—  SPECIALTY CONFERENCE  —

Genitourinary Pathology

Case 2 - Transurethral Resection: Nephrogenic Adenoma

Esther Oliva
Massachusetts General Hospital/Harvard Medical School
Boston, MA


Click on each slide thumbnail image for an enlarged view
Clinical history
A 70-year-old man underwent a transurethral resection for urinary retention secondary to bladder outflow obstruction. Relevant prior clinical history includes invasive esophageal carcinoma diagnosed and treated in 1995 and an incidental prostatic adenocarcinoma, Gleason score 6/10 (present in 3 of more than 100 chips), in a background of florid benign prostatic hyperplasia diagnosed in a transurethral resection done for urinary retention in 2003.


Case 2 - Figure 1 - Round to elongated tubules are present in between muscle fibers.
Case 2 - Figure 2 - Small and irregularly defined tubules are composed of cells with eosinophilic or vacuolated cytoplasm and rounded to elongated nuclei with slightly prominent nucleoli.
Case 2 - Figure 3 - Florid and complex papillae are lined by cells with slightly clear cytoplasm and some of them contain prominent intracytoplasmic basophilic secretions.



Case 2 - Figure 4 - Tiny tubules with prominent luminal basophilic secretion closely simulate signet ring cells.
Case 2 - Figure 5 - Small tubules are admixed with slightly dilated tubules in an edematous and inflamed background.



Case 2 - Figure 6 - Dilated tubules with irregular outlines are lined by flat eosinophilic cells that focally have a slight hobnail appearance.
Case 2 - Figure 7 - Cystically dilated tubules contain eosinophilic secretion and are juxtaposed to elongated thin tubules.


Microscopic description
The lesion showed different architectural patterns. It formed well-defined tubules with a pseudo-infiltrative appearance into the fibromuscular prostatic tissue. The tubules were lined by a single layer of cells displaying tall cytoplasm and slightly enlarged nuclei. ( Figure 1) Some of the tubules contained intraluminal basophilic secretions. ( Figure 2) In other areas, a complex papillary growth was present. The papillae were lined by a single layer of cells, some of which had intracellular mucin while others displayed clear cytoplasm. ( Figure 3) In still other areas, the lesion formed tiny tubules, some resembling signet ring cells, also containing intracytoplasmic mucin. (Figure 4) Lastly, the tubules became dilated focally (Figures 5, 6, 7) and the different patterns were present side by side. ( Figure 6) In the cystic areas, the cells were flattened or had a hobnail configuration. ( Figure 7) However, overall cytologic atypia was minimal and no mitotic figures were identified. The stroma was edematous and associated with a chronic inflammatory infiltrate.

Diagnosis
Transurethral Resection: Nephrogenic Adenoma

Discussion
This is a rare benign lesion of the urothelium, first described by Davis in 1949, but characterized in detail by Friedman and Kuhlenbeck in 1950 [12]. The term nephrogenic adenoma (NA) was coined because of the morphologic similarity of the lesion to the distal nephron. Predisposing factors include genitourinary trauma, surgery, mechanical irritation, chronic inflammation, and renal calculi [10, 29, 41]. Nephrogenic adenoma has also rarely described in bowel conduits [15, 32]. The lesion also has been noted in immunosuppressed patients, especially those with a transplanted kidney [4, 16, 31, 36]. Some authors prefer the term nephrogenic metaplasia, as this lesion was initially thought to arise from a metaplastic process. More recently, it has been shown that at least a subset of NAs that develop in patients with a kidney transplant derive from renal tubular cells that implant in the bladder mucosa; NAs in female recipients of transplants from male donors and male recipients of transplants from female donors showed the same sex-chromosome status as the donor kidney, but not the same sex-chromosome status as the recipient's surrounding bladder tissue. The rationale behind these findings is that in renal diseases and hypoxic conditions, including immunosuppression, there is an increased detachment of viable renal tubular cells that secondarily seed, implant, and grow in the urothelial mucosa [19, 23]. However, the origin of NA in non-immunocompromised patients is still unclear, as there is some type of injury related to most NAs, and consequently, these lesions could also have a similar pathogenesis.

The lesion occurs mainly in adults, where it is more common in males, but the reverse pertains to children [5, 10, 18]. Approximately 80% of the lesions occur in the bladder, with the remainder involving the urethra (15%) or ureter (5%) and, rarely, the renal pelvis [10, 14, 26, 33, 41]. In most cases, it is an incidental finding, but in 1/3 of the cases, the lesions are sizable and 10% are 4 cm or even larger [3, 30, 38] In those cases, it may be potentially confused with a malignant tumor, most commonly a low-grade papillary transitional cell carcinoma.

