Shah, Rajal B. MD*; Zhou, Ming MD, PhD†
There is a broad spectrum of prostatic lesions with cribriform or solid architecture. These lesions range from benign, such as central zone glands, to proliferative, such as clear cell cribriform or basal cell hyperplasia, to frankly malignant, such as invasive cribriform carcinoma (Table 1). Infrequently these cribriform or solid lesions may display malignant cytology yet have complete or partial basal cell lining.1,2 Referred to as “atypical cribriform lesions (ACLs) of the prostate,” they may represent cribriform “high-grade prostatic intraepithelial neoplasia” (HGPIN) or “intraductal carcinoma of the prostate” (IDC-P). Cribriform HGPIN is a morphologic variant of HGPIN, which can be an isolated finding not necessarily associated with prostate cancer (PCa). HGPIN is a widely accepted putative PCa precursor. In early studies, HGPIN was associated with a significant risk of cancer in subsequent follow-up prostate biopsies. However, recent data suggest that patients with isolated HGPIN (with HGPIN involving 1 core out of the entire biopsy set) on needle biopsy have a risk for carcinoma in subsequent biopsy similar to that in patients with a benign diagnosis.3–5 In contrast, IDC-P has been reported to be almost always associated with a high Gleason score, large tumor volume, extraprostatic extension of carcinoma, and accelerated disease progression in radical prostatectomy (RP) specimens.2,6–9 Although the origin of IDC-P is not yet clear, recent clinical, immunohistochemical, and molecular studies suggested that IDC-P is a late event in carcinoma progression and most likely represents the intraductal spread of established PCa.1,2,6,7,10–12 A diagnosis of IDC-P in biopsy mandates immediate repeat biopsy or definitive therapy even in the absence of documented invasive PCa. Therefore, the distinction between 2 lesions and recognition of IDC-P is critical, especially when observed in needle biopsy specimens.
This articles reviews the morphologic and genetic characteristics and the clinical significance of IDC-P and cribriform HGPIN with an emphasis on the diagnosis, differential diagnosis, and reporting of IDC-P.
INTRADUCTAL CARCINOMA OF THE PROSTATE: AN EVOLVING CONCEPT
The concept of ACL and IDC-P is not new but has been evolving. In Gleason era, ACLs were probably classified as Gleason pattern 4 or 5 cancer. When basal cell markers became available, ACLs were found to have basal cell lining and were thought to represent a part of PIN morphologic spectrum. The study by Kovi et al10 in 1985 drew attention to the phenomenon of intraductal spread by PCa. Of 139 cases of PCa diagnosed on transurethral resection, suprapubic prostatectomy, and needle biopsy specimens studied by them, spread of PCa cells into preexisting prostate ducts and acini was found in 48% of the cases. Intraductal spread was associated with both the Gleason grade and tumor extent, but on multivariate analysis only tumor extent remained significantly associated with the intraductal spread. McNeal et al8 later observed that most PCa cases with cribriform morphology were predominantly located within prostatic ducts and acini with cancer cells following normal duct contour or showing a basal cell layer on morphologic examination or basal cell immunostaining. Cribriform PCa with intraductal location was equivalent to Gleason patterns 4 and 5 PCa in biological behavior. This phenomenon was also associated with high-grade and high-volume PCa in the majority of cases. The term “intraductal carcinoma of the prostate (IDC-P)” was coined to emphasize the unique histologic and clinical features of this lesion.
As cribriform HGPIN, a morphologic subtype of PIN, is also characterized by lumen-spanning proliferation of cytologically atypical cells, the relationship between HGPIN and IDC-P has been explored. McNeal et al8 demonstrated that in some cases IDC-P was associated with HGPIN, with direct transition between the 2 or with both lesions adjacent to each other, suggesting that IDC-P arose primarily within ducts by evolution from the premalignant PIN. In a subsequent study, McNeal and Yemoto9 demonstrated that IDC-P was different from PIN and suggested rather that it represented a distinct form of PCa with peculiar propensity for intraductal spread and growth. They noted that the presence of cancer cells within prostatic ducts and acini, or IDC-P, was almost never seen in the absence of invasive carcinoma, and the concomitant invasive component was almost always high grade. Furthermore, PCa with IDC-P component had a significantly worse prognosis than those without. The authors concluded that IDC-P was an entity with precisely defined histologic criteria and unique biological and clinical significance.
