Prominence as a Diagnostic Variable in Prostatic Carcinoma. Cancer 1990; 65:1017-1020. 26. Socking A, Auffermann W, Schwarz H, Bammen J, Dorrjer G, Vucicuja S. Cytology of Prostatic Carcinoma: Quantification and Validation of Diagnostic Criteria. Analyt Quant Cytol 1984; 6:74-88. 27. Layfield W, Goldstein NS. Morphometric Analysis of Borderline Atypia in Prostatic Aspiration Biopsy Specimens. Anal Quant Cytol Histol 1991; 13:288-292. 28. O'Malley FP, Grignon OJ, Shum DT. Usefulness of Jmmunoperoxidase Staining with High Molecular-Weight Cytokeratin in the Differential Diagnosis of Small-Acinar Lesions of the Prostate Gland. Virchows Archiv(A) Pathol Anat 1990; 417:191-196. 29. Hedrick L, Epstein Jl. Use of Keratin 903 as an Adjunct in the Diagnosis of Prostate Carcinoma. Am J Surg Pathol 1989; 13:389-396. 30. Sakamoto N, Tsuneyoshi M, Enjoji M. Sclerosing Adenosis of the Prostate. Histo pathologic and Immunohistochemical Analysis. Am J Surg Pathol 1991; 15:660-667. 31 . Jones EC, Clement PB, Young RH. Sclerosing Adenosis of the Prostate Gland. A Clinicopathologic and Immunohistochemical Study of 11 Cases. Am J Surg Pathol 1991; 15:1171-1180. 32. Amin MB, Schultz OS, Zarbo RJ. Analysis of Cribriform Morphology in Prostate Neoplasia Using Anitbody to High Molecular Weight Cytokeratins. Modern Palhol 1992; 5:50A (abstract). 33. Fuchs ME, Brawer MK, Rennels MA, Nagle RB. The Relationship of Basement Membrane to Histologic Grade of Human Prostatic Carcinoma. Modem Pathol 1989; 2:105-111. 34. Humphrey PA. Mucin in Severe Dysplasia in the Prostate. Surg Patho l 1991 ;4:137-143. 35. Ro JY. Grignon OJ. Troncoso P, Ayala AG. Mucin in Prostatic Adenocarcinoma. Semin In Diag Pathol 1988; 5:273-283. 36. Srigley JR. Small-Acinar Patterns in the Prostate Gland With Emphasis on Atypical Adenomatous Hyperplasia and Small-Acinar Carcinoma. Semin in Diag Pathol 1988; 5:254-272. 37. Young RH, Clement PB. Sclerosing Adenosls of the Prostate. Arch Pathol Lab Med 1987; 11 :363-366. Bostwick -31- 38. Collina G. Botticelli AR, Martinelli AM, Fano RA, Trentini GP. Sclerosing Adenosis of the Prostate . Report of Three Cases with Electronmicroscopy and Immunohistochemical Study. Histopathol 1992; 20:505-51 o. 39. Sesterhenn lA, Mostofi FK. Davis CJ . Fibroepithelial nodules of the prosta te simulating carcinoma (Abstract) Lab Invest 1988; 58:83A. 40. Chen KTK, Schiff JJ. Adenomatoid Proslatic Tumor. Urology 1983; 21 :88-89. 41 . Hulman G. 'Pseudoadenomatoid' Tumor of Prostate. Histopathol 1989; 14:317-323. 42. Grignon DJ, Ro JY, Srigley JR, Troncoso P, Raymond AK, Ayala AG. Sclerosing Adenosis of the Prostate Gland. A Lesion Showing Myoepithelial DlHerentlatlon. Am J Surg Pathol 1992: 16;383-391. 43. Srigley JR, Dardicl< I, Hartwick RWJ, Kotz L. Basal Epithelial Cells of Human Prostate Gland are Not Myoepithelial Cells. A Comparative Immunohistochemical and Ultrastructral Study With Human Salivary Gland. Am J Surg Pathol 1990: 136:957. 44. McNeal JE. Bostwick DG. Intraductal Dysplasia: A Premalignant Lesion of the Prostate. Hum Pathol 1986: 17:64-71. 45. Tsukamoto T. Kumamoto Y, Masumori N, Miyao N. Studies on Incidental Carcinoma of the Prostate. Nippon Hinyo Gakki Zasshi 1990; 81:1343-1350. 46. Aragona F, Franco V, Rodolioo V, Dardanani G, Cabibi D, Melloni D, Pavone C, Campesi G, Pavone-Macaluso M. Interactive Computerized Morphometric Analysis for the Differential Diagnosis Between Dysplasia and Well Differentiated Adenocarcinoma of th e Prostate. Urol Res 1989; 17:35-40. 4 7. Helpap B. The Biological Significance of Atypical Hyperplasia of the Prostate. Virchows Arch A Path Histol 1980: 387:307-317. 48. Bostwick DG, Cooner WH , Denis L, Jones GW, Scardino PT, Murphy GP. The Association of Benign Prostatic Hyperplasia and Cancer of the Prostate. Cancer 1992; 70:291 -301. Bostwick -33- CASE 3 GRANUOMATOUS PROSTATITIS Granulomatous prostatitis is a group of morphologically distinct forms of chronic is made after routine digital examination and biopsy. The majority of patients (71 %) have a prior history of urinary tract infection up to 34 weeks prior to diagnosis. Digital rectal examination reveals diffuse induration (80%) or hard, fixed, localized nodules (20%), with clinical suspicion of malignancy in up to 77% of patients. Urinalysis shows pyuria (82%) and hematuria (46%). Laboratory studies are usually not helpful in the diagnosis, with normal serum acid phosphatase and alkaline phosphatase levels, erthocyte sedimentation rate, and hematology studies. Excretory urogram may reveal non-specific prostatic obstruction. Biopsy is required for definitive diagnosis. The clas.sification of granulomatous prostatitis is controversial. Idiopathic (non-specific) granulomatous prostatitis ("of unknown cause") comprises the majority of cases (69%), and should be differentiated from other causes of granulomatous prostatitis due to significant differences in treatment and clinical outcome (see Table). Towfighi et al proposed a classification based on histopathologic findings which divided non-specific granulomatous prostatitis into two categories: eosinophilic and non-eosinophilic. Each category was subdivided into those with and without fibrinoid necrosis and vasculitis. The association of eosinophilic granulomatous prostatitis with an allergic and asthmatic history, particularly when fibrinoid necrosis and vasculitis were present, led Towfighi et al and other authors to classify such forms of prostatitis as allergic. Epstein and Hutchins observed that eosinophilic prostatitis was also frequently seen in patients with no allergic or asthmatic history, regardless of the presence of fibrinoid necrosis and necrobiotic granulomas. They concluded that eosinophilic granulomatous prostatitis could be attributed to many causes, and should not be considered synonymous with allergic granulomatous prostatitis (see below), a view shared by subsequent authors. A new classification was proposed, based on clinical and pathologic findings: specific, non-specific, post-transurethral section, malakoplakia, sarcoid, and allergic. Stillwell et al emphasized the separation of systemic granulomatous disease-associated cases of granulomatous prostatitis from other causes due to significant differences in treatment and prognosis. Infectious Granulomatous Prostatitis Numerous microorganisms can induce granulomatous prostatitis, including bacteria, fungi, parasites, and viruses (see Table). Bostwick -34- CLASSIFICATION OF GRANULOMATOUS PROSTATITIS (MODIFIED FROM LOPEZ-PLAZA AND BOSTWICK, 1990) I. Infectious A. Bacterial 1. Tuberculosis 2. Brucellosis 3. Syphilis B. Fungal 1. Coccidioidomycosis 2. Cryptococcosis 3. Blastomycosis 4. Histoplasmosis 5. Para=idiodomycosis C. Parasitic 1. Schistosomiasis 2. Ecbi!!ococcus 3. Enterobius 4 . Ungua!Uia D. Vi ral 1. Herpes zoster II. {atroqeajc A. Post-surgical B. Postradiation c. BCG-associated Ill. Malakoplakia IV. Svstemjc Granulomatous Disease A. Allergic ("eosinophilic") B. Sarcoidosis C. Rheumatoid D. Autoimmune/Vascular 1. Wegener's granulomatosis 2. Polyarteritis nodosa 3. Benign lymphocytic angiitis and granulomatosis (SLAG) V. Idiopathic ("non-specific") Bostwick -35- Bacterial When observed, Mycobacterium tuberculosis infection of the prostate is only seen after pulmonary and miliary infection. Microscopically small 1-2 mm caseating granulomas coalesce within the prostatic parenchyma, forming yellow nodules and streaks. Caseation and cavitation can be extensive. Acid-fast stain (Ziehi-Neelsen} and fluorescent stains may be useful in identifying organisms within granulomas.The histologic appearance may be identical to BCG-induced granulomatous prostatitis. Although rare, involvement of the prostate by brucellosis can mimick tuberculosis clinically and pathologically. Brucella is a gram-negative coccobacillus which is not acid-fast. It is best identified in tissue by MacCallum Goodpasture stain; cultures are usually negative. Syphilitic granulomatous prostatitis, due to Treponema pa!!idum,is rare, although it was occasionally observed in the pre-antibiotic era. Fungal Mycotic infections of the •prostate are rare, and virtually always follow fungemia. Most of the deep mycoses induce necrotizing and non-necrotizing granulomas and fibrosis, but Candidiasis is usually associated with acute inflammation. Schwartz suggested that prostatic massage is useful for diagnosis due to the large number of organisms present. The prostate is involved in up to 4.6% of patients with disseminated Coccidiodomycosis. Pathologic findings include microabscesses and small granulomas, with large 30-60 micron diameter spherules containing numerous endospores wrthin giant cells, easily identified by periodic acid-Schiff and methenamine silver stains. Cryptococcosis rarely involves the prostate, but should be considered in the differential diagnosis of granulomatous prostatitis, particularly in patients with pulmonary infection. Mucicarmine stain reveals characteristic 4-7 micron diameter budding yeast with thick capsules. Blastomycosis causes granulomas and acute necrotizing inflammation. The prostate is involved in up to 11.5% of cases, with characteristic 8-15 micron diameter budding yeast within giant cells. Histoplasmosis and paracoccidiodomycosis rarely involve the prostate. Parasitic Platyhelminthes are frequent found in the prostate in patients living in tropical countries. Schistoso':Tliasis (bilharziasis} involves the prostate in 50% of males at autopsy in Zambia, and the bladder and seminal vesicles are even more frequently involved (62% and 58%, respectively}. The organisms lodge in vesicular and pelvic venous plexuses as the final habitat. The adult female Bostwick -36- migrates into the submucosa of the urinary bladder and prostatic stroma, where she lays eggs that induc,e granuloma formation and fibrosis. Rare cases have been associated with adenocarcinoma. Involvement of the prostate by echinococcus is characterized by hydatid cysts with prominent fibrosis. Other unusual parasites in the prostate have been reported, including Enterobius and Linguatula, both inducing granulomatous prostatitis. Interestingly, the prostate is widely and heavily infiltrated by eosinophils in these infections, with marked peripheral eosinophilia. Viral Herpes zoster infection in association with granulomatous prostatitis was first reported by Clason et al. In their two cases, acute urinary retention occurred within days of sacral eruption of herpes zoster. Transurethral resection of the prostate demonstrated caseating granulomas typical of herpes, although ' no inclusion bodies were identified; the bladder was uninvolved. Spontaneous micturition occurred following l'UR. Iatrogenic Granulomatous Prostatitis Post-Surgical Necrotizing rheumatoid-l ike granulomas occur up to 5 years after TUR and needle biopsy due to cauterization and surgical disruption of tissues. The granulomas are characteristically circumscribed, rimmed by palisading histocytes with central fibrinoid necrosis. Multinucleated giant cells are frequently but not invariably present, and are usually of the foreign body type, although occasional Toulon's and Langhans's types may be present. No polarizable or birefringent foreign material is observed. Mies et al noted that prostatic glands and ducts were not disrupted in post-surgical granulomatous prostatitis, unlike non-specific granulomatous prostatitis. Post-surgical granulomas are usually focal, and should be differentiated from other forms of granulomatous prostatitis which are diffuse and more serious clinically. A similar post-surgical granulomatous lesion occurs in the kidney and other organs. The striking histologic resemblance of post-surgical granulomatous prostatitis to rheumatoid nodules suggest a hypersensitivity reaction or cell mediated immune response. Tissue eosinophilia is present in many cases, and this finding has probably been misinterpreted as allergic prostatitis in the past, particularly in patients without a history of allergy or asthma. Epstein and Hutchins noted that eosinophils were most prominent in early lesions of post surgical granulomatous prostatitis, and decreased in number with time. No treatment is necessary for post-surgical prostatitis. Bosrwick -37- Ppstradiation Granulomatous inflammation is a rare complication of radiation therapy. Bacillus Calmette-Guerin {BCG) Induced Since its clinical introduction in the U.S. in t976, intravesicular E03 Immunotherapy has been shown to decrease the recurrence rate and progression of superficial transitional cell carcinoma of the bladder. Complications of this therapy include granulomatous prostatitis, urethritis, hepatitis, cystitis, and pneumonitis. Oates et al identified granulomatous prostatitis in 100% of 13 BeG treated patients undergoing prostatic biopsy for nodular hyperplasia and carcinoma. BCG-induced granulomas are characteristically discreet, wi th and without necrosis. There is no evidence of tissue eosinophilia. Acid-fast bjlcilli may be identified, particularly within necrotizing granulomas, similar to tuberculous prostatitis. Fine needle aspiration cytology is useful in establishing the diagnosis. No therapy is required. Recognition of th is entity is necessary to avoid diagnostic and therapeutic confusion. Malakoolakia Malakoplakia is a granulomatous disease due to defective intracellular lysosomal digestion of bacteria. It is most commonly found in the bladder and urinary tract, and occasionally presents in the prostate. Patients have obstructive symptoms, including frequency, urgency, dysuria, nocturia, and fever. It occurs in men over 50 years of age with systemic illnesses and other debilitating conditions. Digital rectal examination reveals diffuse induration suggestive of prostatic carcinoma. f. ~ is commonly isolated from urine cultures. Prostatic involvement by malakoplakia is characterized by discreet and confluent soft yellow-brown plaques, with central umbilication or ulceration and peripheral hyperemia. Microscopicall y, the prostatic architecture is effaced by dense sheet-like aggregates of hi stocytes (Van Hansemann cells) admixed with lymphocytes and plasma cells. Intracellular and extracellular Michaelis Gutmann bodies are identified, appearing as sharply demarcated spherical structures with concentric •owl's eyes: measuring 5 to 10 microns in diameter. Michaelis-Gutmann bodies stain with th e following: PAS (polysaccharides) Ali zarin red (calcium), Prussian blue (Iron), and Von Kossa (anionic component of calcium ions). Gram stain, acid-fast stain, and fungal stains are negative. Electron microscopy shows degenerating bacteria within phagolysomes, with progressive calcification and maturation of these Michaelis-Gutmann bodies. Biopsy is necessary fo r diagnosis. Recommended treatment is long term Bostwick -38 antibiotic therapy directed against .!;. ~ . Surgery is occasionally useful when disease progresses despite antibiotic therapy. Systemic Granulomatous Disease Allergic ("eosinophilic") Allergic granulomatous prostatitis is a clinicopathologic entity which requires the following features for diagnosis: clinical history of asthma or allergy with peripheral eosinophila and systemic lesions (Churg-Strauss syndrome); histologic identification of eosinophilic granulomatous prostatitis with fibrinoid necrosis and vasculitis; prostatic lesions which usually correlate with exacerbation of asthma or allergies. Allergic granulomatous prostatitis can be confused histologically with po-st-surgical granulomatous prostatitis and parasitic granulomatous prostatitis due to the presence of tissue eosinophilia. The first reported case of allergic granulomatous prostatitis ,was in a patient with a history of asthma whose symptoms increased in severity in association with acute urinary obstruction. Systemic granulomas were found at autopsy, involving the seminal vesicles, bladder, rectum, heart, and esophagus. Of 12 documented cases reviewed by Epstein and Hut chins, 9 had active asthma when the prostatic granulomas were first identified, 4 had peripheral eosinophilia, and 3 had extra-prostatic granulomas, eosinophilic infiltrates, or systemic allergic reactions. Allergic granulomatous prostatitis has been successfully treated with steroids. This exceedingly rare condition Is reflective of a more generalized allergic reaction, and should be diagnosed with caution, only after complete clinical and pathologic evaluation. Sarcoidosis Non-necrotizing granulomas are rarely observed in the prostate in patients with sarcoidosis. Rheumatoid Nodules The discrete linear necrotizing granulomas of post-surgical granulomatous prostatitis are histologically identical to rheumatoid nodules. The recent widespread identification of post-surgical granulomas calls Into question the diagnosis of older cases of rheumatoid-like nodules in the prostate, although rheumatoid involvement in the prostate would not be unexpected in such a systemic disease. Autoimmune-Vascular The clinical diagnosis of autoimmune and vascular disease is confirmed by histologic Identification of necrotizing granulomas and vasculitis in tissue Bostwick -39- specimens from many organs, including the prostate (see below). Wegener's granulomatosis Wegener's granulomatosis is characterized by systemic necrotizing granulomas with vasculitis. It involves the upper respiratory tract, lungs, kidneys, and other organs in men and women in the fifth decade and older. Prostatic involvement is rare, occurring in 2.3-7.4% of men with Wegener's granulomatosis. Patients present with urinary obstruction, Infection, hematuria, and acute retention, usually after clinical presentation in the upper airways, lungs, or kidneys. Rarely prostatic involvement is the ini-tial clinical manifestation, although most reported cases have been diagnosed port-mortem. Rectal examination reveals diffuse enlargement of the prostate with or without areas of induration. Laboratory tests may reveal microhematuria, red cell casts, or proteinuria, features indicative of renal involvement. The sedimentation rate is frequently elevated. At cystoscopy, the. prostatic urethra has a ragged, friable mucosa. Biopsy reveals necrotizing• granulomatous prostatitis with vasculitis. Stellate and geographic granulomas are observed, rimmed by palisading histocytes and scattered multinucleated giant cells. Vasculitis involves small arteries and veins. Special stains and cultures for bacteria, fungi, and parasites are helpful in excluding other causes. Stillwell et al considered biopsy diagnosis of prostatic Wegener's granulomatosis to be mandatory. Symptomatic prostatic involvement usually responds to chemotherapy, similar to pulmonary and renal involvement, with treatment consisting of cyclophosphamide and steroids. TUR may also be helpful. Other vasculitides may involve the prostate, including, polyarteritis nodosa. Idiopathic Idiopathic (non-specific) granulomatous prostatitis composes the majority of cases of granulomatous prostatitis (69%). As suggested by Stillwell et al, classification of eosinophilic and non-eosinophilic categories is probably not helpful. It is important to recognize the wide variety of i nciling agents of granulomatous prostatitis and the occasional histologic clues which allow distinction of these different entities, but most cases will elude definitive classification. Granulomatous prostatitis probably originates in blockage of prostatic ducts and stasis of secretion, regardless of etiology. The epithelium is destroyed, and cellular debris, bacterial toxins, and prostatic secretions escape into the stroma, eliciting an intense localized inflammatory response. Prostatic secretions include corpora amylacea, sperm, and semen pro·ducts. This process is siniilar to intraprostatic sperm granuloma formation. Recent evidence indicates Bostwick -40- that granulomatous prostatitis is not a late stage of chronic prostatitis. In idiopathic granulomatous prostatitis, the granulomas are usually non caseating. The inflammation resolves slowly, producing areas of parenchymal loss with marked fibrosis. Fox described a form of non-necrotizing granulomatous prostatitis composed of histocytes which he termed nodular histiocytic prostatitis. Treatment has Included steroids, antihistamines, antibiotics, and surgery. As described above, specific infections, systemic diseases, and other causes should receive treatment appropriate to the condition. As Sti llwell et al noted, up to 10o/o of patients with idiopathic granulomatous prostatitis will be refractory to conservative management, with severe prostatic obstruction, and such patients may warrant TUR. However, surgery is unsuccessful in up to 50o/o of cases, with several patients requiring multiple procedures. Non-specific local therapy is probably the treatment of choice, including sitz baths, lluids, and temporary urinary catheterization as necessary. Spontaneous remissions occurs in the majority of patients, although induration may persist on physical examination for years. Adenocarcinoma may deVelop as a late complication, but most authors do not consider granulomatous prostatitis as a cause of malignancy. REFERENCES Lopez·Pia.J:a I and Bostwick DG: Prostatitis. In: Bostwick DG (Ed) Pathology of the prostate, Churchill Livingstone. NY,NY, 1990. Stillwell TJ, Engen DE, Farrow GM: The clinical spectrum of granulomatous prostatitis: a report of 200 cases. J Urol 138:320·323. 