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A retrospective analysis of 111 canine prostatic samples: histopathological findings and classification

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The purpose of this retrospective study is to evaluate the frequency and further characterize the pathological features of common and uncommon histological lesions in 111 canine prostatic samples. Benign prostatic hyperplasia, suppurative and
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  A retrospective analysis of 111 canine prostatic samples:Histopathological findings and classification C. Palmieri  a, *, F.Z. Lean  a , S.H. Akter  a , S. Romussi  b , V. Grieco  b a School of Veterinary Science, The University of Queensland, Gatton Campus, Gatton, Queensland 4343, Australia b Department of Veterinary Science and Public Health, Universita’ degli Studi di Milano, via Celoria 10, Milan 20133, Italy A R T I C L E I N F O  Article history: Received 16 August 2014Accepted 6 November 2014 Keywords: ProstateHistologyClassificationDog A B S T R A C T The purpose of this retrospective study is to evaluate the frequency and further characterize the patho-logical features of common and uncommon histological lesions in 111 canine prostatic samples. Benignprostatic hyperplasia, suppurative and non-suppurative prostatitis, and prostate cancer were observedindividually or in combination in 45, 11, 68 and 50 samples, respectively. Six growth patterns of pros-taticcarcinomaweredifferentiated:papillary,cribriform,solid,smallacinar/ductal,signetring,mucinous.In a few cases, perineurial invasion and collagenous micronodules were observed. Lesions consideredpreneoplastic in men, such as high-grade prostatic intraepithelial neoplasia (HGPIN) and prostatic in-flammatory atrophy (PIA), were observed in 27 and 21 histological samples, respectively.This study represents a detailed characterization of the different histological subtypes of canine pros-tatecancer.Theawarenessoftheunusualpatternsmightbecriticalinavoidingdiagnosticmisinterpretation.The high prevalence of PIA and HGPIN underlines the reasonable chance of their detection in routinebiopsy specimens.© 2014 Elsevier Ltd. All rights reserved. 1. Introduction Dogshavebeenusedtostudybenignandmalignantdysregulationof prostate growth since the early 20th century. Benign prostatic hy-perplasia (BPH) is a spontaneous and age-related condition in menandintactmaledogs(StrandbergandBerry,1985),andthedogisone ofthefewotherspeciesinwhichspontaneousprostatecanceroccurs(Maini et al., 1997). Canineprostatecancerhasbeenreportedtoshowheterogeneityinits histopathology and divergent differentiation. The traditionally ac-ceptedclassificationmadebytheWorldHealthOrganizationincludestwomajortypesofcanineprostatecancer,adenocarcinomaandpoorlydifferentiated carcinoma, with the alveolar and acinar subtypes rec-ognized within the group of adenocarcinoma (Kennedy et al., 1998).In men, the histological patterns that prostatic adenocarcinoma canassumeareextensive(Humphrey,2012;Randolphetal.,1997),andfor mostofthemthearchitecturalpatternshavespecificclinico-pathologicalfeatureandprognosis(Aminetal.,2004).Indogs,severalstudieshavedescribedadditionalhistologicalsubtypesormixedmorphologies(Bellet al., 1991; Cornell et al., 2000; Lai et al., 2008; Waters et al., 1998), emphasizingthelackofapathologyconsensusoncanineprostatecancerclassification.The interpretation of a prostatic needle biopsy or tissue samplecollected during necropsy examination frequently represents achallenge to the pathologist, especially in those cases in which alow-grade lesion or non-specific histological findings are observed,and most veterinary pathologists are not aware of the potentialoccurrence of pre-neoplastic lesions whose role and importance incanineprostaticcarcinogenesisarestillunderinvestigation.Theso-calledhigh-gradeprostaticintraepithelialneoplasia(HGPIN),whichis believed to be a precursor of carcinoma in men (Bostwick, 1995),isalsofoundinthemajority(55%)ofelderlysexuallyintactmaledogswithout clinical evidence of prostate cancer (Waters and Bostwick,1997). Moreover, the vast majority of lesions containing chronic in-flammation in the prostate are associated with atrophic epitheliumor focal epithelial atrophy, and surprisingly an increased fraction of epithelial cells appear to be proliferating, therefore the term prolif-erativeinflammatoryatrophy(PIA)(DeMarzoetal.,1999).DeMarzo et al. (1999) have suggested that PIA may give rise to carcinomadirectly or indirectly via development