On microscopic examination, NAs may show tubular or tubulocystic, papillary, and, much less frequently, solid growth. The tubular pattern is the most common, present in 96% of cases in the largest review of NAs (80 cases) [26]. The tubules frequently grow in a band-like pattern with a sharp demarcation from the underlying stroma. The tubules vary in size and shape, and although the majority are small and contain either basophilic or eosinophilic secretions, on rare occasions the tubules may be solid. An appreciable basement membrane may be seen surrounding some of the tubules. The cysts are frequently admixed with the tubules but in most cases are not really conspicuous. The papillary pattern has an exophytic growth in most cases, but it can be endophytic. The papillae do not branch and it is very rare to see this component in the absence of tubules. The final and least common pattern is solid, and when present typically represents a minor component of the lesion. Of note, the tubules of NA may be intermixed with muscle fibers of the muscularis mucosa in the bladder, ureter, or, more often, with the muscle fibers present in the wall of the prostatic urethra, as happened focally in the case under discussion. In these cases, the specimens are more often obtained by transurethral resection.

The cells that line the tubules, cysts, and papillae are cuboidal to columnar to flattened with scant eosinophilic to slightly clear and granular cytoplasm. Hobnail cells are typically present, most often lining the cysts, but are rarely conspicuous [6, 26]. The cells lining tiny tubules have a compressed nucleus with a single vacuole containing basophilic material resembling signet-ring cells. The nuclei are round to oval with minimal cytologic atypia. Nucleoli are inconspicuous and mitotic figures rare (<1/10 high power fields). In the largest study of 80 NAs, mitotic activity was only seen in 5% of the lesions [26]. The term" atypical NA," introduced by Cheng and colleagues, identifies lesions characterized by severe cytologic atypia, including nuclear enlargement, nuclear hyperchromasia, and enlarged nucleoli [6]. One of these features, prominent nucleolus, was also observed at least focally in 16 NAs in the largest published series, and in 14 out of 26 NAs involving the prostatic urethra in another series [1, 26]. The stroma associated with NA is focally edematous and contains variable amounts of inflammatory cells. Stromal calcification may be seen. It is not unusual that NA is seen in association with other reactive benign lesions of the bladder, including cystitis glandularis, polypoid cystitis or squamous metaplasia.

The immunohistochemical profile of NA is characterized by diffuse positivity for wide spectrum keratins, CK 7, EMA, vimentin, and PAX2 (an antigen found during nephrogenesis). Different types of lectins are expressed, as seen in renal tubular epithelium [8]. There is frequent staining for CA-125 as well as focal positivity for CEA, CK 20, CD10, and, in some cases, for RCC antibody [28]. Kidney-specific cadherin (KSP-CAD) is a recently characterized calcium-dependent cell adhesion molecule that appears to be kidney-specific in its distribution, with expression localized primarily in the distal nephron [20]. We have stained 10 NAs and all were negative for this antibody. Aquaporin 1 (marker of the proximal and descending thin limb of Henle's loop renal tubular cells) has been shown to be positive in one study of NAs in immunosuppressed patients [23]. However, in our experience, most NAs in patients without known immunosuppression are negative for aquaporin 1, whether by immunohistochemistry or immunofluorescence; thus, it is still unclear whether the origin of these lesions is related to the proximal nephron, at least in non-immunocompromised patients. Nephrogenic adenoma does not show the typical membranous/luminal staining for uroplakin as seen in transitional epithelium, and the immunohistochemical profile just described raises questions about the metaplastic nature of NA overall. It is important to be aware that P504S (AMACR), which is an enzyme normally present in the mitochondria of renal tubular epithelium and hepatocytes but absent or minimally expressed in benign prostatic glands and urothelium, is expressed in NAs, including those involving the prostatic urethra [17, 34]. Further increasing the confusion with prostatic adenocarcinoma, NAs are negative for p63 and may not express 34BE12 [17, 34]. It is noteworthy that the finding of AMACR and 23BE12 in renal tubules would support the hypothesis that NA may have a renal origin [17]. Finally, one recent study has reported focal weak positivity for PSA and PSAP in some cases [1]. This overlapping profile highlights the importance of clinicopathologic correlation and careful histologic examination, and demonstrates the importance of using a panel of antibodies in differentiating these tumors through immunohistochemistry.

p53 and Ki-67 expression are typically negative in NAs [6, 31]. Ploidy analyses have shown that these lesions are typically diploid [11, 31, 39], while cytogenetic studies have shown that NA cells are characterized by monosomy 9 [6, 31].

