Abstract

Context.—Carcinoid tumors are exceedingly rare in the genitourinary tract and may occur in the kidney, urinary bladder, urethra, or prostate.

Objective.—To review the clinical and pathologic features of carcinoid tumors occurring in the urinary tract and prostate.

Data Sources.—We searched the English language literature using MEDLINE and Ovid.

Conclusions.—Carcinoid tumors of the urinary tract and prostate share similar morphologic features with their counterparts in other organs. The differential diagnosis includes metastatic carcinoid tumor, paraganglioma, and nested variants of urothelial and prostatic carcinomas. Correlation of the clinical presentation and histopathologic features (including the immunohistochemical profile) will ensure accurate diagnosis of these rare tumors.

There is an increasing call for the traditional diverse and often organ-specific nomenclature of epithelial neuroendocrine neoplasms to be replaced by more straightforward, uniform, and reproducible terminology. In this new scheme, (a) carcinoid tumors, (b) atypical carcinoid tumors, and (c) small and large cell neuroendocrine carcinomas are termed (a) well-differentiated (grade 1) neuroendocrine tumors/carcinomas, (b) moderately differentiated (grade 2) neuroendocrine carcinomas, and (c) poorly differentiated (grade 3) neuroendocrine carcinomas, respectively.1,2 Although we acknowledge the value of the newer nomenclature, the traditional terminology is retained in this review, as most of the reports to date refer to these terms, which are still widely used and recognized.

Carcinoid tumors have been described in several locations, including the lung, gastrointestinal tract, liver, kidney, and ovary.3,4 Rare cases occurring in the bladder and prostate have been reported.5–7 

Carcinoid tumors are thought to arise from neuroendocrine cells. These cells are also known as enterochromaffin cells or amine precursor uptake and decarboxylation (APUD) cells and are widely distributed throughout the body. In the urogenital tract, they have been described in the urinary bladder (especially in the region of the trigone), the prostate, the urethra, and the renal pelvis, but not in the renal parenchyma.8–11 

RENAL CARCINOID TUMORS

The features of reported cases of renal carcinoid tumor are summarized in Table 1.

Table 1. 

Features of Reported Cases of Renal Carcinoid Tumor*

Features of Reported Cases of Renal Carcinoid Tumor*
Features of Reported Cases of Renal Carcinoid Tumor*

Histogenesis

Although they exhibit morphologic and immunohistochemical features consistent with a hindgut neuroendocrine phenotype,12 the precise histogenesis of renal carcinoids is uncertain. Neuroendocrine cells have been described in the renal pelvis but not in renal parenchyma.13–15 Various authors have proposed that renal carcinoids arise from neural crest tissue entrapped within the metanephros during embryogenesis, or that they represent metastases from an occult carcinoid tumor elsewhere in the body. The most popular hypothesis is that primary renal carcinoids arise from a primitive totipotential cell line that differentiates in a neuroendocrine direction.8,13,15,16 Although conclusive evidence for this theory is lacking at present, El-Naggar et al13 reported loss of heterozygosity at 1 locus on chromosome 3p21 in a case of renal carcinoid and suggested that 3p aberrations (which are common in renal cell carcinomas) “may constitute a predifferentiation tumorigenic event in the majority of renal cortical neoplasms including carcinoid tumor.” Coexistent areas of carcinoid and renal cell carcinoma within the same tumor have not been documented, although 1 case of synchronous renal carcinoid and contralateral multilocular cystic renal cell carcinoma has been described.17 

The origin of renal carcinoids arising in association with teratomas or in horseshoe kidneys may be somewhat different. Cases of renal carcinoid arising in association with renal dysplasia or teratoma (see below) lend weight to the theory that endocrine cells that comprise the carcinoid tumors may arise by divergent differentiation from a common stem cell, which also gives rise to the epithelial and mesenchymal components of the teratoma.18,19 Horseshoe kidneys are thought to occur as a result of teratogenic factors.20 In some of the reported cases of renal carcinoids arising in horseshoe kidneys, glandular, transitional, and neuroendocrine epithelial cells have been noted in the vicinity of the tumors, suggesting that carcinoid tumors occurring in horseshoe kidneys may arise from preexisting hyperplastic neuroendocrine cells located within foci of aberrant epithelium within the kidney. This aberrant epithelium may represent intestinal metaplasia within the lining of the renal collecting system, or it may be a manifestation of teratomatous elements within the kidney.21–23 Genetic study of a case of renal carcinoid arising in a horseshoe kidney revealed 2 cell lines, 1 with trisomy 13 and 1 with a reciprocal translocation between 13q and 14q, suggesting that structural aberrations in chromosome 13 may play a role in the genesis of carcinoids in horseshoe kidneys.24 