HISTOLOGIC FEATURES OF IDC-P: A MORPHOLOGIC SPECTRUM
McNeal and Yemoto provided the first detailed description of the morphologic features of IDC-P as the “complete spanning of the ductal or acinar lumen by several trabeculae of malignant epithelial cells, with foci of trabecular fusion.” More proliferative, denser lesions with cribriform or solid architecture were also included in their definition.9
We recently studied the morphologic features of IDC-P in comparison with cribriform HGPIN. Using a RP specimen cohort, we evaluated the topographic relationship of ACLs retaining basal cells, which represent IDC-P or HGPIN, with PCa, to better understand the morphologic and clinical differences between HGPIN and IDC-P.1,2 ACLs that were intermixed with, or were within 3 mm from, the border of infiltrative cancer were considered cancer associated (ACL-PCa) and equivalent to IDC-P. ACLs that were not intermixed with and were at a distance of >3 mm from the border of infiltrative cancer were considered as noncancer associated or isolated, equivalent to cribriform HGPIN. This approach was validated by our later genetic study.1 Isolated ACLs or cribriform HGPINs were uncommon, and the overwhelming majority of ACLs was associated with high-grade (GS≥7) and high-volume PCa and represented IDC-P. ACL-PCa or IDC-P usually comprised of many glands, often >6 per RP specimen, and the glands were larger than normal peripheral zone glands with markedly irregular and branching contours (Figs. 1A, B). The IDC-P glands have several architectural patterns, including trabecular, loose cribriform, dense cribriform, and solid (Fig. 1C). The dense cribriform and solid architecture were present exclusively in IDC-P. Intraluminal necrosis was present in 30% of and exclusively in IDC-P (Fig. 1D). The pleomorphic nuclei or giant nuclei at least 6 times the size of the adjacent nuclei were present in 28% of and exclusively in IDC-P (Fig. 1E). However, some IDC-P glands can also exhibit “low-grade” architectural and cytologic features that are also observed in cribriform HGPIN glands, including small cribriform architecture with uniform nuclei (Fig. 2). Therefore, although high-grade architectural and cytologic features including large gland size (>1 mm), large focus involving many glands (>6), dense cribriform or solid architecture, comedonecrosis, and high-grade nuclei, are characteristic and diagnostic of IDC-P (Tables 2, 3), a low-grade morphology does not exclude IDC-P.
DIAGNOSTIC CRITERIA OF IDC-P
Since its original description, several studies in the last decade have attempted to establish histologic criteria for IDC-P such that IDC-P becomes an entity that can be reproducibly diagnosed and is associated with adverse prognostic significance. Cohen et al13 proposed a set of criteria for diagnosing IDC-P, which included 5 major and 3 minor criteria. The first 4 major criteria are always present in IDC-P and include: (1) large-caliber glands that are more than twice the diameter of normal peripheral zone glands; (2) preserved basal cells as identified with basal cell markers; (3) cytologically malignant cells; and (4) an expansile cell mass that spans the glandular lumen. The fifth major criterion, central comedonecrosis, is diagnostic of IDC-P but not always present. Minor criteria include glands with: (1) right angle branching or (2) smooth rounded outlines, and (3) 2 cell populations with an outer perimeter cell group composed of tall, pleomorphic, and mitotically active cells that stain poorly for prostate-specific antigen (PSA), and a central group that is cuboidal, monomorphic, and quiescent with abundant cytoplasm containing abundant PSA and occasional extracellular mucin.