1987. · Towfighi J, Sadeghee $,Wheeler JE and Enterline HT: Granulomatous prostatitis with emphasis on the eosinophilic variety. Am J Clln Pathol 58:630·641 , 1972. Stewart MJ, Wray S, Hall M: Allergic prostatitis in asthmatics. J Pathol Bacterial 67:423·430, 1954. Yonker RA and Katz P: Necrotizing granulomatous vasculitis with eosinophilic infiltrates limited to the prostate. Am J Med 77:362·364, 1984. Epstein Jl, and Hutchins GM: Granulomatous prostatitis: Distinction among allergic, non-spe.;ific, and posttransurethral resection lesions. Human Pathol 15:818·825, 1984. Kelalis PP. Greene LF, Weed LA: Brucellosis of the urogenital tract: a mimic of tuberculosis. J Urol 38:347·348, 1962. Better LF,: Brucellosis. In: Binford CH and Connor DH (Eds) Pathology of Tropical and Extraordinary Diseases. Vol 1, Armed Forces Institute of Pathology, Washington, D.C, 1976, p 174 Schwarz J: Mycotic prostatitis. Urology 19:1·5, 1982. Bostwick -41- Kuntze JR, Herman MH and Evans SG: Genitourinary coccidioidomycosis. J Urol 140:370-374, 1988. Braman RT: Cryptococcosis (Torulosis) of prostate. Urology 17:284-285, 1981. lnoshita T, Youngberg GA, Boelen LJ and Loangston J: Blastomycosis ;presenting with prostatic involvement Report of 2 cases and review of the literature. J Urol 130:1 60-162, 1983. Patil PS and Elem B:Schistosomiasis of the prostate and the. seminal vesicles: observations in Zambia. J Trop Mad Hygiene 91 :245-248, 1988. Alexis R and Domingo J: Schistosomiasis and adenocarcinoma of the prostate: A morphologic study. Human Pathol 17:757-761, 1986. Deklotz RJ: Echinococcal cyst involvins the prostate and seminal vesic.les: A case repon. J Urol 115:116-117, 1976. Symmers W ST.C: Two cases of eosinophilic prostatitis due to metazoan infestation (with Oxyuris vermjcularjs. and with a loroa of Linguatula serrata J Pathol Bacterial 73 :549-555, 1957. Cla.son AE, McGeorge A, Garland C, Abel BJ: Urinary retention and granulomatous prostatitis following sacral Herpes-Zoster infection. A rep6n of 2 cases with a review of the literature. Brit J Urol 54: 166-169, 1982. Pieterse AS, Aarons I and Jose JS: Focal prostatic granulomas. Rheumatoid like-probably iatrogenic in origin. Pathology 16:174·177, 1984. Mies C,Balogh K,. Stadecker M: Palisading prostate granulomas following surgery._ Am J Surg Pathol 8:217·221. 1984. Castrillon JV, Maurine MLG, Carcavilla CG, Sarraga G. U and Espejo GP: Palisading lower urinary tract granuloma. Brit J Urol 62:489·491, 1988. Koptovic J, Rivkind f>., Sherman Y: Granulomatous prostatitis with vasculitis. A sequel ol transurethral prostatic rescetion. Arch Pathol Lab Med 108:732-733, 1984. Schned AR: Prostatyic granuloma (letter) Am J Su rg Pathol 8:797, 1984. Feiner, HD: Reparative granulomas of the prostate (letter). Am J Surg Pathol 8:7g7-798, 1984. Evans CS. Goldman RL, Klein HZ: More on prostatic granulomas (letter). Am J Surg Pathol 8:798-799, 1984. Eyre RC, Aaronson AG.. Weinstein BJ: Palisading granulomas of the prostate associated with prior prostatic surgery. J Urol 136:121·122. 1986. Lee G,Shepherd N. Necrotizing granulomata in prostatic resection speci mens-A sequel to previous operation. J Clin Pathol 36:1067-1070, t983. Hedelin H, Johansson S and Nilxon S: Focal prostatic granulomas. A sequel to transurethral resection. Scand J Urol Nephrol 15:193-196, 1981 . Bostwick ·42· Balogh K. Pali.sading granuloma in the kidney after open biopsy. Am J Surg Palhol 10:441-442,1986 Bostwick DG, Egben BM, and Fajardo LF: Radiation injury of the normal and neoplastic prostate. Am J Surg Pathol 6:541·551 . 1982. Oates RD. Stllmant MM, Fredlund MC and Siroky MB:Granulomatous prostatitis following bacillus Cafmene·Guesin immunotherapy of bladder cancer. J Urol 140:75 1754, 1988. Stanton MJ and Maxted W: Malacoplakia: A study of the literature and current concepts of pathogenesis, diagnosis and treatment. J Urol 125:139-146, 1981 . McClure J: Malakoplakia of the prostate: A repon of two cases and a review of the literature. J Clln Pathol 32:629·632, 1979. . Altafler, LF. Enghardt M: Malakoplakia of prostate gland. Urology 24:196·198, 1984. Makek M and Lagler U: Malakoplakia der Prostata Urologe A 19:89·92, 1980. Shimizu S, Takimoto Yukie, Niimura T, et al: A case of prostatic malakoplakia. J Urcl 126:277-279, 1981. .. Melicow MM:AIIergic granulomas of the prostate gland. J Urol 65:288-290, 1951. Stillwen TJ, DeRemee RA. McDonald TJ. et al: Prostatic involvement in Wegener's granulomatosis.J Urof 138: 1251·1253, 1987. Weiss MA, Rolfes DB, Alvir MA, Cohen LJ: Benign lymphocytic angiitis and granulomatosis: A case repon with evidence of an autoimmune etiology. Am J Clin Pathol 81 :110·116, 1984. Nelson G,Culberson DE. and Gardner WA Jr. Human Pathol 19:541-544, 1988. Fox H: Nodular histiocytic prostatitis. J Urol 96:372·374, 1966. Blumenfeld W, Tucci S, Narayan P: Incidental Lymphocytic Prostatitis. Selective Involvement with Nonmalignant Glands. Am J Surg Pathol 1992: 16:975-981. Bostwick -43- CASE 4 " NUCLEOLUs-POOR" CLEAR CELL ADENOCARCINOMA (AFTER ANTI-ANDROGEN THERAPY) CASE 5 FOCAL PROSTATIC ADENOCARCINOMA IN A NEEDLE BIOPSY SPECIMEN CASE 8 ADENOCARCINOMA ARISING IN THE TRANSITION ZONE MICROSCOPIC DESCRIPTION (CASE 5 ) The majority of the specimen consists of normal prostatic tissue. In a single microscopic focus, there is a small cluster of small to medium sized glands which are disorganized in their arrangement and stand in contrast with the adjacent normal glands. The contours of the suspicious glands are somewhat irregular, and no basal cell layer is seen at the periphery, although this i s frequently a difficult feature to identify by light microscopy. Cytologically, there is evidence of nuclear enlargement and nucleolar enlargement. The combination of architectural and cytologic abnormalities is diagnostic of adenocarcinoma despite the diminutive size of the focus of concern. MINIMUM REQUIREMENTS FOR THE DIAGNOSIS OF ADENOCARCINOMA Evaluation of small glandular proliferations of the prostate can be a major challenge for the diagnostic surgical pathologist, particularly when the specimen or suspicious focus is small. The diagnosis should rely on the combination of architectural and cytologic findings, and may be aided by ancillary studies such as immunohistochemistry. Architectural Features: A thorough understanding of the Gleason grading system is of value in interpretation of small foci because of its reliance on architectural patterns., The glands in suspicious foci are usually small to medium sized with irregular glandular contours which deviate from the usual smoothly sculpted rounded contours of normal prostatic glands. The arrangement of the glands is also useful; malignant glands exhibit irregular haphazard arrangement, sometimes with splitting or distortion of muscle fibers in the adjacent stroma. Variation in gland size can also be of value, particulary when there are small irregular abortive glands wi th primitive lumens, usually at the periphery. Comparison with the adjacent uninvolved prostatic glands is always of value. Bostwick -44- Cvtology: After assessing the architectural features at low to medium power magnification, it is useful to confirm or deny one's suspicions by searching for evidence of nuclear enlargement and nucleolar enlargement. Enlargement should be seen in the majority of the suspicious cells. It is important to remember that every cell has a nucleolus. so one searches for "prominent• nucleoli, which are at least 1.25·1.50 microns in diameter or larger.2 The identification of more than one nucleolus. (chromocenter) is virtually diagnostic of malignancy, according to Helpap;a also, the nucleoli are frequently eccentrically located in the nucleus, although this is a difficult feature to evaluate objectively. Evaluation of the basal cell layer is also critical in the diagnosis of adenocarcinoma. Compressed stromal fibroblasts can mimic basal cells, but are usually only seen focally at the periphery of the glands; an intact basal cell layer will usually exhibit multiple cells at the periphery of benign glands, whereas carcinoma lacks a basal cell layer entirely. Sometimes, small foci of adenocarcinoma cluster around larger glands which have an intact basal cell layer, compounding the difficulty.·· In problematic cases, it may be useful to employ monoclonal antibodies directed against high molecular weight keratin (3413E12, available from Dako Corporation) to evaluate the basal cell layer. 4-6 Remember to ask for superficial recuts through the suspicious focus ii one intends to do immunohistochemistry, as the lesion may disappear on deeper sections. Assocjated Features: Luminal crystalloids are of considerable value in the diagnosis of adenocarcinoma, but are not specific, often seen in atypical adenomatous hyperplasia and other conditions.2.7 Also, corp·ora amylacea can lie seen in both benign and malignant glands. The presence of wispy delicate pale blue mucin within the gland lumens is of value in supporting the diagnosis of adenocarcinoma, but is not definitive.a.9 Acid mucin stains may be of value in determining the nature of the lumenal secretions. Perineural invasion is useful when observed, and is extremely rare with benign glan·ds. It should be noted that perineural invasion is not evidence of extraprostatic extension as there are numerous nerves within the prostatic capsule, particuUarly in the inner portion. The presence of inflammation is extremely important to note, particularly when the architectural features are equivocal and one is relying on the cytologic findings of nucleomegaly and nucleolomegaly for the diagnosis of carcinoma. Reactive atypia within glands may result from inflammation, radiation, infarcts, and other insults to the prostate, mimicking adenocarcinoma. Also, granulomatous prostatitis is a vexing problem, and caution is warranted in interpretation of needle biopsies with such a finding.1 o Many authors, including Gleason, suggest grading prostate needle biopsies to Bosmick -45- include the primary and secondary Gleason grades. We believe that the potential for sampling error is so great in a needle biopsy that describing the secondary Gleason grade is an academic exercise which can be very misleading; accordingly, we only give the primary Gleason grade on our reports. Also, atlhough no correlation has been found between the amount of tumor on needle biopsy and that observed in radical pro~atectomy specimens, we consider I t useful to provide a rough estimate of the percentage of involvement of the needle core specimen,. similar to our approach with transurethral resection specimens. In some cases, the small glandular proliferation is highly suspicious for carcinoma, but failt to meet the minimum requirements. In such cases, ft Is appropriate to sign the case out as atypical small glandular proliferation ·and suggest rebiopsy. R.ecognizing the serious clinical implications of the diagnosis of adenocarcinoma (radical proStatectomy, radiation therapy, etc.), it seem prudent to render an unqualified diagnosis of adenocarcinoma only when one has absolute coniidence in the histologic findings. FOUR COMMON PROBLEMS IN NEEDLE BIOP5Y INTERPRETATION 1. Prostatic lntraepithelial Neoplasia versus large gland variant of Gleason grade 3 carcinoma. Prostatic intraepithelial neoplasia (PIN) r~fers to the putative precancerous (dysplastic) end of the morphologic continuum of cellular proliferations within prostatic ducts. duclules, and acini, characterized by anaplasia and nucleomegaly.1 1,12 High grade PIN is characterized by cells with large nuclei and nucleoli similar to invasive carcinoma, and is separated from cancer by the absence of stromal Invasion. Thus. PIN encompasses the spectrum of dysPlastic cytologic abnormalities within pre-existing structures in the prostate which are invariably _invested wtth an intact basal cell layer. In contrast, the large gland · variant of Gleason grade 3 carcinoma, including the cribriform variant. does not have a circumferential basal cell layer, and is usually associated with areas of small gland adenocarclnoma.13 Equivocal cases may be aided by the use of basal cell-specific high molecular weight keratin 348E12 stain i ng.o~.s.6,11 , 13 If the glands are small to medium sized and exhibit large nucleoli, · it Is probably invasive carcinoma rather than PIN. 2. Clear cell pattern of carcinoma versus benign glands. Adenocarcinomas with optically cle.ar cytoplasm (sometimes called 'hypernephroicf' pattern) frequently arise in the transition zone of the prostate, and are usually well or moderately differentiated. 1-4- 16 In some cases, Gleason grade 4 carcinoma contain cells with clear cytoplasm which mimic histiocytes, vacuolated stromal smooth muscle cells, or metaplastic glandular cells. Bostwick -46- However, the nuclear features are usually of value, with nucleomegaly and nucleolomegaly. 3. Atypical adenomatous hyperplasia versus invasive carcinoma. Small glandular proliferations in the prostate form a morphologic continuum ranging from benign proliferations with minimal architectural and cytologic atypia to those in which the degree of atypia is such that they are easily recognized as well differentiated adenocarcinoma.2 Lesions with a degree of atypia that raises the possibility of carcinoma have recently been the subject of much interest; despite this, criteria lor their clear separation from cancer are not firmly established. We recommend the term atypical adenomatous hype rp l~sia (AAH), and divide AAH into Tablol. Prostatic Carcinoma: Compari•on Based on ... natomic Sit• o( Ori&in • Tunsition ton.t anctr Ptriph~ ul t-on~ c.u ..cu I!"'C'ldtncr S"J' AI :; ... St~gt A2 79'1. All Stogt A ;,... A!IS:.gts :I... ; {\, On!;In In or nr-ar SPH ~·a Sur a~lli Yts Oc-trcnun n i t by n:RP Pa:holopc fur.:r~ Tumor volume t:s"•lly sm•ll Sm...U to lust Tumor patlem AJ ,:t"O I.a r... medu !Ia ry Tubulat-iQJ'Thous Tumor g:•d• (Ciu.sonl l:slJ .J. Uy 1 or 2 t:su.1Uy 2. 3. or -4 Our cell y.etem ~Oil (I~ Ra ... Srretr..U Dtrcs~ t.:'ncommon Common I Alsoci1ted put;~dvc PrrmaUgnanl chanses PL'I A.nouploidyt ll"" Cl.i.n.lca.l boe!u .. ior Uo:raupsuiar nttruion t II'!!. ... , She of t1e-acapsul.ar e"tef".sion A.nterolatl1'd A:-td •ric.ll urn~ Average tt;mor si.z.e 'Nith t:r;traupsulu 4.96 cc ) .86 cc ex:ensiont Risk of ~minal vtck lt invasion t 0'!(, 19, Risk oi l~'YJ\?h nodt metastases low f'jg!l BPK. ~ ~:.~oc hyre-:r-w~ n:~ :r.~~t:..'"'.:al :nte""'..on otlhe ~UI(. M.H~ "~~ ~ft\OCN.to'~ hr· p "Reprinted from Bostwick et al14" Bostwick -47- low grade (clearly benign, also known as adenosis) and high grade {possibly benign, but having many features of carcinoma). In a study of 54 sele.cted lesions from 44 transurethral resection specimens, we found that AAH is distinguished from well differentiated carcinoma primarily by the fo llowing: (1) inconspicuous nucleoli1 (2) infrequent crystalloids, (3) lack of basophilic muc[n, and (4) fragmented basal cell layer seen with basal cell-specific anti-keratin antibodies. 4. Carcinoma versus reactive post-therapy atypia. In addition to small sample size, needle biopsies of the prostate following therapy such as radiation or anti-a-ndrogen treatment present other significant challenges. After irradiation, needle biopsy is probably not of value until about 12 months have elapsed due to the delayed effect of tumor cell death which occurs up to this time.11,1e After this period, however, needle biopsy appears to be the best method ' · Ql:\GNOSIJC CRITERIA FOB AIYplCAJ. !,PENOMAIOJIS HYPFRPl ASrA .u.H .u.H C!.BCI~Q;\iA (L.ow Grade) (Higb Gr:ade) (Gieoson 1 and 2) ARCHITECTURE Low powu Circumscribed Circumscribed Circumscribed Borders Pushing Pushingfinfi1t Pushin~/inntt. Usioit Si::t Variable. Variable Variable • A.uoc. with BPH Yes Us-ually Sometimes Sclerosis Sometimes Sornetimt$ Sometimes CYTOLOGY Nucltor S:':t 51. enlarged 51. enlarged SJ. enJarged Chromatin Unirorm Uniform Unirorm • NUt/coli Inconspicuous Occ: promi.nent Prominent • Nudeoli(/crgut) 2:.5 u(rare) 3.0 u 3.0 + u • Nuclcoll(a'tif,) < 1.0 u 1.3 a 1.8 u • Nudeoli > 1 u 19% 56~ 78'.10 • c,.,sta/loidt Very r:are Very rare Common IMMUNOHISTOCHEMISTRY • Basal-Cell Spuific AMi·Ktratin (903) (ks ~OS( usduJ f~rurcs "Reprinted from Bostwick et al2" available for objective assessment of local tumor control, with a low level of sampling error which is minimized by taking serial specimens. No definitive method exists for assessment of tumor viability after irradiation. Musselman and associates19 demonstrated monolayer growth from Bostwick -48- explants of prostatic carcinoma two years or more after definitive radiation. Conversely, Mollenkamp et a12 o were unable to culture any of 19 Irradiated tum ors, and they concluded that radiation suppressed mitotic activity and growth potential; however, their success rate for in vitro cultivation of untreated carcinoma was also poor (less than 7%). Mahan et al21 identified intense cytoplasmic immunoreactivity for PAP in 23 of 27 irradiated adenocarcinomas leading them to suggest that tumor cells capable of protein production probably retain the potential for cell division and consequent metastatic spread. Other reports have claimed that if prostatic carcinoma is not histologically ablated by radiotherapy after 12 months, it is probably biologically active. Wels studied pre and post-irradiation samples of 40 patients, and concluded that malignant glands identified 12 to 18 months or more following radiation therapy should be considered viable; the consequences • of denying viability of such foci of apparent residual neoplasm outweigh the side effects incurred by additional therapeutic intervention. We found that the only feature indicative of radiation injury was a decrease in the number of tumor glands. with ablation of tumor in 43% of the samples which we evaluated. Keisling et al22 noted that the ultrastructural features of p rostatic adenocarcinoma after irradiation were indistinguishable from those of untreated carcinoma, suggesting that residual tumor is viable. Following anti-androgen therapy, there is an increase in the architectural (Gleason) grade of th e tumor.23·25 We noted in a study of 25 cases treated w it h anti-androg en therapy (Lupron and Zoludex) compared with 2 5 grade and stage matched controls that there was a significant increase in Gleason grade, decrease in nuclear grade, and decrease in extent of Prostatic lntraepithelial Neoplasia.2s This "uncoupling• of the architectural and cytologic pattern i s vexing due to theidentification of cytologically banal nuclei within malignant glands. REFERENCES 1 . Gleason OF. Histologic Grading of Prostatic Carcinoma. In: Bostwick DG (Ed). Patholooy of the Prostale, Churchill-livingstone, New York 1990; pp 83·93. 2. Bostwick DG, Srlgley J, Grignon D, Maksem J, Humphrey P, van der Kwast T. Bose D, Harrison J. Young A. Atypical adenomatous hyperplasia (AAH) of the prostate. Modern Pathology 1991; 44A (abstract) (Manuscript in final preparation.) 3. Helpap B. Observations on the number. size, and localization of nucleoli in hyperplastic and neoplastic prostatic disease. Histopathol 13:203·21 1, 1988. 4. Brawer MK, Peehl OM, Stamey TA, Bostwick DG . Keratin immunoreaclivity in the benign and neoplastic human prostate. Cancer Res 45:3663, 1985. Bostwick -49- 5. Bostwick DG, Srigley J. Premalignant·Lesions. In: Bostwick DG (Ed) . Pathology of the Prostate, Churchi!!-llvlngstone, New York 1990; pp 37-.59. 6. Hedrick L, Epstein J!. Use of keratin 903 as an adjunct in the diagnosis of prostate carcinoma. Am J Surg Pathol t3:389-396, 1989. 7. Holmes EJ. Crystalloids of prostatic carcinoma: relationship to Bence-Jones crystals. Cancer 39:2073, 1977. 8. Ro JY, Grignon DJ, Troncoso P, Ayala AG. Mucin in prostatic adenocarcinoma. Seminars in Diagnostic Pathology 5:273-283, 1 ~88 . 9. Humphrey PA. Mucin in severe dysplasia in the prostate. Surg Pathol 4:137-143, 1991. 1 0. Lopez-Plaza I, Bostwick DG. Prostatitis. In: Bostwick DG (Ed). PatholOgy of the Prostate, Churchii!