Epidemiology

Primary renal carcinoid tumors are rare; since the original description by Resnick et al25 in 1966, only approximately 50 cases have been reported. The majority of patients present in the fourth to seventh decades (range, 13– 68 years; mean, 47 years), and there is no gender predilection.8,12,14,16–58 No familial clustering has been reported.8 Some tumors arise in association with horseshoe kidney or benign cystic teratoma, or both (2 reported cases).* The relative risk of developing carcinoid tumor in a horseshoe kidney (compared with a normal kidney) has been estimated between 62 and 120.21,49,56 

Presentation

The tumors usually present with abdominal or flank pain, weight loss, abdominal mass, or hematuria. Up to 20% of cases have been asymptomatic, with the tumor discovered incidentally during investigations for other conditions.8,12,23,58,59 Presenting symptoms due to hormone production are rare8 and include a case of oncocytic carcinoid tumor presenting with episodic Cushing syndrome due to ectopic adrenocorticotrophic hormone (ACTH) secretion,35 a case of watery diarrhea–hypokalemia–achlorhydria due to vasoactive intestinal peptide secretion,31 and a case presenting with symptoms of glucagon secretion by tumor.26 Symptoms of the carcinoid syndrome are uncommon and are seen in <10% of cases.8,25,39,59 

Imaging

Ultrasound reveals a hyperechoic mass with an incomplete hypoechoic rim.19,36,39,46,50,58 Central hypoechoic areas may indicate the presence of central necrosis.39 Computed tomography shows a well-circumscribed enhancing or nonenhancing mass, which is usually solid. A cystic component and focal calcification may be present in some cases,8,19,37–39,46,50,59 and occasional tumors are largely cystic with a multiloculated appearance.17,38 The tumors may be avascular, hypovascular, or hypervascular on angiography.8,19,36,37,39,46,50 Somatostatin receptor scintigraphy is useful for diagnosis, staging, and monitoring posttreatment for the development of recurrence or metastasis.51,59 

Macroscopic Features

The tumors are usually unilateral and solitary. They are well circumscribed with a lobulated appearance and exhibit a yellow or tan-brown color. Foci of hemorrhage, calcification, and cystic change may be present. Necrosis is unusual.8,12,23,45,59 Rare cases that exhibit grossly evident areas of necrosis22,38,43,45 or a uniloculated or multiloculated cystic appearance17,21,27,28,38,42,46,57 have been described; 1 case arose in association with autosomal dominant polycystic kidney disease.53 Most cases arise in the renal parenchyma, although rare cases in the renal pelvis have been reported.44,45 

Microscopic Features

Urine cytology is usually noncontributory. One case occurring in the renal pelvis showed small monolayered sheets of small polygonal cells with ill-defined cytoplasm, containing mildly pleomorphic nuclei with chromatin clumping and small nucleoli, the appearance raising the possibility of low-grade urothelial carcinoma or adenocarcinoma.45 

Renal carcinoids exhibit typical histologic features of carcinoids at other sites. They are well demarcated from the adjacent renal parenchyma. Trabecular/gyriform, insular, glandular, solid, and mixed architectural patterns may be seen. The cells are round or polygonal with granular amphophilic to eosinophilic cytoplasm. A single oncocytic carcinoid, composed of tumor cells containing voluminous eosinophilic cytoplasm, has been reported.35 The nuclei are round to oval with evenly distributed granular (“salt and pepper”) chromatin and exhibit minimal pleomorphism. Microscopic foci of necrosis and focal areas of cytologic atypia (nuclear pleomorphism and hyperchromasia) are not uncommon (Figure 1, A through F). Mitotic activity (usually minimal, but may be up to 6 mitotic figures per 10 high-power fields) and lymphovascular invasion may be seen. Hyalinization and focal microcalcification may also be present,8,21,23,38 and rarely metaplastic ossification may be seen.14,20,23,45 Capsular invasion with extension into perinephric fat and renal vein invasion (Figure 1, C) have been reported.14,23,38,59 Rare cases of renal carcinoid associated with renal dysplasia and/or mature teratomatous components (papillary and mucinous epithelial elements, and chondroid and neural mesenchymal elements) have been documented.8,18,19,28 

Figure 1.

Renal carcinoid tumor. Case 1; A, Carcinoid tumor (top right of figure) arising in the region of renal pelvis (bottom left of figure) (hematoxylin-eosin, original magnification ×40); B, Gyriform/trabecular architecture (hematoxylin-eosin, original magnification ×200); C, Vascular invasion (hematoxylin-eosin, original magnification ×200). Images contributed by Jonathan I. Epstein, MD. Case 2; D, Carcinoid tumor (bottom right of figure) with renal parenchyma (top left of figure) (hematoxylin-eosin, original magnification ×40); E, Trabecular/glandular architecture (hematoxylin-eosin, original magnification ×200); F, Metastatic carcinoid tumor within a lymph node (hematoxylin-eosin, original magnification ×200). Images contributed by Pamela D. Unger, MD

Figure 1.

