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Advances in Anatomic Pathology:
doi: 10.1097/PAP.0b013e31825c6b92
Review Articles

Variants and Unusual Patterns of Prostate Cancer: Clinicopathologic and Differential Diagnostic Considerations

Fine, Samson W. MD

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Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY

The author has no funding or conflicts of interest to disclose.

Reprints: Samson W. Fine, MD, Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Room C505, New York, NY 10065 (e-mail:

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Beyond the typical acinar morphology observed in the majority of prostatic adenocarcinomas, a spectrum of morphologic variants and prostate cancer subtypes exists. These unusual entities may be classified as: (1) cancer morphologies arising by divergent differentiation of prostatic ductal, acinar, or basal cells and associated with unique clinical features and/or therapeutic approaches, and (2) histologies occurring in the context of usual prostatic adenocarcinoma that may result in diagnostic misinterpretation or difficulties in Gleason grade assignment, especially in limited samples. This article details a number of variants, with emphasis on diagnostic criteria, differential diagnoses, and clinical significance.

The aphorism, “common things occur commonly” is relevant to prostatic adenocarcinoma, as acinar architectural configurations will account for over 90% of the 242,000 prostate cancers (PCa) newly diagnosed in 2012.1 Although major educational efforts in PCa have focused on the identification, grading, and staging of the usual-type adenocarcinoma, a host of infrequent patterns exist. Because of their rarity, it is important for pathologists to be able to recognize, accurately diagnose, and when applicable, grade these tumors and understand their prognostic and therapeutic implications. In this manuscript, the most frequently encountered and clinically relevant subtypes are discussed. These include: ductal carcinoma, PCa with neuroendocrine (NE) differentiation, squamous cell carcinoma (SQCC), sarcomatoid carcinoma, basaloid carcinoma, mucinous (colloid) carcinoma, signet ring cell carcinoma, and atrophic, foamy gland, and pseudohyperplastic carcinomas. Gleason grading recommendations for these variants are summarized in Table 1.

Table 1
Table 1
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Historically termed “endometrioid” because of its nuclear stratification and a proposed origin from the prostatic utricle,2–6 it is now accepted that prostatic ductal adenocarcinoma (PDA) is a variant of adenocarcinoma with unique gross and microscopic features. Although pre–prostate-specific antigen (PSA) era studies reported an incidence of “pure” PDA in 0.4% to 1.3% of cases,3,4,7 foci of PDA are more typically admixed with usual acinar adenocarcinoma (PCa). Cystoscopically, these tumors show exuberant polypoid or villous intraurethral projections, grossly mimicking both benign and malignant lesions, such as prostatic urethral polyp and papillary urothelial carcinoma (UC).7,8 Early studies on patients with high-stage disease diagnosed on transurethral resection (TUR) specimens found an equal number of PDA with an obstructive, grossly infiltrative appearance.

Histologically, a spectrum of features has been ascribed to PDA, with 2 major architectural patterns—papillary and cribriform—being recognized.4 The former, presenting as large papillary masses within central (periurethral) ducts, has been termed “adenocarcinoma of primary ducts”7,9 or “Type A”5 (Fig. 1A), whereas multicentric growth of ducts with cribriforming/small papillary projections has been labeled “adenocarcinoma of secondary ducts”7,9 or “Type B”5 (Fig. 1B) due to its more peripheral location in the gland. In practice, however, these 2 patterns often merge10 and are characterized by either large papillary structures with fibrovascular cores lined by stratified tall columnar cells and/or complex glandular arrangements with closely apposed acini showing slit-like lumina and multilayered nuclei.2–4,6,11 A third, significantly less frequent, pattern of PDA consists of individual glands lined by tall pseudostratified columnar cells.4,12,13 The latter finding has been recently highlighted among a spectrum of PCas with nuclear stratification in single glands, so-called “prostatic intraepithelial neoplasia (PIN)-like” carcinoma, which is more frequently associated with the usual Gleason pattern 3 PCa and may behave in a more indolent manner when compared with classic PDA.12,13 A recent report detailed rare histologic features of PDA, including mucinous/goblet cell, foamy, micropapillary, and cystic papillary patterns.14 Regardless of the architecture, PDA typically displays enlarged, hyperchromatic nuclei with prominent nucleoli11 and is almost always seen with some component of usual PCa.

Figure 1
Figure 1
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The application of the Gleason grading system to ductal carcinoma has been controversial, with some reports initially advocating for not assigning a Gleason score (GS),15 whereas more recent publications assign scores of 3 (single glands with pseudostratified cells, ie, “PIN-like”), 4 (more complex papillary or cribriform architecture), and 5 (when comedonecrosis is present).3,13 Although no large-scale examination of the GSs of the acinar carcinomas associated with PDA has been attempted, empiric evidence suggests that this accompanying PCa component is more often of Gleason pattern 4 or 5. Studies that have examined pathologic outcomes in cases with PDA on either needle biopsy (NB) or radical prostatectomy (RP) have found that a high percentage of these cancers, akin to high-grade PCa counterparts,7,16 are associated with adverse features, including extraprostatic extension, seminal vesicle invasion, and margin positivity.8,17 Similarly, an early report of 15 radical prostatectomies with PDA found that 47% of these patients experienced biochemical recurrence within a period of 3 to 18 months.17 Finally, a recent study examining the impact of % PDA in RP specimens found that any quantity correlates with a higher rate of extraprostatic extension.18 These data, coupled with older reports of dismal survival3,5 and high metastatic rates,4 have led to the conclusion that classic PDA should be regarded as high-grade PCa.19 On a practical level, the International Society of Urologic Pathology (ISUP) conference on Gleason grading recommended reporting cases with classic PDA as Gleason pattern 4 with ductal features or alternatively, when seen in pure form, as PDA (GS 4+4=8).20