-Livingstone, New York 1990; pp 15-30. ' . 11 . Bostwick DG, Brawer MK. Prostatic intraepithelial neoplasia and early invasion in prostate cancer. Cancer 59:788-794, 1987. 12. McNeal JE, Bostwick DG, Kindrachuk RA, eta!. Patterns o·f progression in prostate cancer. Lancet 1 :60-63, 1986. 1 3. Am in MB, Schultz DS, Zarbo RJ. Analysis of cribriform morphology in prostate neoplasia using antibody to high molecular weight cytokeratins. Arch Pathol Lab Med (in press). 14. Bostwick DG, Cooner WH, Denis L. Jones GW. Scardino PT. Murphy GP. The association of benign prostatic hyperplasia· and cancer of the prostate. Cancer 70:291 -301, 1992. 1 5. McNeal JE. Redwine EA, Freiha FS, Stamey TA. Zonal disJribution of prostatic adenocarcinoma: correlation with histologic pattern and direction of spread. Am J Surg Pathol 12:897-906, 1988. 1 6. Greene DR, Egawa S, Neerhut G, Flanagan W, Wheeler TM, Scardino PT. The distribution of residual cancer in radical prostatectomy specimens in stage A prostate cancer. J Urol 145:324-329, 1991. - 1 7. Brawer MK, Bostwick DG. lnterpretatio.n of Postradiation Prostate Biopsies. In: Bostwick OG (Ed). Pathology of the Prostate, Curchi!!-Livingstone, New York 1990; pp 193-205. 18. Bostwick DG, Egbert BM, Fajardo LF. Radiation injury of the normal and neoplastic prostate. Am J Surg Pathol 6:541, 1982. 1 9. Musselman PW, Tubbs R. Connelly RW, et a!. Biological significance of prostatic carcinoma after definitive radiation therapy. J Urol 137: 114A, 1987. Bostwick -50- 20. Mollenkamp JS, Cooper JF, Kagan AR. Clinical experience with supervoltage radiotherapy In carcinoma of the prostate: a preliminary report. J Urol 113:374, 1975. 21 . Mahan DE, Bruce AW, Manley PN, Franchi L. Immunohistochemical evaluation of prostatic carcinoma before and after radiotherapy. J Urol 124:488, 1980. 22. Kiesling VJ, Friedman HI, McAninch JW, et al. The ultrastructural changes of prostatic adenocarcinoma following external beam radiation therapy. J Urol 122:633, 1979. 23. Tetu B, Srigley JR, Boivin J, Dupont A, Monfette G, Pinault S, Labrie F. Effect of combination endocrine therapy (LHRH agonist and flutamide) on normal prostate and prostatic adenocarcinoma. Am J_ Surg Pathol 15(2):111-120, 1991. · 24. Murphy WM, Soloway MS, Barrows GH. Pathologic changes associated with androgen deprivation therapy for prostate cancer. Cancer 68:821-828, 1991. 25. Ferguson J, Bostwick D, Ellison E, Zincke H. Decrease in Prostatic lntraepithelial Neoplasia Following Total Androgel) Blockade Therapy (Submitted) 26. Ellison E, Bostwick DG, Ferguson J, and Zincke H. "Nucleoli-Poor" Clear Cell Adenocarcinoma of the Prostate. A Distinctive Histologic Pattern Following Total Androgen Blockade. Lab Invest 1993 (in press--abstract) Bostwick -51- CASE 6 BASAL CELL ADENOMATOSIS OF THE PROSTATE (Excerpcedfrom Oeveraj L. Bostwick 0: ATYPICAL BASAL CELL HYPERPLASIA OF THE PROSTATE: IMMUNOPHENOTYPIC PROFILE AND PROPOSED CLASSIFICATION OF BASAL CELL PROLIFERATIONS, ArnJ Surg Pathol (in press)) Abstract Prostatic basal cell proliferations range from focal basal cell hyperplasia (BCH) to florid adenoid basal cell tumor (ABCT). We reviewed thirty-six cases of basal cell proliferation in order to evaluate the architectural and cytologic spectrum of these lesions, and identified four distinct patterns by light microscopy: basal cell hyperplasia (BCH) (12 cases) including 2 cases with stromal sclerosis; atypical BCH with nucleolomegaly (8); basal cell adenom.a (BCA) (9); and adenoid basal cell tumor (ABCT) (7). Twenty-three ' cases were evaluated immunohistochemically, and all displayed cytoplasmic immunoreactivity in basal cells witi'J basal cell-specific high molecular weight keratin 34BE12, but with increased staining in BCH compared with BCA and ABCT. Prostate specific antigen and prostatic acid phosphatase reactivity was seen at least focally in all cases except for two cases each of BCA and ABCT. Chromogranin, S-100 protein, and neuron specific enolase reactivity was rare or negative in all cases. Nucleolar diameter, measured in 18 of 36 cases, was significantly gfeater in atypical BCH (mean, 1.96 microns) than other forms of basal cell proliferation (mean, < 1.0 microns) (P<.05). These results Indicate that the spectrum of basal cell pro liferations in the prostate can be separated into four distinct groups (BCH, atypical BCH, BCA, and ABCT) based on the combination oi light microscopic, immunohistochemical, and morphometric findings. Introduction Basal cell proliferations in the prostate exhibit a morphologic continuum ranging from focal basal ce ll hyperplasia in the setting of nodular hyperplasia to florid adenoid basal cell tumor. These diverse proliferations have been referred to by a variety of terms, including fetalization of the prostate,36 embryonal hyperplasia,2 basal cell atypia,1 0 basal cell hyperplasia, 10,17,21 ,27 basal cell tumor,21 basal cell adenoma,23 basaloid carcinoma,8 adenoid basal cell tumor,15,32 prostatic adenoma oi ductal origin,29 adenoid cystic-like tumor,44 and adenoid cystic carcinoma.12,23,32 Some basal cell proliferations can mimic prostatic intraepithelial neoplasia (PIN)4 and carcinoma due to the presence of significant cytologic abnormalities, including anisonucleosis. nucleomegaly, and nucleolomegaly. These cases may be a source of diagnostic confusion, particularly in small samples such as needle Bostwick -52- biopsies. However, to our knowledge, there have been no published reports describing cyto.logic atypia (nucleolomegaly} in basal cell hyperplasia. We undertook a study of 36 cases of basal cell proliferation in order to evaluate the architectural and cytologic spectrum of these lesions. A battery of immunohistochemical stains was employed, including basaJ cell-specific high molecular weight keratin 34BE1~. prostate specific antigen , prostatic acid phosphatase, chromogranin, S-100 protein, and neuron specific enolase. Routine ocular micrometer-based morphometry was used to determine average nucleolar diameters in 18 cases. Our results indicate that there are four patterns of basal cell proliferation which can be distinguished based on light microscopic, immunohistochemical, and morphometric evaluation: basal cell hyperplasia (including sclerosing basal cell hyperplasia}, atypical basal cell hyperplasia, basal cell adenoma, and adenoid basal c.ell tumor. Results Clinical FindinQS Patients ranged in age from 42 to 83 years (mean, 67.7 years}. Tissue was obtained by transurethral resection of the prostate (25 cases), random needle biopsy (4}, transrectal ultrasonographically-guided needle biopsy (2), cystoprostatectomy {2}, suprapubic prostatectomy {1), and retropubic radical prostatectomy {2}. All patients had clinical evidence of benign nodular hyperplasia, and this was confirmed histologically in those patients undergoing transurethral resection or prostatectomy. Also, 4 patients had prostatic carcinoma {acinar type}, one of which was associated with significant radiation changes in the prostate, and 2 patients had a history of transitional cell carcinoma of the bladder (the 2 undergoing cystoprostatectomy). In Normal Prostatic Basal Cell Layer The normal prostatic epithelium frequently displayed foci oi basal cell proliferation which were not considered sufficient to warrant the diagnosis of basal cell hyperplasia. Normal prostatic basal cells were arranged circumferentially at the periphery of prostatic ducts, ductules, and acini, and usually appeared as a nearly-continuous layer of elongated or spindled cells surrounding a continuous layer of cuboidal to columnar secretory lumenal cells (Fig. 1A). The long axis of the basal cell layer was usually parallel to the Bostwick -53· basement membrane. Nuclei were elongate or ovoid, small to medium sized, with uniform pale chromatin which was occasionally vesicular; nucleoli were inconspicuous or absent. The cytoplasm was difficult to identify by light microscopy, and appeared as a dark narrow rim with inconspicuous cell margins. Basal Cell Hyperplasia Typical basal cell hyperplasia (without atypia) consisted of a proliferation of basal cells forming 2 or more cells in thickness at the periphery of prostatic glands and acini. This proliferation sometimes appeared as small, round, solid aggregates surrounded by a few concentric layers of compressed stroma. Frequently, the proliferation was more than 2 cells in thickness and protruded into the acinar lumen, retaining the overlying secretory luminal epithelium. Symmetric circumferential thickening of the basal cell layer was less frequent than eccentric thickening, and these changes were not attributed to tangential sectioning (Fig. 1 B to F, Fig 2A and B). The hyperplastic basal cells were usually larger than the usual elongate or spfndled basal cells, with nuclear enlargement, and some displayed distinctive optically clear cytoplasm. Rarely, the luminal proliferation formed a cribriform pattern reminiscent of clear cell cribriform hyperplasia. There were no cases associated with atypical adenomatous hyperplasia (adenosis). Sclerosing basal cell hyperplasia consisted of typical basal cell hyperplasia enmeshed in and surrounded by fibrous connective tissue and hyperplastic smooth muscle. The fibrosis ranged from delicate lace-like strands to dense irregular sclerotic stroma with impingement upon the glands. The 2 cases in our study showed inconspicuous nucleoli (Fig 4A, B, and C). Atypical Basal Cell Hyperplasia Atypical basal cell hyperplasia consisted of basal cell hyperplasia with prominent nucleoli. A morphologic spectrum of nucleolar size was observed, and only those with more than 10% of cells exhibiting "prominent" nucleoli were considered atypical. Morphometric study revealed that "prominent" meant larger than 1.25 microns (mean) (see Morphometry below). Architecturally, atypical basal cell hyperplasia varied from small solid masses of cells to larger rounded aggregates with lumens; occasionally, a cribriform pattern was seen (Fig 3A and 3B). Optically clear cytoplasm was infrequently observed (Fig 3C). Basal Cell Adenoma Basal cell adenoma consisted of a large round, usually solitary circumscribed nodule in the setting of nodular hyperplasia containing uniformly-spaced aggregates of hyperplastic basal cells varying from small solid nests to cystically dilated glands (Fig. SA and B) .. The basal cells were Bostwick -54- plump, with large nuclei, scant cytoplasm , and inconspicuous nucleoli, although one case showed large prominent nucleoli. Many of the cells were cuboidal or ·epithelioid", particularly towards the center of the cell nests, and some showed distinctive optically clear cytoplasm . One case displayed prominent calcific debris within gland lumens (Fig. 5C). Condensed stroma was seen at the periphery of the nodule. In addition, stromal connective tissue traversed the adenomatous nodule, creating incomplete lobulation in some cases. Stroma was normal or slightly increased in density, and occasionally displayed mild basophilia without myxoid change adjacent to cell nests. One case of basal cell adenomatosis was composed of multiple basal cell adenomas present on 11 of 16 slides in a TURP specimen. Basal cell adenoma invariably arose in association with nodular hyperplasia, and appeared to be a variant. Adenoid Basal Cell Tumor Adenoid basal cell tumor consisted of basaloid cell nests of varying size infiltrating the stroma without circumscription, in contrast to basal ce II adenoma. The cell nests were frequently large and round to angular, wi th peripheral basaloid cells exhibiting elongate nuclei, often with palisading (Fig. SA, B. and C). Cell crowding was prominent, with lumenal spaces of varying size. Pale yellow amorphous material was seen within the lumens in hematoxylin and eosin stained sections. The cells were similar to those in basal cell hyperplasia except for mild nuclear enlargement. In some cases, a pale loose myxoid fibrous stroma accompanied the basal cell nests. One case displayed extensive perineural invasion and spread into the periprostatic soft tissues. Associated Findings Nodular hyperplasia was a common finding in all cases, as was chronic inflammation. Squamous metaplasia was found infrequently, usuall y associated with infarction. Clear cell change was noted in all forms of basal ce II proliferation, some wi th a cribriform pattern; however, a cribriform appearance without clear cell change was rarely seen. Occasional nuclear grooves and nuclear "bubble" artifact were observed. Focal calcification was evident in some of the lesions, mingled with basal cell nests in one case of basal cell adenoma (Rg 5C). Immunohistochemical Findings Basal cell-specific anti-keratin 34BE12 stained virtually all of the normal basal cells of the prostate, with absence of staining in the secretory and stromal cells. Many basal cells displayed fine "dendritic" extensions partially encircling glands. These cytoplasmic extensions were frequently in contact with each other, forming a continuous but thin and inconspicuous layer. Normal Bostwick -55- prostatic basal cells did not display immunoreactivity for PSA, PAP, or S-1 00 protein, and only rare single cells stained with chromogranin and NSE. Conversely, the normal secretory luminal cell layer invariably stained with PSA and PAP. Basal cell hyperplasia (6 cases) displayed intense cytoplasmic immunoreactivity in virtually all of the cells with keratin 34BE12 (Table 1) (Fig. 7). PSA and PAP immunoreactivity were seen in 38% and 45% of basal cells, respectively, in most cases, although 90% stained in one case. Rare basal cells stained with chromogranin in 3 cases, S-100 in 1, and NSE in 2. Sclerosing BCH (one case) stained strongly with keratin 34BE12, and 13% and 25% of cells stained with PSA (Fig. 8A) and PAP, ·respectively; rare cells in that case stained with chromogranin (Fig. 9A} and NSE, but not with S-100 protein. Atypical basal cell hyperplasia (6 cases) showed intense im munoreactivity in all basal cells with keratin 34BE12. PSA and PAP stained 5-50%, respectively, of basal cells in 3 of 4 cases. Rare cells stained with chromogranin and S-1 00 in 2 cases; MSE was negative in all cases. In basal cell adenoma (BCA) ( 6 cases), basal cells stained intensely (100% of cells) with anti-keratin 34BE12 in 3 of 5 cases, and weakly in 2 other cases (5 to 10% of cells). Five of 6 cases showed immunoreactivity with PSA (Fig. 88) and PAP, varying from <5% to 50% of basal cells. Rare positive cells were seen with chromogranin in 2 cases and S-100 in 1 (Fig. 98); NSE was negative in all cases. One 'case of BCA fai led to display immunoreactivity with any of the antibodies employed. Adenoid basal cell tumor (ABCT) (4 cases) showed variable immunoreactivity with keratin 34BE12; two cases showed 20% of luminal cells staining, and one showed 50% of luminal cells and 75% of peripheral basal cells staining; one other case with extra-prostatic extension showed 10% keratin staining at the periphery of the lesion. Two of 4 cases showed rare scattered cells with PSA (Fig. 8C) and PAP immunoreactivity; also, rare cells showed chromogranin staining in one case. S-100 protein and NSE stains were negative. It should be noted that the amorphous luminal material was negative with all stains. Morphometry Nucleolar size was evaluated in 6 cases of basal cell hyperplasia (BCH) (including 1 with sclerosis), 5 cases of atypical BCH. 3 cases of basal cell adenoma (BCA), and 4 cases of adenoid basal cell tumor (ABCT). In all 6 cases of BCH, mean nucleolar diameter was less than 1 micron, and the majority of nucleoli measured less than 0.5 micron in diameter (range, 0.5-2.4 microns). In 5 cases of atypical BCH, mean nucleolar diameters were 1.94, 2.25, 1.25, 2.05, and 1.61 microns respectively. The mean (1.96 microns) was significantly greater than other forms of basal cell proliferation (P<:.05, Chi square). In BCA, mean nucleolar diameter was less than 1.0 micron in 2 cases and 2.24 microns in Bostwick -5(r the third (range, 0.5-3.6 microns}. In ABCT, mean nucleolar diameter was less than 1 micron (range, 0.5-2. 4 microns) (including the case with extra-prostatic extension). Di s cussion Basal cell proliferations are uncommon lesions, compnsmg 22 of 247 cases of nodular hyperplasia in our files which were coded as basal cell hyperplasia, atypical hyperplasia, atypia, and atypical adenomatous hyperplasia (8.9%), and 10 of 172 (5.8%} cases in another series.30 We identified four distinct patterns, including basal cell hyperplasia (BCH}, atypical BCH, basal cell adenoma (BCA}, and adenoid basal cell tumor (ABOT} (Table 2}. Light microscopic findings were sufficient in th e majority of cases to separate these proliferations. Immunohistochemical staining with keratin 34BE12 was useful in confirming the presence of basal cells in equivocal cases.6,20,31,36,37 ' In the normal prostate, basal cells form an inconspicuous and almost-continuous layer of elongate cells with scant cytoplasm at the periphery of the glands interposed between the luminal secretory cells and basement membrane.4,5,6,9 The long axes of the basal cells are parallel to the basement membrane and perpendicular to the secretory cells. Nuclei are thin and tapering, with fine evenly-dispersed pale chromatin and inconspicuous nucleoli which usually measure less than 0.3 microns in diameter. Prostatic basal cells do not display myoepithelial differentiation, 15,38 in contrast with basal cells in the breast, salivary glands. pancreas, and other sites.22 Basal cell hyperplasia (BCH} was characterized by small nests of basal cells surrounded by a few concentric layers of compressed stroma, often associated with chronic inflammation. The nests varied from solid to cystically dilated glands; when these nests were punctuated by irregular rounded luminal spaces, they displayed a cribriform pattern. BCH frequently Involved only part of a gland, and sometimes protruded into gland lumens: less commonly, there was symmetric duplication of the basal cell layer at the periphery of the glands. We required a minimum of two cells in thickness to diagnose BCH, recognizing that this is an arbitrary criterion; however, we rarely observed this in •normal" prostatic epithelium, and felt that a minimum standard was needed lor the diagnosis of BCH. The basal cells in BCH we re usually enlarged, ovoid or round, and plump (epithelioid), with large pale ovoid nuclei, finely reticular chromatin, and a moderate amount of cytoplasm. Nucleoli were ususally inconspicuous (less than 1 micron in diameter} except in atypical BCH (see below). Sclerosing OCH was Identical to typical BCH except lor the presence of delicate lace-like fibrosis or dense irregular sclerotic fibrosis and hyperplastic smooth muscle surrounding and distorting hyperplastic basal cell aggregates. Although no nucleolomegaly was observed in our cases of sclerosing BCH, it seemed Bostwick -57- reasonable to expect th at other cases might show reactive atypia and nucleolomegaly. Atypical BCH was identical to BCH except lor the presence of large prominent nucleoli (mean diameter, 1.96 microns, with a maximum of 4.8 microns}. The nucleoli are round to oval and lightly eosinophilic. There was chronic inflammation in the majority of cases, suggesting that nucleolomegaly was a reflection of reactive atypia. BCA was identical to BCH except that the proliferating basal cell masses were usually large and circumscribed, with a nodular or adenoma-like pattern. The stroma was peripherally condensed, forming a pseudo-capsule which was usually complete. Bands of stroma partially intersected the adenoma, dividing it Into "lobules•. BCA was occasionally multilocal ("adenomatosis'), and invariably observed in the presence of nodular hyperplasia. Nucleoli were not prominent (m ean diameter less than one micron) except for one case (mean olameter 2.2 microns. with a range of 0.5 to 3.6 microns). ABCT was histologically similar 10 BCH and BCA, but the tumor usually involved large areas of the prostate with little or no circumscription.24.44 The basal cell nests were large and irregular in outline, separated by benign myxoid stroma,32.44 and the tumor cells were predominately elongate, with narrow tapering nuclei and peripheral palisading.15 Cell crowding was prominent, and the basal cell masses frequently displayed multiple lumens.12.34,44 some of which were sharply circumscribed and rounded ("punched-out"}. Nucleoli were inconspicuous, similar to BCH. In limited samples such as TURP specimens, it may be difficult to separate basal cell adenomatosis and adenoid basal cell tumor. The first descri ption of basal cell hyperplasia, including solid, acinar, and adenoid