Renal carcinoid tumor. Case 1; A, Carcinoid tumor (top right of figure) arising in the region of renal pelvis (bottom left of figure) (hematoxylin-eosin, original magnification ×40); B, Gyriform/trabecular architecture (hematoxylin-eosin, original magnification ×200); C, Vascular invasion (hematoxylin-eosin, original magnification ×200). Images contributed by Jonathan I. Epstein, MD. Case 2; D, Carcinoid tumor (bottom right of figure) with renal parenchyma (top left of figure) (hematoxylin-eosin, original magnification ×40); E, Trabecular/glandular architecture (hematoxylin-eosin, original magnification ×200); F, Metastatic carcinoid tumor within a lymph node (hematoxylin-eosin, original magnification ×200). Images contributed by Pamela D. Unger, MD

The tumors are usually nonargentaffin and are positive for argyrophil stains such as Grimelius.8,14,34,37,43 They exhibit strong, diffuse immunohistochemical staining for cytokeratins (broad-spectrum and low-molecular-weight), neuron-specific enolase, chromogranin, Leu-7, and synaptophysin. Pancreatic polypeptide, vasoactive intestinal peptide, glucagon, somatostatin, and serotonin staining has been reported in some cases.13,21,24,37,38,42,46,59 Prostatic acid phosphatase (PAP) positivity has been reported in some cases, but prostate-specific antigen (PSA) is negative.12,13,38,42,49,53,59 Vimentin and S100 are negative.42 

Ultrastructurally, the tumors are composed of uniform small round cells with large, indented, heterochromatic nuclei and small nucleoli. The cells contain variable numbers of intracytoplasmic membrane-bound, electron-dense neurosecretory granules ranging in size from 100 to 400 nm. Perinuclear aggregates of intermediate filaments, prominent Golgi complexes, abundant rough endoplasmic reticulum, and swollen mitochondria are also seen.§

Prognosis

Renal carcinoid tumors exhibit heterogenous behavior; some patients die within 6 months of diagnosis, but others survive for many years even in the presence of metastases.22 

Because of their rarity, incomplete documentation of clinicopathologic features, and absent or short-term follow-up in many reports, the prognosis and clinical behavior of these tumors remain unclear.19 The stage of disease at presentation appears to be an important prognostic factor.8 The prognostic value of histologic parameters is uncertain. Although varying combinations of mitotic activity, cytologic atypia, tumor necrosis, and lymphovascular invasion have been seen in tumors that have behaved aggressively, such features are also not uncommonly noted in tumors that have an indolent clinical course8; in fact, 1 patient with renal vein involvement, tumor necrosis, and lymph node metastases survived without significant impairment for more than 10 years.52 Thus, splitting them into typical and atypical carcinoids (using the 1999 World Health Organization classification of pulmonary neuroendocrine tumors), as suggested by some authors,22 may not be easy or prognostically useful. Renal carcinoids arising in horseshoe kidneys appear to exhibit particularly indolent behavior, even in the presence of lymph node metastases.21,22,49,50,56 

Surgical excision is the treatment of choice and even hepatic metastases have been managed with surgical resection. The tumors are chemoresistant.8 

CARCINOID TUMORS OF THE URINARY BLADDER

The features of reported cases of carcinoid tumor of the urinary bladder are summarized in Table 2.

Table 2. 

Features of Reported Cases of Carcinoid Tumor of the Urinary Bladder*

Features of Reported Cases of Carcinoid Tumor of the Urinary Bladder*
Features of Reported Cases of Carcinoid Tumor of the Urinary Bladder*

Histogenesis

Similar theories to those suggested to explain the origin of carcinoid tumors in nonhorseshoe kidneys have been proposed with regard to the histogenesis of bladder carcinoids. In addition, some authors have proposed origin from metaplastic bladder urothelium. The documented presence of enterochromaffin cells in the bladder (especially in the region of the trigone, where many carcinoids are located) supports the concept that bladder carcinoids may arise from transformed neuroendocrine cells.60 

Epidemiology

Primary carcinoid tumors of the urinary bladder are very rare.5,60–68 

Three cases of mixed carcinoid tumor have been reported, of which 2 were associated with small cell carcinoma; the carcinoid and small cell carcinoma components were admixed in 1 case and independent in the other.65,66 In the third case, the carcinoid arose in association with a mucinous adenocarcinoma.67 Hemal et al68 reported a case of “malignant carcinoid tumor,” but a preceding transurethral biopsy of the tumor revealed high grade adenocarcinoma, suggesting that their case likely represents a fourth mixed carcinoid tumor in association with an adenocarcinoma. One case of carcinoid arising in an ileal neobladder has been reported.69 

