Production of beta-human chorionic gonadotropin by prostatic adenocarcinoma and transitional cell carcinoma of the upper urinary tract

Ectopic production and secretion of hormones by a wide variety of tumours has been known for many years. Recently human chorionic gonadotropin (HCG) production and/or secretion have been noted in 15 cases with prostatic adenocarcinoma (Fukutani et al. 1983; Papapetrou et al. 1980: Broder et al. 1977; Menon & Stefani 1980; McManus et al. 1976) and in two with upper urinary tract transitional cell carcinoma (Fukutani et al. 1983; McManus et al. 1976). In this study we utilised the indirect immunoperoxidate technique to demonstrate beta-HCG production in prostatic adenocarcinoma and upper urinary tract urothelial tumours. Of 100 cases of prostatic adenocarcinoma beta-HCG production was demonstrated in nine cases, eight of which were poorly differentiated, and of 14 urothelial tumours of the upper urinary tract beta-HCG production was present in two high grade transitional cell carcinomas.     

Colonic adenocarcinoma metastatic to the urinary tract versus primary tumors of the urinary tract with glandular differentiation: a report of 7 cases and investigation using a limited immunohistochemical panel

OBJECTIVE: To determine whether a limited immunohistochemical panel can help differentiate metastatic colonic adenocarcinoma from primary enteric-type adenocarcinoma of the urinary tract and urothelial (transitional cell) carcinoma with glandular differentiation, which appear morphologically similar but most often necessitate different treatment protocols. DESIGN: We examined lower urinary tract tumors (5 urinary bladder, 2 urethral) from 7 patients with a history of colonic adenocarcinoma. The differential diagnoses in these cases included metastatic colonic adenocarcinoma, primary enteric-type adenocarcinoma of the urinary tract, and urothelial carcinoma with glandular differentiation. An immunohistochemical panel consisting of cytokeratin 7 (CK-7), cytokeratin 20 (CK-20), and villin was evaluated in all cases. Four primary enteric-type adenocarcinomas of the urinary tract and 5 conventional urothelial carcinomas were also studied to compare morphologic features and immunohistochemical staining patterns. RESULTS: Of the 7 cases, 6 were determined to be metastatic colonic adenocarcinoma and 1 was diagnosed as a primary urothelial carcinoma with glandular differentiation. All 6 metastatic colonic adenocarcinomas, 6 of the 7 primary colonic adenocarcinomas, and all 4 primary enteric-type adenocarcinomas of the urinary tract were CK-20 positive (1 was CK-20 negative), villin positive, and CK-7 negative. The single urothelial carcinoma with glandular differentiation and all 5 control cases of urothelial carcinoma were CK-7 and CK-20 positive, and villin negative. CONCLUSIONS: We conclude that (1) villin is expressed in primary enteric-type adenocarcinoma of the urinary tract; (2) in difficult cases, urothelial carcinoma with glandular differentiation can be distinguished from colonic adenocarcinoma because the former is CK-7 positive, CK-20 positive, and villin negative, whereas the latter is CK-20 positive, villin positive, and CK-7 negative; (3) clinical information is essential when evaluating lower urinary tract tumors that are clinically and morphologically similar to enteric-type adenocarcinoma of the urinary tract; and (4) the similar immunohistochemical profiles of metastatic colonic adenocarcinoma and primary enteric-type adenocarcinoma of the urinary tract may be in keeping with the hypothesis that the latter arise from intestinal metaplasia.     

