Pathology of prostate gland adenocarcinoma and its histologic variants

Prostate cancer is now the sixth most common cancer in the world, and third in importance in men. The incidence and mortality have increased in the last several decades, due in part to the introduction of newer diagnostic tests, such as PSA screening. The incidence varies greatly with geographic location, ethnic background, and age. The highest incidence is seen in the United States, Australia, and Scandinavian countries, whereas prostate carcinoma is relatively uncommon in countries of the Far East. In the United States, blacks have a much higher incidence and mortality than whites. The incidence rises dramatically with age. The clinical disease is uncommon before the age of 50 years. The 2004 World Health Organization (WHO) classification of neoplasms of the prostate is given in Table 1.

Prostate adenocarcinoma, an invasive carcinoma with prostatic secretory cell differentiation is the most common form of prostatic cancer.

Macroscopy

Gross diagnosis of prostatic carcinoma is possible in radical prostatectomy tissues but not in needle biopsy or TURP chip tissues. On section, grossly evident cancers are firm, solid, and range in color from white-gray to yellow-orange; the tumors contrast with the adjacent benign parenchyma, which is typically tan and spongy. (Fig 1.)

Figure 1. A, B Section of prostate showing peripheral zone adenocarcinoma. C Section of prostate showing transition zone adenocarcinoma, difficult to distinguish from nodules of BPH.

Microscopy

Adenocarcinomas of the prostate range from well-differentiated gland forming cancers, where it is often difficult to distinguish them from benign prostatic glands, to poorly differentiated tumors, difficult to identify as being of prostatic origin. Prostate carcinoma has a constellation of architectural, cytoplasmic, nuclear, and intraluminal features. They can be divided into major and minor diagnostic criteria. (Table.2)

Major criteria

1. Architectural features. Benign glands tend to grow either as circumscribed nodules within benign prostatic hyperplasia, radiate in columns out from the urethra in a linear fashion, or are evenly dispersed in the peripheral zone. In contrast, gland-forming prostate cancers typically contain glands that are more crowded than in benign prostatic tissue, although there is overlap with certain benign mimickers of prostate cancer. Glands of adenocarcinoma of the prostate typically grow in a haphazard fashion. Glands oriented perpendicular to each other and glands irregularly separated by bundles of smooth muscle are indicative of an infiltrative process. Another pattern characteristic of an infiltrative process is the presence of small atypical glands situated in between larger benign glands. (Fig.2) With the loss of glandular differentiation and the formation of cribriform structures, fused glands, and poorly formed glands, the distinction between benign glands based on the architectural pattern becomes more apparent. Tumors composed of solid sheets, cords of cells, or isolated individual cells characterize undifferentiated prostate cancer.

2. Basal cell absence, can sometimes be difficult to evaluate in H&E-stained sections, so in difficult cases and for small foci of adenocarcinoma, immunohistochemical staining for basal cells using antibodies against high-molecular-weight cytokeratins and p63 may be performed. (Fig.2) While a positive basal cell immunostain effectively rules out invasive adenocarcinoma, benign glands can focally lack a basal cell layer, so basal cell ummunostains should be interpreted in the context of the H&E histological findings.

3. Nuclear atypia. Typically, prostate carcinoma displays nuclear characteristics distinct from surrounding benign glands, including enlarged nuclei and prominent nucleoli. (Fig.2) Some prostate carcinomas lack prominent nucleoli yet have enlarged and hyperchromatic nuclei. Mitoses and apoptotic bodies are more common in prostate carcinoma, although they are rarely found in benign glands and still not frequently seen in malignant glands. Cancer nuclei, even in poorly differentiated ones, show little variation in size and shape.

Figure 2. A Haphazard distribution of small acini indicative of infiltrative growth. B Fused acinar adenocarcinoma. C Nuclear atypia in adenocarcinoma: appearance of nuclei D p63 immunohistochemical stain highlights the invasion of the malignant glands, which lack basal cells (brown signal).

Minor criteria tend to be found more often in adenocarcinoma, but are not specific for adenocarcinoma.

1. Intraluminal blue mucin. Acidic sulfated and non-sulfated mucin is often seen in the acini of adenocarcinoma, appearing in routine sections as amorphous or delicate thread-like basophilic secretions. (Fig.3) This mucin stains with Alcian blue and is best demonstrated at pH 2.5, whereas normal prostatic epithelium contains periodic acid-Schiff-reactive neutral mucin. Acidic mucin is not specific for carcinoma, and maybe found in PIN and rarely in BPH.