PDA metastasizes to similar sites as usual acinar carcinoma, including lymph nodes, bone, and lung,6,10,21 with some noting a higher incidence of visceral metastasis.22 Importantly, we have seen some especially challenging cases in clinical practice, in which diagnostic difficulty was engendered by predominant papillary growth in distant locations. Examples include metastasis to the lung mimicking primary papillary lung adenocarcinoma and metastasis to testis with spread along the rete testis closely simulating embryonal carcinoma. In such cases, immunohistochemistry (IHC), principally for PSA/prostatic acid phosphatase (PAP), may be utilized.

In routine settings, moderate to diffuse labeling with PSA and PAP is characteristic of PDA,3,4,6 whereas α-methylacyl-CoA racemase (AMACR) may be positive in up to 75% to 80% of cases, similar to usual high-grade PCa.23 Importantly, high–molecular weight cytokeratin (HMWCK) positivity—highlighting basal cells in ducts involved by PDA—has been reported in up to 30% of cases,6,23 emphasizing the “intraductal” growth in a significant proportion of PDA (Fig. 1B). Pathologists viewing PDA at the time of RP may have the benefit of observing both “intraductal” and overtly invasive components of this variant. However, distinction of PDA from high-grade PIN on NB when only an “intraductal” component is present may be difficult as these entities overlap in both architectural features and enlarged nucleoli coupled with a focally retained basal cell layer.8 Furthermore, papillary fronds of PDA may occasionally exhibit more bland cytology with elongated, banal-appearing nuclei lacking significant cytologic atypia,2,8,11 compounding the diagnostic challenge. Features that aid in distinguishing PDA from PIN on NB include: the presence of true papillary fronds (ie, with fibrovascular cores), evidence of invasion (such as stromal alteration or perineural invasion), and glandular crowding (all seen in PDA).8

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Focal Neuroendocrine Differentiation in Prostate Cancer

Around 30% to 100% of conventional PCas contain scattered NE cells,24–26 which resemble prostatic secretory cells on light microscopy, may express PSA/PAP, and label immunohistochemically for chromogranin and other NE markers.27,28 Whether this finding has prognostic importance is controversial, with some investigators reporting worse prognosis for cases with increased numbers of chromogranin-positive cells29–31 and others finding no independent effect on survival, due to a close association with increasing tumor grade.32–34 Likewise, in metastatic PCa, there is evidence of NE cells,35 which do not express androgen receptor (AR) 36–38 and may not be suppressed by androgen ablation.35 This has led to conjecture that NE cells possess the ability to “escape” usual hormonal therapy in advanced PCa. Whether increased NE differentiation in androgen-insensitive cases has prognostic significance is controversial, with some authors arguing that the degree of NE marker–positive cells depends on the mode of androgen deprivation.33,36,39

Occasionally, PCa may display NE cells with banal nuclei and cytoplasmic eosinophilic granules, resembling gastrointestinal tract Paneth cells.40,41 These may present as single cells, cords, or nests of tumor cells, architecturally reminiscent of Gleason pattern 5, yet displaying bland cytology and frequent association with lower-grade PCa.41 In one series, clinical progression in cases with Paneth cell-like–rich areas was associated with typical parameters such as high GS, extraprostatic extension and/or seminal vesicle invasion in the conventional PCa and not this particular NE finding. Diagnostically, it has been suggested that only the conventional PCa component be graded in this scenario, as applying Gleason grading to such foci may lead to inaccurate upgrading.41

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Prostatic Carcinoid

Although a fair number of cases have been termed “prostatic carcinoid tumor,”42–45 distinguishing this entity from the far more prevalent “carcinoid-like” adenocarcinomas (ie, usual PCa with architectural features suggesting NE differentiation and exhibiting at least focal NE differentiation by IHC) may be challenging.42 Especially in Gleason grade 4/5 tumors, these entities may share nested and microacinar/“rosette-like” patterns of growth with nuclear uniformity (Fig. 1C), PSA positivity, and immunohistochemical/ultrastructural evidence of NE differentiation.46 Hence, tumors with expression of both PSA and NE markers and/or histologically mixed prostatic “carcinoid” and conventional PCa are best considered “carcinoid-like” adenocarcinomas. This phenomenon may explain early reports of aggressive behavior for “prostatic carcinoids,”47 likely reflecting high-GS tumors with varying degrees of NE differentiation. Using these guidelines, tumors exhibiting typical carcinoid architecture and features, PSA negativity, and absence of admixed adenocarcinoma are exceedingly rare.48

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High-grade Neuroendocrine Carcinoma