Only 9 cases of pure carcinoid tumor of the urinary bladder have been reported in the English-language literature.5,60–64,70,71 However, figures of the tumor reported by Aozasa et al71 show small cell carcinoma, and the tumor reported by Yang et al70 as carcinoid lacked argyrophilic and argentaffin granules, and ultrastructural micrographs appear to show lysosomes rather than neurosecretory granules.5 

The 7 well-documented cases of bladder carcinoid occurred in middle age (mean, 57 years; median, 61 years; range, 30–73 years) with no gender predilection (male-female ratio 4:3).5,60–64 

Presentation

Patients most commonly present with hematuria and less often with voiding difficulties,5,7,60,61 the latter occurring because of transient ball-valve occlusion of the vesicourethral junction by the pedunculated tumor.63 Occasionally, these tumors are incidentally found.64 Carcinoid syndrome has not been reported.7 

Excretory urography reveals a smooth, rounded, polypoid filling defect in the bladder. Cytologic examination of urine often demonstrates hematuria; atypical cells are not seen on urine cytology.5,60,70 

Cystoscopy often reveals a polypoid, smooth-surfaced, submucosal lesion, which may be pedunculated.5,7,60–64,70 

Macroscopic Features

The tumors have a predilection for the trigone and neck of the bladder. They are generally rounded, smooth-surfaced tan masses that range from 3 to 12 mm in maximal size. The cut surface is solid, homogenous, and tan in color.5,7,60–64 

Microscopic Features

Carcinoid tumors of the bladder are usually found in a subepithelial location and show similar morphologic features to their counterparts in other locations. The tumor cells are arranged primarily in a glandular or cribriform pattern within a vascular stroma, although trabecular, insular, or mixed patterns have been reported. The cells are cuboidal to columnar and possess abundant amphophilic cytoplasm and nuclei with finely stippled chromatin and inconspicuous nucleoli (Figure 2, A through C). Occasional enlarged nuclei may be present.5,61,63 Mitotic figures are infrequent and tumor necrosis is absent.5,7,61–64 Intact but variably attenuated urothelium is usually present overlying the tumor,7,60,61 and focal continuity of the tumor with the basal layer of the surface urothelium has been reported.60 

Figure 2.

Bladder carcinoid tumor. A, Polypoid tumor containing cystic ductlike structures beneath intact overlying urothelium (hematoxylin-eosin, original magnification ×100); B and C, Predominantly glandular architecture with bland tumor cells (hematoxylin-eosin, original magnifications ×200 [B] and ×400 [C]); D, Positive staining of tumor cells with chromogranin A (original magnification ×200). Images contributed by Jonathan I. Epstein, MD

Figure 2.

Bladder carcinoid tumor. A, Polypoid tumor containing cystic ductlike structures beneath intact overlying urothelium (hematoxylin-eosin, original magnification ×100); B and C, Predominantly glandular architecture with bland tumor cells (hematoxylin-eosin, original magnifications ×200 [B] and ×400 [C]); D, Positive staining of tumor cells with chromogranin A (original magnification ×200). Images contributed by Jonathan I. Epstein, MD

Occasional cases may coexist with inverted papilloma63 or adenocarcinoma.67 Von Brunn nests, cystitis cystica, cystitis glandularis, and/or Paneth cell metaplasia may be seen adjacent to the tumor.60,61,67 

The tumor cells are nonargentaffin or weakly argentaffin (with Fontana Masson stain) and strongly argyrophilic (positive with Grimelius stain); scattered argyrophilic cells are also present in the overlying urothelium. Immunohistochemically, positive staining of tumor cells with cytokeratins, neuron-specific enolase, chromogranin (Figure 2, D), synaptophysin, serotonin, CD56 (NCAM), and Leu-7 is seen; immunoreactivity for PSA, PAP, CD99, and S100 protein is absent.5,7,60,63–64 Focal thyroid transcription factor-1 staining has been reported in 1 case, the significance of which is uncertain.5 

The ultrastructural features are similar to those of renal carcinoids (see previous discussion of renal carcinoids).

DNA flow cytometry performed in 1 case demonstrated an aneuploid cell population with a DNA index of 1.20.60 

Prognosis

More than 25% of patients have regional lymph node or distant metastases, but the majority are cured by excision.7 The behavior of carcinoid tumors of the bladder is difficult to predict because of the paucity of bona fide cases of pure carcinoid and the lack of long-term follow-up data. Size and extent of the lesions appear to be most important, and flow cytometric analysis of DNA ploidy may provide adjunctive prognostic information.60 Mixed carcinoid tumors appear to exhibit aggressive behavior, in line with that expected of the noncarcinoid (usually carcinomatous) component.65–68 

URETHRAL CARCINOID TUMORS

The features of reported cases of urethral carcinoid tumor are summarized in Table 3.

Table 3. 