patterns was by Komprecher21 in 1925 who suggested that basal ce ll carcinoma arose from regenerating basal cells. Numerous reports in the literature have subsequently described a variety of basal c e II lesions;2,7,8,10,12,1 7,23,29,32,40,42,44 in a recent review, Grignon et al15 suggested a continuum of BCH, ABCT, and adenoid cystic carcinoma. Our findings confi rm the presence of a morphologic continuum of basal cell proliferations, and we identified 4 distinct patterns: BCH, atypical BCH, BCA, and ABCT. Clear cell cribriform hyperplasia may also be part of the spectrum of BCH. Some might reasonably prefer to combine atypical BCH, sclerosing BCH, and BCA within the spectrum of BCH because of the benign nature of these lesions; however, our classification is purposely meant to assist the pathologist in Interpretation of these varied lesions and allow diagnostic separation from histologic mimicks. Also, some cases of ABCT may represent adenoid cystic or basaloid carcinoma. The differential diagnosis of basal cell proliferations includes a wide variety of benign and malignant lesions. Atypical adenomatous hyperplasia (AAH, Bostwick -58- or adenosis)3,5,38 is a benign small glandular proliferation which usually arises in the setting of nodular hyperplasia and may be confused with BCH; however, AAH does not usually have a prominent basal cell layer, and displays a fragmented keratin 34BE12-immunoreactive basal cell layer. Sclerosing adenosis may be difficult to separate from sclerosing BCH and these lesions may coexist; however sclerosing adenosis is distinguished by the absence of smooth muscle in the sclerotic stroma and the presence of myoepithelial differentiation (intense cytoplasmic immunoreactivity with keratin 34BE12, S-100 protein, and muscle-specific actin, as well as ultrastructural evidence of cytoplasmic myofilaments).16,35,43 It should be noted that BCH and sclerosing adenosis may coex ist.33 Seminal vesicle and ejaculatory duct epithelium may also be confused with BCH and BCA, particularly in small specimens such as needle biopsies and rarely in transurethral resection specimens. The proliferation and stratification of lining cells with cytologic atypia may resemble small foci of solid BCH. The seminal vesicular epithelium Is distinguished by the presence of secretory luminal cells, significant cytologic atypia (particularly in the senile seminal vesicle), and distinctive abundant yellow to golden brown lipochrome pigment. The normal transitional epithelium of the prostatic urethra or periurethral ducts resembles BCH histologically and immunohistochemically. Also, transitional metaplasia can occur in the medium sized and small ducts in the prostate, sometimes in association with inflammation and reactive atypia with mild nucleolomegaly. Urethral polyps, although uncommon, may also be confused with BCH and BCA, particularly in small cystoscopic specimens and needle biopsies. These polyps include proliferative papillary urethritis, ectopic prostatic tissue, nephrogenic adenoma, and inverted papilloma. Prostatic intraepithelial neoplasia (PIN) is a putative premalignant lesion of the prostate characterized by proliferation and anaplasia of cells lining pre-existing glandular structures.4 High grade PIN exhibits nucleomegaly and nucleolomegaly which is indistinguishable from adenocarcinoma, and these cytologic abnormalities may be mistaken for atypical BCH (1 of the cases of atypical BCH in this series was submitted in consultation with a provisional diagnosis of high grade PIN). However, PIN is distinguished from atypical BCH by the presence of cytologic abnormalities in secretory luminal cells of medium sized to large glands, PSA and PAP immunoreactivity in the abnormal cells, and an intact or fragmented keratin 34flEi2-immunoreactive basal cell layer. Well differentiated adenocarcinoma is distinguished from BCH by the presence of PSA and PAP-immunoreactive luminal secretory cells with nucleolomegaly, frequent luminal crystalloids,42 and absence of a keratin 3413E 12-immunoreactive basal cell layer. Similar criteria allow separation of Bosrwick -59· the cribriform variant of adenocarcinoma, ABCT, basal cell hyperplasia with or without clear cell change, and clear cell cribriform hyperplasia.1 Adenoid basal cell tumor (ABCT) shows two distinct architectural patterns: adenoid cystic32,44 and basaloid.8 The first of these consists of irregular clusters of crowded basaloid cells punctatetl by rounded fenestrations, many of which contain mucinous material resembling salivary gland adenoid cystic carcinoma. The basaloid pattern consists of variably sized rounded basaloid cell nests with prom inent peripheral palisading. These patterns frequently coexist in the same lesion,44 although pure forms have been described.S The malignant potential of ABCT remains uncertain due to the small number of reported cases. These tumors are · best classified as adenoid basal cell tumors, as suggested by Young et al;44 they differ from adenoid cystic carcinoma by the absence of cytoplasmic myofilaments, absence of consistent basal lamina proliferation around cell nests, and absence of documented malignant behavior. A recent case reported as basal cell carcinoma was considered malignant by the identification of tumor on a perineal' biopsy; however, there was no definite evidence of extra-prostatic extension, and the tumor followed a benign clinical course.8 One of the cases in our series exhibited prominent perineural invasion and extra-prostatic spread suggestive of malignancy; however, follow"up at five months indj,cated no evidence of recurrence or metastasis, and pelvic lymph nodes were uninvolved at the time of radical prostati:lctomy. At present, ABCT i s probably be~t considered as a tumor of low malignant potential pending long-term follow-up study of other cases. Wernert and Seitz41 reported positive immunoreactivity of fetal and prepubertal prostatic epithelium with a broad spectrum of keratin antibodies including high molecular weight keratin. They noted progressive dichotomy of keratin immunoreactivity of the basal cell and secretory cell layers with age, with the normal adult phenotype appearing at the time of puberty. Several authors have suggested that basal cells act as "reserve" cells wh ich are capable of dividing and replenishing the prostatic epithelium, including the ability to differentiate into other cell types such as secretory cells.7,9, 13,42 Others have shown that both basal cells and secretory cells retain the ability to divide.11 Transition forms have only rarely been identified, and usually in in vitro13 conditions. Basal cells apparently retain the ability to undergo metaplasia, including squamous differentiation in the setting of prostatic in farction5, 17,21 and myoepithelial differentiation in the setting of sclerosing adenosis.16,35,43 Grignon et al12 observed PSA and PAP immunoreactivity i n some of the proliferating basal cells in all entities, similar to our findings; suggesting that basal cells can acquire the immunophe notype of secretory cells. Recently, epidermal growth factor receptors have been identified in basal cells but not in secretory cells, suggesting that these cells play a role in growth Bostwick -60- regulation.25,26 Our results indicate that there is a spectrum of basal cell proliferations in the prostate which can be separated into four distinct groups based on a combination of light microscopic, immunohistochemical, and morphometric findings. These groups include basal cell hyperplasia with and w ithout sclerosis , atypical basal cell hyperplasia, basal cell adenoma, and adenoid basal cell tumor. High molecular weight keratin 34BE12-immunoreactivity was useful in the identification of most of these lesions.4,5,6, 12 References 1. Ayala AG, Srigley JR, Ro JY, Abdul-Karim FW, John son DE. Clear cell cribriform hyperplasia of prostate. Am J Surg Pathol 1986 ;1 0:665-671. 2. Bennett BD, Gardner WA. Embryonal hyperplasia of the prostate. Prostate 1985;7:411-417 . . 3. Bostwick DG, Srigley J, Grignon D, Maksem J, Humphrey P, van der Kwast TH, Bose D, Harrison J, Young R. Atypical adenomatous hyperplasia (AAH) of the prostate. (submitted) 4 . Bostwick DG, Brawer MK. Prostatic intra-epithelial neoplasia and early invasion in prostatic cancer. Cancer 1987;59:788-794. 5. Bostwick DG, Srigley JR. Premalignant Lesions. In: Bostwick DG (Ed): Pathology of the Prostate, New York: Churchiii-Livingstone 1990:37-59. 6. Brawer MK, Peehl DM, Stamey TA, Bostwick DG. Keratin immunoreactivity in the benign and neoplastic human prostate. Cancer Res 1985;45:3663-3667. 7. Cleary KR, Choi HY, Ayala AG. Basal cell hyperplasia of the prostate. Am J Clin Path 1983;80:850-854. 8. Denholm SW, Webb JN, Howard GCW, Chisholm GD. Basaloid carcinoma of the prostate gland: histogenesis and review of the literature. Histopathol 1992;20:151-1 55. 9. Dermer GB. Basal cell proliferation in benign prostatic hyperplasia. Cancer 1978;41 :1857-1862. 1 0. Elbadawi A. Benign proliferative lesions of the prostate gland. Male Accessory Sex Glands, edited by E. Spring-Mills & E.S.E. Hafez Elsevier/North Holland Biomedical Press 1980;387- 408. 11 . Evans GS, Chandler JA. Cell proliferation studies in the rat prostate: The effects of castration and androgen-induced regeneration upon basal and secretory cell proliferation. Prostate 1987;11 :339-351 . 12. Grignon OJ, Ro JY, Ordonez NG, Ayala AG, Cleary KR. Basal cell hyperplasia, adenoid basal cell tumor, and adenoid cystic carcinoma of the prostate gland: an Immunohistochemical study. Hum Pathol 1988;19:1 425-1433. 13. Heatfield BM, Sanefuji H. Trump BF. Long-term explant culture of normal human prostate. Methods in Cell Biology 1980;21 :171-194. 1 4. Hoda SA, Reed RJ. Morphologic characteristics of nucleoli in the differential diagnosis of well-diHerentiated prostatic adenocarcinoma. Am J Clin Path 95:271, 1991 (abstract) . 15 . Howat AJ, Mills PM, Lyons TJ, Stephenson TJ. Absence of S-100 protein in prostatic glands. Hlstopathol 1988;13:468-470. 1 6. Jones EC, Clement PB, Young RH. Sclerosing adenosis of the prostate gland. Am J Surg Pathol 1991 ;15:11 71-1180. 1 7. Kasman LP, Gold J. Metaplastic changes in the prostate gland. J Lab Clin Med Bostwick -61· 1933 ;301 -308 . 1 8. Kelemen PR, Buschmann RJ, Weisz-Carrington P. Nucleolar prominence as a diagnostic variable in prostatic cancer. Cancer 1990:65:1017·1 020. 19. Kirkland KL, Bale PM . A cystic adenoma of the prostate. J Urol 1967;321-327. 20. Kitajima K, Tokes ZA. Immunohistochemical localization of kerain in human prostate. The Prostate 1986;9:183·190. 21 . Krompecher E. Uber basalzellenhyperplasien und basalzellenkrebse der prostata. Eingegangen 1925;284-293. 22. Lawrence JB, Mazur MT. Adenoid cystic carcinoma: a comparative pathologic study of tumors in salivary gland, breast, lung, and cervix. Human Pathol 1982;1 3.:916-924. 23. Un Jl. Cohen EL, Villacin AB, Garcia MB, Tseng CH. Basal cell adenoma of prostate. Urology 1978;11 :409-41 0. 24. Lui PD, McNeal JE, Stamey TA. Adenoid cystic carcinoma of the prostate: case report with analysis of radical prostatectomy findings. (in preparation) 25. Maygarden S, Strom S, Ware JL Localization of epidermal growth factneoplasms. Am J Pathol 1980;1 01:41 -50. 37. Shah lA, Schlageter MO. Stinnett P, Lechago J. Cytokeratin immunohistochemistry as a diagnostic tool for distinguishing malignant from benign epithelial lesions of the prostate. Modern Pathol 1991 ;4:220-224. 38. Srigley JR. Small-acinar patterns in the prostate gland with emphasis on atypical adenomatous hyperplasia and small-acinar carcinoma. Sem in Dlag Pathol 1988;5:254-27. 39. Srigley JR, Dardick I. Hartwick RWJ, Klotz L. Basal epithelial cells of human prostate gland are not myoepithelial cells. A comparative immunohistochemical and ultrastructural study with the human salivary gland. Am J Pathol 1990;136:957-966. Bostwick -62- 40. Tannenbaum M. Adenoid cystic or "salivary gland" carcinomas of prostate. Urol 1975; 6:2338. 41 . Wernen N, Seitz G. Immunohistochemical investigation of different cytokeratins and vimentin In the prostate from the fetal period up to adulthood and in prostate carcinoma. Path Res Pract 1987;182:617-626. 42. Young RH. Pseudoneoplastic lesions of the prostate gland. Path Annual 1987;105-128. 43. Young RH, Clement PB. Sclerosing adenosis of the prostate. Arch Pathol Lab Med 1987;11 :363-366. 44. Young RH, Frierson HF, Mills SE, Kaiser JS, Talbot WH , Bhan AK. Adenoid cystic-like tumor of the prostate gland. A report of two cases and review of the literature on "adenoid cystic carcinoma• of the prostate. Am J Clln Pathol 1988;89:49-56. Bostwick -63- DIFFERENTIAL DIAGNOSIS OF BASAL CELL PROLIFERATIONS OF THE PROSTATE Benign Low grade atypical adenomatous hyperplasia (AAH, or adenosis) Sclerosing AAH (sclerosing adenosis) Seminal vesicles and ejaculatory ducts Transitional epithelium and transitional metaplasia Proliferative papillary 1:1rethritis Ectopic prostatic tissue Nephrogenic adenoma Inverted papilloma Squamous metaplasia Putative premalignant and Malignant Lesions Well differentiated adenocarcinoma Prostatic intraepithelial neoplasia (PIN) Cribriform patterns of adenoearcinoma Carcinoid and Neuroendocrine Tumors Transitional cell carcinoma Adenocarcinoma (metastatic and contiguous spread) TJ.31..E 2 , BASAL CaL PROUF""eAATlClNS OF iHE PROSTATE • OtAGN0snc CRITERIA AND l)JMUNOHISTOCH!:M!CAL PROFILE Normal SasaJ Basal CeJI Atypical B;asal Cell Sasal C Near--continuous Small eel nes1s SameasBCH RoW>d l nfilaating single cetl layer (solid or cystic), circumscribed ·adenoid c:yslfc• usually in nooular nodule of BCH partem or h)1)e-rptasla: 2 cell l>asalokf panem; layer minimum myxoid stcoma Small elonga1e Larqe ovoid nudei; Same as BCH b.zl Same as BCH; e.asaloid eells cells: ovoid indistinct nucfeoli; with may have wltn large nueltl nuclti: scant sea."ll C)'lopltlsm; n\odeosome9aty nueiQ:Oiom.tQaly cy;o;:.tasm may have dear ~1oplasm lmmlmohiS'gcp .. mfcal .~indinn$ S~! cell speeifle .l<.era:il"' ""' • • • tpotchy) 34G·E12 Ptostate Specific Antige.n ... (oa·tchy) • (Palcl'ly) • (foc al) ~ Pros1a1ic Acid • (Patchy) •IP31Chy) •(focal) ~ i'tlcspc-.atase Chrom~an in ;. .. ~ :. S-100 Prolein ~ ~ :. Neuron spe.eil'ie enotase ;. :. ~ • tndic::a1es <5% of celrs positive Bostwick -64- CASE 7 LOW GRADE PHYLLODES TUMOR OF THE PROSTATE (Recurrence after 12 years is low grade sarcoma) CASE 11 CYSTADENOMA OF THE SEMINAL VESICLES CASE 12 CYSTOSARCOMA PHYLLOOES OF THE SEMINAL VESICLE . Primary malignant seminal vesicle neoplasms are rare, and most are carcinoma, with fewer than 50 cases reported.1 The seminal vesicle is more frequently involved secondarily by tumors originating elsewhere, . particularly prostatic carcinoma. Sarcomas of the seminal vesicle are even more rare. Tripathi and Dick reviewed 46 primary urogenital sarcomas encountered at multiple Boston hospitals between 1923 and 1968, and found only one sarcoma (leiomyosarcoma) of the seminal vesicle.2 Schned et al reviewed 11 reported cases of primary sarcoma of the seminal vesicle, including leiomyosarcoma, fibrosarcoma, liposarcoma colliding with prostatic carcinoma, "primary sarcoma•, "large cell alveolar sarcoma", "pleomorphic cell sarcoma", "malig nant myoblastoma", leiomyoma of vascular origin with "some suggestion of malignant potential", •round cell sarcoma", and "fibrosarcoma with evidence of smooth muscle differentiation by electron microscopy " ,3 A hemangiosarcoma of the seminal vesicle has recently been reported.4 We report a unique case (CASE 12) of primary cystosarcoma phyllodes of the seminal vesicle. The tumor was composed of cystically dilated glands lined by cuboidal to columnar epithelium set in a variably cellular mitotically-active stroma. The tumor was considered malignant at the time of diagnosis because oi its expansive and destructive growth pattern, densely cellular stroma, moderate stromal atypia, focal hemorrhage and necrosis, and high mirtotic counts, and this impression was confirmed by metastasis four years after presentation. Heterologous differentiation was not apparent histologically or ultrastructurally, although desmin reactivity was observed in 30% of the stromal cells, particularly in myxoid areas, suggesting muscular differentiation. Phyllodes tumors usually arise in the female breast, displaying an admixture of variably cellular stroma and benign glandular elements. The density and cytologic features of the stroma determine wh ether the tumor is a fibroadenoma, low grade phyllodes tumor, or high grade phyllodes tumor (cytosarcoma phyllodes). Features considered predictive of malignancy of phyllodes tumors include infiltrating margins, stromal atypia, increased Bostwick -65- numbers of mitoses, and overgrowth of glands by stroma.s However, no single parameter has consistently been correlated with prognosis.s Phyllodes tumors with varying degrees of malignant potential have been described in the prostate, including cystosarcoma phyllodes. The histogenesis is uncertain, but is not considered mullerian for the following reasons: (1) no mullerian remnants e,xist in the adult prostate; the mu.llerian epithelium in the prostatic utricle is replaced by the urogenital sinus early in life ;7.8 (2) prostate specific antigen and prostatic acid phosphatase have been demonstrafed in the adult utricle, indicating the endodermal (prostate-like) nature of this tissue;9 and (3} prostate specific antigen has been demonstrated in the epithelium of prostate phyllodes tumors (CASE 7).10,11 Adenofibroma and adenosarcoma of the female genital tract are histologically similar to phyllodes tumors. These tumors are of mullerian origin, characterized by stromal proliferation with varying degrees of pleomorphism and mitotic activity with, benign glands. In the original description of these tumors, Clement and Scully considered these to be mullerian, nosologically within the category of mullerian mixed tumor.12 There appears to be a spectrum of epithelial-stromal neoplasms arising in the seminal vesicle, analogous to fibroadenomas and phyllodes tumors in the breast and prostate (Table 2). Rare cases of benign "cystadenoma" (CASE 11) and "cystomyoma· have been documented in the seminal vesicle.l3-16 These lesions ranged in size from 5 to 15 em in diameter, with a grossly multiloculated appearance. Histologically, they contained cystic glands lined by cuboidal to columnar epithelium separated by a fibrous or fibromuscular stroma without hypercellularity, atypia, or mitotic activity. One case of cystadenoma reported from our institution did not recur 25 years after the initial resection (unpublished observation) (CASE 11 ). Although the term cystadenoma is appropriate for such a lesion, it could also be considered as a fibroadenoma or fibroadenoma-like lesion, similar to the terminology used for benign epithelial stromal neoplasms in the breast and prostate. In t 987, Mazur et al described a cystic seminal vesicle tumor similar to our case composed of atypical glands set in a cellular stroma which resembled phyllodes tumor of the breast or low-grade· adenosarcoma of the female genital tract.1 7 Despite the presence of pleomorphism of the stroma, their tumor did not show any mitotic activity. Two years after excision, the tumor recurred in the pelvis; it was re-excised and did not recur with 18-months follow-up. The authors preferred the descriptive term "cystic epithelial-stromal tumor" rather than "cystosarcoma" or "atypical cystadenoma" pending study of additional cases with long term follow-up. We consider our case (CASE 12) to be the malignant end of the spectrum of phyllodes tumors of the seminal vesicle (cytosarcoma phyllodes). Our case Bostwick -6Cr diHers from that of Mazur et al by exhibiting significant mitotic activity and metastasis, warranting the diagnosis of sarcoma. Like similar tumors in the breast and prostate, phyllodes tumors in the seminal vesicle should be considered high grade (malignant) when there is signiiicant mitotic activity, pleomorphism of stromal cells, and stromal overgrowth. References • Fain JS, Cosnow I, King BF, Zlncke H, and Bostwick DG. Cystosarcoma Phyllodes oi the Seminal Vesicle. Cancer t 993 (in press) (CASE 12) • Hailing A, Bostwick DG, Fa rrow GM, and Zlncke H. Phyllodes Tumor of the Prostate . Reporl of Six Cases (in preparation) (CASE 7) 1. Benson RC Jr, Clark WR, Farrow GM. Carcinoma of the seminal vesicle. J Urol 1984; 132:483-485. 2. Trlpathl VNP, Dick VS. Primary sarcoma of the urogenital system in adults. J Ural 1969; 101 :898-904. 3. Schned AA, Ledbetter JS, Sellkowitz SM. Primary leiomyosarcoma o,f the seminal vesicle. Cancer 1986;57:2202·2206. 