Small cell carcinoma of the prostate (SmCC)49 may be a component of 1% to 5% of all prostatic malignancies50 and is a relatively common extrapulmonary site for SmCC.51 Unlike SmCC at other sites, prostatic SmCCs seldom manifest clinically evident hormone production.52 High-grade NE carcinoma of the prostate histologically resembles the spectrum of NE carcinoma described at other sites,53,54 with approximately one half of cases being composite tumors with conventional PCa.50 Furthermore, within the NE carcinoma component, tumors exhibit a range of morphology, from “classic” SmCC features, as seen in the lung, that is diffuse sheets of round blue hyperchromatic cells exhibiting nuclear molding, granular chromatin, inconspicuous nucleoli, scant cytoplasm, and frequent mitoses/apoptotic bodies to lesions with a large cell NE phenotype, including better-defined organoid, palisaded, or trabecular architecture and large cells with abundant cytoplasm and macronucleoli (Fig. 1D).55 Diagnostically, high-grade NE carcinoma should not be assigned a Gleason grade,20 and given its potential array of findings, we prefer the terminology of “small cell/neuroendocrine” as a descriptor on pathology reports. It should be noted that due to overlapping constellation of features, large cell NE carcinoma may be mistaken for GS 5+5=10 PCa, potentially leading to underdiagnosis.53

In assessing a high-grade NE carcinoma involving the prostate, one must exclude direct extension or metastasis from nonprostatic NE carcinoma, which, in addition to morphologic overlap, share immunohistochemical and ultrastructural similarities, including cytoplasmic chromogranin and synaptophysin positivity, “dot-like” cytokeratin (CK) positivity,56,57 and sparse intracytoplasmic membrane-bound dense core granules.57,58 Although initially proposed as a specific marker for pulmonary SmCC,59,60 thyroid transcription factor-1 has subsequently been demonstrated in up to three quarters of reported prostatic SmCC (Figs. 1E, F),60–62 limiting its utility in this differential diagnosis. Given these similarities, metastatic high-grade NE carcinoma (eg, from lung) secondarily involving the prostate must be excluded on clinical and radiologic grounds, taking into account the fact that solitary metastasis to a genitourinary site would be highly improbable. Regarding direct extension, approximately half of the SmCCs involving the bladder have an associated UC component. In difficult cases, the presence of usual PCa and/or immunopositivity for PSA/PAP may be helpful in distinguishing primary from secondary lesions.

A number of studies have reported the immunophenotype of SmCC and conventional PCa,62–64 finding strong labeling for PSA/PAP in most PCas, with at least focal expression in approximately 25% of SmCC and conversely, diffuse NE marker labeling in SmCC with substantially less staining in usual PCa.62,64 Although many authors maintain that malignant NE cells do not express AR,36–37 recent evidence suggests that focal AR staining may be seen in SmCC.62 The presence of admixed PCa in many high-grade NE carcinomas, coupled with evidence of cells that may coexpress PSA/PAP/AR and NE markers,53,54,62,64 strongly implicates evolution (divergent differentiation) of a subset of multipotent non-NE prostatic tumor cells as the derivation for prostatic high-grade NE carcinoma.53,63,65,66

Comparable to other sites, prostatic SmCC and large cell NE carcinoma present at advanced stage are often unresectable and display a high frequency of visceral metastases and abysmal survival.53,54,67,68 Nonetheless, accurate recognition and reporting of high-grade NE carcinoma is crucial, as this diagnosis provides medical oncologists with an additional therapeutic modality, that is cisplatin-based chemotherapy, for treating advanced prostatic disease, which is otherwise managed by androgen deprivation therapy (HT) alone. Although some modern series have suggested managing prostatic SmCC with a combination of HT and cisplatin-based therapies followed by consolidative surgery or radiotherapy,67–69 most current chemotherapy-treated patients tend to progress rapidly. Looking forward, novel, small-molecule therapeutic approaches developed for pulmonary high-grade NE carcinoma70 may be considered for similar-appearing tumors in the prostate. To this end, Yao et al62 have demonstrated high levels of labeling for CD56, bombesin/gastrin-releasing peptide, c-KIT, Bcl-2, and epidermal growth factor receptor in a small series of prostatic SmCC, suggesting future therapeutic targets.

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Four scenarios may lead to malignant squamous elements being present in the prostate: (a) primary “pure” SQCC; (b) PCa with a malignant squamous component; (c) UC with squamous differentiation arising from the prostatic urethra; and (d) UC with squamous differentiation of the urinary bladder growing into the prostate.71 Only the first 2 subgroups—pure SQCC and adenosquamous carcinoma—should truly be termed “prostatic SQCC.” As most reports of these entities and their subsequent outcomes involve cohorts with limited prostatic sampling, that is TUR or NB specimens, the distinction between “pure” and “mixed” SQCC may be artificial. It is clear, however, that this disease is highly uncommon, accounting for <1% of all prostatic tumors.71–74