In 2006, Guo and Epstein proposed diagnostic criteria for IDC-P in prostate biopsy specimens that have subsequently been used in a larger study of IDC-P from the same institution.14,15 In these 2 studies, in addition to the presence of malignant epithelial cells filling large acini and prostatic ducts with preservation of basal cells, the diagnosis of IDC-P required the presence of: (1) a solid or dense cribriform pattern, in which punched-out luminal spaces account for <50% of the central cellular mass; or (2) marked nuclear atypia, in which nuclei are at least 6× larger than adjacent benign nuclei; or (3) nonfocal comedonecrosis. Lesions that fall short of these criteria but are still felt to be more ominous than HGPIN are labeled as “atypical intraductal proliferations” in which the differential diagnosis rests between HGPIN and IDC-P.
These diagnostic approaches use stringent morphologic criteria to ensure that ACLs diagnosed as “IDC-P” are associated with a poor clinical outcome. In contrast, IDC-P with “low-grade” morphology that does not satisfy the diagnostic criteria should not be diagnosed as “IDC-P” as there is morphologic overlap between IDC-P with low-grade morphology and cribriform HGPIN.
There have been attempts to understand differential genetic aberration and immunohistochemical staining between IDC-P and HGPIN. Dawkins et al16 reported that loss of heterozygosity was infrequent in HGPIN (9%) but common in IDC-P (60%). The most frequently lost foci in IDC-P were 8p22 and 16q23.1-qter. Using comparative genomic hybridization, Bettendorf et al17 found that the majority of IDC-P showed several chromosomal imbalances, strikingly different from HGPIN, which showed no comparative genomic hybridization changes.
The most convincing evidence that IDC-P and cribriform HGPIN are genetically different and the former is closely related to PCa came from our study of ETS gene fusions in IDC-P, HGPIN, and PCa. The fusion of androgen-regulated gene TMPRSS2 or other unique 5′ fusion partner genes to ETS family members ERG, ETV1, ETV4, ETV5, and ELK 18–25 is the most common recurrent genetic rearrangements in PCa. TMPRSS2-ERG is the most common fusion and is present in approximately 50% to 70% of PSA-screened localized PCa and in 15% to 30% of population-based cohorts.18 By contrast, approximately 20% of the HGPIN lesions harbor TMPRSS2-ERG fusion.26–28 Importantly, all HGPIN lesions with ERG rearrangement analyzed using fluorescence in situ hybridization are always intermingling with ERG rearrangement–positive carcinoma.27,28 As TMPRSS2 and ERG are located ∼3 Mb apart on chromosome 21, the rearrangement between them occurs either through insertion or by an interstitial deletion (EDel).29 Emerging data have suggested that TMPRSS2-ERG fusion associated with Edel is associated with an aggressive phenotype in clinically localized and in androgen-independent metastatic PCa.30,31 Notably, duplication of TMPRSS2-ERG in combination with deletion of 5′-ERG (EDel 2+) was suggested to be an indicator of poor prognosis in PCa.32 Previously, we have shown that EDel 2+ occurred in 57% (4/7) of small cell carcinomas of the prostate.33 Recently, several studies have shown that positive immunostains with anti-ERG antibodies correlate highly with the ERG gene fusion status.34,35 Therefore, the ERG gene fusion status can be determined using routine immunohistochemistry (Figs. 3A–C). We studied the ERG gene fusion in 16 isolated cribriform HGPIN and 48 IDC-P lesions in RP specimens.1 Of 48 IDC-P cases, 19 (40%) had high-grade morphology and fulfilled the diagnostic criteria of IDC-P (marked nuclear atypia with nuclear size 6× normal or larger and/or comedonecrosis) as suggested by Guo colleagues (referred to as group A ACLs). The remaining 29 (60%) were intimately associated with PCa but had low-grade morphology and did not fulfill the diagnostic criteria of IDC-P and were morphologically similar to cribriform HGPIN (referred to as group B ACLs). It is noteworthy that a minor group B component was present in predominantly group A glands in some cases. Overall, ERG gene rearrangement was observed in 75% (36/48) of IDC-P, of which 64% (23/36) were through deletion and 36% (13/36) through insertion. Notably, EDel 2+ was identified in 17% (6/36) of the IDC-P in this cohort. No case with ETV1, ETV4, or ETV5 rearrangement was identified in this cohort. Similar incidence of ERG gene rearrangement was found in group A (78%, 15/19) and group B (72%, 21/29) lesions. EDel 2+ was identified in 20% (3/15) of group A and 14% (3/21) of group B lesions. In contrast, ERG gene rearrangement was never found in isolated cribriform HGPIN (0/16, 0%). These findings suggest that IDC-P, not cribriform HGPIN, is genetically closely related to invasive PCa and probably represent intraductal spread of the invasive PCa. In addition, IDC-P can have both high-grade morphologic features that are easily recognizable as IDC-P, and low-grade morphologic features that overlap with and are challenging to distinguish from HGPIN.