into HGPIN.Therefore, the goals of this study are (a) to present the diagnostichistopathological features of the different conditions commonly oruncommonlyobservedinthecanineprostate,(b)toevaluatetherealfrequencyofpreneoplasticlesions,and(c)todescribethehistologicalvariantsof canineprostaticcarcinomasinordertoprovideacompre-hensive and consistent presentation of the different subtypes. * Correspondingauthor.SchoolofVeterinaryScience,TheUniversityofQueensland,GattonCampus,Gatton,Queensland4343,Australia.Tel.: + 61754601828;fax: + 00617 5460 1922. E-mail address:  c.palmieri@uq.edu.au (C. Palmieri).http://dx.doi.org/10.1016/j.rvsc.2014.11.0060034-5288/© 2014 Elsevier Ltd. All rights reserved.Research in Veterinary Science 97 (2014) 568–573 Contents lists available at ScienceDirect Research in Veterinary Science journal homepage: www.elsevier.com/locate/rvsc  2. Materials and methods  2.1. Specimens, clinical findings and histopathology Formalin-fixedparaffin-embeddedprostaticspecimensfrom111dogs were collected from the archives of the School of VeterinaryScience, The University of Queensland, Gatton Campus (Australia)(98outof111),andtheDepartmentofVeterinaryScienceandPublicHealth, The University of Milan (Italy) (13 out of 111). History, clin-ical signs and associated lesions were recorded where available.Specimens were represented by: a) biopsies (22 out of 111), b)tissuesexcisedduringlaparotomyorprostatectomy(15outof 111),c) tissues collected during necropsy of euthanized animals with asuspected prostate cancer on clinical examination, laparoscopy orlaparotomy(18outof 111),d)tissuescollectedduringnecropsyper-formed on euthanized dogs with a confirmed prostate cancer bybiopsyandhistopathology(7outof 111),e)tissuescollectedduringnecropsy of animals without any clinical suspicion of prostaticdisease (20 out of 111). In 29 out of 111 cases, no data on the typeof specimen were available.Five-micron-thick sections stained with hematoxylin and eosinwere prepared from each routinely processed paraffin wax-embedded tissue block if not available. The samples werehistologicallyclassifiedin:1)BPH;2)squamousmetaplasia;3)sup-purative and non-suppurative prostatitis; 4) HGPIN; 5) PIA; 6)prostatic carcinoma. The histological lesions observed in combina-tion on the same section were not classified as mixed lesions butthe frequency was considered separately for each lesion.The presence or absence of HGPIN and PIA was determined usingpreviously described criteria (De Marzo et al., 1999; Matsuzaki et al.,2010).Prostaticcarcinomadiagnosiswaslimitedtothosecasesshowingnoevidenceofurinarybladderinvolvement.Wheneverpossible,tissuesections from metastatic lesions were evaluated to confirm the pres-enceofmetastases.TheclassificationofprostaticcarcinomawasadaptedfromLaietal.(2008)andfromthehumanWHOclassificationofTumorsoftheUrinarySystemandMaleGenitalOrgans(Ebleetal.,2004).The key histological features of HGPIN, PIA and the different subtypes of prostatic carcinomas are summarized in Table 1.  2.2. Bacteriology Whereclinicallyindicated(suspectedprostatitis),resultsof bac-teriological examination were retrieved from the archive. Aerobicand anaerobic culture and further identification of bacterial iso-lateswereconductedusingastandardprotocol(Nielsenetal.,2013). 3. Results  3.1. Clinical findings and associated lesions BPH was clinically characterized by hematuria (6.7%), stranguria(2.2%) and abdominal pain (2.2%). In 17 dogs, testicular interstitialcell tumor (4 out of 17), perineal gland adenoma (3 out of 17), me-sothelioma(2outof 17),hemangiosarcoma(2outof 17),pulmonarycarcinoma (2 out of 17), Sertoli cell tumor, intestinal neuroendo-crine carcinoma, lymphatic leukemia and chemodectoma (1 case/each) were also diagnosed.The asymptomatic dog with prostatic squamous metaplasia wasalso affected by interstitial cell tumor and perianal gland adenoma.Suppurative prostatitis was associated with epididymitis (1 outof 11), urethral calculi (1 out of 11) and cystitis (1 out of 11).In prostatic carcinoma-affected dogs, the most common clini-cal signs referable to the urinary tract were dysuria (30% of cases),hematuria (14%), stranguria (14%), anuria (6%), and urinary incon-tinence (2%). Tenesmus due to prostatic enlargement was reportedin 22% of cases. Overall, signs referable to the involvement of themusculoskeletal system or spinal cord (hind limb weakness, lame-ness) were seen in 16% of dogs. Signs of systemic disease (anorexia,lethargy, dysorexia) were reported in 16% of dogs. Abdominal painand vomiting were described in 12% and 2% of cases, respectively.In 5 dogs, other concurrent extra-prostatic tumors were observedand, specifically, leiomyosarcoma of the gall bladder, leiomyoma of the colon, hemangiosarcoma, perineal gland adenoma and mixedtesticulartumor.Hydronephrosiswasreportedin4dogsandchronicinterstitial nephritis in one animal.Clinical signs observed in dogs affected by suppurative prosta-titis included dysuria (27.3%), anorexia (18.2%), lethargy (9.1%),abdominal pain on palpation (9.1%) and vomiting (9.1%).  