Akin to other advanced prostatic disease, patients with SQCC present with obstructive urinary symptoms,74–76 yet often do not have elevated PSA. Multiple authors have noted that prostatic SQCC more commonly arises in the setting of prior radiation therapy (RT) or HT,74,76,77 with a typical history for this disease in a patient being a diagnosis of PCa, followed by treatment with RT and/or HT, and subsequent development of SQCC.76 Accordingly, some have asserted that adenosquamous PCa is simply adenocarcinoma with divergent differentiation secondary to RT/HT effects,71,78–80 a notion supported by other admixed morphologies (eg, sarcomatoid) in some cases.76 Hence, similar to other variants such as SmCC, prostatic SQCC most likely derives from pluripotent PCa cells capable of multidirectional differentiation. It should be noted that early investigators believed that SQCC of the prostate represented evolution from benign squamous metaplasia, either de novo or in the setting of prior HT.73 However, as opposed to squamous metaplasia, which may be present in up to 13% of benign untreated81 and 53% of lupron/flutamide-treated prostates,77 SQCC is extremely rare, making this association unlikely. In addition, 8-year follow-up of patients with squamous metaplasia has revealed no evidence of carcinoma.73

Before rendering a diagnosis of primary prostatic SQCC, 2 principal differential diagnostic considerations must be ruled out. The first is benign squamous metaplasia, secondary to prostatic infarct, prior HT, or inflammatory/reactive post-TUR change.73 This distinction is usually accomplished using Mott criteria for SQCC, which include nuclear anaplasia and irregular cellular architecture in the presence of keratinization, squamous pearls, and intercellular bridges, accompanied by disordered growth and evidence of invasion.72,77 Parwani et al76 have noted that a range of malignant findings (mild, moderate, or severe) may be present in prostatic SQCC, which may be especially relevant in biopsy material, in which distinguishing exuberant reactive changes from a well-differentiated SQCC with mild cellular atypia may be difficult.74 In that setting, clinical history (ie, HT), presence of inflammation/fibrosis, or conversely, the presence of adjacent PCa may be helpful in arriving at a final diagnosis.

Another common possibility that must be eliminated is secondary SQCC involving the prostate.72,73 Indeed, the majority of SQCC in the prostate is due to urothelial disease, either in the form of primary UC with squamous differentiation of the prostatic urethra or a similar tumor arising in the bladder and extending into the prostate.73,74,77 Although some authors have postulated that true prostatic SQCC may arise de novo or in association with schistosomiasis,82 given the suboptimal sampling of most reported prostatic SQCC (ie, no resection specimen available for study) it is highly likely that a significant proportion of “pure” SQCC cases without prior history of PCa and/or RT/HT actually represent UC with predominant squamous features. Therefore, clinically, urethral-based and vesical-based disease should be excluded and a careful search for accompanying PCa or conventional UC undertaken. Unfortunately, IHC, which may be a useful adjunct in other situations, is not helpful here, as SQCCs of any site label strongly with HMWCK, whereas PSA/PAP are usually negative or at best focally and weakly positive.74–76,83

Analogous to other divergent morphologies, prostatic SQCC is widely regarded as an aggressive disease. This contention is supported morphologically by its association with predominantly high-grade, acinar PCa with GS≥7 (Fig. 1G). Diagnostically, the squamous features should be noted and the adenocarcinoma component graded, except in the event of profound treatment (HT related) changes.76 These tumors often present with metastatic disease and specifically osteolytic bone involvement as opposed to the blastic lesions seen with usual PCa.74,75 From a therapeutic standpoint, radical surgical extirpation with negative margins will likely yield the most favorable outcomes,74 yet the advanced nature at presentation typically precludes this intervention. Moreover, the refractory nature of “pure” SQCC to HT, as indicated by an average survival of 12 months among 11 series,75 makes standard nonoperative therapies largely ineffective.74,75,77,84 In recent years, individual patients undergoing combined surgery or RT with cisplatin-based SQCC chemotherapeutic regimens and showing sustained 1.5- to 5-year progression-free periods have been reported85–87; however, despite these encouraging results there is currently insufficient evidence to comment on the chemotherapeutic efficacy and long-term prognosis for this disease.

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Sarcomatoid carcinoma refers to a spectrum of lesions with malignant epithelial (adenocarcinoma) and sarcoma-like components in which the latter represent multipotent cells with capacity for both epithelial and mesenchymal differentiation.88,89 This derivation is strongly supported by ultrastructural evidence of well-developed desmosomes—typical of epithelial cells—in spindled areas.88 Whereas in the past, some have distinguished “sarcomatoid carcinoma,” that is tumors with mixed adenocarcinoma and undifferentiated spindle cells, from “carcinosarcoma,” that is PCa cases with admixed heterologous elements,90 all such tumors are currently grouped together as sarcomatoid carcinoma, owing to their similar clinical features and outcomes.91

Sarcomatoid carcinomas typically occur in older patients, often present with locally expansile growth resulting in obstructive symptoms and have an antecedent history of PCa. Multiple investigators have noted an association with RT,92,93 including 19 of 21 patients with PCa who subsequently developed sarcomatoid carcinoma in 1 large series.94 Histologically, the adenocarcinoma is typically high grade, with nearly all reported cases having a GS≥7.92,94 The sarcomatoid component may display a variety of findings, from haphazardly arranged spindle cells and/or admixed pleomorphic giant cells and numerous mitoses (Fig. 1H) to more distinct sarcomatous proliferations, including osteosarcoma, chrondrosarcoma, rhabdosarcoma, and angiosarcoma. In terms of Gleason grading, the poorly differentiated nature of the spindle cell component qualifies as Gleason pattern 5, yet the report should also reflect the sarcomatoid features, for future diagnostic and prognostic implications. It is essential to recognize that IHC findings in the 2 components differ, with adenocarcinoma showing diffuse CK and PSA/PAP positivity and the sarcomatoid elements exhibiting more focal CK positivity and rare PSA/PAP labeling.88,92,94