Features of Reported Cases of Urethral Carcinoid Tumor*

Features of Reported Cases of Urethral Carcinoid Tumor*
Features of Reported Cases of Urethral Carcinoid Tumor*

Epidemiology and Presentation

Primary urethral carcinoid tumor is an exceedingly rare entity, and only 3 cases have been reported to date.3,72,73 We have seen an additional case.

Three of the cases occurred in men and 1 in a woman, the age at presentation ranging from 39 to 57 years (median 44 years). The tumors in the male patients occurred in the penile (mid) urethra, while that in the woman occurred at the urethral orifice.3,72,73 The tumors present with penile mass,72 back pain,73 or bleeding.3 

Sylora et al72 reported the first case of primary urethral carcinoid tumor in 1975. The patient initially presented with a urethral nodule, which was interpreted as a transitional cell carcinoma; this tumor recurred locally and subsequently metastasized, to both inguinal lymph nodes and the liver (with development of clinical carcinoid syndrome) during a period of 16 months, followed by death of the patient. Autopsy revealed extensive replacement of the liver and bone marrow by tumor, and multiple metastatic deposits in the lung and pancreas. The correct diagnosis of primary urethral carcinoid tumor was made retrospectively after review of tissue sections of the urethral tumor and the metastases.

Pathologic Features

Macroscopically, the tumors are small polypoid nodules (Figure 3, A), ranging in size from 3 to 8 mm in maximal dimension.3,72,73 

Figure 3.

Urethral carcinoid tumor. A, Cystoscopic view of smooth-surfaced polypoid tumor in bulbar urethra; B, Polypoid, largely solid tumor containing cystic ductlike structures (hematoxylin-eosin, original magnification ×20); C, Nests and tubules of tumor cells with overlying attenuated urothelium (hematoxylin-eosin, original magnification ×200); D, Nests of tumor cells separated by thin-walled blood vessels; cells show some nuclear pleomorphism and abundant granular cytoplasm (hematoxylin-eosin, original magnification ×200); E, Positive staining of tumor cells with chromogranin A (original magnification ×200)

Figure 3.

Urethral carcinoid tumor. A, Cystoscopic view of smooth-surfaced polypoid tumor in bulbar urethra; B, Polypoid, largely solid tumor containing cystic ductlike structures (hematoxylin-eosin, original magnification ×20); C, Nests and tubules of tumor cells with overlying attenuated urothelium (hematoxylin-eosin, original magnification ×200); D, Nests of tumor cells separated by thin-walled blood vessels; cells show some nuclear pleomorphism and abundant granular cytoplasm (hematoxylin-eosin, original magnification ×200); E, Positive staining of tumor cells with chromogranin A (original magnification ×200)

The original urethral tumor in the case reported by Sylora et al,72 the tumors in the other reported cases,3,73 and our case have shown similar microscopic appearances in keeping with carcinoid tumor. The tumors are composed of uniform epithelioid cells arranged in nests, sheets, and/ or trabeculae, separated by varying amounts of fibrovascular stroma. The cells contain bland, round, or ovoid nuclei, small nucleoli, and moderate amounts of cytoplasm, which have a variably granular appearance (Figure 3, B through D). Mitotic figures are scarce. Interestingly, the photomicrographs of the nodal and hepatic metastases in the case reported by Sylora et al72 show carcinoid-like architectural features, but with readily identifiable mitotic figures in both and foci of tumor necrosis in the latter, connoting a more aggressive phenotype (“atypical carcinoid tumor”). Immunohistochemically, the tumor cells show positive staining for neuron-specific enolase, chromogranin A (Figure 3, E), synaptophysin, and cytokeratin. Neurosecretory granules are identified on ultrastructural examination.3,72,73 

Prognosis

Given the small number of reported cases of primary urethral carcinoid tumor, the course and prognosis of these tumors is uncertain. Although 3 of the reported cases have shown long recurrence-free intervals,3,73 1 case metastasized and resulted in death of the patient.72 At present, complete excision with histopathologic evaluation, particularly in search of atypical features (criteria such as marked nuclear atypia, mitotic figures, and/or necrosis akin to those described for pulmonary atypical carcinoid tumors4), allied with close clinical follow-up, appears to be a reasonable approach to the management of these patients.