3.2. Histopathology In 7 cases, the prostates were free from lesions, while the otherlesions (BPH, prostatitis, HGPIN, PIA, prostatic carcinoma) were ob-served individually or in variable combination in 104 samples. BPH(epithelial hyperplasia, cystic glandular acini and mild stromal fibro-sis)wasidentifiedin45cases.Thefrequencyof normalprostatesandhistological lesions observed in this study is summarized in Table 2.Eleven dogs were affected by moderate to severe suppurativeprostatitis characterized by the infiltration of moderate to highnumberof neutrophilsintheinterstitialtissueandwithintheglan-dular lumen, occasionally associated with mild epithelial celldegeneration. Non-suppurative prostatitis was the most commonhistological finding (68 out of 111 cases) with a prevalentlymphoplasmacytic (59 out of 68) or lympho-histiocytic inflam-matory infiltrate (9 out of 68). A diffuse squamous metaplasia of the prostatic glands with the affected epithelium converted to  Table 1 Key histological features of high-grade prostatic intraepithelial neoplasia (HGPIN),proliferative inflammatory atrophy (PIA) and prostatic carcinomas.HGPIN a Foci of proliferation of pre-existing ducts and aciniwith nuclear stratification, cellular crowding, mild tomoderate pleomorphism and nuclear and nucleolarenlargementPIA b •  Overall hyperchromatic appearance of theinvolved glands, occurring often as a discretefocus among normal-appearing glands •  Acini containing at least two layers of epithelialcells, with the luminal ones appearing asattenuated cuboidal cells •  In some lesions, atrophic acini so attenuated asto appear to have only one layer of flattenedepithelial cellsProstatic carcinoma c a.  Papillary  Dilated ducts containing papillary projections of neoplastic cells with occasional central necrosis(comedonecrosis)b.  Cribriform  Ducts extended by neoplastic cells forming irregularfenestrae, often accompanied with central necrosisc.  Solid(undifferentiated) Solid sheets, cord of cells or isolated individual cellslacking any specific histological growth patternd.  Small acinar/ductal  Variably sized small acini and tubules admixed withmoderate to high amount of fibro-muscular stromae.  Signet ring   Neoplastic cells arranged in sheets, small clustersor as single cells, and characterized by a clearcytoplasmic vacuole displacing the nucleus to oneside; signet ring cells made up over 25% of thetumor volumef.  Mucinous  Adenocarcinoma with at least 25% of the tumorcomposed of lakes of extracellular mucin, withexclusion of a non-prostatic srcin; tumor growthpatterns included cribriform, cords or strands,tubules a Matsuzaki et al. (2010). b De Marzo et al. (1999). c Lai et al. (2008), WHO Classification of Tumors: Pathology and Genetics of theUrinary System and Male Genital Organs (Eble et al., 2004). 569 C. Palmieri et al./Research in Veterinary Science 97 (2014) 568–573  stratified squamous from the surface of which squames were shedinto the lumen was diagnosed in one dog.PIA (Fig. 1a) and HGPIN (Fig. 1b) lesions were observed in 27 and21outof 111histologicalsamples,respectively.In11cases,PIAand HGPIN were identified in tissue biopsies. In 30 samples, PIAand HGPIN lesions were associated with lymphocytic aggregates.Canine prostate carcinoma (50 out of 111 cases) showed con-siderable morphologic heterogeneity. Thirty-one carcinomaswere characterized by a single histological growth pattern, whilea combination of different histological features within the samecross-section was observed in 19 out of 50 cases. The most com-mon single morphological patterns (31 cases out of 50) were smallacinar/ductal(12outof31cases)(Fig.2a),solid(8outof31)(Fig.2b), cribriform (8 out of 31) with comedonecrosis (Fig. 2c) in 5 cases,and papillary (3 out of 31) (Fig. 2d) with comedonecrosis in 2cases.Regarding the mixed morphologies of prostatic carcinoma (19cases out of 50), the following combinations were observed: crib-riformandpapillary(3),smallacinar/ductalandsolid(3),cribriformand solid (3), cribriform, small