When both the epithelial and mesenchymal portions of sarcomatoid carcinoma are visualized at the microscopic level, the main differential diagnostic consideration is with phyllodes tumor, a form of prostatic stromal sarcoma displaying overtly malignant spindle cell elements, albeit with benign admixed prostatic glands showing typical “leaf-like” architecture. Identification of the latter should enable the pathologist to accurately distinguish these 2 entities. A potentially more challenging situation involves tumors with sarcomatoid elements alone, either due to partial sampling or due to overgrowth of the sarcomatoid component in the setting of recurrent disease. In the absence of biphasic morphology, true prostatic sarcomas and pseudosarcomatous lesions such as leiomyosarcoma and inflammatory myofibroblastic tumor must be excluded. In this setting, correct interpretation of CK labeling represents an additional diagnostic pitfall, as focal positivity may also be observed in all of these lesions.94 The optimal diagnostic approach combines characteristic morphologic features and classic IHC labeling, that is fascicular growth of malignant spindle cells, necrosis, and diffuse muscle marker immunopositivity (leiomyosarcoma) or pleomorphic spindle cells in a myxoid background and ALK positivity (inflammatory myofibroblastic tumor).95

All significant studies of sarcomatoid carcinoma have reported a poor prognosis independent of the presence of heterologous elements. Frequent local recurrence manifested as bulky disease involving the urinary bladder and penis, as well as metastases to bone, liver, and lung, has been observed.94 Sampling of sarcomatoid carcinoma at distant sites may yield either the epithelial or sarcomatoid component exclusively or an admixture of both. Sarcomatoid carcinoma is associated with early death from disease,92,96 with 1 large study showing 18 of 21 patients dead at a median of 9.5 months.93 Among 8 patients treated with chemotherapy in another series, 3 patients died within 1 year, whereas the remaining 5 showed no response.94

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Multilayering of basal cells is the hallmark of a continuum of prostatic lesions ranging from benign usual basal cell hyperplasia (BCH) to carcinomas with a basal cell phenotype.97 Most investigators recognize malignant “basaloid” neoplasms, which include tumors classified as either basal cell or adenoid cystic carcinoma.97–99 Clinically, these carcinomas rarely demonstrate elevated PSA and are commonly diagnosed on TUR secondary to presentation with obstructive symptoms.99,100 Although limited case numbers within published series have given a precise definition of malignant features, elusive, haphazard infiltrative growth, perineural invasion, extraprostatic extension—with the bladder neck as a preferred site—and the presence of necrosis are widely accepted features.97,99,101–103

Histologically, it is thought that basaloid carcinomas of the prostate originate from basal/reserve cells rather than acinar/secretory cells involved in usual PCa,104 and hence, the Gleason system should not be applied to these tumors. Basaloid carcinomas may be characterized by varying extents of 3 main morphologic patterns: (1) basal cell carcinoma pattern (Fig. 2A)—composed of small to large nests, islands, or cords with peripheral palisading, architecturally similar to that seen in cutaneous basal cell carcinoma, in which marked cytologic atypia and high mitotic counts are frequent and larger nests may show central necrosis; (2) adenoid cystic carcinoma pattern (Fig. 2B)—replete with the cribriform nests and intraluminal basal lamina-like material/mucin seen in salivary gland tumors of the same designation; (3) tumors resembling BCH, that is single, rounded, solid nests with occasional central lumen formation, yet displaying extensive infiltrative growth and extraprostatic extension. Another cardinal feature present in many basaloid carcinomas is prominent desmoplastic or myxoid stroma.97,99 All basal cell lesions of the prostate share immunopositivity for HMWCK, often with a peripheral pattern, which spares the innermost cell layers.97,98

Figure 2
Figure 2
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Given the distinctive appearance of basaloid carcinomas in the prostate, the main differential diagnoses are primary benign or atypical basal cell proliferations. Lesions such as: (a) florid usual BCH; (b) atypical BCH, that is those cases with classic BCH architecture, yet showing nuclear enlargement, prominent nucleoli, and rare mitoses97,105; (c) basaloid adenoma; and (d) cribriforming BCH, subsuming such entities previously classified as “adenoid cystic tumor,”106 “adenoid basal cell tumor,”98,105 “adenoid cystic-like tumor,”107 and “adenoid cystic-like hyperplasia”102 may fall within this spectrum. In resolving challenging cases, it is important to recognize that florid BCH with or without nuclear atypia may represent a localized process arising among benign or hyperplastic prostatic glands, giving the impression of an infiltrative process.99 Furthermore, although some adenoid cystic-like proliferations may be multifocal and/or exhibit focal cribriform architecture, they typically show well-defined lobulated growth and lack the confluent, expansile cribriform architecture or widely irregular infiltrative patterns of basaloid carcinomas.102 Beyond assessment of architectural (infiltrative growth, perineural invasion, extraprostatic extension) and cytologic features, Yang and colleagues have reported that IHC for Bcl-2 and Ki67 may be used as an ancillary tool to distinguish florid BCH from basaloid carcinoma. Unlike usual PCa and BCH, in which Bcl-2 staining is absent or is focal/weak, basaloid carcinomas often demonstrate diffuse Bcl-2 positivity. In a similar vein, the proliferative rate for basaloid carcinomas is often significantly higher than that of BCH.108

The small number of cases, lack of long-term follow-up, and significant differences in terminology among published series preclude definitive comment on the natural history of basaloid carcinomas. Nonetheless, it is evident that these tumors may behave in a locally aggressive (eg, bladder neck invasion; penile urethra) and, more rarely, systemically aggressive manner, with metastases to liver, lung, bowel, and bone.99,101,108 Given this potential, complete removal of the prostate with negative surgical margins is likely the best curative option for these patients.