4. Chiou RK, Limas C, Lange PH. Hemarrgiosarcoma of the seminal vesicle: Case reporl and literature review. J Uro l 1985; 134:371-373. 5. Hawkins RE, Schofield JB, Fisher C, Wlltshaw E, McKinna JA. The clinical and histological criteria that predict metastases from cystosarcoma phyllodes. Cancer 1992; 69:141· 147. 6 . Cohn-Cedermark G, Rutqvist LE, Rosendahl I, Siltversward C. Prognostic factors in cystosarcoma phyllodes: A clinicopathologic study of 77 patients. Cancer 1991;68:2017-2022. 7. Langman J. Medical embryology, 3rd Edition. Baltimore. Wilkins and Wilkins. Baltimore, MD. 1975, p. 181. 8. McNeal JE. The prostate and prostate urethra: A morphologic synthesis. J Urol 1972; 1 07:1008·1 086. 9. Bostwick DG, Klndrachuk RW, Rouse RV. Prostatic adenocarcinoma with endometrioid features: Clinical, pathologic. and ultrastructural findings. Am J Surg Path 1985:9:595-609. 10. Ma nlvel c, Shenoy BV, Wick MR, Dehner LP. Cystosarcoma phyllodes of the prostate. A pathologic and immunohistochemical study. Arch Pathol Lab Med 1986;1 10:534-538. 11. Young JF, Jensen PE, Wiley CA. Malignant phyllodes tumor of the prostate. A case report with immunohistochemical and ultrastructural studies. Arch Pathol Lab Med 1992;11 6:296-299. 12. Clement PB, Scully RE. Mu llerian adenosarcoma of the uterus. A clinicopathologic analysis of ten cases of a distinctive type of mullerian mixed tumor. Cancer 1974;34:1 138·1149. 1 3. Soule EN, Doc:kerty MB. Cysadenoma of the seminal vesicle, a pathologic curiosity. Report of a case and review ot the literature concerning benign tumors of the seminal vesicle. Staff meetings of the Mayo Clinic (Mayo Clinic Proceedings) 1951; 26 :406-414. (CASE 11) 14. Lundhus E, Bundgaard N, Sorensen FB. Cystadenoma of the seminal vesicle. Scand J Urol Nephrol 1984:18:341·342. 15. Damjanov I,Radenko A. Cystadenoma of seminal vesicles. JUrol1 974:1 11: 808·809. 16. Plaut A, St andard S. Cystadenoma of seminal vesicle. Ann Surg 1944;199:253·254. 17. MalUr MT, Myers JL, Maddox WA. Cystic epithelial-stromal tumor of the seminal vesicle. Am J Surg Pathol 1987:11 :210-217. 18. Laurila P, Leivo I, Makisaio H, Ruutu M, Ml ettlnen M: Mullerian Adano-sarcomalike Tumor of the Seminal Vesicle. A Case Report with Immunohistochemical and Ultrastructural Observations. Arch Path Lab Mad 1992;116:1 072·1 076. 19. Mazzucchelll L, Studer UE, Zimmermann A: Cystadenoma of !he Seminal Vesicle: Case Repon and Uterature Review. J Urol 1992: 147: 1621· 1624. Bostwick -67- CASE 9 GRADE 3 LEIOMYOSARCOMA OF THE PROSTATE (Abstract axcarped from Manesa MF, Bostwick DG. Kleer E. Kunin PJ, Nascimento AG, Oesterling JE: Leiomyosarcoma of the prostate. Lab Invest. Jan 1993. In press (abstract)) Sarcomas of the prostate are rare, accounting for less th an 0.1% of prostate neoplasms. We present ten cases from the files of the Mayo Clinic from 1929 to 1991. The patients' mean age was 59 years old (range, 42-73 years). Presenting symptoms including prostatism and pelvic pain; in four cases pelvic pain was refractory to medical management. Tumors measured 3-8 em in diameter, and were usually soft with areas of necrosis. Two tumors were grade 1, two were grade 2, five grade 3, and one was grade 4 (Broders' grading system). Mitotic counts varied from 1.2 to 19 mitoses per ten high power fields (hpf). There were two cases with low mitotic counts (2.4 and 1.2 per ten hpf), one with marked atypia and focal necrosis aod the other with malig nant behavior (patient died from tumor within 6.5 years); both cases were small specimens (needle biopsy and small prostatic chips) with possible sampling error. One other patient had radiation 2.5 years prior to the diagnosis of sarcoma. Tissue was available for immunocytochemistry in 7 cases. Six displayed intense cytoplasmic immunoreactivity for smooth muscle spe-cific actin and vimentin and three displayed weak desmin immunoreactiv ity; the one negative case was unreactive to any antibody probably due to prolonged fixation. All tumors were negative for keratin (AE1 /AE3) and S-1 00 protein. Treatment included radical surgery (1/9 cases) with post-operative radiation (4/9), or radiation therapy alone (4/9). Follow up in 8 patients revealed that mean survival after diagnosis was 2. 75 years (range, 0.2 to 6.5 years); all died from tumor. Our results indicate th at prostatic leiomyosarcoma has a poor prognosis; we recommend radical surgery as the principle treatment recognizing the limited data available. Bostwick -68- CASE 10 LEUKEMIA/ MALIGNANT LYMPHOMA OF THE PROSTATE Malignant lymphoma involving the prostate, whether presenting as primary extranodular lymphoma or as secondary spread to the prostate from another site, is rare. Difficulty has been encountered in the interpretation of some of the early reported cases, with classification of many as "sarcomas·, "lymphosarcomas· , "lymphoblastomas," and "round cell sarcomas." Fewer than one hundred primary and secondary malignant lymphomas involving the prostate have been reported with complete clinical and pathologic documentation. The majority of the cases were diagnosed antemortem, and patients ranged in age from 14 to 86 years, with a mean of 61 years. Patients with prostatic lymphoma usually present with symptoms of urgency and frequency which are usually attributed to concomitant prostatic;: hyperplasia or carcinoma. Even in patients with a previous diagnosis of lymphoma, these obstructive symptoms were considered due to nodular hyperplasia. Systemic symptoms associated with lymphomas, such as fever, chills, night sweats, and weight loss were uncommon, and only in patients with widespread lymphoma. The prostate was usually diffusely enlarged, and soft and rubbery i n consistency. The median furrow was obliterated. Primary prostatic lymphomas are much less common than secondary lymphomas. Most are diffuse large cell and small cleaved cell types, with rare mixed cell lymphomas. Nodular lymphomas and T-cell lymphomas are exceptional. Small non-cleaved cell lymphomas of Burkit1's and high grade non-Burkitt's types and Hodgkin's disease have also been rarely observed. A recent case of angiotrophic lymphoma previously misinterpreted as malignant angioendotheliom atosis appeared in the literature. Malignant lymphoma involving the prostate appears to carry a poor prognosis regardless of stage of presentation, histologic classification, or treatment regimen. Prostatectomy is not effective in prolonging survival, but may offer symptomatic relief of urinary obstruction. There is no consensus regarding treating for lymphoma in the prostate, although treatment of systemic tum or may relieve prostatic symptoms. Rrftrcntcs Bostwick DG and Mann RB: Malignant Lymphoma involving the prostate. A study of 13 cases. Cancer 56: 2932, 1985. Banerjee SS . Harris M: Angiorrophic lymphoma presenting in the prostate. Histopathology 12:667·683. 1988. Boe S, Nielsen H. Ryuov N: BurkitlS Lymphoma Mimicking Prost.atitis. I Urol 125:891·892, 1981. Amin MB, Osborne, Discigel G, Bostwick DG: Malignant Lymphoma Involving the prostate: report of 52 cases. (Uib Invest (absuact), Jan. 1993--in press) CASE 1 3 INVERTED PAPILLOMA OF THE BLADDER Since the initial description of "inverted papilloma" of the urothelium by Paschkis in 1927 and its rediscovery by Potts and Hirst in 1963, more than 200 cases of this unique and rare neoplasm have been reported. Most arise in th e bladder neck, trigone, and ureteral ostia, but other sites in the urinary tract have been reported. Patients are usually male and range in age from 14 to 94 years, with most between 50 and 79 years. Presenting signs and symptoms Include hematuria and outlet obstruction. Cystoscopically, inverted papilloma appears as a "bald" smooth-surfaced nodular polyp which may be sessile or pedunculated. The lesions are usually 1-2 em in diameter and single, but may rarely be as large as 8 em in diameter or multiple. Histologic Features The "typical" inverted papilloma is characterized by smoothly-contoured invaginated cords and columns of urot.helial cells with an intact urothelium on the luminal surface. The arrangement of the epithelial cells is virtually diagnostic, with outer basaloid cells of the cords showing peripheral palisading perpendicular to the prominent enveloping basement membrane and central cells arrayed in a parallel orientation. Central cells may show incomplete squamous metaplasia and microcystic change with PAS positive material. The complex arborizing invaginations are in continuity with the overlying mucosa, and there is usually no significant cytologic atypia (see below). Mitotic figures are rarely observed. Stroma is usually scant and surrounds the endophytic epithelial cords, rather than form ing a central fibrovascular core as is seen in exophytic papillary transitional cell tumors. The tumor is contained within the lamina propria without involvement of the muscularis propria. The "glandular• variant of inverted papilloma is similar to the typical pattern but is composed chiefly of cystitis cystica and/or glandularis. Mild cytologic atypia and mitotic activity may be identified, but changes which approach those seen in Grade 2 papillary transitional cell carcinoma should raise the serious consideration of "inverting " carcinoma. "Atypical" inverted papilloma accounted for 15% of cases in one large series. Inverted papilloma should not recur if entirely excised. Malignant transformation has been rarely described in recurrences of inverted papilloma, but may represent underdiagnosis oi "inverted" carcinoma. It is also likely that many inverted papillomas have been misinterpreted In the past as low grade transitional cell carcinoma. Rare reports of malignancy in association with inverted papilloma have been noted, including papillary transitional cell carcinoma arising in or adjacent to the papilloma. Bostwick -70- Histogenesis The histogenesis of inverted papilloma is unknown, but is related to metaplastic changes such as von Brunn's nest formation, cystitis cystica, and cystitis glandularis. References 1. Potts IF, Hirst E: Inverted p~i llo ma of the bladder. J Urol 1963; 90: 175. 2. Kunze E. Schauer A. Schmitt' M: Histology and histogenesis of two different lypes ol inverted urothelial papillomas. cancer 1983; 51 :348. 3. Cameron KM, Lupton CH: Inverted papilloma of the lower urinary tract Br J Urol 1976; 48:567. 4. Talbert ML, Young RH: Carcinomas of the urinary bladder with deceptively benign-appearing foci. A report of three cases. Am J Surg Pathol 1989; 13:374. 5. Paulson J, Metwalli N, Nochomovitz L, et al: Transitional cell carcinoma of bladder with features of inverted papilloma. Lab Invest 1988; 58:71A. 6. Kyriakos M, Royce RK: Multiple simultaneous inverted papillomas of the upper urinary tract A case report with a review of ureteral and renal pelvic inverted papillomas. Cancer 1989; 63:368. 7. AltaHer LF II!,, Wilkerson SY, Jordan GH, Lynch DF: Malignant inverted papilloma and carcinoma in situ of the bladder. J Urol 1982; 128:816. 8. DeMeester W. Farrow GM, Utz DC: Inverted papillomas of the urinary bladder. Cancer 1975; 36:505. 9. Lazarevic B, Garret R: Inverted papilloma and papillary transitional cell carcinoma of urinary bladder. Cancer 1978 ; 42:1904. 10. Palvio DHB: Inverted papillomas of the urinary traci. A case of multiple recurring inverted papillomas of the renal pelvis, ureter, and bladder associate.d with malignant change. Scan J Urol Nephrol 1985; 19:299. 11 . Schultz RE, Boyle DE: Inverted papilloma of renal pelvis associated with contralateral ureteral malignancy and bladder recurrence. J Urol 1988; 139:1 11 . 12. Stein DS, Rosen S, Kendall AR: The association of inverted papilloma and transitional cell carcinoma oi the urothellum. J Urol 1984; 131:751. 13. Uyama T, Nakamura S, Moriwaki S: Inverted papilloma of bladder. Urology 1980; 16:1 52. 14. Renfer LG, Kelley J, Belville WD: Inverted papilloma of the urinary tract: histogenesis, recurrence and associated malignancy. J Urol 1988; 140:832. 15. Phillips DEH, Blenklnsopp WK: Inverted papilloma and papillary transitional cell carcinoma of bladder. Br J Urol 1988: 61 :162. 16. Alroy J, Miller AW Ill, Coon, et al: Inverted papilloma of the urinary bla~der: ultrastructural and immunologic studies. Cancer 1980; 46:64. 17. Anderstrom C, Johannsson s, Pettersson S: Inverted papiiloma of the urinary tract. J Urol 1982: 127: , , 32. 18. Khoury JM. Stutzman RE, Sepulueda RA: inverted papilloma oi the bladder with local transitional cell carcinoma: A case report. Milit Med 1985: 150:562. Bostwick -11- CASE I~ IDIOPATHIC MIDLINE DESTRUCTIVE DISEASE OF THE PERINEUM Patients with midline granuloma usually present with inv·olvement of the head and neck or lungs. Five principle entities comprise midline granuloma, including Wegener's granulomatosis, localized Wegener's granulomatosis, idiopath.ic midline destructive disease, lymphatoid granulomatosis, and angiocentric T -cell lymphoma It is )"eC()gnized that midline granuloma is frequently of unknown origin and can also include infectious processes. In 1982, Tsokos et al. described a subgroup of patients with the "midline granuloma syndrome" which was characterized by locally de~tructive lesions with systemic involvement, acute and chronic inflammation and necrosis with no atypical or malignant cells and no vasculitis, and inability to demonstrate an infectious origin by culture or special stains. Follow-up in this group of 11 patients with upper respiratory tract involvement ranged from 6 months to 18 years (mean, 7.3 years) during which time none of the patients developed systemic disease. The cause of this foaminate inflammatory response is unknown. It is separated from polymorphic reticulosis, lymphatoid granulomatosis, and frank lymphoma by the absence of atypical cells. Angiottophic T-celllymphoma has been described in the kidney and prostate in solitary case IeJNI ts. However, to dale, there have been no reported e,ases of idiopathic midline destructive disease of the perineum. References 1. Costa I, Delacretaz F: The midline granuloma syndrome. Pathol Annual1986; 21:159- 171. 2. Tsokos M, Fauci AS, Costa J: Idiopathic midline destructive disease (IMDD). Am 1 Clin Patholl982; 77:162-168. 3. Ho FCS, Choy D, Loke SL, Kung ITM, Fu KH, Liang -R, Todd D, Khoo RKK. Polymorphic reticulosis and conventional lymphomas of the nose·and upper aerodigestive tract: A clinicopatholgic study of 70 cases,. and immunophenotypic studies of 16 cases. Hum Patholl990; 21:1041-1050. 4. Guthman DA, Bostwick DG, Letendre L, Banks PM, Texter IH, Lieber MM. Polymorphic reticulsosi of the penis, scrotum, and perineum (idiopathic midline destructive disease). (in preparation) Bosrwick -72- Case 15 PHEOCHROMOCYTOMA OF THE URINARY BLADDER Pheochromocytoma (paraganglioma) of the bladder constitutes about 1% of all cases (10% of extra-adrenal cases), originating from th~ chromaffin cells of autonomic paraganglia in the waii.About 130 cases have been reported arising in the bladder. Extra-Adrenal Pheochromocytomas: Sites (Account for 15% of pheochromocytomas) Superior para-aortic: 43% Inferior para-aortic: 28% Chest: 12% Urinary bladder: 10% Neck: 3% Other: 4% (Fries and Chamberlain: Surgery 63:2.68, 1986) Clinical features Pheochromocytoma of the bladder has a slight female predilection (59%). Patients range in age from 11 to 84 years, with 70% less than 50 years. Patients typically present with attacks of gross hematuria and hypertension during voiding due to excess catecholamines; other symptoms inciude headaches, palpitations, sweating, and blurred vision. More than 80% of bladder pherochromocytomas are hormonally active. Hypertensive crisis may occur during cystoscopy and biopsy, and general anesthesia is recommended. Serum and urine vanillylmandelic acid levels are usually elevated. Pathologic features Tumors measure up to 13 em, usually arising in the trigone and dome. They appear as solid highly vascular pink-gray mural masses with intact urothelium, sessile mucosal plaques,or exophytic nodular gr.owths. Formalin fixation produces a brown color which may be reversible with alcohol immersion. f rozen sections of tumor immersed in buffered formal calcium display white fluorescence after 2 hours. Microscopically, pheochromocytoma of .the bladder is identical to adrenal pheochromocytoma or other paragangliomas, characterized by cell clusters (zellballen), cords, and sheets of tumor cells with abundant eosinophilic cytoplasm. Two cell types are present: round or polygonal chief cells (type 1 ), and sustentacular cells (type II). Nuclear pleomorphism is frequently prominent Bostwick -73- ("endocrine anaplasia j . The tumors usually display argentaffinity and argyrophilia, and may stain with Fontana-Masson stain. Neurosecretory cells are present in the chief cells (type I cells). PHEOCHRCMOCYraM: lmmunophenotype Chief Cells (Type I) Chromogranin: Positive NSE: Positive Synaptophysin:Positive Sustentacular Cells (Type II) S-1 OO:Positive GFAP: Positive 1\GF: Positive (Kiiewar and Cochran: Arch Pathol Lab Med 113:1209, 1989) Pifferentjal Oiagnosjs The histologic differential diagnosis includes granular cell tumor, sarcomatoid transitional ce ll carcinoma, rhabdomyosarcoma, lymphoma, metastatic renal cell carcinoma, and paraganglioma/pheochromocytoma originating elsewhere. Prognostic Factors, Treatment, and Fol low-Up Metastases develop in about 15% o·f patients with bladder pheochromocytoma, and are not related to age or sex; histologic factors are also unreliable in predicting recurrence or metastases. Treatment consists of surgical excision. Long-term fo llow-up is indicated, with serum VMA level and blood pressure monitoring . References 1. Fries JG, Chamberlain JA: Extra-adrenal pheochrom9cytoma: Literature review and report of a cervical pheochromocytoma. Surgery 63:268, 1968. 2. Mayana TN, Kontozoglou T: Urinary bladder paragangliomas: An immunohistochemical study. Arch Pathol Uib Med 11.2:70, 1988. 3. Kliwer KE, Cochran AJ: A review of the histology, ultrastructure, immunohistology, and molecular biology of extra-adrenal paragangliomas. Arch Pathol Lab Med 113:1209, 1989. 4. Goldfarb DA, Novick AC, Bravo EL, et al : Experience with extra-adrenal pheochromocytoma. J urol 142:931, 1989. 5. Jurincic C, Gasser A, Me.tz KA, et al: Pheochromocytoma of the Urinary Bladder. Urol Int. 48:232, 1992. Bostwick -7 4- CASE 1 6 ADENOCARCINOMA OF THE BLADDER {Signet Ring Cell Type} Primary adenocarcinoma of the urinary bladder accounts for about 2% of all bladder malignancies, and is the third most common histologic type after transitional cell and squamous ce ll carcinoma. Patients range in age from 6 to 92 years (mean, about 58. years)1 , with a prominent male predominance for the non-urachal type. Presenting signs and symptoms are similar to other bladder cancers {hematuria and irritative symptoms), although up to 17% of patients also present with mucosuria. 1 Histologic Types of Adenocarcinoma Grignon et found five histologic types in a study of 72 case of adenocarcinoma from M.D. Anderson Cancer Center: adenocarcinoma NOS (28%); mucinous (24%}; colonic (enteric} (f9%); signet ring cell (17%); ahd mixed type (12%)1 .2; they had no cases of clear cell (mesonephroid} adenocarcinoma, although this has been rarely described by others (fewer than 1o reported cases).3 Grading of adenocarcinoma is based on a scale of 1 to 3, according to the World Health Organization classification. 4 Most adenocarcinomas present with advanced stage, accounting for the poor prognosis, and stage is the most significant predictor of outcome. Radical cystectomy is the treatment of Ghoice for non-urachal adenocarcinoma, although partial cystectomy with removal of the urachal tract and umbilicus is preferred by most for urachal tumors localize d to the dome. The 5-year survival rate for mixed type was 64%; colonic: 55%; mucinous: 51%; adenocarcinoma NOS: 31 %; and signet ring cell: 27%; these differences were not significant when tested in a univariate analysis 1, although patients with the signet ring cell type declined rapidly over the first 2 years after diagnosis. 5·23 DNA plo.idy pattern had no significant influence on survival. 