Central Zone Histology [1, 2]
The prostate is divided into four zones:

1. Anterior fibromuscular stroma
   
   
2. Central zone
   
   
3. Peripheral zone
   
   
4. Preprostatic region which encompasses the periurethral ducts and the larger transition zone (1)

Reactive Glands
In areas of intense chronic inflammation, glands may show some architectural abnormalities such as pseudocribriform formation with budding off of little glands. The prostatic acini appear atrophic with a high nuclear to cytoplasmic ratio. There is also streaming of the basophilic epithelium resembling urothelial metaplasia. The finding of occasional large nucleoli is not uncommon in areas of intense chronic or acute prostatitis. The distinction of these inflammatory atypias from carcinoma first relies on the recognition that the atypical glands are located in an area of intense inflammation. In addition, the glands have a very basophilic appearance in contrast to the usual gland forming prostatic adenocarcinomas that have abundant often pale staining cytoplasm. The streaming appearance of the cells is also characteristic of these reactive glands. Careful examination of these basophilic glands will also demonstrate the finding of a basal cell layer in most instances.

Clear Cell Cribriform Hyperplasia [3, 4]
Clear cell cribriform hyperplasia (CCCH) occurs within the transition zone and is mostly seen in TURP specimens removed for urinary obstructive symptoms, and rarely seen on needle biopsy. It is considered by some to be a cribriform variant of BPH.

In its most readily recognized form, CCCH is composed of numerous cribriform glands separated from one another by a modest amount of stroma in a pattern of nodular hyperplasia. In florid cases, the glands infiltrate the stroma more diffusely. The epithelial cells have distinctive clear cytoplasm and small bland nuclei with inconspicuous or small nucleoli. Around many of the glands of CCCH is a strikingly prominent basal cell layer, consisting of a row of cuboidal darkly staining cells beneath the clear cells. The basal cells may form small knots at the periphery of some of the glands. The basal cell layer may be incomplete and in some glands may be invisible in routine sections. Tangential sections can also result in the appearance of occasional nests of clear cells without cribriform architecture or basal cells. Although usually unnecessary, immunostains for high molecular weight cytokeratin can highlight the basal cell layer.

The distinction between CCCH and cribriform PIN may be difficult. Cribriforming PIN would similarly show large cribriforming glands which fit within the normal architectural pattern of the prostate. However, in cribriform PIN towards the exterior portion of the cribriform glands up against the basement membrane, there is significant nuclear atypia composed of enlarged nuclei with prominent nucleoli; towards the center of cribriform PIN glands, there may be more benign appearing nuclei. It is also distinctly unusual to see so many cribriform glands of PIN located within the transiton zone of the prostate sampled on TURP.

The distinction between CCCH and infiltrating cribriform carcinoma is also based on the lack of nuclear atypia within the cribriform glands of CCCH. Infiltrating cribriform carcinoma will always show some nuclear atypia in some of the malignant glands. Furthermore, the diagnosis of infiltrating cribriform carcinoma should be made with great reluctance if there are none of the small infiltrating glands of carcinoma seen between the cribriform glands. Immunoperoxidase stains for basal cells will verify the presence of basal cells in some of the cribriform glands.

CCCH is uncommon, and its natural history is unknown. Although three of 25 reported cases were associated with adenocarcinoma of the prostate, there were no areas of transition from CCCH to carcinoma of the prostate. Taking into account prostate cancer's high incidence in elderly men, it is felt that CCCH is unrelated to adenocarcinoma of the prostate.

Basal Cell Hyperplasia [5, 6]
Basal cell hyperplasia may reveal focal cribriform glands. Cribriform basal cell hyperplasia in most cases resembles back-to-back glands of basal cell hyperplasia rather than true cribriform glands. True cribriform glands of basal cell hyperplasia may also exist. Adjacent to cribriform basal cell hyperplasia are usually more typical individual glands of basal cell hyperplasia. The major differential diagnosis for basal cell hyperplasia with true cribriform glands is between cribriform high grade PIN. In contrast to PIN, glands of basal cell hyperplasia tend to be composed of cells with round nuclei and atrophic luminal cytoplasm. High grade PIN nuclei are typically more columnar with more abundant apical cytoplasm. Basal cell lesions are preferentially located in the transition zone and are seen on TURP, although occasionally, we have seen basal cell hyperplasia on needle biopsy, where high grade PIN preferentially is located in the peripheral zone. Finally, the presence of non-cribriform glands of basal cell hyperplasia adjacent to cribriform glands with similar cytology favors the diagnosis of cribriform basal cell hyperplasia over that of cribriform high grade PIN.