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Mucin secretion within nondilated glands is a feature of between 60% and 90% of all PCas109 and may be useful in its detection and diagnosis. PCa displaying copious mucin that alters glandular or tumor architecture are significantly more infrequent comprising 0.4% of PCa in the largest published series.110–112 Contemporary authors have applied strict criteria for diagnosing mucinous (colloid) carcinoma: (a) ≥25% of the resected tumor should be composed of tumor cells/glands floating in extracellular mucin lakes or pools; (b) markedly distended glands filled with mucin (mucinous cysts) may be seen; and (c) extraprostatic mucinous carcinoma, that is from the colon, bladder, prostatic urethra, or Cowper gland, must be excluded.110,113 From these guidelines, it is evident that this is an RP diagnosis, as NB specimens are insufficient for evaluating overall percentage of the mucinous component. By convention, therefore, NB demonstrating PCa with extracellular mucin should be reported as PCa with mucinous features.

Grossly, a glistening cut surface may be identified, depending on the extent of colloid features. Within the context of the microscopic features described above, small tubules, cords, or cribriform glands of PCa, cytologically identical to the invariably adjacent nonmucinous PCa, are observed within the abundant mucin.110,111 A recent study has highlighted an association in two third of the cases with mucinous fibroplasia/collagenous micronodules, a diagnostic feature of PCa.114,115 Conversely, signet ring cells, commonly seen in colloid carcinomas at other sites, are rarely, if ever, identified in mucinous carcinomas of the prostate.110,111,115 Periodic-acid-Schiff and Alcian blue stains have highlighted neutral or acidic mucin in the extracellular component109 but not in the floating tumor cells.111

As early studies of this entity are from the pre-PSA era in which advanced disease was common, mucinous carcinoma was typically associated with accompanying nonmucinous PCa with Gleason patterns 4 or 5, often in the form of cribriform glands and/or comedonecrosis.110,111 However, in the past 15 years, pathologists have increasingly recognized that some mucinous carcinomas contain discrete and well-formed glands in both the mucinous (Fig. 2C) and nonmucinous components.115 This dichotomy is reflected in the ISUP conference report on Gleason grading in which no consensus could be achieved among expert urologic pathologists, with one half considering colloid carcinoma GS 4+4=8 and the remaining group opting to ignore the extracellular mucin and assess the architecture alone.20

Stage migration of PCa has also affected reporting of outcomes for mucinous carcinoma. Although initial research showed hormone refractory, advanced tumors with markedly elevated PSA at presentation and accompanying high incidence of metastasis (to usual sites) and death from disease,110,116 more contemporary work has asserted that this variant should be treated similarly to usual PCa.111,117–119 Most recently, Lane et al112 and Osunkoya et al115 have reported no death from disease in 14 and 47 patients, respectively, who had mucinous carcinoma and were treated by RP, with a median follow-up of 6 years. The latter series revealed 20/47 patients with extraprostatic extension and 1 case with lymph node metastasis; however, only 1 biochemical recurrence was reported 3 years after RP without clinical evidence of local or distant recurrence.115 These encouraging results suggest that architectural configuration, rather than the presence of extracellular mucin, should determine Gleason grading in these tumors.

Eliminating the possibility of secondary colonic-type colloid carcinomas, arising in the colon, bladder, or prostatic urethra, is a necessary component in the work-up of mucinous prostatic lesions.113 Unlike prostatic mucinous carcinoma, colonic-type lesions are histologically characterized by mucin pools lined by tall, columnar, and occasionally stratified cells with varying degrees of nuclear atypia. They may exhibit papillary growth and signet ring cells and are not associated with usual PCa.110,111,115 When they arise in the prostatic urethra or bladder, they may be associated with colonic metaplasia, villous adenoma, or in situ UC elements,120 typical of urothelial-derived adenocarcinoma. Clinical evaluation with cystoscopy and/or colonoscopy may resolve this dilemma. However, in difficult cases, diffuse, strong staining for PSA/PAP and negative labeling for carcinoembryonic antigen111 and CDX-2115 may be utilized as an adjunct. As opposed to nuclear localization in colonic adenocarcinoma, β-catenin expression in the cytoplasm of PCa, if present, may be another useful marker.121 A final consideration, highly dependent on clinical history, is changes in prostatic stroma of patients treated with RT/HT. Among other findings, these prostates may contain acellular mucin pools, which should not be confused with mucinous adenocarcinoma.122