2 Urachal vs. Non-Urachal Adenocarcinoma Separation of urachal and non-urachal origin Qf adenocarcinoma may be difficult with advanced tumors. Some authors have used restrictive criteria tor urachal adenocarcinoma, including location in the dome, involvement of muscular wall of the bladder and extension into the space of Retzius, presence of a suprapelvic mass, intact or ulcerated epithlium with sharp demaraction from normal surface epithelium, and absence of cystitis cystica and glandularis. We agree with Grignon et cil1 that these criteria are too restrictive, and only require location in the dome or anteriorly, sharp demarcation from the surface epithelium, and exclusion of adenocarcinoma elsewhere. Using these less restrictive. criteria, Grignon .e.t al found that there was no significant difference in survival between adenocarcinoma of urachal and non-urachal origin. Mucin histochemistry and immunohistochemistry were of no value in making this Bostwick •75- distinction. Immunohistochemistry of Adenocar cinoma of t he Urinary Bladder According to Abenoza et al, 94% of adenocarcinomas stain for cytokeratin and epithelial membrane antigen (EMA), 87% for CEA, and 50% for Leu-M1.2• Another study using polyclonal antibodies directed against prostatic acid phosphatase (PAP) showed focal positive staining in 5 of 15 adenocarcinomas of the urinary bladder and 3 of 9 transitional ce ll carcinomas, apparently in chromogranin-postjve cells2S; polyclonal PAP imm unoreactivity was also focally observed in cystitis cystica and glandularis26 and urachal remnants.27 Subsequent studies using monoclonal antibodies against PAP and PSA have failed to identify imm unoreactivity in adenocarcinoma or glandular metaplasias of the urothelium.1 By using stains directed against both PSA and PAP, misinterpretation as prostatic adenocarcinoma can be avoided. Adenocarcinoma of the bladder may contain cells with neuroendorcine differentiation.28 References 1. Grignon OJ, Ro JY, Ayala AG, Johnson DE. Ordonez NG: Primary adenocarcinoma of the urinary bladder. A clinicopathologic analysis of 72 cases. Cancer 1991; 67:2165-2172. 2. Grignon OJ, EI·Naggar A. Ro JY. et al: Deoxyribonucleic acid flow cytometry on primary adenocarcinoma of the bladder: An analysis of 36 cases. J Urol 198'9; 142:1206-1210. 3. Young RH, Scully RE: Clear cell adenocarcinoma of the bladder and urethra: A report of three cases and review of the literature. Am J Surg Pathol 1985; 9:816. 4. Mostofi FK, Sobin LH. Tortoni H: Histologic typing of urinary bladder tumors. In: International Histological Classification of Tumours. No. 10. Geneva, World Health Organization, 1g73 , 5. Wheeler JD, Hill WT: Adenocarcinoma involving the urinary bladder. Cancer 1954: 7: 119 - 135. 6. Shaw JL. Gislason J, lmbriglia JE: Transition of cystitis glandularis to primary adenocarcinoma of the b4adder. J Urol 1958 ; 79: 815- 822. 7. Sagalowsky A, Donohue JP: Sixteen·year survival with metastatic signet-ring cell bladder carcinoma. Urology 1980; 15: 501 -503. 8. Braun EV, Ali M, Fayemi AO, et al: Primary signet-ring cell carcinoma of the urinary bladder: Review of the literature and report of a case. Cancer 1981; 47:1430. 9. Poore E, Egbert B, Jahnke R, et al: Signet·ring cell adenocarcinoma oi the bladder: Linitis plastica variant. Arch Pathol Lab Med 1981; 105:203. 10. Yoshida H, ltawa H, Ochi K, et al: Primary signet-ring cell carcinoma of the urinary bladder. Urology 1981; 17:481. 11 . Kondo A. Ogisu B. Mitsuya H: Signet-ring carcinoma involving the urinary bladder: report of a case and review of 21 cases. Urollnr 1981; 36:373. Bostwick -76- 12. Gonzalez E. Fowler MR. Venable DO: Primary signet ring cell adenocarcinoma of the bladder (linitis plastica of the bladder): Report of a case and review of the literature. J Urolt982; 128:1027. 13. Choi H, lamb S, Pintar K. et al: Primary signet-ring cell carcinoma of the urinary bladder. Cancer 1984; 53: 1985. 14. DeMay AM, Grathwohl MA: Signet-ring cell (colloid) carcinoma of the urinary bladder: Cytologic. histologic. and ultrastructural findings in one case. Acta Cytol 1985; 29; 132. 15. Kitamura H, Sumikawa T. Fukuoka H. et al: Primary signet-ring cell carcinoma of the urinary bladder: Report of two cases with histochemical studies. Acta Pathol Jpn 1985; 35:675. 16. Ponz M. Luzuriaga J. Robles JE, et al: Primary signet-ring cell carcinoma of the urinary bladder (linitis plastica). Eur Ural 1985; 11:212. 17. Kumar PVN, Youssefi A. Ahmad A: Primary signet-ring cell adenocarcinoma cit the urinary bladder with calculi. Br J Urol 1986; 58:342. 18. Tanaka T. Kanai N, Sugie S: Primary signet-ring cell carcinoma of the urinary bladder. Pathol Res Pract. 1987; 182:130. 19. Horne OW. Fauver HE: Primary signet-ring cell carcinoma of bladder_ Urology 1987; 30: 574. 20. Bernstein SA, Reuter VE. Carroll PR. et al: Primary signet·ring cell carcinoma of the urinary bladder. Urology 1988; 31:342. 21 . Blute ML, Engen DE. Travis WD. et al: Primary signet ring cell adenocarcinoma oi the bladder. J Ural 1989; 141 :11. 22. Goble NM, Clarke TJ, Teasdale C: Signet ring cell adenocarcinoma of !bladder secondary to long· term catheterization. Urology 1990; 35:279. 23. Grignon OJ, Ro JY1 Ayala AG, Johnson DE: Primary signet-ring cell carcinoma of the urinary bladder. Am J Clin Pathol 1991 ; 95:13-20. 24. Abenoza P. manivel C, Fraley EE: Primary adenocarcinoma of urinary bladder: Clinicopathologic ~tudy of 16 cases. Urology 1987; 29:9-14. 25. Epstein Jl, Kuhajda FP, Lieberman PH: Prostate-specific acid phosphatase immunoreactivity in adenocarcinomas oi the urinary bladder. Hum Pathol 1986; 17:939·942. 26. Nowels K, Kent E, Rinsho K, Oyasu R: Prostate specific antigen and a.cid phosphatase-reactive cells in cystitis cystica and 9landularis. Arch Pathol Lab Med 1988: 112:734-737. ·27. Golz R, Schubert GE: Prostatic specific antigen: Immunoreactivity in urachal remnants. J Urol 1989; 141: 1480-1482. 28. Abenoza P. Manivel C, Sibley RK: Adenocarcinoma with neuroendocrine .differentiation of the urinary bladder: Clinicopathologic. immunohistochemical. and ultrastructural study. Arch Pathol Lab Med 1986; 11 0: 1062 -1066 . Bos.twick -77- CASE 1 7 BENIGN UROTHELIAL PAPILLOMA (vs. Low Grade Papillary Carcinoma) (Text excerpted from "NATURAL HISTORY OF EARLY BLADDER CANCER", D. G. Bostwick, in J Ce ll Biochem (1993), in press.) Abstract Non-invasive transitional cell carcinoma (TCC} occurs as two distinct growth patterns (papillary and non-papillary (flat)) which display significant differences in biologic potential. Papillary carcinoma usually presents as a low-grade lesion which frequently r.ecurs multiple times prior to invasion; conversely, non-papillary (flat) carcinoma in situ is usually high-grade at presentation (carcinoma in situ} and frequently associated with invasion. These lesions may occur together, although papillary cancer is more easily visualized cystoscopically due to its exophytic growth; flat carcinoma in situ is often cystoscopically invisible. Th is report reviews existing data concerning the prognostic value of pathologic grading and staging of non-invasive and early invasive TCC. Emphasis is placed on those studies reporting surgical treatment rather than other forms of treatment. INTRODUCTION It is difficult to determine the natural history of non-invasive TCC because of numerous problems with pathologic classification and staging[1]. Until recently, grading of urothelial lesions has been inconsistent, with no consensus of opinion or stand-ardization of criteria; however, efforts by the World Health Organization (WHO) in the past two decades have resolved many of these grading issues[2]. Some pathologists accept the existence of benign papill-oma[3) whereas others consider these to be low grade carcinoma[4,5]. Staging of TCC i n superficial biopsies has always been difficult due to sampling error and the frequent inability to determine the presence or extent .of invasion; some reports have provided only the clinical evaluation of stage rather than the pathologic stage(6). Many publications have failed to provide precise information and definitions of grading and staging, making it difficult to compare with other reports (see Tables 1 and 2). Also, intra-vesical immunotherapy with bacillus Calmette-Guerih (BCG} has been shown to reduce the risk of recurrence in many cases[?-10), and its widespread use precludes study of the natural history of TCC in a large number of patients in which only excision is undertaken. PAPILLOMA VS. GRADE 1 NON-INVASIVE PAPILLARY CARCINOMA The separation of benign papilloma and low grade papillary carcinoma Bostwick -78- remains unresolved. As long ago as the late nineteenth century, two leading patholo-gists disagreed on the biologic potential of low grade papillary lesions; Virchow considered these benign (papilloma), whereas Rokitansky classified these as malignant (carcinoma). To day, the papilloma-papillary carcinoma con troversy persists, although the majority of pathologisits in th e United States consider any papillary urothelial lesion to be malignant[4]. Review of the literature reveals that these lesions have a 0-67% likelihood of recurring within about 5 years (Table 1, Figure 1)[ 11 -22]; this wide range reflects the variable diagnostic criteria employed by different authors. Those employing strict criteria (small soli-tary lesion with fewer than 7 cells in thickness and no atypia) have reported recurrence · rates at the low end of this range (closer to 0%). Th e likelihood of developing invasive carcinoma (0-21 %) and cancer-specific death (0-12%) after surgical excision is virtually identical to th at of Grade 1 non-invasive papillary carcinoma. see below. BaSed on these findings, some authors recommended elimination of papilloma as a diagnostic category[3], whereas others argue in favor of retaining the strictly-defined papilloma[4-5]. NON-INVASIVE PAPILLARY CARCINOMA (pTa CARCINOMA) Three grade of non-invasive papillary carcinoma are recognized by the WHO (the most widely used grad-ing scheme)[2], based on the degree of cellular anaplasia: grade 1 has th e least degree of anaplasia, grade 2 is interm ediate. and grade 3 has the most (Figure 1). The utility of the grading scheme has been confirmed in most studies addressing this issue; in a multivariate analysis, Torti et al showed that tumor grade was the most significant prognostic factor[23). The likelihood of recurrence, invasion, and cause-specific death appears to correlate positively with increasing tumor grade (Table 1, Figure 2)[19,21,23-29]. The overlap in ranges of outcomes for different grades may be due to problems in determining the presence or depth of invasion in many biopsies, contributing to significant understag-ing: this problem persists, and appears at present to be unavoidable[30). BCG therapy appears to reduce the risk of recurrence for pTa carcinoma[7,9-10). NON-INVASIVE FLAT CARCINOMA (pTIS CARCINOMA; CARCINOMA IN SITU) In 1964, Melamed[31) demonstrated the prognostic importance of transitional cell carinoma in situ and the need to distinguish it from non -invasive papillary carcinoma (Figure 3). Cumulative data from the literature show that this lesion has a hi gh recurrence rate (6 3-92%) . high likelihood o I invasion (32-83%), and a significant rate of cause-specific death (up to 58%} after surgical excision (Table 2, Figure 4)[31-35]. Recurrences may arise in Bostwick -79- urothelial locations outside of the bladder (renal pelvis, ureters, urethra, or prostate), and are frequently multifocal. Flat urothelial lesions with cytologic abnormalities have also been referred to as "dysplasia," transitional intraepithelial neoplasia (TIN), and intraurothelial neoplasia (UIN)[36). Such proposals describe the morphologic continuum of cytologic changes and pro -vide grading schemes (mild, moderate, and severe, or 1,2,3); carcinoma in situ represents the most severe end of the continuum. However, there is a high degree of interobserver variability in grading of urothelial dysplasia (flat non-invasive lesions which fall short of carcinoma in situ), particularily with low grade lesions[37-38). Carcinoma in situ is frequently invisible cystoscopically, and may coexist with papillary neoplasms. To overcome the potential diagnostic difficulty of CIS, urine cytology is recommended; cytology is of considerable diagnostic value with all urothelial lesions, but is particularily useful with carcinoma in situ in which the exfoliated cells exhibit severe cytologic atypia[39-40]. Some have suggested that unrecognized CIS may be responsible for the poor outcome sometimes seen in patients with low grade papillary carcinoma, particularily those who rapidly develop high grade invasive tumors. CARCINOMA WITH INVASION OF THE LAMINA PROPRIA (pT1 CARCINOMA) Until recently, invasive transitional cell carcinoma was defined as tumor involving the muscularis propria; those without such involvement were classified as "superficial." However, reports In the past decade have demonstrated the prognostic utility of identifying tumors with subepithelial Invasion (invasion limited to the lamina propria), and these are included in the current TNM staging system as pT1 tumors. As expected. these tumors have a likelihood of progression {muscle invasion or cancer-specific death) which is intermediate between non-invasive lesions (pTa and pTIS) and muscle-invasive tumors (pT2+) (Table 2, Figure 2)[21 ,23,27-29 -41]. With widespread recognition of this important subset of tumor staging, we recommend that use of the term "superficial" be discouraged and the more precise terminology of TNM staging be employed. The majority of patients with pT1 carcinoma treated with BCG will still progress with muscle Invasion within 5 years[7,9-10] . OTHER PROGNOSTIC FACTORS In addition to tumor grade, growth pattern, and pathologic stage, numerous factors have been describ-ed which have significant predictive value for transitional cell carcinoma. There Is increased risk of recurrence and progression with large tumors, multiple tumors ("field effect"'), those with vascular/lymphatic invasion and basement membrane discontinuity, and those Bostwick -80. with neuroendocrine different-iation (small cell carcinoma)(40,42-44]. Increased risk of cause-specific death is seen with tumors which lose expression of blood group isoantigen A or oncogene-related protein ORP-p21 [43], or display tumor DNA aneuploidy[43,45]. Acquisition of the invasive phenotype i n bladder cancer is corrrelated with inactivation of tumor suppressor gene p53[46] and loss of expression of two tumor-associated anti-gens detected by antibodies M344 and M9A211 [47]. The identification of other prognostic factors which supplement standard clinical and pathologic findings will provide greater precision in stratifying patients for therapy and predicting individual patient outcome. REFERENCES 1. Friedel! GH, Hawkins I, Heney N, Ahmed S: Minim al papillary urinary bladder cancer. Clin Oncol 1 :599-608, 1982. ' 2. Sobin LH: The WHO histological classification of urinary bladder tumors. Urol Res 6:193-195, 1978. 3. Jordan AM, Weingarten J, Murphy WM: Transitional cell neoplasms of the urinary bladder. Can biologic potential be predicted from histologic grading? Cancer 60:2766-2774, 1987. 4. Eble JN, Yound RH: Benign and low-grade papillary lesions of the urinary bladder: A review of the papilloma-papillary carcinoma controversy, and a report of five typical papillomas. Sem Diag Pathol 6:351 -371 , 1989. 5. Brodsky GL: Pathology of bladder cancer. Hemat/Oncol Clin North Amer 6:59-80, 1992. 6. Sorensen BL, Soeborg Ohlsen A, Barlebo H: Carcinoma of the urinary bladder. Clinical staging and histologic grading in relation to survival. Scand J Urol Nephrol 3:189-192, 1969. ·7. Herr HW, Badalament RA, Amato DA, Laudone VP, Fair WR, Whitmore WF Jr: Superficial bladder cancer treated with bacillus calmette-guerin: A multivariate analysisi of factors affecting tumor progression. J Urol 141:22-29, 1989. 8. ltoku KA, Stein BS: Superficial bladder cancer. Hem/ Oncol Clin North Am 6:99-116, 1992 9. Lamm D.L. Griffith JG: Intravesical therapy: does it .affect the natural history of superficial bladder cancer? Semin-Urol 10:39-44, 1992. 10. Lamm DL, Griffith G, Pettit LL, Nseyo UO: Current prespectives on diagnosis and treatment of superficial bladder cancer. Uro logy 39:301-307, 1992. 11 . Kretschmer HL, Stika ER: Papilloma of the bladder. JAMA 141:1039-1041 , 1949. 12. Deming CL: The biological behavior of transitional cell papilloma of the. bladder. J Urol 63:815-820, 1950. Bostwick -81- 13. Ewert EE, Summons HJ: Papillomas oi the bladder. Surg Clin North Am 31:653-657, 1951. 14. Lund F, Lundwall F: Papillomas of the urinary bl adder. Survey and fo llow-up of 183 cases. Acta Pathol Microbiol Scand (A) (Suppl) 105:118-134, 1955. 15. Nichols JA. Marshall VF: Treatment of histologically benign papilloma of the urinary bladder by local excision and fulguration. J Urol 82:486-489, 1959. 16. Royce RK, Ackerman LV: Carcinoma of the bladder: Clinical, therapeu1ic and pathologic aspects of 135 cases. J Urol 65:66-86, 1951. 17. Pyrah, LN, Raper FP, Thomas GM: Report of a follow- up of papillary tum ours of the bladder. Brit J Urol 36:14-25, 1964. 18. Bergkvist A, Ljungqvist A, Moberger G: Classification of bladder tumours based on the cellular pattern. A preliminary report of a clinical-pathological study of 300 cases with a minimum follow-up of eight years. Acta Chir Scand 130:371-378, 1965. . 19. Miller A, Michell JP, Brown NS: The Bristol Bladder Tumor Re gistry. Brit J Urol 41:7-25, 1969. 20. Lerman Rl, Hutter RVP, Whitmore WF Jr: Papilloma of the urinary bladder. 25:333-342, 1970. 21. Heney NM, Ahmed S, Ranagan MJ, Frable W, Corder MP, Hafermann MD, Hawkins IR: Superficial bladder cancer: progression and recurrence. J Urol 130:1 083-1086, 1983. 22. Ash JE: Epithelial tumors of the bladder. J Urol 44:135-145, 1940. 23. Torti FM, Lum BL, Aston 0, MacKenzie N, Faysel M, Shortliffe LD, Freiha F: Superficial bladder cancer: the primacy of grade in the development of invasive disease. J Clin Oncol 5:125-130, 1987. 24. Gibbons RP, Mandler Jl, Harmann WH: The significance of epithelial atypia seen in non-invasive transitional cell papillary tumors oi the bladder. J Urol 102:1 95-199, 1969. 25. Greene LF, Hanash KA, Farrow GM: Benign papilloma or papillary carcinoma of the bladder. J Urol 110:205-207, 1973. 26. Gilbert HA, Logan JL, Kagan AR , Friedman HA, Cove JK, Fox M, Muldoon TM, Lenni YW, Rowe JH, Cooper JF, Nussbaum H, Chan P, Rao A, Starr A: The natural history of papillary transitional cell carcinoma of the bladder and its treatment in any unselected population on the basis of histologic grading. J Urol 119:488-492, 1978. 27. England HR, Paris AMI, Blandy JP: The correlation of T1 bladder tumour history with prognosis and follow-up requirements. Brit J Urol 53:593-597, 1981 . 28. Pocock RD, Ponder BAJ, O'Sullivan JP, Ibrahim SK, Easton OF, Shearer RJ: Prognostic factors in non -infiltrating carcinoma of the bladder: A preliminary report. Brit J Urol 54:71 1-715, 1982. Bostwick -82- 29. Takashi M, Sakata T, Murase T, Hamajima N, Miyake K: Grade 3 bladder cancer with lamina propria invasion (pT1): characteristics of tumor and clinical course. NagoyaJ Med Sci 53:1-8, 1991. 30. Hankey BF, Edwards BK, Ries LA, Percy CL, Shambaugh E: Problems in cancer surveillance: delineating in situ and invasive bladder cancer. J Natl Cancer lnst 83:384-385, 1991. 31. Melamed MR, Voursa NG, Grabstald H: Natural history and clinical behavior of in situ carcinoma of the human urinary bladder. Cancer 17:1533-1545, 1964. 32. Utz DC, Hanash KA, Farrow GM: The plight of the patient with carcinoma in situ of the bladder. J Urol 103:160165, 1970. 33. Yates-Bell AJ : Carcinoma in situ of the bladder. Brit J Surg 58:359-364, 1971. 34. Althausen AF, Prout GR Jr, Daly JJ: Non-invasive papillary carcinoma of the bladder associated with carcinoma in situ. J Urol 116:575-580, 1976. 35. Lieber M, Farrow GM: Transitional cell carcinoma of the bladder. J Urol, 1984 (abstract). 36. Mostofi FK, Sesterhenn lA: Pathology of epithelial tumors and carcinoma in situ of the bladder. Prog Clin Bioi Res 55:162A, 1984 (abstract). 37. Robertson AJ, Beck JS, Burnett RA, Howatson SR, Lee FD, Lessells AM, Mclaren KM, Moss SM, Simpson JG, Smith GO, Tavadia HB, Walker F: Observer variability in histopathological reporting of transitional cell carcinoma and epithelial dysplasia in bladders. J Clin Pathol 43:17-21, 1990. 38. Richards B, Parmar MKB, Anderson CK, Ansell K, Grigor K, Hall RR, Morley AR, Mostofi FK, Risdon RA, Uscinska BM: Interpretation of biopsies of "normal" urothelium in patients with superficial bladder cancer. Brit J Urol 67:369-375, 1991. 39. Farrow GM: Pathologist's role in bladder cancer. Sem Oneal 6 :198-206, 1979. 40. Johansson SL, Cohen SM: Premalignant and non-invasive lesions of the urinary bladder. In: Mechanisms of Carcinogenesis (Ed): EK Weisburg·er, Netherlands, Kluwer Academic Publishers 43-50, 1989. 41. Younes·M, Sussman J, True LD: The usefulness of the level of the muscularis mucosae in the staging of invasive transitional cell carcinoma of the urinary bladder. Cancer 66:543-548, 1990. 