The differential diagnosis of ACLs includes a broad spectrum of other prostate lesions with cribriform and/or solid architecture, ranging from normal histologic structures to benign proliferative lesions to frank malignancies (Table 1), but most importantly invasive cribriform PCa and cribriform HGPIN.
Cribriform High-grade Prostatic Intraepithelial Neoplasia
The distinction between isolated IDC-P from cribriform HGPIN in prostate biopsy is the most important differential diagnosis as management for these 2 conditions is drastically different. The pathologic features that distinguish IDC-P and cribriform HGPIN are summarized in Tables 2 and 3. Both HGPIN and IDC-P contain cytologically atypical or malignant cells within prostatic glands, although the architectural and cytologic atypia is usually more pronounced in IDC-P. The presence of many large glands with branching contour, dense cribriform or solid architecture, pleomorphic nuclei or nuclei 6× the size of adjacent nuclei, and intraluminal necrosis reliably suggest IDC-P over cribriform HGPIN, but these features may not always be present and both lesions may overlap at the “low-grade” spectrum. Therefore, any cribriform or lumen-spanning atypical lesion containing basal cells may represent IDC-P, and its presence in prostate needle biopsy merits aggressive work-up (Fig. 4).
Molecular markers, such as ERG gene rearrangement, may help the work-up of ACL without concurrent invasive PCa on the biopsy.1 The presence of ERG rearrangement would suggest that the presence of adjacent carcinoma that was not sampled as ERG rearrangement in isolated HGPIN without concurrent invasive carcinoma has not been reported. We propose a diagnostic approach to isolated atypical lesion with cribriform or solid architecture containing basal cells in needle biopsy using morphologic, immunohistochemical and genetic features (Fig. 5).
Invasive Cribriform Acinar Adenocarcinoma of Prostate
Invasive cribriform acinar adenocarcinoma (Gleason pattern 4 or 5 if comedonecrosis is present) closely mimics cribriform IDC-P. Invasive cribriform cancer, unlike IDC-P, lacks a basal cell lining. In some cases, the contour and branching pattern of normal duct architecture distinguishes IDC-P from infiltrating cribriform acinar adenocarcinoma. Cribriform carcinoma often has glandular confluence, which is lacking in IDC-P. The distinction between invasive high-grade PCa and IDC-P, though, is not critical, as IDC-P is almost always associated with a high-grade and high-volume PCa. Some studies, however, suggest the importance of documentation of IDC-P even when associated with invasive high-grade carcinoma as it is associated with a higher risk of an accelerated disease progression.6,36
Ductal Adenocarcinoma of the Prostate
Ductal adenocarcinoma is an aggressive form of PCa. It can originate in and grow within and expand the prostatic urethra and periurethral ducts. Most commonly, it is a component of an aggressive acinar PCa. Histologically it is defined by tall pseudostratified columnar epithelium arranged in cribriform patterns with slit-like spaces and/or true papillary fronds. The papillae in ductal adenocarcinoma have true fibrovascular cores, and the cells may show significant nuclear atypia with a high mitotic rate and extensive necrosis. Nuclei are large, mostly elongated or oval, and often contain a single macronucleolus. In contrast, IDC-P has cuboidal cells, cribriform pattern with rounded lumina, and micropapillary tufting without fibrovascular cores.