CARCINOID TUMORS OF THE PROSTATE

Histogenesis and Classification

Neuroendocrine cells in the prostate are thought to regulate growth and exocrine secretory activity of the gland and may be involved in paracrine regulation of adjacent epithelial cells. They contain a wide variety of neurosecretory granules and produce a corresponding diversity of secretory products including serotonin, chromogranins, calcitonin, and somatostatin. Neuroendocrine differentiation in prostatic tumors may take several forms: (a) pure neuroendocrine tumors (such as small cell neuroendocrine carcinoma or carcinoid tumor); (b) “carcinoid-like” adenocarcinomas, which are conventional adenocarcinomas that morphologically resemble carcinoid tumors; (c) focal Paneth cell-like change in adenocarcinoma; and (d) focal individual cell neuroendocrine differentiation in an otherwise typical adenocarcinoma. The last is by far the most common (reported in up to 50% of carcinomas in various series); small cell carcinomas and carcinoid tumors represent less than 5% of all prostatic tumors.9,10,74–82 

Because of their prognostic import (as discussed later, in the section on prognosis), it is important to distinguish carcinoids, adenocarcinomas with neuroendocrine differentiation (either carcinoid-like or individual cell), and small cell carcinomas. Arguably the most difficult distinction is between carcinoids and carcinoid-like adenocarcinomas, and some authors have questioned the very existence of “primary prostatic carcinoid tumors,” since most such reported cases represent adenocarcinomas with carcinoid-like areas.83 

Carcinoid-like adenocarcinomas may exhibit a nested architecture and uniform nuclei, mimicking carcinoids; their distinction from carcinoids is especially difficult when these tumors also exhibit immunohistochemical and/or ultrastructural evidence of neuroendocrine differentiation (a common occurrence in prostatic adenocarcinomas).78,81,83,84 However, unlike true carcinoid tumors, “carcinoid-like” prostate carcinomas show nucleolar prominence and immunohistochemical staining with PSA.6,42,78,81,83–87 Ultrastructurally, the carcinomas show prominent intercellular junctions, a feature that distinguishes them from carcinoids.78 Some authors6,78,83 consider immunohistochemical staining with PSA a key discriminator; true prostatic carcinoids are negative, and carcinoid-like carcinomas are positive.

Studies of PSA and PAP immunohistochemical staining in neuroendocrine cells in the prostate have shown a PAP+/PSA+ phenotype82 or PAP+/PSA phenotype.88 Whether the PSA+ and PSA cells represent differing populations that have the potential to transform to adenocarcinomas or carcinoid tumors, respectively, is not known.

Stratton et al89 described 2 cases of conventional adenocarcinoma (containing small foci of neuroendocrine cells) that evolved into “carcinoids” following hormonal treatment, leading the authors to postulate that the endocrine component of the original tumors was more resistant to the therapy than the conventional adenocarcinoma (which regressed); however, the positivity for PSA in the “carcinoids” suggests that they more likely represent adenocarcinomas with carcinoid-like differentiation.

Thus, true prostatic carcinoids may be defined as tumors exhibiting morphological features similar to their counterparts in other organs, immunohistochemical and ultrastructural features of neuroendocrine differentiation, lack of an associated or admixed adenocarcinoma component, and/or lack of immunohistochemical reactivity for PSA.

Several descriptions of prostatic “carcinoid” in the literature have been in association with a conventional adenocarcinoma component, which may be admixed with or in continuity with the carcinoid-like component11,78,79,84,90,91; however, it is likely that the carcinoid-like components of these mixed tumors represent foci of carcinoid-like neuroendocrine differentiation within the typical adenocarcinoma.78,79,90 Exceptions are cases reported by Wasserstein and Goldman92 and Ghannoum et al,93 which represent true prostatic carcinoids arising synchronously, but independently, with conventional adenocarcinoma; these cases are included as primary prostatic carcinoids.

Two recent reports of apparent prostatic carcinoid tumor are worthy of mention. Tash et al94 reported a case of “metastatic carcinoid” of the prostate, which they described as a well-differentiated neuroendocrine tumor/ carcinoma expressing chromogranin, synaptophysin, and serotonin. Their report did not include information on the presence or absence of associated adenocarcinoma or PSA immunohistochemical staining. Zarkovic et al95 reported a prostatic “carcinoid” present in one chip of a transurethral resection specimen. This tumor exhibited typical morphologic and immunohistochemical features (including PSA negativity) of carcinoid tumor. Resection of the tumor bed showed no residual tumor. However, Cohen80 raised concerns that the peripheral zone of the prostate was not sampled and that the possibility that the lesion represented part of an adenocarcinoma with neuroendocrine differentiation could not be excluded based on a single prostate (transurethral resection) chip.

Epidemiology and Clinical Presentation

As defined above, primary prostatic carcinoid tumors are extremely rare. They occur predominantly in elderly men.6,92,93,96–98 A single pediatric case occurring in a 7-year-old boy in the setting of multiple endocrine neoplasia type IIb has been reported.97 

Patients may present with hematuria, burning micturition, urinary frequency, oliguria, or symptoms of urinary retention.6,96,97 The tumors may be discovered incidentally.93 One case presenting with elevated serum cortisol and ACTH (but without clinical Cushing syndrome) has been described.96 

Pathologic Features

Macroscopically, the tumors are generally firm, well-defined or poorly defined masses, which are variable in size and may occupy the entire prostate.6,93,96,97 

The histologic features are similar to those of carcinoid tumors occurring elsewhere. The tumors exhibit an insular, trabecular, glandular, or mixed architectural pattern and are composed of uniform rounded, polygonal, or spindle-shaped cells invested by delicate fibrovascular stroma. The nuclei are round and contain moderately clumped chromatin without conspicuous nucleoli. The cytoplasm is abundant, amphophilic or eosinophilic, and granular (Figure 4, A through D). Mitotic figures are rare.6,93,96,97 The adjacent prostate may show hyperplasia of chromogranin-positive neuroendocrine cells.97 

Figure 4.