42. Raghavan Derek, Shipley WU, Garnick MB, Russell PJ, Rjchie JP: Biology and management of bladder cancer. New Engl J Med 322:1129-11 38, 1990. 43. Lopez-Beltran A, Croghan GA, Groghan I, Huben RP, Mettlin C, Gaeta JF: Prognostic factors in survival of bladder cancer. Cancer 70:799-807, 1992. 44. Schapers RFM, Pauwels APE, Havenith MG, Smeets WGB, van den Brandt P, Bosman FT. Prognostic significance of type IV collagen and laminin immunoreactivity in urothelial carcinomas of the bladder. Cancer Bostwick -83- 66:2583-2588, 1990. 45. Badalament RA, O'Toole RV, Keyhani-Rolagha S, Barl PAPILLOMA NON-f1\'V ASIVE CARCINOMA IN SffiJ (pTa) Grade 0 PAPILL<\RY CARCINOMA (Flat Dysplasia) (pTa) Grades 1-3 (pTIS) Grade 3 I I 1 1 [ - RECU'RRENCE NO NO Grade 1:40-73% NO RECURRENCE RECURRENCE RECURRE."'CE Grade 2:45-67% RECURRENCE RECURRENCE (33-100%) (0-67%) (15-60%) Grade 3:65-85% (8-37%) ' (63-92'i:) ' t INVASIVE CARCINOMA (pTl, pT2, etc.) 0-21%ofpTaGO 0-20% of pTa Gl 0-20% of pTa G2 20-52% of pTa G3+ 0-12% of pTIS CANCER-SPECIFIC DEATH 0-12% of pTa GO 0-10% of pTa Gl 13-20% of pTa G2 0-35% ofoTa G3+ 2-58% ofpTIS Figure 1: Recurrence and progression in predominately surgically treated non-invasive transitional cell carcinoma. (Data from Table 1) Bostwick -85- GRADE I (pTI) GRADE 2 (pTI) GRADE 3 (pTI) ~ II . NO NO NO RECURRENCE RECURRENCE RECURRENCE RECURRENCE RECURRENCE RECURRENCE (29%) (71%) (20-33%) (67-80%) (29-54%) (46-71%) IN"V ASIVE CARCINOMA (pT2, etc.) 0-12%ofpTaG1 21-49% of pTa G2 24-48% of pTa G3+ CANCER-SPECIFIC DEATii ' 0-39% of pTa G 1 17-51%ofpTaG2 25-71% of pTa G3+ Figure 2: Recurrence and progression in predominately surgical ly tTeated tTansitional cell carcinoma with lamina propria invasion. (Data from Table 2) Bostwick -86- CASE 1 8 INTESTINAL METAPLASIA OF THE BLADDER The epithelial lining of the urinary bladder and urinary tract can un dergo a small but significant number of metaplastic changes, including cystitis cystica and glandularis, intestinal (colonic) metaplasia, squamous metaplasia, and nephrogenic metaplasia. The histogenesis of many of these remains controversial, but all have been associated with irritative and inflammatory conditions. Morgagni noted in 1760 that renal pelvic calculi caused mucus production, a process now known as pyelitis glandularis. Intestinal (colonic) metaplasia refers to the appearance of colonic-type mucin-producing goblet cells in the bladder which may be focal or diffuse; when seen in association with von Brunn's nests, if is reierred to as cystitis glandularis. Paneth cell differentiation may also be seen, indicative of "complete" intestinal metaplasia. The normal urothelium contains a small number of cells which produce cytoplasmic mucin, and the number of such cells can increase following irritation. There are also mucin-producing cells in the urachal remnants at the dome of the bladder and the subepithelial trigonal glands (glands of Albarran). Intestinal metaplasia is usually the result of an underlying disease state, including chronic cystitis, extrophy, calculi, parasites, and fistulae, although sometimes it may be idiopathic.1-S Pathogenesis of Intestinal Metaplasia and the Absence of Urine The pathogenesis of intestinal metaplasia is uncertain, and two theories have been proposed. The first theory considers metaplasia to be an acquired change resulting from chronic irritation, perhaps due to absence of urine as suggested by Aiken in 1955.9 Urine is characteristically acidic and contains solutes thought to be essential for maintainance of the transitional epitheli urn. In the setting of irritation, the urothelium undergoes hyperplasia with the formation of inverted epithelial buds (von Brunn's nests). Aiken noted that nest urachal carcinomas were mucin-producing adenocarcinomas, perhaps following glandular metaplasia of the urachal urothelium due to absence of contact with urine. Also, the extrophic bladder is also commonly associated with intestinal metaplasia and adenocarcinoma, usually in the superior and lateral areas which are free of urine contact. 4.6 The second theory of pathogenesis considers metaplasia to be an embryonic abnormality in which endodermal glandular cells remain in the bladder after the rectum separates from the urogenital tract. 7 This theory is unable to account for the change from transitional epithelium at birth to glandular epithlium post natally in the extrophied bladder, and is not favored by most authors. Bostwick -87- Malignant Potential of Intestinal (Colonic) Metaplasia Intestinal metaplasia is considered a significant risk iactor for the development of adenocarcinoma of the bladder, particularily when extensive or diffuse.1.4-8 In a recent report of 3 cases followed for more than two years (from a series of 11 cases}, all developed carcinoma. 1 There is a similar association of cystitis cystica and "leukoplakia" of the bladder and squamous cell carcinoma.7 Lesions which resemble villous adenoma of the colon have been described in the bladder.s The goblet cells of intestinal metaplasia of the urothelium produce a mixture of sialomucins, 0 -acetylated sialomucins, and sulphomucins.10· 11 Also, neuraminidase-resistant binding of the lectin peanut agglutinin was found in the brush border of columnar cells of intestinal metaplasia and diffusely i n dysplastic columnar cells, similar to dysplastic colonic epithelium In ulcerative colitis and in colonic adenocarcinoma., o References 1. Bullock PS, Thoni DE. Murphy WM: The signifiCance of colonic mucosa (intestinal metaplasia) involving the urinary tract. Cancer 1987; 59: 2086-2090. 2. Davis EL, Goldstein AMB, Morrow JW: Unusual bladder mucosal metaplasia in a case of chronic prostatitis and cystitis. J Ural 1974; 111: 767-769. 3. Gordon A: Intestinal metaplasia of the urinary tract epithelium. J Path Bact 1963; 85:441- 444. 4. Goyanna R, Emmett JL, McDonald JR: Exstrophy of the bladder complicated by adenocarcinoma. J Uro/1951; 65:391 -399. 5. Miller DC, Gang DL, Gavris V, Alroy J, Ucci AA, Parkhurst EC: Villous adenoma of the urinary bladder: a morphologic or biologic entity? Am J Clln Patho/1983; 79:728-731. 6. O'Kane HO, Maegaw JM: Carcinoma in the exstrophic bladder. Brit J Surg 1968; 55:631 - 635. 7. Ward AM: Glandular neoplasia within the urinary tract. the aetiology of adenocarcinoma of the urothelium with a review of the literature. l.lntroduction: the origin of glandular epithelium in the renal pelvis, ureter, and bladder. Virchows Arch Abt A: Path Anat 1971; 352: 296-31 1. 8. Young RH, Parkhurst EC: Mucinous adenocarcinoma of the bladder. Case associated with extensive intestinal metaplasia of urothelium in patient with nontunctioning bladder tor twelve years. Urology 1984; 24:192-195. 9. Aiken 0: Pyelitis glandularis. Brit J Surg 1955; 42: 412-416. 10. Barresi G. Maratioti T: Mucin histochemistry and lectin binding sites in intestinal metaplasia of the urinary bladder. Histopathology 1990; 17: 219-223. 11. Lapertosa G, Baracchini P, Fulcheri E, Tanzi R: 0-acetylated sialic acid varints in intestinal glandular metaplasia of the urinary tract. Histopachology 1986; 10: 707-712. Bostwick -88- CASE 1 9 CHROMOPHOBE CELL RENAL CELL CARCINOMA In 1985, Thoenes and colleagues in Germany reported a unique variant of renal cell carcinoma which they termed chromophobe carcinoma characterized by the presence of abundant intracytoplasmic vesicles ultrastructurally and positive histochemical stains for Hale's colloidal iron. This variant has not gained widespread recognition, and fewer than 50 cases have been reported, most trom the original group. The tumors are grossly more uniformly dark than most renal cell carcinomas, often with hemorrhage and necrosis. Microscopically, tumor cells are clear or slightly granular, and usually exhibit peripheral eosinophilic granularity and prominent thickened cell membranes. Diagnostic confirmation requires histochemistry and EM The prognosis of chromophobe renal cell carcinoma appears to be similar to Grade 1 renal cell carcinoma, according to a case-control study by Crotty and Farrow. This is similar to the other reports with follow-up in which metastases have only rarely been seen. References 1. Thoenes W, Starkel ST, Rumpelt HJ: Human chromophobe renal cell carcinoma. Virchows Arch (8) 1985; 48; 207. 2. Thoenes W, Starkel ST. Rumpel! HJ: Histopathology and classification of renal cell tumors (adenomas, oncocytomas, and carcinomas). Pathol Res Pract. 1986; 181:125. 3. Bon sib SM. Lager OJ: Chromophobe renal cell carcinoma: An analysis of five cases. Am J Surg Pathol. 1990; 14:260. 4. Crotty T, Farrow GM: Chromophobe Cell Renal Cell Carcinoma (CH): Clinicopathologic features of 35 cases and comparison with clear cell renal carcinoma (CL). Modern Pathol 5:51A, 1992 (abstract). Bostwick -89- CAS E 20 RHABDOID TUMOR OF THE KIDNEY References I. Beckwith JB, Palmer NF: Histopathology and prognosis of Wilms' rumor: results from the first National Wilms' Tumor Study. Cancer 1978; 41:1937. 2. Haas JE, Palmer NF, Weinberg AG, eta!: Ultrastructure of malignant rhabdoid tumor of the kidney: A distinctive renal tumor of children. Hum Pathol. 1981; 12:646. 3. Fung CHK, Gonzalez-Crussi F, Yonan TN, et a!: "Rhabdoid" Wilms' tumor: An ultrastructural study. Arch Pathol Lab Med 1981; 105:521. 4. Gonzalez-Crussi F, Goldschmidt RA, Hsueh W, eta!: Infantile sarcoma with intracytoplasmic filamentous inclusions: Distinctive rumor of possible histiocytic origin. Cancer 1982; 49:2365. 5. Schmidt D, Hanns D, Zeiger G: Malignant rhabdoid tumor of the kidney: Histopathology, ultrastructure and comments on differential diagnosis. Virchows Arch (A) 1982; 398:101. 6. Weeks DA, Beckwith JB, Mierau GW: "Pseudorhabdoid" rumors of the kidney. Lab Invest 1986; 54:10P 7. Weeks DA, Beclcwith JB, Mierau GW: Rhabdoid IUmor: An enitiry or a phenotype? Arch Pathol Lab Med 1989; 113:113. 8. Chandra RS, eta!: Malignant rhadoid rumor of the kidney and soft tissues: Evidence for a diverse morphological and immunocytochemical phenotype. Arch Pathol Lab Med 1989; 113:115. 9. Lowe W, Weiss RM, Todd MB, eta!: Malignant rhabdoid rumor of the kidney in an adult J Urol !990; 143:110. Bostwick -90- CASE 21 MESOBLASTIC NEPHROMA OF ADULTHOOD Mesoblastic nephroma rarely occurs in adulthood, and eight cases have been reported, including our cases (Table 1). Patients ranged in age from 19 to 6 6 years, and most were female (6 fe male, 2 male). Clinical signs and symptoms were similar to other adult renal tumors, Including gross and microscopic hematuria and flank pain. Imaging studies were useful in identifying the masses.The tumors involved the renal cortex, with occasional spread to the pelvis, calyces, and ureter, and were histologically identical to congenital mesoblastic nephroma. Ancillary studies were of value in confirming the diagnosis of mesoblastic nephroma. Immunohistochemistry in our cases revealed immunoreactivity for vimentin, desmin, actin HHF-35, and smooth muscle actin in the 'spindle cell component, and keratin and epithelial membrane antigen in the tubular epithelial component, similar to the results of others with congenital mesoblastic nephroma.!19) S-100 protein immunoreactivity was reported in cartilaginous areas by Pettinato et al (1 9). Ultrastructural examination revealed varying amounts of fibroblasts, myofibroblasts, smooth muscle cells, and collagen.(7,1D,21.22.8.12.4.24.19.9) > We identified smooth muscle differentiation in two cases, and collagen in three, similar to the reported results. All of our cases were diploid by flow cytometry, similar to the results of Pettinato et (19) with classis congenital mesoblastic nephroma; interestingly, the cellular area in the case of Pettinato et al was aneuploid DIFFERENTIAL DIAGNOSIS Adult mesoblastic neophroma must be distinguished from other spindle cell lesions of the kidney, including adult Wilms' tumor, sarcomatoid renal cell carcinoma, rhabdoid tumor of the kidney, angiomyolipoma, and multilocular cyst. WILMS' TUMOR Wilms' tumor is rare in adults, and the incidence is unknown; Ki lton et ai.(14J accepted less than 50 of the 192 cases reported prior to 1980 due to incomplete pathologic documentation. Wilms' tumor characteristically has a triphasic appearance, including blastematous, stromal, and epithelial components with glomeruloid structures and tubules. Adult Wilms' tumor is usually separated from mesoblastic nephroma by the presence of blastema. Biphasic and monophasic variants of Wilms' tumor have been described, and these may be difficult to separate from mesoblastic nephroma unless the tumor is thorou ghly sampled. Anaplasia, a common finding in childhood Wilms' tumors which connotes an unfavorable prognosis (2), is infrequent in adult Wilms' tumors. Lurie et aJ.(1Sl described the ultrastructural features of a case of adult Wilms' Bostwick -91- tumor, identifying fibroblast-like cells in the stromal component, polygonal cells with large central nuclei lacking heterochromatin with 1-3 nucleoli in the blastematous component, and tubular epithelial cells with numerous junctional complexes and sparse luminal microvilli. SARCOMA TOlD RENAL CELL CARCINOMA Sarcomatoid renal cell carcinoma is easily separated from adult mesoblastic nephroma by the presence prominent cytologic atypia and numerous mitotic figures; immunohistochemistry and electron microscopy reveals epithellial differentiation in the spindle cell component. This separation is important since sarcomatoid renal cell carcinoma· is an aggressive tumor with a poor prognosiswhich requires adjuvant therapy is required. Rhabdoid tumor of the kidney is separated from mesoblastic nephroma by the presence of plasmacytoid cells with large eosinophilic hyaline cytoplasmic globules of and prominent nucleoli.. The globules are ultrastructurally composed of intermediate filaments.l11 > ANGIOMYOUPCMA Angiomyolipoma may be similar to mesoblastic nephroma grossly and microscopically. Grossly, it is circumscribed, yellow to gray-tan, and soft. Microscopically, angiomyolipoma consists of variable amounts of smooth muscle, thick walled vessels, and adipose tissue. If the smooth muscle and vessels predominate, it may be mistaken for mesoblastic nephroma. CYSTIC NEPHROMA Multilocular cyst of the kidney is separated from cystic mesoblastic nephroma by the following: the cyst are unilateral, solitary, and multiloculated; the locules do not communicate with the pelvis and have an epithelial lining; the remaining kidney is normal, without fully developed nephrons or portions of nephrons in the septa of the cystic lesion.(3l HISTOGENESIS The histogenesis of mesoblastic nephroma re mains controversial. One theory contends that mesoblastic nephroma originates from metanephric blastema (primary mesenchyme) which is capable of forming epithelial structures, and the bizarre and dysplastic tubules are a part of the tum or and not just entrapped.(S) This theory considers mesoblastic nephroma to be a cytodifferentiated or maturing form of Wilms' tumor. Ganick et al.(9) hypthesized that these tumors are related in a circular fashion, with mesoblastic nephroma representing the central stromal portion or the spectrum, and multilocular cyst, nephroblastomatosis, and Wi lms' tumor displaying variable levels of cystic/ Bosrwick -92- epithelial predominance. Another theory contends that mesoblastic nephroma i s derived from secondary mesenchyme which is incapable of forming epithelial structures. Kumar et al. (1 5) proposed that mesoblastic nephroma arises from nephrogenic blastema based on immunophenotypic sim ilarity (both are fibronectin positive and laminin negative); conversely, Wilms' tumor arises from metanephric blastema (both are laminin positive). TREATMENT AND CLINICAL BEHA VIOR The clinical behavior of adult mesoblastic nephroma appears to be benign, although the number of patients reported and the length of follow-up is limited; one patient followed for 21 years had local recurrence which was histologically similar to the original renal tumor. Nephrectomy is probably curative in most cases. The light microscopic appearance is usually diagnostic, but may be assisted by the use of immunohistochemistry, flow cytometry ana electron microscopy. REFERENCES 1.Amnamunthodo, H., Hutchings, R. F. Nephroblastoma: Case Report. Journal of Urology 1957;78:197-204. 2.Beckwith, J. B. Wilms' Tumor and Other Renal Tumors of Childhood: An Update. Journal of Urology 1986;136:320-324. 3.Bennington, J . L, Beckwith, J. B. Tumors of the Kidney, Renal Pelvis and Ureter. In: Eirminger, H., ed. Atlas of Tumor Pathology. Bethesda: Universities Associated for Research and Education in Pathology, Inc., 1975; Fasicle 12:1-353. 4.Biock, N. L., Grabstald, H. G., Melamed, M. R. Congenital Mesoblastic Nephroma (Leiomyomatous Hamartoma): First Adult Case. Journal of Urology 197.3 ;110:380-383. S.Bolande, R. P.. Brough, A. J., lzant. R. J. Congenital Mesoblastic Nephroma of Infancy: A Report of Eight Cases and the Relationship to Wilms' Tumor. Pediatrics 1967;40:272-278. 6.Bolande, R. P. Congenital Mesoblastic Nephroma of Infancy. In: Rosenberg, H. S., Bolande. R. P., ed. Perspectives in Pediatric Pathology. Chicago: Year Book Medical Publishers, Inc., 1973:227-250. 7.Favara, B. E. , Johnson, W., Ito, J. Renal Tumors in the Neonatal Period. Cancer 1968;22:845-855. a.Fu, Y-S., Kay, S. Congenital Mesoblastic Nephroma and Its Recurrence. Arch. Pathol. Lab. Med. 1973;96:66-70. 9.Ganick, D. J., Gilbert, E. F., Beckwith, J. B., Kiviat, N. Congenital Cystic Mesoblastic Nephroma. Human Pathology 1981 ;12:1 039-1043. 10.Garcia-Bunuel, R., Brandes, D. Fetal Hamartoma of the Kidney: Case Report, with Ultrastructural Cytochemical Observations. John Hopkins Med. J. 1970;127:213-22 1. 11.Haas, J. E., Palmer, N. F., Wernberg , A. G., Beckwith, J. B. Ultrastructure of Malignant Rhabdoid Tumor of the Kidney. A Distinctive Renal Tumor of Children. Human Pathology 1981 ;1 2:646-657. 12.Joshi, V. V.. Kasznica, J., Walters, T. R. Atypical Mesoblastic Nephroma. Arch. Bostwick -93- Pathol. Lab. Med. 1986;11 0:100-106. 13.Kay, S., Pratt, C. B., Salzberg, A. M. Hamartoma (leiomyomatous Type) of the Kidney. Cancer 1966;1 9:1825·1832. 14.Kilton, l., Matthews, M. J., Cohen, M. H. Adult Wilms' Tumor: A Report of Prolonged Survival and Review of Literature. Journal of Urology 1980;124:1. 15.Kumar. S., Marsden, H. B., Carr, T., Kodet, R. Mesoblastic Nephroma Contains Fibronectin but Lacks laminin. J. C/in. Pathol. 1985;38:507·511. 16.Levin, N. P., Damjanov, 1., Depillis, V. J. Mesoblastic Nephroma in an Adult Patient: Recurrence 21 Years after Removal of the Primary Lesion. Cancer 1982;49:573-577. 17.Lopez, J. P., Redorta, J. P., Robles, J. M.. Perez, E. M., Marcellan, C. R. Leiomyomatous Renal Hamart9ma in an Adult. Eur. Urol. 1988;14:80-82. 18.Lurle, M., Sova, 1., Mecz, Y., Lurie, A. Adult Nephroblastoma. Cancer 1988 ;61 :2342·234 7. 19.Pettinato, G., Manivel, J. c .. Wick, M. R., Dehner, L. P. Classical and Cellular (Atypical) Congenital Mesoblastic Nephroma: A Clinicopathologic: · Ultrastructural, Immunohistochemical, and Flow Cytometric Study. Human Pathology 1989;20:682-690. 20.Potter, E. L, Craig, J. M. Pathology of the Fetus and the Infant, 3rd Edition. Chicago: Year Book Medical Publishers, Inc., 1975. 21.Shen, S. C., Yunis, E. J. A Study of the Cellularity and Ultrastructure of Congenital Mesoblastic Nephroma. Cancer 1980;45:306·314. 22.Snyder, H. M., Ill, Lack, E. E., Chetty-Baktavizian, A., Baver, S. B., Colodny, A. H., Retik, A. B. Congenital Mesoblastic Nephroma: Relationship to Other Renal Tumors of Infancy. Journal of Urology 1981 ;126:513-516. 23.Trillo, A. A. Adult Variant of Congenital Mesoblastic Nephroma. Arch. Pathol. Lab. Med. 1990;1 14:533-535. 24.Van VeJden, D. J. J., Schneider, J. W., Allen, F. J. A Case of Adult Mesoblastic Nephroma: Ultrastructure and Discussion of Histogenesis. Journal of Urology 1990 ;143:1216·1219. 25.Wang, N., Minassian, H. The Formaldehyde-fixed and Paraffin-embedded Tissues for Diagnostic Transmission Electron Microscopy: A Retrospective and Prospective Study. Human Pathology 1987;18:715-727. 26.Wigger, H. J. Fetal Mesenchymal Hamartoma of Kidney: A Tumor of Secondary Mesenc)lyme. Cancer 1975;36:1 002-1008. 27.Zuckerman, I. C., Kershner, D., Laytner, B. D., Hirschel, D. Leiomyoma of the Kidney. Ann. Surg. 1947;126:220-228. 28. Durham J, Bostwick DG, Farrow G, and Ohorodinck J. Mesoblastic Nephroma of Adulthood. Report of Three Cases. Lab Invest Jan., 1993 (in press-- abstract) 29.Tomlinson GE, Argyle JC, Velasco S, Nisen PO: Molecular Characterization of Congenital Mesoblastic Nephroma and Its Distinction from Wilms Tumor. Cancer 1992: 70:2358-2361 . 