Pathology of Small Cell Prostate Carcinoma

Small cell carcinoma of the prostate is a high-grade malignant neoplasm with neuroendocrine differentiation. The morphologic features characteristic of the disease's pathology include small tumor cells with minimal cytoplasm, nuclear molding, fine chromatin pattern, extensive tumor necrosis/apoptosis, and a brisk mitotic rate. ^[1]

Small cell carcinoma of the prostate is rare, accounting for less than 1% of all prostate cancers. Approximately 50% of patients have pure small cell carcinoma at initial presentation. Some 25-50% of cases are mixed with a conventional prostatic adenocarcinoma. ^[2] Another 25-40% of cases are initially diagnosed as prostatic adenocarcinoma and recur as small cell carcinoma after hormonal therapy. The median interval between initial diagnosis of prostatic adenocarcinoma and recurrence of small cell carcinoma is 25 months. Unlike prostatic adenocarcinoma, small cell carcinoma of the prostate may present with metastases in up to 25% of patients.

Tumor distribution

The distribution of prostatic small cell carcinoma is similar to that of prostatic adenocarcinoma. Most patients have multifocal disease but also have a dominant nodule located in the peripheral zone. These tumors may be felt by digital rectal examination and can be diagnosed by needle core biopsy. The transitional zone and central zone are not common locations for clinically important prostate cancers.

The risk factors for prostatic small cell carcinoma are related to those for prostatic adenocarcinoma and include age, race, and family history. ^[3] The overall risk of developing prostatic small cell carcinoma increases with age, with disease occurrence typically being in men older than 60 years. The mean age of diagnosis is 65-69 years, similar to the average age for prostatic adenocarcinoma; this finding is not surprising, since many patients actually have prostatic adenocarcinoma with a component of small cell carcinoma. (An estimated 30% of the population older than 50 years has prostatic adenocarcinoma.)

In the United States, African Americans have a 1.8-fold relative risk of prostatic adenocarcinoma over white people. Black people in other countries, such as Brazil, also show an increased risk versus other populations.

Some of the ethnic differences in the incidence of prostate cancer are attributed to diets. ^[4] For example, Asians have the lowest incidence of prostate cancer, while Asian immigrants who have adopted Western-style diets have an increased incidence of the disease, although still less than that of the white population. Red meat consumption and a high-fat diet are considered possible risk factors.

Other lifestyle factors, such as sexual practices and occupation, are currently not considered important with regard to the development of prostate cancer.

Genetics

Some prostate cancers may have a genetic component. There is a 10-fold increased relative risk for patients with 2 or more affected first-degree relatives. A patient with a first-degree relative with prostatic adenocarcinoma has a 2-fold increased relative risk. The risk of prostate cancer decreases with distance in the family tree; eg, first versus second cousin.

Potential genetic factors in prostatic adenocarcinoma include gene mutations or polymorphisms in androgen, the androgen receptor (AR), and steroid 5-alpha reductase type II (SRD5A2), an enzyme responsible for converting testosterone to dihydrotestosterone (DHT). ^[5] The length of a polymorphic CAG repeat region in the first exon of the AR gene appears to explain the racial differences in the incidence of prostate cancer. An exciting finding is that in approximately half of the cases, there are recurrent chromosomal rearrangements resulting in the fusion of transmembrane protease serine 2 (TMPRSS2 ) and a member of the ETS family transcription factors , most commonly ERG. ^[6]

The genetic changes specific to prostatic small cell carcinoma have not been studied in great detail. ^[7] The genetic features may be similar to prostatic adenocarcinoma but may contain additional genetic alterations that make these tumors androgen independent and more aggressive. This may be particularly true in those tumors that are recurrent in patients who were treated with hormonal therapy for a conventional adenocarcinoma. ^[8]

It has been shown that 45-47% of prostatic small cell carcinomas harbor ERG gene rearrangement, a rate similar to that seen in prostatic adenocarcinoma. ^[9] Among patients with coexisting small cell carcinoma and conventional (acinar type) adenocarcinoma, the majority of cases show concordant ERG gene rearrangement in the 2 components. ^[10] These findings suggest that prostatic small cell carcinoma may share a common origin with adenocarcinoma.