Prostatic carcinoid tumor. Case 1. A, Low-power and B, high-power views of tumor composed of nests and tubules of tumor cells with adjacent prostatic glandular epithelium in A (hematoxylin-eosin, original magnifications ×200 [A] and ×400 [B]). Images contributed by Jonathan I. Epstein, MD. Case 2. C, Irregular nests and trabeculae of tumor infiltrating between benign prostatic glands (hematoxylin-eosin, original magnification ×20); D, Tumor cells are relatively uniform, with ‘salt-and-pepper’ chromatin (hematoxylin-eosin, original magnification ×400). Images contributed by Sandra J. Shin, MD

Figure 4.

Prostatic carcinoid tumor. Case 1. A, Low-power and B, high-power views of tumor composed of nests and tubules of tumor cells with adjacent prostatic glandular epithelium in A (hematoxylin-eosin, original magnifications ×200 [A] and ×400 [B]). Images contributed by Jonathan I. Epstein, MD. Case 2. C, Irregular nests and trabeculae of tumor infiltrating between benign prostatic glands (hematoxylin-eosin, original magnification ×20); D, Tumor cells are relatively uniform, with ‘salt-and-pepper’ chromatin (hematoxylin-eosin, original magnification ×400). Images contributed by Sandra J. Shin, MD

The tumor cells are argyrophilic.96 They are strongly and diffusely positive for cytokeratin and chromogranin B and variably positive for synaptophysin, chromogranin A, secretogranin II, and serotonin.6,76,83,93,97 Some tumors stain positively with PAP, a feature they share with carcinoid tumors of hindgut derivation, such as rectal carcinoids; this is likely explained by the shared cloacal derivation of the prostate and rectum, giving rise to cells with both endocrine and prostatic epithelial differentiation.76,83,87 They are negative for PSA6,76,83,97 or stain weakly.93 Azumi et al99 described positivity for both PAP and PSA in their “carcinoid”; though this tumor exhibited convincing histochemical and ultrastructural evidence of neuroendocrine differentiation, the PSA reactivity suggests that this tumor may in fact represent a “carcinoid-like” adenocarcinoma.6 Secretion of ACTH by tumor has been demonstrated in the single case that presented with elevated serum ACTH.96 

Ultrastructurally, electron-dense, membrane-bound, cytoplasmic neurosecretory granules are identified.83,87,96,97,99 

It is worth noting that the diagnosis of carcinoid tumor in biopsy specimens of prostate is challenging. The finding of carcinoid-like areas in biopsy material raises several possibilities: (a) the lesion may be part of a true carcinoid; (b) the lesion may represent part of a carcinoid-like adenocarcinoma; or (c) the lesion may be a focus of carcinoid-like differentiation in an otherwise conventional adenocarcinoma. Correlation with the serum PSA levels and the immunohistochemical findings is important in arriving at the correct diagnosis.6,83 

Prognosis

There appears to be a correlation between neuroendocrine differentiation and poor prognosis in prostatic tumors. Small cell neuroendocrine carcinomas of the prostate are associated with aggressive behavior, poor treatment responsiveness, and poor outcome. Neuroendocrine differentiation in prostatic carcinomas has been associated with poorer prognosis in some studies but not in others.74,77,82,93 

If the finding by Stratton et al89 of relative resistance to hormonal therapy of the endocrine (carcinoid-like) components of prostatic adenocarcinomas is a universal feature, it may partly explain the poorer prognosis associated with endocrine differentiation.

Carcinoid and carcinoid-like tumors of the prostate have been reported to behave in an aggressive fashion when compared to their counterparts originating in other body sites.77 However, many of these reports of aggressive behavior represent carcinoid-like carcinomas, such as the case reported by Azumi et al,99 which was associated with lymph node metastases but likely represents a “carcinoid-like” adenocarcinoma rather than a carcinoid tumor.6 The reports of true prostatic carcinoid tumors6,93,96,97 appear to show a relatively indolent course for these tumors, although the scarcity of bona fide cases makes definitive prediction of prognosis impossible.83 

DIFFERENTIAL DIAGNOSIS OF UROGENITAL CARCINOID TUMORS

The differential diagnosis of carcinoid tumors includes several entities, the majority of which can be readily distinguished using a combination of morphologic and immunohistochemical evaluation.