Expression of carbonic anhydrase IX in genitourinary and adrenal tumours

Donato D P, Johnson M T, Yang X J & Zynger D L
(2011) Histopathology  59 , 1229–1239
Expression of carbonic anhydrase IX in genitourinary and adrenal tumours Aims: High expression of carbonic anhydrase IX (CAIX) is reported for clear cell renal cell carcinoma (RCC), with a paucity of data for non‐renal genitourinary or adrenal tumours. This study investigated the immunohistochemical expression of CAIX throughout the genitourinary tract and adrenal gland. Methods and results: High expression in the renal cortex was restricted to clear cell, papillary and clear cell papillary RCC and carcinoid. Core biopsies of clear cell RCC were consistently positive. Positivity within the urothelial tract was seen in urothelial carcinoma including squamous, small‐cell, sarcomatoid and adenomatous differentiation and clear cell adenocarcinoma. Signet ring and plasmacytoid variants of urothelial carcinoma were negative. Phaeochromocytoma, adrenal cortical adenoma, seminoma, yolk sac tumour, choriocarcinoma, Leydig cell tumour and prostatic adenocarcinoma were predominately negative, with variable reactivity in adrenal cortical carcinoma, embryonal carcinoma, teratoma and Sertoli cell tumour. Conclusions: Carbonic anhydrase IX is a sensitive marker for clear cell RCC in core biopsies. However, other genitourinary or adrenal tumours that can have a clear cell appearance including urothelial, squamous cell, clear cell adeno and adrenal cortical carcinoma and Sertoli cell tumour express CAIX. Knowledge of expression overlap between these entities may prevent incorrect interpretation of immunohistochemical results, particularly if limited tissue is available.     

Expression of c-erbB-2 and cytokeratins 7 and 20 in urothelial carcinoma with gland-like lumina

Urothelial carcinoma with gland-like lumina is an uncommon type of tumor, reported only occasionally in literature. Its diagnosis usually does not offer any difficulties, and its prognosis is determined by the accompanying classic transitional or squamous component. It is important though, not to misdiagnose it as a mixed transitional cell adenocarcinoma. In that respect, features such as the type of epithelium lining, the gland-like structures, as well as the type of luminal mucin have been used to make the diagnosis. Recently, an immunohistochemical panel of antibodies has proven helpful in differentiating primary and metastatic adenocarcinomas of urothelial tract from urothelial carcinoma with gland differentiation. In their series of 16 cases, Tamboli et al included only one case of transitional cell carcinoma with gland differentiation. We present two additional cases of urothelial carcinoma with gland-like lumina in two men, 60 and 79 years old, respectively. Both tumors were grade 2 of Ash-Bergkvist, and the stage was pT(1) in both cases. Immunohistochemical study with cytokeratins 7 and 20, and with c-erbB-2, was performed. Both tumors expressed cytokeratins 7 and 20; c-erbB-2 was only expressed in one, in spite of the same staging. Although some relation has been found in animals between gland-like lumina phenotype and expression of epidermal growth factor (the receptor of which is homologous to c-erbB-2), it seems that this relationship might not be constant in humans.     

Prostatic adenocarcinoma diagnosed by urinary cytology

Prostatic adenocarcinoma rarely may involve the urinary bladder. Prostatic adenocarcinoma and high-grade transitional cell carcinoma (TCC) may coexist and account for the malignant cells seen in urinary cytology. Differentiating prostatic adenocarcinoma cells from those of TCC is important for therapy but remains difficult. A 10-year retrospective search identified 250 patients with high-grade carcinoma in urinary cytology. Among them, 6 cases of tissue-documented prostate adenocarcinoma were identified. The cytologic features of these cases were compared with those of 15 similarly documented cases of high-grade TCC. By using these criteria, 2 additional cases of prostatic adenocarcinoma were diagnosed prospectively. An oval nucleus with smooth borders; fine, powdery, evenly distributed nuclear chromatin and a large prominent nucleolus when present; and lack of significant pleomorphism are most helpful to differentiate prostatic adenocarcinoma from high-grade TCC. Recognizing these cells may be the first clue for the diagnosis of prostate adenocarcinoma.     