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Signet ring cell carcinoma of the prostate, defined by diffusely infiltrative sheets and/or cords of cells with a displaced round to ovoid hyperchromatic nucleus, is exceptionally uncommon. Previous authors have adopted varying extents of signet ring morphology as a requirement for this diagnosis, ranging from ≥25% to ≥50%.123–126 Much more frequently, signet ring cells may be seen focally within otherwise high-grade PCa and should be considered Gleason pattern 5. In either instance, GSs of 9 or 10 are typical and are usually associated with high stage, early spread to bones (Fig. 2D) and viscera, and poor outcomes. The largest series to date has shown a 3-year survival of <30% among 17 cases.127

Even in examples with a large extent of signet ring cells, some confusion exists regarding the definition of this entity, on the basis of 3 main considerations: (1) classic signet ring cell carcinoma, as seen in the gastrointestinal tract, associated with detectable mucin production, represent a minority of prostatic signet ring carcinomas123,125,128,129 as most are negative for mucin stains124,127,130 and reveal intracytoplasmic lumina or empty vacuoles at the ultrastructural level; (2) PSA/PAP labeling, a hallmark of tumors of prostatic origin, has not been detected in up to one half of well-documented prostatic signet ring cell carcinomas124,128,129,131; (3) the rare occurrence of prostatic adenocarcinoma with abundant mucin and associated signet ring cells127,132 has been reported as “signet ring cell” carcinoma, but is more appropriately designated as mucinous (colloid) carcinoma as previously discussed. Nonetheless, after ruling out metastasis (stomach, colon) and direct extension (bladder, prostatic urethra) from more prevalent signet ring carcinomas, it seems reasonable to consider cells with this morphology as “signet ring-like” cells, whether or not they contain mucin, as available evidence implicates these cells as a manifestation of high-grade disease, and it is well known that high-grade PCa may be negative for PSA/PAP.133

There are 2 additional primary prostatic findings that may result in cells mimicking signet ring carcinoma. The first is signet ring-like changes in lymphocytes or stromal cells, typically seen as a reactive change.134,135 Although these are readily distinguishable from cytologically malignant cells, IHC for PSA/PAP and a histiocyte marker, such as CD68, may resolve this dilemma in limited material. PCa glands that have been exposed to HT may exhibit loss of glandular architecture and cytoplasmic vacuolization136 simulating signet ring cells. In these cases, relevant clinical history, the pyknotic nuclei characteristic of androgen-deprived PCa, and ancillary findings such as squamous metaplasia should aid in their distinction.

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Benign atrophy is a frequent mimic of PCa because of its small acinar architecture and basophilic low-power appearance. Conversely, moderate to abundant, dark (amphophilic, eosinophilic, basophilic) cytoplasm, considered a cardinal feature of conventional PCa, is not present in 3% to 7% of malignant foci.137,138 The flattened epithelium and resulting high nuclear to cytoplasmic ratio seen in such cases (Fig. 2E) create significant morphologic overlap between these atrophic cancers and benign atrophy/postatrophic hyperplasia.138 As benign atrophy is especially common in the peripheral zone, this diagnostic dilemma may be heightened by limited material present in NB specimens. Hence, this pattern of PCa, which is more easily distinguished from benign atrophy on RP on the basis of its invariable infiltration between benign acini, often requires convincing cytologic evidence of malignancy (ie, enlarged nuclei and nucleoli) and recognition of adjacent nonatrophic PCa to render a cancer diagnosis on NB. It is especially important to discern features such as associated inflammation and fibrosis that may lead to reactive atypia in benign atrophy.137,138 Negative IHC labeling for HMWCK may be integral to establishing a diagnosis in examples lacking ideal nuclear features,137 whereas AMACR staining may be a useful adjunct in up to 70% of the cases.139 Although these markers may lend support in suspicious foci, caution is urged in interpretation of negative HMWCK staining of a few glands, as even limited quantities of benign glands may not react uniformly.137

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The foamy gland pattern of PCa is characterized by acini lined with abundant foamy, reticulated cytoplasm, small pyknotic-appearing nuclei, absence of prominent nucleoli, and, in approximately 50% of the cases, amorphous pink secretions.140 A foamy gland component was seen in up to 15% to 23% of RP cases in a recent large series.141 Although the initial report of this entity described “xanthomatous” cytoplasm, subsequent work has shown that foamy gland cancer contains numerous empty cytoplasmic vacuoles at the ultrastructural level.142 Histochemical staining has confirmed the absence of mucin, glycogen, or lipid in these cells.140,142 With regard to diagnosis, it is generally agreed that the architecture of the foamy glands should be assessed and assigned a GS, whereas the cytoplasmic and nuclear features should be ignored. Hence, aggressive PCa with a foamy gland pattern may exist, with GS≥7 in up to two third of the cases,141 and extraprostatic extension, lymph node metastasis, and biochemical recurrence rates similar to those in its nonfoamy PCa counterpart.140–142