The possibility that the tumor represents a metastasis from a carcinoid tumor elsewhere needs to be excluded.93 Although PAP positivity is not uncommon in renal carcinoids, raising the possibility of a metastasis from an occult rectal primary, the latter can usually be ruled out by clinical investigations, including endoscopy.42,87 Only 1 case of metastatic carcinoid tumor in the kidney (from a primary lung tumor) has been reported.100 Focal continuity of bladder carcinoids with overlying urothelium, mainly at or near areas of proliferation and/or metaplasia provides supportive evidence of bladder origin.60 Reports of metastatic carcinoid involving the prostate are extremely rare and include a case of metastatic appendiceal goblet cell carcinoid that stained negatively with PSA and PAP. Clinical correlation and comparison with the histologic features of the primary tumor are important in their distinction from primary prostatic carcinoids.101 

At low magnification, the rounded polypoid structure, general architecture, and covering of normal urothelium seen in carcinoid tumors may resemble inverted papilloma. But the typical oval grooved nuclei and lack of neuroendocrine marker positivity in the latter tumors aid in their distinction.5 However, inverted papilloma may coexist with carcinoid tumors in the bladder, with the tumors exhibiting characteristic morphologic and immunohistochemical features.60 

Nephrogenic metaplasia (nephrogenic adenoma) shows some similarities to carcinoid tumor in the bladder.60 

Paragangliomas rarely occur in the urinary tract and are most commonly located in the bladder.60,62,70,102,103 Less often, they occur in the ureter and urethra. Paragangliomas are irregularly circumscribed tumors located in the lamina propria with intact overlying mucosa. They are composed of nests (“zellballen”), trabeculae, and sheets of tumor cells, separated by a delicate fibrovascular stroma. The tumor cells are large, ovoid, and polygonal with uniform or mildly pleomorphic nuclei. The cells possess abundant finely granular amphophilic or eosinophilic cytoplasm. Mitotic figures are rare, necrosis is absent, and lymphovascular invasion is not seen. The tumor cells show immunohistochemical staining with neuron-specific enolase, chromogranin, synaptophysin, and PGP 9.5. Thus morphologically, paraganglioma may closely resemble carcinoid tumors. However, unlike carcinoid tumors, paragangliomas exhibit S100-positive sustentacular cells surrounding cell nests and are negative for cytokeratins.85,102–104 

The nested variant of urothelial carcinoma may show bland nuclei and resemble carcinoid tumor, but unlike the latter, shows focal areas of prominent cytologic atypia; shows strong staining with cytokeratin, uroplakin, and thrombomodulin; and lacks staining for neuroendocrine markers. Urothelial carcinoma is also more extensively infiltrative and myoinvasive.85,105 

The distinction of “carcinoid-like” prostatic carcinoma from carcinoids has been discussed in a prior section of this review.

Small cell neuroendocrine carcinoma is readily distinguished from carcinoid tumor, the former being composed of sheets of uniform small to medium cells with scant cytoplasm, nuclear molding, hyperchromatic nuclei, and inconspicuous nucleoli. Ulceration, necrosis, and mitotic activity are common.106 

Oncocytoma enters into the differential diagnosis of renal oncocytic carcinoid tumor, but in contrast to the latter, oncocytomas are not associated with ectopic ACTH hypersecretion and lack neuroendocrine features on immunohistochemistry and electron microscopy.35 

Note.—Subsequent to the submission of this paper, 2 further cases of carcinoid tumors arising in kidney107,108 and 1 each in bladder109 and prostate110 have been reported.

One of the renal tumors arose in association with a teratoma.107 To our knowledge, the bladder tumor represents the first case of oncocytic carcinoid tumor arising in the bladder.109 The prostate tumor showed neuroendocrine marker positivity, but PSA staining in the tumor is not documented.110 

Table 1. 

Extended

Extended
Extended

Acknowledgments

We gratefully acknowledge the images contributed by Jonathan I. Epstein, MD; Sandra J. Shin, MD; and Pamela D. Unger, MD.

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The authors have no relevant financial interest in the products or companies described in this article.

*References 18–24, 28, 34, 46, 49, 50, 56, 58, 59.

†References 8, 33, 36–38, 40–43, 51, 57, 59.

‡References 8, 12, 14, 16, 32, 33, 37, 38, 40, 42.

§References 12–14, 16, 21, 32–34, 38, 45, 59.

Author notes

Reprints: Rajmohan Murali, MBBS, FRCPA, Department of Anatomical Pathology and Sydney Melanoma Unit, Royal Prince Alfred Hospital, Missenden Road, Camperdown NSW 2050, Sydney, Australia (rajmohan.murali@email.cs.nsw.gov.au)