Primary and secondary prostatic adenocarcinoma of the urinary bladder

Urinary bladder involvement by prostatic adenocarcinoma (PAC) is not well characterized in the literature. Fifteen consecutive cases of PAC diagnosed in the urinary bladder over a period of 10 years were reviewed. All bladder and prostate slides from each patient were evaluated. Eleven patients (group A) had synchronous PAC in the prostate. In these patients, bladder PAC occurred 2 to 11 years after the initial diagnosis of PAC in the prostate and tended to have a higher Gleason score than the original prostatic PAC. Four cases of bladder PAC in group A had areas with features of urothelial carcinoma, with focal positive immunoreactivity for thrombomodulin in 2 cases. Two patients (group B) had undergone radical prostatectomy for PAC 15 years earlier. The lesions in the urinary bladder in both cases showed histopathologic features similar to those seen in the previous prostatic malignancies. Two patients (group C) had histories of previously resected urothelial carcinoma. Bladder PAC was diagnosed at routine follow-up, and repeated prostate biopsy up to 2 years after the diagnosis of bladder PAC showed no evidence of prostatic PAC. PAC in the urinary bladder may be either primary or secondary. Secondary PAC is usually associated with high-grade and high-stage carcinoma in the prostate and may mimic transitional cell carcinoma. Primary bladder lesions may or may not be associated with a history of PAC in the prostate. The prognosis of patients with the primary carcinoma is favorable. HUM PATHOL 32:434-440.     

Transitional carcinoma of the upper urinary tract: a histological and cytopathological study.

A histological and cytopathological study of 54 patients with transitional carcinoma of the upper urinary tract was undertaken. There were 17 patients with grade 1 tumours, 35 with grades 2 or 3, and two with carcinoma in situ. Only 16 had non-invasive tumours. A preoperative cytological diagnosis of tumour was made in 67% of the group as a whole and in 75% of patients with grade 2 or 3 tumours. Seventy per cent of voided urines and 80% of ileal conduit urines were positive for tumour. Cytological grading correlated with histology in 12 of 14 grade 1 tumours and 26 of 35 grade 2 or 3 tumours, with seven assigned grade 1. Two cases of pelvicalycine carcinoma in situ were graded 3 by cytology. Cytological investigation by those experienced in urinary cytology has an important diagnostic contribution to make in transitional carcinoma of the upper urinary tract.     

Nephrogenic adenoma of the urinary tract: a review

Nephrogenic adenoma (NA) is an uncommon and intriguing lesion in the urinary tract. The pathogenesis of NA is not entirely clear. NA was considered to be a metaplastic process of the urothelium in response to chronic irritation of the urinary tract. However, recent evidence has shown that NA is not a metaplastic lesion but rather a proliferation of exfoliated and implanted renal epithelial cells in the urinary tract. Histologically, NAs exhibit, singly or in combination, tubules, small papillae, and microcystic structures lined by cells with little cytological atypia and focal hobnail changes. Solid formations and compressed spindled cells within a fibromyxoid background are rarely observed. Differential diagnosis includes, but is not limited to, malignant neoplasms occurring at the same sites, in particular urothelial carcinoma with deceptively bland morphology (with small tubules, microcystic and nested variants), prostatic adenocarcinoma, and clear cell adenocarcinoma. Immunohistochemical studies with antibodies targeting members of the paired box gene family (PAX2 and/or PAX8) in NAs may be helpful in the differential diagnosis of urothelial lesions and prostatic adenocarcinoma. NAs are most likely to be confused with clear cell adenocarcinoma, especially in small biopsy specimens. This is confounded by both lesions being frequently positive for PAX2, PAX8, and CK7 and not infrequently positive for p504S (α-methylacyl-CoA-racemase, AMACR) by immunohistochemistry. Recognition of its characteristic morphological patterns and awareness of its unusual architectural and cytological features are important in making the diagnosis of NA and distinguishing this lesion from its mimickers.     