30. Johnson AD, Silva F: Atrophic Tubules and lnterstltial Structures in End-Stage Renal Disease (ESRD). A Lectin and Immunohistochemical Study. (submitted) 3·1. Nadasdy T, Roth J, Johnson DL, Bane BL, Weinberg A, Verani R, Silva F: Congenital Mesoblastic Nephroma: An Immunohistochemical and Lectin Study. Human Pathology (in press) · Bostwick -94- CONGENITAL MESOBLASTIC NEPHROMA OF ADULTHOOD: REPORTED CASES Author/ Agel Signs/ Radiographic Gross Pathologic Year Sex Symptoms Findings Tr.eatment Findings Follow-Up Block at al 31/F Flank paln Angiogram: Righi 3.8 em. firm, tan, 48 years, NED 1973 4 em. mass Nephrectomy uniform mass levin at al 19/F NIA NIA Right Encapsulated mass Recurrence 1982 Nephrectomy at 21 years Lopez at al 50/M Left upper CT scan: Left 8 X 5 em. 4.5 years. NED 1988 quadrant mass in lower Nephrectomy unencapsulated mass mass third of kidney with fibrosis " Van Vaiden 20/F Right flank CT scan: solid Right Cin::umscrlbed 8 em. 1 year, NED at al mass mass in kidney Nephrectomy solid grayish-yellow 1989 trabeculated mass Trillo at al 41 IF Right flank Arteriogram: Right Cin::umscribed 4 em. 3 years, NED 1990 pain ndiolucent, Nephrectomy firm yellow whorled hypovascular mass with cystic mass areas Durham at al 661F Hematuria; CT scan: Right Encapsulated 3 em. 8 months, NED (current case recurrent 3.5 em solid Nephrectomy solid muC Durham at al 641F Hematuria; CT scan: Right Nodular 8 em. cystic 2 years, NED (current case flank mass large solid Nephrectomy mass filling pelvis # 2) tumor; uro- and calyces, with graphy: non- ureteral extension functional right kidney Durham at al 4SIM Hematuria; CTscan: Left Polypoid 8 em. soft, 2 years, NED (current case intermittent 7 em. solid Uretero- yellow, variegated, # 3) flank pain mass in nephrectomy partially hemorrhagic lower pole and necrotic mass in conex, pelvis, and calyces NED~ No evident disease; NIA: Data not available Bostwick -95- CASE 2 2 SARCOMATOID RENAL CELL CARCINOMA MIMICKING MFH In the initial description of this variant of renal cell carcinoma by Farrow et al in 1968, its aggressive clinical behavior was emphasized; even now, the median survival of all patient is 6 months. Most have metastases at the time of diagnosis, and tumor stage is the most significant prognostic factor. Sarcomatoid carcinoma accounts for about 5% of renal cell carcinomas. It frequently appears as part of other patterns of carcinoma.. It may resemble malignant fibrous histiocytoma, leipmyosarcoma, or fibrosarcoma, and heterologous elements such as osteoid and chondroid have been described. Ultrastructural studies have demonstrated desmosomes indicative of epithelial differentiation. Reference:; 1. Farrow GM, Harrison EG Jr, Utz DC: Sarcomas and sarcomatoid and mixed malignant tumors of the kidney in adults: Ill. Cancer 1968; 22:556. 2. Ro JY, Ayala AG, Sella A, et at: Sarcomatoid renal cell carclnom: Clinicopathologic: A study of 42 cases. Cancer 1987; 59:516. 3. Bonsib SM, Fischer J, Plattner S, et al: Sarcomatoid renal tumors: Clinicopathologic correlation of three cases. Cancer 1987; 59:527. 4. Bertoni F, FerriC, Benati A, et al: Sarcomatoid carcinoma of the kidney. J Urol 1987; 137:25. 5. Macke RA, Hussain MB, lmray TJ, et al: Osteogenic and sarcomatoid differentiation of a renal cell carcinoma. Cancer 1985; 56:2452. 6. Sella A. Logothetis CJ , Ro JY, et al: Sarcomatoid renal cell carcinoma: A lreatable entity. cancer 1987; 60:1313. 7. Piscioli F, Micoli G, Oliveni G: Differential morphologic criteria in sarcomatous-like renal carcinoma. Tumori 1976; 38: 2469. 8. Tomera KM , Farrow GM, Lieber MM: Sarcomatoid renal carcinoma. J Urol 1983; 130:657. 9. Deitchman B, Sidhu GS: Ultrastructural study of a sarcomatoid variant of renal cell carcinoma. Cancer 1980; 46:1 152. Bostwick -96- CASE 2 3 BLADDER CANCER WITH MIXED DIFFERENTIATION (TRANSITIONAL CELL AND SMALL CELL CARCINOMA) Multidirectional differentiation Is common in urothelial malignancies, and all possible combinations have been reported. H About half of all cases of small cell carcinoma of the bladder occur In association with transitional cell carcinoma.4·21 Mixed transitional cell and adenocarcinoma has been described, but may confused with pseudogland formation in transitional cell carcinoma., Also, rare examples have been reported of separate concurrent malignancies.2·3 Most authors believe that the predominant pattern should be given in the diagnosis, although it is uncertain whether focal areas with high grade tumor such as small cell carcinoma indicate a worse prognosis. Small Cell Undifferentiated (Oat Cell) Carcinoma of the Bladder Less than 100 cases of small cell carcinoma of the bladder have been described, all in the past 11 years. 4-21 Patient age ranges from 40 to 83 years, and there is a male predominance. Presenting signs and symptoms are similar to other urothelial malignancies, although rare patients have been reported with paraneoplastic syndrom es (hypercalcemia and hypophosphatemia). Small cell carcinoma may appear in pure form {56% of cases), combined with transitional cell carcinoma (20%), or with combinations of transitional cell, squamous cell, adenocarcinoma, and carcinoid tumor (14%). 4 Occasionally, poorly differentiated transitional cell carcinoma will recur or metastasize with emergence of areas of small cell carcinoma. The histologic appearance and spectrum of small cell undifferentiated carcinoma in the bladder is similar to its pulmonary counterpart. The prognosis of patients with smRII cell carcinoma of the bladder is poor, with only 5 of 55 reported cases living more than 2 years, according to a recent review.4 The immunophenotype of small cell carcinoma of the bladder is similar to similar tumors in other sites: NSE (86% positive); keratin (77%); synaptophysin (67%); chromogranin (25%); EMA (64%); serotonin (3.1%); and Leu -7 (27%). References 1. Grace OA. Winter CC: Mixed differentiation of primary carcinoma of the urin ary bladder. Cancer 1968; 21:1239. 2. Fegen JP, Albert OJ, Persky L: Adenocarcinoma and transitional call carcinoma occurring simultaneously in the urinary bladder (mixed tumor). J Surg Oncol 1971: 3:387. 3. Wiener M, Sarma DP, Weilbaecher TG: Simultaneous occurrence of adenocarcinoma and transitional cell carcinoma as two separate primary tumors In the bladder. J Surg Oncol 1984; 25:48. 4. Peterson RO. Urologic Pathology, JB Uppincon Co. Philadelphia. 1992. pp. 339-344. Bostwick -97- 5. Cramer SF. Aikawa M, Cebelin M: Neurosecretory granules in small cell Invasive carcinoma of the urinary bladder. Cancer I 981: 47:724. G. Davis BH. ludwig ME. Solon R. et al: Small cell neuro·endocrine carcinoma of the urinary bladder: repon of three cases with ultrastructural analysis. Ultrastru Pathol I 983; 4:197. 7. Ibrahim NBN, Briggs JC, Corbishley CM: Extrapulmonary oat cell carcinoma. Cancer 1984: 54:1645. 8. Kim CK, lin Jl, Tseng CH: Small cell carcinoma of urinary bladder: Ultrastructural study. urology 1984: 29:384. 9. Pananen S, Asikainen U: Oat cell carcinoma of the urinary bladder with ectopic adrenoconicotropic hormone production. Hum Pat hoi 1985; I 6:3 I 3. t o. Reyes CV, Soneru 1: Small cell carcinoma of the urinary bladder with hypercalcemia. Cancer 1985; 56: 2530. 11. Ordonez NG, Khorsand J, Ayala AG, at al: Oat cell carcinoma of the urinary tract: An immunohistochemical and electron microscopic study. Cancer 1986; 58; 2519. 12. Lee JY-Y, Tang CK, Rodriguez F: Anaplastic carcinoma of the urinary bladder with oat cell features. Urology 1986; 27:474. 13. Williams MR, Dunn M, Ansell ID: Primary oat cell carcinoma of the urinary bladder. Br J Ural I 986; 58:225. 14. Abenoz:a P, Manlvel C, Sibley RK: Adenocarcinoma with neuroendocrine differentiation of the urinary bladder: Clinicopathologic, immunohistochemical, and ultrastructural study. Arch Pathol Lab Mad I 986; 1I 0: I 062. t 5. Mills SE, Weiss MA, Wick MR, et al: Small cell undifferentiated carcinoma of the urinary bladder: A light microscopic, immunocytochemical, and ultrastructural study of 12 cases. Am J Surg Pathol. 1987; I 1:606. t6. lwamura M,Masui N, Nishimura K, at al: Small cell neuroendocrine carcinoma of the urinary bladder: A case repon. Jpn J Ural I 988; 79:2021. 17. Swanson PE, Brooks R, Pearse H, at al: Small cell carcinoma oi the urinary bladder. Urology 1988; 32:558. 18. Podesta AH, True LD: Smail cell carcinoma of the bladder: Repon of five cases with immunohistochemistry and review of the literature with evaluation of prognosis according to stage. Cancer 1989; 64:710. t9. Blomjous CEM. Vas W, De Voogt HJ. et aJ: Small call carcinoma of the urinary bladder: A clinicopathologic, morphometric, immunohistochemical, and ultrastructural study of 18 cases. Cancer I 989; 64:1347. 20. Golomb J, Klutke CG, Lewin KJ, at al: Bladder neoplasms associated with augmentation cystoplasty: Repon of 2 cases and literature review. J Urol 1989; 142:377. 2t . Grignon OJ , et al: Small cell carcinoma of the urinary bladder. Cancer 1992. Bostwick -9&- CASE 24 HEMANGIOPERICYTOMA OF THE KIDNEY About 25 cases of hemangiopericytoma arising in the kidney have been reponed through 1991. The patients range in age from 30-60 years, similar to hemangiopericytoma arising in other sites. Patients present with hematuria., flank pain, with or without palpable mass. Interestingly, three patients had rumor-associated hypoglycemia. Angiography has described both hypervascular and hypovascular rumors. Patholoe;y Grossly, renal capsular renal hemangiopericytomas are large solid to cystic masses with scattered areas of hemonilage. These demarcated non-encapsulated masses compress the uninvolved kidney. Microscopically, the rumors display the histologic spectrum of hemagiopericytoma' seen at other locations. This spectrum includes typical perivascular proliferation of cells with spindle-shaped nuclei The vessels tend to be arranged in slit-like spaces without endothelial enlazgement. Mitotic figures may be infrequent Electron microscopy reveals basal lamina sw:rounding tl1e rumor cells, interdigitating cell processes, intracytoplasmic filaments, scattered desmazomes and pinocytotic vesicles. Differential Djagnosj s The main differential diagnostic considerations are sarcomatoid renal cell carcinoma. malignant fibrous histiocytoma, leiomyosarcoma, and juxtaglomerular cell rumor. Clinical Follow-up Six of the 23 reported patients in the literature have died as a result of the rumor, most within three years. References 1. Asa SL, Bedard YC. Buckspan MB, eta!: Spontaneous hypoglycemia associated with bemangiopericytoma of the kidney. U Urol 125:864, 1981. 2. Monda! A. Choudhury S, Mukhezjce PK: Primary malignant hemangioperlcytoma of kidn.ey: A case report. 1 Postgrad Med29:12_D. 1983. 3. Weiss JP, Pollack HM, McCormick JF, eta!: Renal hemangiopericytoma: Surgical, radiological and pathological implications. 1Uroll32:337,1984 4. Srivivas V, Sogatri PC, Hajdu ST, et al: Sarcomas of the kidney. 1 Uroll32:13, 19&4. 5. Dufeuil P, Vidal V, Guille F, et al: Hemangiopericytoma renal: Revue de la literature propos d'un cas. 1 Urol (Paris) 94:103, 1988. 6. Siniluoto TMJ, Paivansalo MJ, Hellstrom PA, et al: Hemangioperieytoma of the kidney: A case with preoperative ethanol embolization. 1 Urol 140:137. 1988. Bostwick -99- CASE 25 LEYDIG CELL TUMOR OF THE TESTIS Leydig cell tumor is classified as a sex cord/stromal tumor according to the World health Organization. It can occur at all ages, but is more common in adults, usually seen between age 20 and 50 years. Presenting signs. and symptoms are variable, including testicular enlargement. decreased libido with or without gynecomastia (30% of adult patients}, and precocious puberty (most prepubertal patients}; hormonal assays show variable results. The tumor is usually unilateral and well-circumscribed, measuring from 1 to 10 em in diameter. It tends to be soft and yellowish-brown, often with fibrous bands causing lobulation, and rarely with necrosis, hemorrhage, and cystic change. Microscopically, tumor cells display sheet-like growth or cellular cords with fibrosis. Tumor cells are polygonal and uniform, with moderate to atiundant eosinophilic cytoplasm and central round to elongate nuclei. Occasional cells with "endocrine anaplasia" may be seen, and multinucleated cells are rarely present. Mitotic figures are usually absent. Lipofuscin pigment may be present within tumor cells, and eosinophilic rectangular sharp-edged crystalloids of Reinke may be found in up to 40% of cases; trichrome stain is useful in identifying crystalloids in problem cases. Blood vessels are indistinct and thin-walled. Ultrastructurally, normal and neoplastic Leydig cells contain abundant smooth endoplasmic reticulum, lipofuscin pigment; mitochondria with tubular cristae, and lysosomes. lmmunohistochemically, Leydig cells express testosterone, estrogen, and vimentin; keratin and EMA staining is negative. Almost all Leydig cell tumors are benign, but about 40 cases have been reported with malignant behavior. Most patients with malignant Leydig cell tumors are over age 40 years, with no difference in hormonal activity or presenting symptoms from those with benign tumors. About 20% present with metastases. Malignant tumors tend to be large (5-10 em diameter} and may show epididymal involvement at the time of diagnosis. The identification of capsular invasion and vascular invasion is useful diagnostically, but about 25% will not have these features; generous sampling is indicated. Ultimately, the only definite evidence of malignant behavior is metastasis, and this may occur up to 9 years alter orchiectomy. Patients with malignant Leydig cell tumors usually die from tumor within 3 years. The main differential diagnostic considerations include Leydig cell hyperplasia, malignant lymphoma, adrenal rests, and metastatic carcinoma (prostatic adenocarcinoma is most common}. Bostwick -100· References 1. Schwarzman MI. Basso P, Bosl GJ, et al: Hormone-secreting metastatic interstitial cell tumor of the testis. J Urol 1989; 141:1620. 2. Haas GP, Pittaluga S, Gomella, et al: Clinically occult Leydig cell tumor presenting with gynecomastia. J Urol. 1989; 142:1325. 3. Glavind K, Sondergaard G: Leydig cell tumor: Diagnosis and treatment. Scand J Urol Nephrol 1988; 22:343. 4. Grem JL. Robins HI, Wilson KS, et al: Metastatic Leydig cell tumor of the testis: Report of three cases and review of the li!erature. Cancer 1986; 58:2116. 5. Castle WN, Richardson JR: Leydig cell tumor and metachronous Leydig cell hyperplasia: A case associated with gynecomastia and elevated urinary estrogens. J Urol 1986; 136:1307. ' 6. Zein TA, Khauli RB, Kramer HC: Interstitial cell tumor of testis. Urology 1985; 26:590 7. Czernobilsky H, Czernobilsky B, Schneider HG, et al: Characterization of a feminizing testicular Leydig cell tumor by hormonal profile, immunocytochemistry, and tissue culture. Cancer 1985: 56:1167. 8. Kim I, Young RH, Scully RE: Leydig cell tumors of th e testis: A clinicopathologic analysis of 40 cases and review of the literature. Am J Surg Pathol 1985; 9:177. 9. Feldman PS, Kovacs K, Horvath E. et al: Malignant Leydig cell tumor: Clinical, histologic and electron microscopic features. Cancer 1982; 49:714. 10. Chen KTK, Spaulding RW, Flam MS. et at: Malignant interstitial cell tumor of the testis. Cancer 1982; 49:547. 11. Davis S, Oi Martino NA, Schneider G: Malignan t Interstitial cell carcinoma of the testis: Report of two cases with steroid synthetic profiles, response to therapy, and review of the literature. Cancer 1981; 47:425. 12. Sworn MJ, Buchanan R: Malignant interstitial cell tumor of the testis. Hum Pathol 1981 ; 12:72. 13. Gabrilove JL, Nicolls GL. Mitty HA, et al: Feminizing interstitial cell tumor of the testis: Personal observations and a review of the literature. Cancer 1975; 35:1 184. 14. Mahon FB Jr. Gosset F. Trinity RG, et al: Malignant interstitial cell testicular tumor. Cancer 1973; 31 :1208. 15. Mostofi FK, Price ER Jr: Tumors of the male genital system. In: Atlas of Tumor Pathology, 2nd Series, Fascicle 8. Washington, DC, Armed Forces Institute of Pathology, 1973. HANPLI'-'G Of R.A. DI CAL PR OSTATQ SE~11'-'0V'ESI ClJ.ECfOYIY SPECIMENS 9/1/92 David G. Bo s r~>.~c k, M.D. Mayo Clinic 1. Weigh inuct specimen. 2. Measure prostate and separately measure seminal vesicles. 3. Ink left side of specimen with red or blue ink; right side of specimen with black (lndia) ink. 4. Place specimen intact into neutral buffered formalin for overnight fixation (If fresh or frozen tissue is desired for molecular genetics, proceed to step #6 immediately; note location of tissue saved for such Studies to allow correlation with light microscopy of adjacent sections). 5. Handle pelvic lymph nodes as frozen sections (no change from previous procedures). 6. Cut off 3 mm thick slice of~ and orient in quadrants as shown (urethra is central) with inked side facing up: · , •.,rr,...... ( .l•• t.t .....f_) • Submit entire apex after curling pewendjcular to the surgical margin (similar to cervical conization); submit for frozen section s ~ if requested by the urologist. * Ifdistal urethra fonns a sleeve (easily distinguished from apex) then submit the margin for frozen section. 7. Repeat step 6 for bladder base, noting that slice should be perpendicular to the long axis of the urethra at that site; because of the 35 degree bend at the verumontanum, the urethral angle at the base is considerably different from the apex. 8. Section the entire specimen from apex to base every 3-S mm at right angles tO the apical prostatic urethra. 9. Mark apical faces with a different color ink and dry. (The histotechnologists axe instructed to embed the sections with inked face down, thereby resulting in sections of the apical face as desired--ensures precise orientation.) 10. Place sections in large cassenes and flll out routine cas sene section sheet with sections submitted in order from apex to base; include seminal vesicles at junction with prostate. 11. Submit to histology laboratory no later than 10 a.m. the morning after surgery. Bostwick -5- CASE PIAGNOSES 1. HIGH GRADE PROSTATIC INTRAEPITHELIAL NEOPLASIA 2. LOW GRADE ATYPICAL ADENOMATOUS HYPERPLASIA (AAH) (Adenosis) OF THE PROSTATE 3. GRANULOMATOUS PROSTATITIS WITH FOCAL GLEASON GRADE 2 ADENOCARCINOMA 4. ADENOCARCINOMA WITH ANTI-ANDROGEN EFFECT("Nucleolus Poor Clear Cell Prostatic Adenocarcinoma") 5. FOCAL GLEASON GRADE 2 ADENOCARCINOMA ON NEEDLE BIOPSY 6. BASAL CELL ADENOMATOSIS 7. RECURRENT PROSTATIC PHYLLODES TUMOR (LOW GRADE SARCOMA) 8. PROSTATIC ADENOCARCINOMA ARISING IN THE TRANSITION ZONE 9. GRADE 3 LEIOMYOSARCOMA OF THE PROSTATE 10. CHRONIC LYMPHOCYTIC LEUKEMIA INVOLVING THE PROSTATE 11. BENIGN CYSTADENOMA OF THE SEMINAL VESICLE 12. CYSTOSARCOMA PHYLLODES OF THE SEMINAL VESICLE 13. INVERTED PAPILLOMA OF THE BLADDER 14. IDIOPATHIC MIDLINE DESTRUCTIVE DISEASE(POLYMORPHIC RETICULOSIS; LETHAL MIDLINE GRANULOMA) 15. PHEOCHROMOCYTOMA OF THE URINARY BLADDER Bostwick -6- j::J- ).6'. BENIGN UROTHELIAL PAPILLOMA (VS. GRADE 1 PAPILLARY TRANSITIONAL CELL CARCINOMA) /b .if. ADENOCARCINOMA OF THE URINARY BLADDER, SIGNET RING CELL TYPE ~~ JS'. CHROMOPHOBE RENAL CELL CARCINOMA l~ _;t9. INTESTINAL METAPLASIA OF THE URINARY BLADDER 20. RHABDOID TUMOR OF THE KIDNEY 21 . ADULT MESOBLASTIC NEPHROMA OF THE KIDNEY 22. SARCOMATOID RENAL CELL CARCINOMA MIMICKING MFH 23. BLADDER CANCER WITH MIXED DIFFERENTIATION (TRANSITIONAL CELL AND SMALL CELL UNDIFFERENTIATED CARCINOMA) 24. HEMANGIOPERICYTOMA OF THE KIDNEY 25. LEYDIG CELL TUMOR OF THE TESTIS SfO>'SOO.S. CALIFORNIA MEM&E~ PAw.ot.OOlSTS ~ l.OMA LIND.~ UNMllSITY \:.!,!, TUMOR TISSUE REGISTRY SCHOOL Of MEDICINE "nwriwf\ C.norr Soo<'l'f O liibml& Oiv"lon 011~1. Mcdicll A~OOun, TO: ALL REGISTRANTS/ATIENDANTS OF THE 93RD SEMI-ANNUAL SLIDE SEMINAR FROM: Anne E. Chism, Executive Secretary, CTTR DATE: April 23, 1993 .RE: Missing pages of Dr. Bostwick's handout. 1 am glad to announce that I have obtained the missing pages (#45 and #83) from the handout prepared by Dr. Bostwick. (Ifyou check your addend& you will notice that the other missing page (#32) was simply a numbering error.) The delay in obtaining these lies strictly with me, and for tltis I apologize. It's been very hard to foUow in the footstepS of someone who had run the CTTR for thirty-some odd years, and I hope you will bear with me as 1 suuggle to learn aU that I need to keep things running smoothly -like proofreading the addenda before sending it to the printers! Please know that! welcome any helpful hints and/or criticisms that you have, as overall it will improve my job performance and help me to serve your better. In C3re of: Lorn• Linda University • School of Medicine Department of Pathology • AH 335 • Lorna Unda, California 92350 (909) 824-4788 F."'x (909) 824-488t