There is a broad spectrum of prostatic lesions that can display a cribriform and
pseudocribriform morphology. These patterns can be found in variants of normal histology, reactive
conditions, benign proliferative lesions, premalignant entities, and variants of prostatic carcinoma.
Despite sharing this common feature, differentiating histologic features allow one to distinguish amongst
Central Zone Histology
The prostate is divided into four zones:
The central zone forms a cone-shaped volume surrounding the ejaculatory
ducts with its apex at the verumontanum and its base at the bladder neck. Glands within the central zone
up at the base of the prostate are complex and large with numerous papillary infoldings and may
demonstrate Roman bridge and cribriform patterns. Cytologically, the glands are often re lined by
tall-pseudostratified epithelium with eosinophilic cytoplasm. In contrast to high grade PIN, the nuclei
stream parallel to the glandular bridges (compared to the more rigid bridges seen in PIN) and they lack
cytologic atypia. Occasionally, a prominent basal cell layer surrounds these glands. Often glands with
this histology will be seen at the end of the core and may be associated with thick muscle bundles
typical of bladder neck.
- Anterior fibromuscular stroma
- Central zone
- Peripheral zone
- Preprostatic region which encompasses the periurethral ducts and the larger transition zone (1)
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
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
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
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 
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.
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
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
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)
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
The presence of a dense stromal response is more likely to be
associated with basaloid carcinoma, as compared to the adenoid basal cell pattern of basal cell
- Extensive infiltration in between normal prostate glands or
- Extension out of the prostate or
- Perineural invasion or
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