Villous adenoma of the urinary tract: a lesion frequently associated with malignancy

Villous adenomas arising in the urinary tract are rare. We identified 18 cases of villous adenomas of the bladder, urachus, and prostatic urethra. Patients ranged in age from 53 to 93 years with an average age of 69.6 years and a male preponderance of 67%. In six cases (33%), the lesion was pure villous adenoma. In three cases (17%), there was villous adenoma with in situ adenocarcinoma. In six cases (33%) there was villous adenoma with in situ and infiltrating adenocarcinoma. One case (6%) had villous adenomas with in situ (noninvasive) papillary urothelial carcinoma. One case (6%) had villous adenomas with in situ adenocarcinoma and in situ papillary (noninvasive) and infiltrating urothelial carcinoma. The remaining case (6%) had villous adenoma with in situ and infiltrating adenocarcinoma and in situ (noninvasive) papillary and infiltrating urothelial carcinoma. Clinical outcome was available in eight of the cases, with a mean follow-up of 4.6 years. No evidence of recurrence was found in two patients with pure villous adenoma or in two patients with villous adenoma and only in situ adenocarcinoma, all of whom were treated by nonradical excision. However, two of three cases with infiltrating cancer developed distant metastases despite radical surgery; the remaining patient was disease-free 11 years after transurethral resection. The case with villous adenoma and in situ urothelial carcinoma progressed to sarcomatoid urothelial carcinoma following partial cystectomy. Eight of 10 villous adenomas cases studied expressed the epitope for mAbDas1, found on colonic epithelium and primary adenocarcinomas of the bladder and urachus but not on normal or neoplastic urothelium. This study expands the spectrum of histologic features accompanying villous adenomas of the urinary tract. Coexisting infiltrating adenocarcinoma is often present, necessitating thorough sampling of any lesion diagnosed by biopsy as villous adenoma. Pure villous adenoma and those well-sampled lesions also containing in situ adenocarcinoma portend a favorable prognosis, even without radical treatment. Coexisting in situ or infiltrating carcinoma suggests a more aggressive course. Histologically, immunohistochemically, and prognostically, these lesions appear analogous to their counterparts in the intestine.     

Uroplakin gene expression in normal human tissues and locally advanced bladder cancer

The uroplakins are widely regarded as urothelium-specific markers of terminal urothelial cytodifferentiation. This study investigated the expression of the four uroplakin genes, UPIa, UPIb, UPII and UPIII, in a wide range of normal human tissues to determine tissue specificity and in advanced transitional cell carcinoma (TCC) to examine gene expression in primary and metastatic disease. In the urinary tract, all four uroplakins were expressed by urothelium and UPIII was also expressed by prostatic glandular epithelium. UPIa and UPII appeared to be urothelium-specific, but UPIb was detected in several non-urothelial tissues, including the respiratory tract, where it was associated with squamous metaplasia of tracheal and bronchial epithelia. The ten cases of primary TCC and corresponding lymph node metastases demonstrated that each uroplakin gene could be expressed at the mRNA level. No single uroplakin gene was expressed in all primary tumours or metastases, but 80% of the primary tumours and 70% of the lymph node metastases expressed at least one uroplakin gene. UPIII mRNA was often expressed in the absence of UPIII protein. These results confirm that in human tissues the expression of UPIa and UPII genes is highly specific to urothelium and suggest that the tight differentiation-restricted expression of uroplakin genes in normal urothelium is lost following malignant transformation.     

Papillary tumour of the vagina resembling transitional cell carcinoma

A case of a peculiar papillary neoplasia of the vagina resembling a urothelial tumour is presented. Four vaginal tumours were excised from a 76-year-old woman. Five years before this patient had undergone a uretero-nephrectomy for a non-invasive papillary transitional cell carcinoma of the renal pelvis. The four vaginal tumours demonstrated gross and microscopic similarities to low-grade papillary transitional cell carcinoma of the urinary tract. This observation indicates that multicentric, non-invasive, papillary tumours may affect the whole uro-genital area. The vaginal wall was not overlaid by a normal squamous epithelium, but by a peculiar "transitional-like" epithelium. Variegated endocrine cells were documented within this lining, using immunohistochemical and ultrastructural techniques. The eventuality of a histogenetic link between the tumour and the adjacent epithelial lining remains unresolved.     