In cribriform basal cell hyperplasia, high-molecular-weight cytokeratin shows multilayered staining of the basal cells in some of the glands and a continuous layer of immunoreactivity. Cribriform high grade PIN demonstrates an interrupted immunoreactive single cell layer of basal cells.

High Grade PIN [7]
High grade PIN is charaterized by preexisting benign glands lined by atypical cells showing prominent nucloli. There is a normal overall architectural pattern with glands of the size of normal benign glands separated by a modest amount of stroma. These glands resemble benign glands in that they are large, branch, and often have papillary and undulating luminal surfaces. At low magnification, glands with high grade PIN have a basophilic appearance. This basophilic appearance is due to a combination of features including: enlarged nuclei; hyperchromatism; overlapping nuclei; and epithelial hyperplasia. The various patterns of PIN have been designated as flat, tufting, micropapillary, and cribriform. Within cribriform high grade PIN, the nuclei towards the center of the gland tend to have a more bland cytologic appearance, as compared to the nuclei peripherally located up against the basement membrane. The grade of PIN is assigned based on assessment of the nuclei peripherally located up against the basement membrane. High grade PIN may also show focal necrosis.

In some cases there are atypical cribriform glands in which the differential is between cribriform PIN and cribriform Gleason pattern 3 cancer, where small glands of acinar adenocarcinoma are absent. Glands diagnostic of cribriform PIN usually occur in the setting of more ordinary high grade PIN. The cribriform glands tend to be few in number, may only focally involve a gland, and their glandular size, contour, and relationship to other glands are consistent with preexisting benign glands whose cells have been replaced by neoplastic cells. When basal cells are identified, infiltrating cancer is ruled out (see below for discussion of intraductal carcinoma). The diagnosis of cribriform Gleason pattern 3 cancer and its distinction from cribriform PIN in some cases is virtually impossible without the use of special stains for basal cells or the identification of the neoplastic glands exterior to the prostate. The distinction between cribriform PIN and ductal adenocarcinoma is discussed below.

Intraductal Carcinoma [8, 9, 10, 11, 12]
In recent years, some authors have proposed that certain cribriform patterns of high grade PIN should be considered as "intraductal carcinoma of the prostate". In studies of radical prostatectomy specimens, the presence and extent of "intraductal carcinoma" correlates with post-prostatectomy progression of cancer, tumor volume, advanced stage, and higher Gleason grade. However, other authors feel that there is significant morphological overlap between high grade PIN and "intraductal carcinoma" and adenocarcinoma involving secondary ducts, questioning whether reproducible criteria could be developed to distinguish the spread of a cancer within ducts ("intraductal carcinoma") from high grade PIN. I diagnose "intraductal carcinoma" on needle biopsy when there are numerous cribriform glands composed of cells with a much greater degree of nuclear atypia than the usual case of cribriform high grade PIN. Although not an absolute requirement, the majority of cases diagnosed as intraductal carcinoma have multiple foci of central comedo-necrosis. Immunohistochemistry demonstrates a basal cell layer around the markedly atypical cribriform glands, such that a diagnosis of infiltrating cancer can not be rendered.

Whether these lesions represent cancerization of ducts and glands by invasive carcinoma or a de novo lesion arising within the ducts is unknown. In practice, this distinction rarely poses a problem in the evaluation of a prostatectomy specimen as invasive cancer is always concurrently present. In prostate needle biopsies and TUR-P, this process may rarely be present without small glands of adenocarcinoma, where some experts consider it prudent to refer to the lesion as high grade cribriform PIN with a strong recommendation for repeat biopsy. Other experts will use the term "intraductal carcinoma" on biopsy with the recognition that definitive therapy may be undertaken, recognizing that infiltrating cancer will be identified upon further prostatic sampling.