Small-cell carcinoma may arise from adenocarcinoma after additional genetic alterations. Recently, retinoblastoma protein loss (RB) has been demonstrated in small-cell carcinomas of the prostate (85% loss of RB1; 11 of 13 cases). ^[11] High-grade conventional (acinar type) adenocarcinomas do not typically harbor this genetic abnormality (7%; 10 of 150 cases), which may indicate a genetic breakpoint for the divergence of conventional (acinar type) prostatic adenocarcinoma and small-cell carcinoma of the prostate.

Traditionally, all small cell carcinomas, regardless of organ of origin, have been considered to possess the identical morphology and immunohistochemical profile, thus possibly possessing similar genetic alterations. ^{[12, 13, 14]} However, a study showed that CD44, a putative cell-surface marker for normal and cancerous stem cells in multiple organs, including the prostate, is expressed in small cell carcinomas of the prostate but is infrequently expressed in small cell carcinomas of other organs. ^[15]

The presentation of small cell prostate carcinoma is similar to that of prostatic adenocarcinoma. Localized tumors produce few, if any, symptoms. Symptomatic patients usually have locally advanced or metastatic disease. Some patients notice a change in their urine stream with trouble starting or stopping. Patients may also have a feeling of urgency, hematuria, hematospermia, or trouble defecating. Bone pain or fracture is associated with bone metastasis. A firm nodule may be detected by digital rectal examination.

Unlike patients with prostatic adenocarcinoma, in most patients with small cell carcinoma of the prostate, the serum prostate-specific antigen (PSA) level is not elevated. About 10% of prostatic small cell carcinomas secrete hormones, such as ACTH or ADH, and these patients may present with paraneoplastic syndromes. ^[16]

Small cell carcinomas tend to invade outside of the prostate and more commonly involve the surrounding organs, regional lymph nodes, and distant organs than conventional prostatic adenocarcinoma. ^[4] The findings of atypical metastatic spread or paraneoplastic syndromes should raise the suspicion of a small cell carcinoma.

Gross findings

The tumor is not always identified on gross examination of the resected prostate. Hyperplastic nodules are commonly seen in such specimens, as most patients are older than 50 years.

Prostate cancer tends to produce a subtle, yellow-white color and feels firm; it is usually identified in the peripheral zone. Small cell carcinomas have the same appearance as prostatic adenocarcinomas, but they may feel somewhat softer if significant necrosis is present.

Microscopic findings

The microscopic features are similar to those seen in small cell carcinoma in other organs. ^[17] The low-power view shows sheets of dark blue tumor cells with focal rosette formation and extensive necrosis. The chromatin of the tumor cells is delicate and may be damaged easily during tissue processing, leading to crush artifact. The basophilic deoxyribonucleic acid (DNA) of the tumor cells may escape the nuclei and become entrapped in the blood vessel wall, a phenomenon known as the Azzopardi effect.

On the high-power view, the individual cells are oval or angulated with scant cytoplasm, indistinct borders, and nuclear molding. The nuclei are small (less than the diameter of 3 resting lymphocytes), although occasional larger cells can be present. The nuclear chromatin is finely granular (a salt-and-pepper pattern). The nucleoli are absent or small. Necrosis is a common feature, as are frequent mitotic and apoptotic figures. The Gleason grading system is not used for prostatic small cell carcinomas, as such tumors are poorly differentiated and high grade.

In patients with coexisting prostatic adenocarcinoma and small cell carcinoma of the prostate, the 2 components are intermixed in most cases, whereas in about 20% of cases, there are distinct zones of small cell carcinoma and adenocarcinoma. ^[2] The adenocarcinoma is usually high grade (combined Gleason score >7) and makes up a smaller portion than the small cell carcinoma does. Distinguishing small cell carcinoma from high-grade adenocarcinoma, especially Gleason pattern 5, is often difficult. In such cases, the presence of rosettes, nuclear molding, and a fine chromatin pattern without prominent nucleoli help to identify small cell carcinoma. Immunohistochemistry may also be useful.