Divergent differentiation in urothelial carcinoma and other bladder cancer subtypes with selected mimics

Conventional urothelial carcinoma accounts for most carcinomas of the urinary tract lining. However, neoplastic urothelium has the capacity to demonstrate enormous plasticity. A variety of unusual architectural patterns of urothelial carcinoma, such as the nested, microcystic and inverted variants, can be mistaken for reactive processes or benign tumours. Others such as the micropapillary, plasmacytoid and discohesive variants, can mimic metastatic tumour from other sites. The micropapillary variant in particular is more aggressive. In addition, urothelial carcinoma has a propensity to demonstrate divergent differentiation with glandular, squamous, small cell neuroendocrine, lymphoepithelioma-like, sarcomatoid or other elements. Pure squamous carcinoma or adenocarcinoma (the latter in particular) can be difficult to distinguish from contiguous or metastatic spread. Some variants have prognostic and potential therapeutic implications. Molecular genetic evidence has emerged recently supporting a close relationship between urothelial carcinoma and various divergent elements. Sarcomatoid carcinoma and its differential diagnosis with other spindle cell lesions of urinary tract will be covered in a separate review.     

Immunohistochemistry of cytokeratin proteins in squamous and transitional cell lesions of the urinary tract.

Expression of low and high molecular weight cytokeratin proteins was investigated immunohistochemically in a variety of transitional and squamous epithelial lesions of the urinary tract with and without schistosomiasis. The monoclonal antibodies used were CAM 5.2 and NCL5D3 for low, PK 63 and 121 for high, and MAK 6 for a broad range of intermediate molecular weight cytokeratins. On staining with CAM 5.2 and NCL5D3, urothelial hyperplasias (n = 12) and grades 1 (n = 5) and 2 (n = 10) papillary transitional cell carcinomas showed labelling patterns quite distinct from carcinoma in situ (n = 4) and non-papillary grades 2 (n = 6) and 3 tumours (n = 3). Among squamous lesions only focal positivity was obtained in 14 of 22 moderate to poorly differentiated squamous cell carcinomas. By contrast, PK 63 and 121 stained squamous lesions exclusively. MAK 6 stained the whole range of urothelial and squamous lesions with the exception of squamous metaplasias. Polyclonal antikeratin adequately labelled spindle cell areas of high grade tumours. The distinctive staining patterns given by these or similar antibodies may help in the identification of squamous metaplasia and in diagnosing tumours of the urothelium.     

Scanning electron microscopy of the upper urinary tract in transitional cell carcinoma of the renal pelvis.

Three nephrectomy specimens with transitional cell carcinoma (TCC) of the renal pelvis were thoroughly examined by both light and scanning electron microscopy. The tumours as well as the urothelium of the upper urinary tract were studied. In all three cases, extensive areas of the urothelium, even in places remote from the tumours, were found by scanning electron microscopy (SEM) to be covered by pleomorphic microvilli. This suggests that there is a widespread failure of differentiation of the urothelium to a much greater extent than can be appreciated by conventional light microscopy.     

Urothelial carcinoma associated with Balkan endemic nephropathy. A worldwide disease

Balkan endemic nephropathy (BEN), a familial chronic tubulo-interstitial disease with a slow progression to terminal renal failure, affects people living in the alluvial plains along the tributaries of the Danube River. One of its most peculiar characteristics is a strong association with upper urothelial cancer. An increased incidence of upper urinary tract (UUT) transitional cell cancer (TCC) was discovered among the inhabitants of endemic settlements and in families affected by BEN. In areas where BEN is endemic, the incidence of upper tract TCC is significantly higher, even 100 times, than in non-endemic regions. A high incidence of urothelial cancer in end-stage BEN patients strongly suggests preventive nephro-ureterectomy in all end-stage patients with BEN treated with either transplantation or dialysis. Better understanding of the molecular mechanisms involved in carcinogenesis and tumor progression, has provided a large number of molecular markers of TCC, with a potential diagnostic and prognostic value. Markers that distinguish among TCC, normal urothelium, and benign urothelial conditions are potentially diagnostic, prognostic, and therapeutic targets. The geographic correlation and presence of AA-DNA adducts in both BEN and associated urothelial cancer, support the speculation that these diseases share a common etiology. Dietary exposure to AA is a significant risk factor for BEN and its attendant transitional cell cancer. These are cases of well-known AA induced urothelial carcinoma, and could be detected worldwide. The presence of more than one risk factors is possible and it is important to test etiological hypotheses in different endemic foci, preferably as a multicentric research.     