The differential diagnosis of NA includes:

Clear cell carcinoma (CCC). This is probably the most common and most difficult problem in differential diagnosis with NA and may arise in biopsy specimens where there is only a small amount of sampled lesion. Clear cell carcinoma is more frequently seen in older women. Patients with these tumors frequently present with hematuria or other clinical symptoms, and the tumors often form a visible mass [13, 27, 40]. On microscopic examination, the histologic patterns of CCC overlap with those seen in NA, although a solid growth is more common. The papillae tend to branch and they may contain hyalinized fibrovascular cores, as seen in CCCs of the female genital tract. Clear cell carcinoma and NA also share the presence of clear and hobnail cells. However, the degree of cytologic atypia and mitotic activity seen in CCC is by far more conspicuous than in NA. Clear cell carcinoma may have a subtle appearance focally; however, the presence of any degree of cytologic atypia or mitotic activity should alert any pathologist, who should be very cautious in making a benign diagnosis [13, 27, 40]. Furthermore, CCC frequently shows areas of hemorrhage and necrosis and infiltrates deep into the vesical wall. Both lesions may arise in association with a diverticulum, especially when located in the urethra [10, 24, 27, 41]. It has been postulated by some investigators that NA may be the precursor lesion of CCC [2]; however, this theory has never been proven. Immunohistochemical stains are not helpful in this differential diagnosis, as the lesions show an overlapping immunohistochemical profile, including positive staining for low-molecular weight keratins, CK7 and CK20 and negative staining for estrogen and progesterone receptors, PSA, and PSAP [6, 13, 27, 28].

Bladder cancer with prominent nested or tubular growth patterns. Helpful features in this distinction include more than one cell layer lining the tubules in cases of bladder cancer (typical of urothelium but not NA); the presence of more appreciable cytologic atypia; and the absence of other patterns typically seen in NA, as well as the invasion into the muscularis propria seen in some carcinoma cases [25, 35]. Immunohistochemically, the nested variant of urothelial carcinoma shares some features with high-risk conventional urothelial carcinomas, such as high proliferation index, and with rare exceptions, this feature contrasts with the absence of Ki-67 expression in most NAs [6, 13]. Nevertheless, p53 immunoreactivity is not frequently seen and cannot be used in this differential diagnosis [21, 37]. Of interest, recent studies have revealed that NA shows the same chromosomic aberrations as superficial bladder cancer, though to a smaller extent [31].

Prostate adenocarcinoma may enter into the differential diagnosis in those cases where NA involves the prostatic urethra as mentioned earlier. Tubules of NA may show a pseudoinfiltrative growth, intercalating between muscle fibers [1, 7, 22, 42]. Furthermore, the cells lining the tubules may show nuclei with prominent nucleolus, and mucinous secretions may be present in the lumens of the tubules [1]. In these cases, it is important to keep in mind the possibility of NA before making the diagnosis of prostate cancer. Immunohistochemical stains for p63, 34 bE12 and P504S are not helpful in this differential diagnosis in many instances [17, 34], and it seems that compared to bladder NAs, urethral NAs express AMARC more often [34]. However, PSA and PSAP are helpful in most cases, as prostatic adenocarcinoma typically shows diffuse and strong positivity, in contrast to the weak and focal positivity seen in some NAs [1]. Most importantly, the tubular pattern is associated with other typical architectural patterns of NA, the cytologic atypia is frequently of degenerative type, and no mitotic figures are found. Finally, the presence of acute or chronic inflammatory cells is not a feature of prostate cancer, whereas it is typically present in NAs.

Signet ring cell carcinoma of the bladder or metastatic to the bladder very rarely may enter into the differential diagnosis, especially when the most prominent pattern is that of very small tubules containing basophilic secretion. This growth is always accompanied by larger tubules and shows neither diffuse involvement of the bladder wall nor the cytologic atypia seen in signet ring cell carcinoma.

Nephrogenic adenoma may recur, and the recurrence rate ranges from 28 to almost 90% [9, 11, 36], but there is no proof that NA may undergo malignant transformation.

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