The absence of classic nuclear and cytoplasmic attributes of PCa in foamy gland cancer may lead to diagnostic confusion, principally with benign entities such as adenosis, mucin cell metaplasia, Cowper gland, and prostatic xanthoma.143 However, this quandary is reserved for foci seen on NB (Fig. 2F), as the permeative growth pattern of foamy gland cancer and common association with nonfoamy PCa is more overt in resection specimens. Nonetheless, even on NB, one should recognize the lobulated architecture seen in adenosis/Cowper gland, corpora amylacea in adenosis, and Cowper gland ducts as opposed to the infiltrative nature and dense pink secretions of foamy gland carcinoma. Likewise, mucin cell metaplasia is a focal phenomenon, not involving entire glands, and labels strongly with mucin stains.140,142 In challenging cases, IHC may be used, as foamy gland cancer will be HMWCK negative and, in approximately 65% of cases, AMACR positive, as opposed to its benign mimics.140,144 It should be noted that AMACR staining alone may be heterogeneous in unusual patterns of PCa and tends to label less intensively than usual acinar adenocarcinoma.144

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In 1934, Muir145 noted that well-differentiated PCa may occasionally mimic benign prostatic hyperplasia (BPH). Tumors exhibiting large gland formations with either cystic dilatation, luminal undulation, and/or complex branching are now termed “pseudohyperplastic,” with a reported incidence of 11% in RP and 2% in NB specimens.146 As opposed to atrophic and foamy gland carcinomas, which cause diagnostic difficulty due to lack of malignant cytologic features, it is the deceptively benign-appearing architecture of individual pseudohyperplastic cancer glands (Fig. 2G) that makes distinction from benign prostatic glands challenging, as these banal glandular patterns tend to belie malignant cytologic features, namely, nucleomegaly and nucleolomegaly. Recently, a subset of these tumors characterized by cystic dilatation/diminished cytoplasm and termed “microcystic” carcinoma, have been described.147 These tumors may mimic cystic atrophy and BPH, yet share the malignant cytologic features of pseudohyperplastic carcinoma. Like usual acinar PCa, many examples of pseudohyperplastic cancer demonstrate dense eosinophilic secretions and/or intraluminal crystalloids that may aid in its diagnosis148 but may also occasionally contain corpora amylacea.

Distinguishing pseudohyperplastic cancer from BPH may be problematic in both the RP and NB settings. In RP, the potential for pseudohyperplastic glands to exhibit nodular (transition zone) or clustered growth (peripheral zone) coupled with clear cytoplasm and basally oriented nuclei may lead to confusion with BPH.146,148,149 Identifying the markedly crowded nature of these glands, absence of characteristic dense BPH stroma, and overtly malignant nuclei should facilitate recognition. As with all forms of prostatic carcinoma, infiltration between obviously benign glands and transitions to more typical acinar PCa will be most helpful. Likewise, the limited material in NB specimens may hinder an accurate diagnosis of pseudohyperplastic cancer, which may present as a localized collection of cystically dilated glands (ie, microcystic carcinoma) or large glands with multiple infoldings that are easily mistaken for usual epithelial hyperplasia.146–148 A prior study has found that only one quarter of pseudohyperplastic cancers on NB demonstrates infiltrative growth and that these tumors are best recognized by their crowded nature and enlarged nuclei.148 Given the potential for overdiagnosis and underdiagnosis of pseudohyperplastic carcinoma on NB, it is prudent to utilize adjunctive IHC stains to support one’s diagnosis. Specifically, the absence of HMWCK (Fig. 2H) or other basal cell markers,146 as well as positive staining for AMACR in 75% to 80% of cases,144,150 may be utilized.

Regarding Gleason grading of pseudohyperplastic foci, it is intriguing to note that included in the spectrum of “clear cell carcinoma,” a pattern described by McNeal et al,151 demonstrating well-differentiated glands of variable size and contour, composed of tall columnar cells with clear to pale pink cytoplasm, basally oriented nuclei with prominent nucleoli, and occasional eosinophilic luminal secretions, were cancers composed of large caliber glands, often arranged in circumscribed nodular masses, closely resembling benign glands of BPH. Subsequent studies and images of this histology revealed closely packed glands with papillary infoldings and branching and/or straight luminal borders lined by a single layer of basally oriented enlarged nuclei often with prominent nucleoli.152–154 Although early reports viewed these “pseudohyperplastic” carcinomas as low grade (Gleason patterns 1 to 2) and of transition zone origin, contemporary studies have established that these cancers are nearly always in continuity with usual Gleason pattern 3 small acinar adenocarcinoma and are evenly distributed between transition and peripheral zones. Furthermore, pseudohyperplastic cancers may be associated with foci of Gleason pattern 4, extraprostatic extension, and, rarely, seminal vesicle invasion.146,148 These developments have led the ISUP conference on Gleason grading to designate individual pseudohyperplastic cancer glands as Gleason pattern 3, rather than as lower grade.20

In summary, a fair number of PCa variants and unusual patterns exist. Although some of these entities are relatively rare, it is important to recognize their morphologic features, to ensure accurate diagnosis and, for certain variants, appropriate therapeutic intervention.

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International Journal of Immunopathology and Pharmacology
Expression of Cd7, Cd20 and Cdx-2 in A Secondary Signet-Ring Cell Tumor of the Prostate: A Case Report
Cimino, S; Russo, GI; Favilla, V; Fragala, E; Collura, Z; Zanghi, A; Castelli, T; Madonia, M; Morgia, G
International Journal of Immunopathology and Pharmacology, 26(1): 269-272.

Back to Top | Article Outline

prostate; variant; pattern; ductal; neuroendocrine; squamous; mucinous; foamy pseudohyperplastic; intraductal

© 2012 Lippincott Williams & Wilkins, Inc.


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