Poorly differentiated adenocarcinomas of prostate versus high-grade urothelial carcinoma of the bladder: a diagnostic dilemma with immunohistochemical evaluation of 2 cases

The differential diagnosis between carcinoma of the urinary bladder and adenocarcinoma of the prostate can be difficult, especially in the poorly differentiated forms infiltrating the neighboring organs. In this article, the authors report 2 cases that pose a diagnostic dilemma to the pathologist. The first is an infiltration of the bladder by a poorly differentiated adenocarcinoma of the prostate, which was clinically suspected as a papillary urothelial neoplasm. The second is a collision tumor composed of prostatic adenocarcinoma and urothelial carcinoma observed on a core needle biopsy of the prostate. In both cases, a large panel of immunohistochemical markers were used and demonstrated positivity for prostate-specific antigen and alpha methyl racemase in the prostatic carcinomas and immunoreactivity for CK7, CK20, Ag 34betaE12, and p53 in the urothelial carcinoma. The differentiating histological and immunohistochemical findings are discussed.     

Scanning electron microscopy of the upper urinary tract in transitional cell carcinoma of the renal pelvis

Three nephrectomy specimens with transitional cell carcinoma (TCC) of the renal pelvis were thoroughly examined by both light and scanning electron microscopy. The tumours as well as the urothelium of the upper urinary tract were studied. In all three cases, extensive areas of the urothelium, even in places remote from the tumours, were found by scanning electron microscopy (SEM) to be covered by pleomorphic microvilli. This suggests that there is a widespread failure of differentiation of the urothelium to a much greater extent than can be appreciated by conventional light microscopy.     

Immunophenotype of high-grade prostatic adenocarcinoma and urothelial carcinoma.

Morphologic features alone can usually be used to distinguish prostatic adenocarcinoma and urothelial carcinoma of the urinary bladder. Poorly differentiated tumors, however, can occasionally have features of both neoplasms, making determination of site of origin difficult. No study has provided a panel of antibodies to assist in the distinction of these two tumors. For this study, 73 examples of moderately and poorly differentiated prostatic adenocarcinoma and 46 examples of high-grade urothelial carcinoma were obtained from radical resection specimens. Immunohistochemical studies were performed using the following panel of antibodies: cytokeratin (CK) 7, CK 20, 34betaE12, Leu M1, carcinoembryonic antigen (CEA)m, CEAp, p53, Leu 7, prostate-specific acid phosphatase (PSAP), prostate-specific antigen (PSA), and B72.3. Mucicarmine was also performed. Intermediate and high-grade prostatic carcinoma were compared and then high-grade prostatic carcinoma was compared with high-grade urothelial carcinoma. PSA and PSAP each stained 94% of prostatic adenocarcinomas, but no urothelial carcinomas. Leu 7 stained 94% of prostate and 17% of urothelial carcinomas. Over half of the urothelial carcinomas showed positivity for 34betaE12 (65%), as did two cases of prostatic carcinoma (6%). Eighty-three percent of urothelial carcinomas and 12% of prostatic adenocarcinomas stained with CK 7. Forty-one percent of urothelial carcinomas and 12% of prostatic carcinomas were reactive for CEAm, and p53 stained 33% and 3% of urothelial and prostatic adenocarcinomas, respectively. No significant difference was seen in the expression of CEAp, CK 20, B72.3, Leu M1, or mucicarmine between prostate and urothelial carcinoma. We propose a panel of six antibodies to assist in the distinction of high-grade prostatic adenocarcinoma from high grade urothelial carcinoma: PSA, PSAP, 34betaE12, Leu 7, CK 7, and p53. The first three antibodies should be used initially; if results are negative, the remaining antibodies may be employed.