Acinar (Usual) Adenocarcinoma [13, 14]
Smoothly circumscribed small cribriform nodules of tumor are classified as Gleason pattern 3 acinar carcinoma. Although the distinction between cribriform Gleason pattern 3 and cribriform PIN may be difficult, from a diagnostic standpoint, this is usually not critical. Almost always when there is cribriform Gleason pattern 3, the cribriform glands are accompanied by small infiltrating glands of cancer where the diagnosis of infiltrating tumor can be made. In the absence of small infiltrating glands, only when the small cribriform glands are either back-to-back, or in a perineural or extra-prostatic location are they inconsistent with cribriform PIN and should be diagnosed as infiltrating cribriform carcinoma. Immunohistochemistry with antibodies to high molecular weight keratin can be used in difficult cases to differentiate these two entities. In the setting of numerous cribriform glands where the differential diagnosis is cribriform PIN versus cribriform carcinoma, a negative reaction in all of the glands is diagnostic of carcinoma; positive staining, even if patchy, verifies the lesion as cribriform PIN. If one is presented with only a few cribriform glands, negative staining is not diagnostic of carcinoma. This results from the patchy nature with which high molecular weight keratin labels PIN and the recognition that even scattered benign glands may not label with antibodies to high molecular weight keratin. When there only one or a few small cribriform glands on needle biopsy material without small glands of infiltrating carcinoma, these cases in general are not diagnostic of infiltrating carcinoma. Instead, the diagnosis is "Focus of atypical cribriform glands" with a comment that "The distinction between cribriform PIN and cribriform carcinoma can not be made with certainty, and repeat biopsy is recommended.

The vast majority of cribriform prostate cancers should be assigned a Gleason pattern 4. In Gleason pattern 4, the cribriform glands are larger have an irregular border as opposed to the smoothly circumscribed smaller nodules of cribriform Gleason pattern 3. On needle biopsy, cribriform Gleason pattern 4 tumor often manifests as detached fragments of cribriform tumor as there is little supporting stroma.

Ductal Adenocarcinoma [15, 16, 17, 18]
Ductal adenocarcinomas are characterized by tall pseudostratified epithelial cells with abundant, usually amphophilic cytoplasm. The cribriform pattern is formed by back-to-back large glands with intraglandular epithelial bridging resulting in the formation of slit-like lumens. This pattern of prostatic adenocarcinoma differs from the cribriform pattern of prostatic acinar adenocarcinoma which is composed of cuboidal epithelium and punched-out round lumina. It is not uncommon to find areas of papillary formation admixed with cribriform patterns.

A difficult distinction may be between cribriform PIN and ductal adenocarcinoma of the prostate. There are several features which distinguish these two lesions. First, ductal adenocarcinomas are often centrally located in the periurethral region and are often sampled on TURP. In contrast, PIN is uncommonly found within the periurethral region and infrequently seen on TURP. Secondly, cribriform ductal adenocarcinomas often are accompanied by a papillary component with true papillary fronds with well-established fibrovascular cores, whereas PIN more frequently reveals micropapillary fronds with tall columns of epithelium without fibrovascular stalks. Ductal adenocarcinomas frequently contain comedo-necrosis, which may be extensive. PIN usually lacks comedo-necrosis, and when present is focal. Finally, ductal adenocarcinomas may consist of very large and/or back-to-back glands, whereas glands involved by PIN are of the size and distribution of benign glands.

Basaloid Carcinoma (Adenoid Cystic Pattern) [19, 20]
The histologic variability of basaloid carcinomas of the prostate is greater than that of basal cell hyperplasia. They may resemble basal cell carcinomas of the skin with large basaloid nests, peripheral palisading, and necrosis. Basaloid carcinomas can also appear identical to the ordinary glandular pattern of basal cell hyperplasia, yet are recognizably malignant because of infiltration out of the prostate. A cribriform pattern exists resembling the adenoid basal cell pattern of basal cell hyperplasia, and have been referred to by some as adenoid cystic carcinoma of the prostate. Diagnostic criteria for malignancy in lesions resembling the adenoid basal form of basal cell hyperplasia are either:

1. Extensive infiltration in between normal prostate glands or
   
   
2. Extension out of the prostate or
   
   
3. Perineural invasion or
   
   
4. Necrosis

References

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3. Ayala AG, Srigley JR, Ro JY, Abdul-Karim FW, Johnson DE. Clear cell cribriform hyperplasia of prostate: Report of 10 cases. Am J Surg Pathol 1986;10:665-671.
   
   
4. Frauenhoffer EE, Ro JY, El-Naggar AK, et al. Clear cell cribriform hyperplasia of the prostate: Immunohistochemical and flow cytometric study. Am J Clin Pathol 1991;95:446-453.
   
   
5. Devaraj LT, Bostwick DG. Atypical basal cell hyperplasia of the prostate: Immunophenotypic profile and proposed classification of basal cell proliferations. Am J Surg Pathol 1993;17:645-659.
   
   
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