Morphology remains the criterion standard to establish a diagnosis of small cell carcinoma. ^[18] However, most pathologists still attempt to confirm a suspected small cell carcinoma with neuroendocrine markers. The following neuroendocrine markers are typically used: chromogranin A, synaptophysin, neuron-specific enolase, and CD56. Typically, 1 or more of these markers are positive in small cell carcinoma. However, in a minority of cases (approximately 10%), all neuroendocrine markers are negative, which, as long as morphology is typical, does not preclude the diagnosis of small cell carcinoma.

Another useful feature is the dot-like perinuclear staining pattern for cytokeratin. Approximately one half of cases are also positive for TTF-1 with a nuclear staining pattern. ^[19]

The above stains are useful in distinguishing small cell carcinomas from Gleason pattern 5 prostatic adenocarcinoma. In addition, nonneuroendocrine stains are useful, because small cell carcinomas, unlike prostatic adenocarcinomas, are often negative for androgen receptor (AR), prostate specific antigen (PSA), prostatic acid phosphatase (PAP), and p504s (AMACR). (See Table 1, below.) ^[20]

Table 1. Immunohistochemical Markers Useful for the Differential Diagnosis of Prostatic Small Cell Carcinoma and Adenocarcinoma (Open Table in a new window)

Neuroendocrine cells are present focally in all prostatic adenocarcinomas. ^[21] Immunohistochemical studies against neuroendocrine markers, such as chromogranin A, highlight a few isolated cells or clusters of neuroendocrine cells among the more abundant adenocarcinoma cells with luminal secretory features. ^[22] Unlike tumor cells in small cell carcinomas, the scattered neuroendocrine cells that are present in prostatic adenocarcinomas are considered postmitotic and nonproliferative. (See the image below.)

Histologic and immunohistochemical features of prostatic small cell carcinoma. A. High-power view of a prostatic small cell carcinoma showing sheetlike growth pattern, high N/C ratio of tumor cells, nuclear molding, fine chromatin, and brisk mitotic and apoptotic figures. B. A case of mixed tumor of the prostate with components of small cell carcinoma and adenocarcinoma. C. Immunohistochemical study of the mixed tumor shows that the small cell carcinoma is positive for chromogranin A, while the adenocarcinoma is negative. D. Immunohistochemical study of the mixed tumor shows that the adenocarcinoma is positive for PSA, whereas the small cell carcinoma is negative.

Prostatic small cell carcinomas may pursue similar routes as prostatic adenocarcinomas to spread to other parts of the body. They may invade through the prostatic capsule to involve the periprostatic soft tissue, seminal vesicles, bladder neck, and rectum locally. They may also metastasize to the pelvic lymph nodes, periaortic lymph nodes, bone, liver, adrenal glands, lung, and brain. ^[23] As such tumors are more aggressive, they tend to spread much earlier. Therefore, they typically present at a higher pathologic stage than prostatic adenocarcinomas. Tumor staging is the same as for prostatic adenocarcinoma.

The prognosis of prostatic small cell carcinoma is poor, with a median survival of less than 1 year. ^[4] There appears to be no significant survival difference between pure prostatic small cell carcinoma and mixed small cell carcinoma/adenocarcinoma. Tumor stage is the single most important predictive factor, although the presence of any amount of small cell carcinoma component is considered to carry a poor prognosis. ^[24]

The experience of treating prostatic small cell carcinomas is limited, as such tumors are rare. These tumors generally do not respond to hormonal therapy or radiation therapy, and surgery is usually not curative. ^[25] Patients are usually treated in the same manner as those with pulmonary small cell carcinomas, with a regimen of cisplatin and etoposide. ^[26]