2. Pink amorphous secretions. Ill-formed secretions are more often found in the lumen of suspicious and cancerous acini than in benign acini, and vary from lightly pink and scant to brightly eosinophilic and extensive. (Fig.3) In contrast, corpora amylacea, which consists of well-circumscribed round to oval structures with concentric lamellar rings, are common in benign glands and only rarely seen in prostate cancer.

3. Mitotic figures may be relatively common in high-grade cancer, yet are infrequent in lower grade tumors.

4. Crystalloids are sharp rhomboid or needle-like eosinophilic structures that are often present in the lumen of well- and moderately differentiated carcinoma. (Fig.3) They are can be found in other conditions such as atypical adenomatous hyperplasia. The presence of crystalloids in metastatic adenocarcinoma of unknown site of origin is strong presumptive evidence of prostatic origin, although it is an uncommon finding.

5. Amphophilic cytoplasm. Glands of adenocarcinoma of the prostate tend to have a discrete crisp, sharp luminal border without undulations or ruffling of the cytoplasm. In contrast, equivalently sized benign glands have an irregular luminal surface with small papillary infoldings and a convoluted appearance. The finding of apical snouts is not helpful in distinguishing benign versus malignant glands as they can be seen both. Cytoplasmic features of low grade prostate cancer are also often not very distinctive, since they are often pale-clear, similar to benign glands. Neoplastic glands may have amphophilic cytoplasm. Prostate cancer cytoplasm of all grades typically lacks lipofuscin, in contrast to its presence in some benign prostatic glands.

Figure 3 Blue-tinged mucin is found in the cancer glandular lumina (A), as are intraluminal pink, acellular, dense secretions (B) and crystalloids (C).

Cancer specific features: There are three histologic features, which are diagnostic of prostate carcinoma, called cancer-specific features. (Fig.4)

1. Collagenous micronodules are a specific but infrequent and incidental finding in prostatic adenocarcinoma, consisting of loose fibrous tissue with an ingrowth of fibroblasts, sometimes reflecting organization of intraluminal mucin. Collagenous micronodules are formed by subepithelial accumulations of fragmented collagen fibers, possibly related to the digestion by collagenase produced by prostatic adenocarcinoma cells.

2. Glomeruloid formation is created by intraluminal cribriform proliferation of malignant cells and is often surrounded by a crescensic space, resembling a renal glomerulus.

3. Perineural invasion with cancer glands completely or near-completely encircling the nerve is pathognomic of prostate carcinoma. Benign glands can occasionally be found to abut a nerve; however, circumferential extension of benign glands entirely around a nerve has not been described.

Figure 4. A Collagenous micronodules. B Glomeruloid formations. C Perineural invasion.

Histologic variants of prostate carcinoma

Histologic variants of prostate carcinoma account for 5% to 10% of all the carcinomas in the prostate and are typically seen in association with ordinary acinar prostate carcinoma. These variants often differ from the latter in clinical, immunophenotypic, ultrastructural, and genetic features. Many also differ in prognosis and may prompt a different therapeutic approach.

Atrophic carcinoma. The cancer glands have scant cytoplasm and may be confused with benign atrophy (Fig.5). The diagnosis is based on several features. First, atrophic prostate carcinoma displays an infiltrative growth pattern, with atrophic cancer glands intermingling with larger benign glands. In contrast, benign atrophy usually has a lobulated configuration. Atrophic prostate carcinoma has significant cytologic atypia, namely, nuclear enlargement and prominent nuclei. Finally, atrophic prostate carcinoma is often intermixed with nonatrophic ordinary prostate carcinoma. Whereas some forms of atrophy, are associated with fibrosis, atrophic prostate cancer lack such a desmoplastic stromal response.

Figure 5. A Cancer acini with round dilated and distorted lumina.

Figure 5. B Higher magnification shows acini lined by flattened cells with scant cytoplasm and enlarged nuclei with prominent nucleoli.

Pseudohyperplastic carcinoma resembles benign prostate glands in that the neoplastic glands are large with branching and papillary infolding. The recognition of cancer with this pattern is based on the architectural pattern of numerous closely packed glands as well as nuclear features more typical of carcinoma. One pattern of pseudohyperplastic adenocarcinoma consists of numerous large glands that are almost back-to-back with straight even luminal borders, and abundant cytoplasm. Comparably sized benign glands either have papillary infoldings or are atrophic. The presence of cytologic atypia in some of these glands further distinguishes them from benign glands. It is almost always helpful to verify pseudohyperplastic cancer with the use of immunohistochemistry to verify the absence of basal cells. Pseudohyperplastic cancer, despite its benign appearance, may be associated with typical intermediate grade cancer and can exhibit aggressive behavior.