Similar to other high-grade and high-volume PCa, ductal adenocarcinoma is also prone to intraductal spread. Residual basal cells are therefore often demonstrated in ductal PCa.37
Intraductal Spread of Urothelial and Colorectal Carcinoma
Intraductal spread of urothelial carcinoma (from a bladder primary, or exceedingly rarely, from a prostate primary) or of colorectal carcinoma may mimic IDC-P. Morphologic features of the tumor cells often yield diagnostic clues. For example, cytologically, urothelial carcinoma is typically more pleomorphic than IDC-P, and it often has a dense pink, “hard” cytoplasmic quality. Mucinous differentiation is often seen in metastatic colorectal adenocarcinoma. A panel of immunostains is often needed to resolve the diagnostic ambiguity. IDC-P stains positive for prostate-specific markers, including PSA, PSAP, PSMA, and P501S, whereas stains for basal cells, such as CK5/6, 34βE12, and p63, are positive only in the basal cells at the periphery of the cancer glands. In contrast, urothelial carcinoma is negative for prostate-specific markers and positive for markers that recognize the prostate basal cells (cytokeratins 34βE12 and p63) (Fig. 3). Colorectal adenocarcinoma is usually positive for CDX-2.
CLINICAL SIGNIFICANCE OF IDC-P
Since the initial studies by Kovi et al10 and McNeal and Yemoto,9 several other studies have investigated IDC-P in RP and found consistently that the presence of IDC-P correlated with other adverse pathologic features, including a higher Gleason score, larger tumor volume, and greater probability of extraprostatic extension, seminal vesicle invasion, and pelvic lymph node metastasis. It also correlated with decreased progression-free survival and postsurgical biochemical recurrence.2,7,11,12,16
IDC-P in needle biopsy is uncommon. In our experience from a prospectively collected 1176 biopsies, the overall incidence of IDC-P was 2.8% and even rarer (0.26%) for isolated IDC-P without associated invasive adenocarcinoma.38 However, IDC-P in prostate biopsy seems to provide prognostic values in addition to other histologic parameters such as Gleason score and tumor volume. Cohen et al6 studied a series of RP with matching preoperative needle biopsies and found that the inclusion of IDC-P in prostate biopsies in a preoperative model could improve the prediction of pathologic stage of RP specimens. Furthermore, the presence of IDC-P on biopsy correlated strongly with biochemical failure. These findings suggest that IDC-P identified in prostate biopsy is a very powerful parameter that counteracts the predictive values of other commonly used clinicopathologic parameters, including serum PSA and biopsy Gleason score. Similarly, a recent study by O’Brien et al36 also found that inclusion of several new pathologic variables including IDC-P significantly improved the predictive accuracy of a postoperative nomogram that used preoperative clinicopathologic variables to predict PSA recurrence after RP. These studies strongly suggest that the presence of IDC-P in prostate biopsies should be reported even when it is associated with an extensive and high-grade PCa, as it may provide additional prognostic information.
Only a few studies have examined the significance of IDC-P as a sole finding in a needle biopsy setting. Guo and Epstein14 initially reported a small series of cases of IDC-P without invasive carcinoma on biopsy, and more recently Robinson and Epstein15 updated and expanded this series to include a total of 66 patients. Both studies found that the presence of IDC-P, even in the absence of documented invasive carcinoma, was associated with an aggressive clinical course. In the more contemporary of the 2 studies,15 8 of 66 (12%) patients developed disease progression after definitive treatment, including 4 patients with distant metastasis at a mean of 22 months after diagnosis, and another 4 patients with PSA recurrence at a mean of only 8 months after definitive therapy. Furthermore, in patients who underwent RP, all PCas had a Gleason score ≥7, and nearly half of the cases contained some Gleason pattern 5 components. Tumors were also of relatively high volume (mean: 2.85 cm3). Eight of 21 men (38%) had extraprostatic extension (pT3a), and another 3 (14%) had seminal vesicle invasion (pT3b). Nodal metastasis was seen in 1 (5%) of the men. Interestingly, 2 patients (10%) had IDC-P only at RP without an invasive PCa component. This latter finding suggests that IDC-P does not always represent intraductal spread of an invasive high-grade carcinoma. On the basis of their studies of needle biopsy with isolated IDC-P, and previous studies in the literature that demonstrated consistent association of IDC-P at RP with multiple adverse prognostic factors, Robinson and Epstein15 recommend definitive therapy in men with IDC-P on needle biopsy even in the absence of pathologically documented invasive PCa.