Figure 6. A Pseudohyperplastic adenocarcinoma. Branching and papillary type of growth is typical. B. Perineural invasion. C Higher magnification, showing prominent nucleoli.

Foamy gland carcinoma. Cancer cells have abundant foamy or “xanthoma’-like cytoplasm with a very low nuclear/cytoplasmic ratio (Fig.7). Although the cytoplasm is xanthomatous in appearance, it contains empty vacuoles rather than lipid. The nuclei of foamy gland prostate carcinoma cells are typically small and hyperchromatic and lack the cytologic features of ordinary prostate carcinoma. The diagnosis of foamy gland prostate carcinoma is based on its architectural pattern of crowded and/or infiltrative glands, abundant foamy cytoplasm, and frequent intraluminal, dense, pink, acellular secretions. Basal cells are absent by immunohistochemistry. Despite its bland cytology, most of the cases that include an associated nonfoamy cancer are Gleason score 6 or greater. Foamy gland prostate carcinoma, therefore, appears best classified as an intermediate-grade carcinoma.

Mucinous (Colloid) carcinoma is defined as a cancer in which 25% or more of the tumor consists of lakes of extracellular mucin. Prostate carcinoma with less than 25% mucinous component should be classified as having mucinous features, whereas prostate carcinoma with intraluminal mucin without lakes of extracellular mucin is not considered as mucinous prostate carcinoma. Clinically, the average age for mucinous prostate carcinoma is often advanced, with locally advanced or metastatic disease. Microscopically, tumor cells float in lakes of extracellular mucin that are sharply demarcated from the stroma. Tumor cells are arranged in cribriform configurations, cords, strands, acini, or tubules. Cytologically, they appear bland with occasional prominent nucleoli. (Fig.7)

Figure 7 A Foamy gland carcinoma. Note pale eosinophilic with finely vacuolated cytoplasm, distinct cell membranes, basal nuclei, and small punctuate nucleoli. B Another case with clear finely vacuolated cytoplasm and hyperchromatic nuclei with indistinct nucleoli. C, D Mucinous (colloid carcinoma). Abundant luminal mucin expands the malignant acinar lumina.

Signet-ring-like carcinoma. Defined as 25% or more of tumor mass consisting of signet-ring-appearing cells, this histologic variant is a rare entity with an aggressive clinical course. Microscopically, the signet-ring-like tumor cells display nuclear displacement and indentation by clear cytoplasmic vacuoles (Fig.8). In the majority of cases, these vacuoles contain lipid rather than mucin, as with true signet cells. The cancer cells grow in sheets, in small clusters, and as single cells. They are invariably mixed with ordinary acinar prostate carcinoma components. Before establishing a diagnosis of prostatic signet-ring carcinoma, a metastasis from other anatomic sites, including stomach, lung, colon, and pancreaticobiliary system, must be excluded. On the other hand, a prostatic signet-ring carcinoma should be considered when one encounters a signet-ring-cell carcinoma of unknown primary, especially if mucin stains are negative.

Sarcomatoid carcinoma (Carcinosarcoma). Sarcomatoid prostate carcinoma is composed of both malignant epithelial and spindle cell elements (Fig.8). It may be a de novo diagnosis, or patients may have a previous history of prostate carcinoma treated with radiation or hormonal ablation therapy or both. Serum PSA is within normal limits in most cases, despite the frequent presence of nodal and distant metastasis. The 5-year survival rate is less than 40%. Microscopically, sarcomatoid prostate carcinoma is biphasic, with a glandular component showing variable Gleason patterns and a sarcomatoid component often exhibiting nondescript malignant spindle cell proliferation. Specific mesenchymal differentiation can also be present, including osteosarcoma, chondrosarcoma, and rhabdomyosarcoma. Immunohistochemically, the epithelial elements are positive for PSA and/or pancytokeratins, whereas sarcomatoid elements react with markers of corresponding mesenchymal differentiation and variably express cytokeratins.

Figure 8. A Signet-ring-like cancer cells display nuclear displacement and indentation by clear cytoplasmic vacuoles.

Figure 8. B This sarcomatoid prostate carcinoma is biphasic, with a glandular component and a sarcomatoid component

exhibiting malignant spindle cell proliferation

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