A DIAGNOSTIC APPROACH TO ATYPICAL CRIBRIFORM LESIONS IN PROSTATE NEEDLE BIOPSY
A practical approach to the work-up of an atypical cribriform prostate lesion is shown in Figure 5. When the prostate biopsy contains glands with lumen-spanning, cytologically malignant cells, one should first consider and rule out metastatic colorectal or urothelial carcinoma. History and morphology often yield clues but immunostains may be required to establish a definitive diagnosis. If the lesion is deemed to be of prostatic origin, one should then rule out cribriform carcinoma by determining whether basal cells are present, either by morphologic examination or immunostains for basal cells. If ACLs have basal cells and have one of the following morphologic features, including multiple (>6) ACLs, complex architecture (branching, dense cribriform, or solid), comedonecrosis, and marked nuclear pleomorphism, the diagnosis is IDC-P. If, however, there is a single or several (<6) ACLs with a round contour, simple architecture, and uniform nuclei, one cannot reliably distinguish between IDC-P and cribriform HGPIN, and such a lesion should be classified as “atypical cribriform lesion, cannot rule out IDC-P.” ERG gene fusion status will be of help in these cases. If ERG gene fusion is present, the ACL lesions should be diagnosed as IDC-P.
REPORTING RECOMMENDATIONS FOR ATYPICAL CRIBRIFORM LESIONS
The reporting recommendation for ACLs, including cribriform HGPIN and IDC-P, is shown in Table 4. Cribriform HGPIN should still be reported, even though the cancer risk associated with HGPIN has declined and is only slightly higher than that associated with a benign diagnosis. The morphologic subtypes of HGPIN do not need to be specified, as they do not confer different cancer risks. One should, however, document the number of biopsy cores involved by HGPIN, as multifocal (involving 2 or more biopsy cores) HGPIN is associated with a significantly higher cancer risk in subsequent biopsy than unifocal HGPIN.4
IDC-P should be reported in prostate biopsy reports because of its frequent association with high-grade and high-volume PCa and adverse prognostic significance.
In the majority of cases, IDC-P is present with an invasive, high–Gleason grade PCa. In these cases, reporting of IDC-P is of questionable value. However, we recommend reporting of IDC-P in these cases as IDC-P may provide additional prognostic information. IDC-P is rarely seen in biopsy with only Gleason pattern 3 PCa. In these cases, IDC-P can be regarded as and graded like invasive PCa (Gleason pattern 4 or 5, depending on whether solid and/or necrosis are present). Alternatively, one can grade only the invasive Gleason pattern 3 PCa and then mention in a comment the presence of IDC-P and its clinical significance.
Rarely, IDC-P is identified on prostate biopsy without a concomitant invasive PCa. It should be reported with a comment stating that IDC-P is almost always associated with a high-grade and high-volume PCa and that definitive therapy is indicated for these patients.14,39 However, some pathologists may still recommend immediate repeat biopsy instead of definitive therapy in these rare situations.
Finally, any ACL comprising cytologically atypical cells that do not satisfy the diagnostic criteria for IDC-P, but exceed the criteria for HGPIN (Fig. 4), should be reported on biopsy as “atypical cribriform lesion (ACLs)” with a recommendation for immediate repeat biopsy.
ACLs are prostate glands with cribriform or solid architecture populated with cytologically malignant cells with partial or complete basal cell lining. It represents either IDC-P or cribriform HGPIN. These 2 lesions have drastically different clinical significance. IDC-P is strongly associated with aggressive PCa with a high Gleason grade and large tumor volume, whereas cribriform HPGIN is a subtype of HGPIN whose cancer risk has significantly declined in recent studies. Therefore, it is critical for pathologists to distinguish these lesions in prostate specimens, especially in prostate biopsy, for patient management. Morphologic criteria have been proposed to distinguish IDC-P from several other lesions with similar histologic appearance such as HGPIN, invasive cribriform PCa, and urothelial carcinoma involving the prostate.
The authors thank Suzanne Ridner for editorial assistance.
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