acinar/ductal and solid (3), smallacinar/ductalandpapillary(2),papillary,cribriformandsmallacinar/ductal(1),smallacinar/ductal,mucinous(Fig.2e)andsolid(1),smallacinar/ductal and cribriform (1), solid and signet ring (Fig. 2f ) (1),solid, papillary and signet ring (1). Overall, the most commonlyobserved growth patterns were the small acinar/ductal (21 out of 50 cases) and cribriform (17 out of 50 cases).Additional histological features observed in carcinoma speci-mens were:1 sarcomatoid transformation (11 out of 50 cases) in 7 solid,3 mixed and 1 papillary carcinomas: neoplastic cells with aspindle-like morphology and irregular or fascicular orienta-tion (Fig. 3a).2 signet ring cells (11 out of 50, excluding the primarysignet ring carcinoma) in 5 mixed, 3 solid and 3 cribriformcarcinomas.3 perineurial invasion (4 out of 50) in 3 mixed and 1 solid car-cinoma:tightcircumferentialornearcircumferentialencirclingof a nerve fiber by cancer glands (Fig. 3b).4 myxoid matrix/mucin production (3 out of 50, excluding theprimary mucinous carcinoma) in 2 mixed and 1 solid type.5 mucinous fibroplasia or collagenous micronodules (3 out of 50) in 1 solid, 1 mucinous and 1 mixed type: acellular orhypocellularhyalinizedstromawithinoroutsidecancerglands(Fig. 3c).6 bone metaplasia (2 out of 50) in 1 solid and 1 mixedcarcinoma.7 urothelial differentiation (2 out of 50) in 1 cribriform and 1solid type: large round neoplastic cells with a low N:C ratioand abundant granular, eosinophilic cytoplasm, often con-taining large vacuoles (Fig. 3d).8 squamous metaplasia in 1 cribriform carcinoma.9 multinucleated giant cells in 1 solid type.10 palisading of neoplastic cells around blood vessels in 1cribriform carcinoma (Fig. 3e).Metastastic lesions were observed in 12 out of 50 prostatic car-cinomas in the following sites: lung (41.7%), regional lymph nodes(33.3%), kidney (25%), intestinal serosa (8.3%), spleen (8.3%), intes-tinallymphnode(8.3%),liver(8.3%),mediastinallymphnode(8.3%).  Table 2 Frequency of normal prostates and histological lesions observed individually or invariable combination in 111 canine prostatic samples.HistologicalfindingNumber of cases/111samples (%)Normal prostate 7 (6.3%)BPH 45 (40.5%)Suppurative prostatitis 11 (9.9%)Non-suppurative prostatitis: 68 (61.2%) • Lymphoplasmacytic 59 (53.1%) • Lympho-histiocytic 9 (8.1%)Squamous metaplasia 1 (0.9%)PIA 27 (24.3%)HGPIN 21 (18.9%)Prostatic carcinoma: 50 (45%)a) Single histological pattern: 31 (27.9%) • Small acinar/ductal 12 (10.8%) • Solid 8 (7.2%) • Cribriform: 8 (7.2%)- with comedonecrosis 5 (4.5%)- without comedonecrosis 3 (2.7%) • Papillary: 3 (2.7%)- with comedonecrosis 2 (1.8%)- without comedonecrosis 1 (0.9%)b) Mixed histological patterns: 19 (17.1%) • Cribriform and papillary 3 (2.7%) • Small acinar/ductal and solid 3 (2.7%) • Cribriform and solid 3 (2.7%) • Cribriform, small acinar/ductal and solid 3 (2.7%) • Small acinar/ductal and papillary 2 (1.8%) • Papillary, cribriform and small acinar/ductal 1 (0.9%) • Small acinar/ductal, mucinous and solid 1 (0.9%) • Small acinr/ductal and cribriform 1 (0.9%) • Solid and signet ring 1 (0.9%) • Solid, papillary and signet ring 1 (0.9%)Legend:BPH = benignprostatichyperplasia;PIA = proliferativeinflammatoryatrophy;HGPIN  =  high-grade prostatic intraepithelial neoplasia. Fig. 1.  a) Proliferative inflammatory atrophy (PIA): acini lined by two layers of attenuated to cuboidal epithelial cells. Note the surrounding lymphoplasmacytic inflamma-tion. Hematoxylin & Eosin (H&E) stain. Magnification 100 × . b) High grade prostatic intraepithelial neoplasia (HGPIN): focal proliferation of epithelial cells characterized bymild pleomorphism and nuclear and nucleolar enlargement. H&E stain. Magnification 400 × .570  C. Palmieri et al./Research in Veterinary Science 97 (2014) 568–573  Fig. 2.  Different histologic growth patterns found in canine prostate carcinoma. a) Small acinar/ductal: several micro-acini arranged in abundant fibrous stroma. H&E. Mag-nification 200 × . b) Solid/undifferentiated pattern: pleomorphic tumor cells lacking any specific histological growth pattern. H&E. Magnification 200 × . c) Cribriform pattern:tumor cells extend pre-existing ducts forming irregular fenestrae with a central area of necrosis (comedonecrosis). H&E. Magnification 100 × . d) Papillary pattern: papillaryprojections formed in duct-like structures. H&E. Magnification 100 × . e) Mucinous carcinoma: pale blue amorphous material (mucin) within the lumen of neoplastic tubules/acini and in the interstitium (asterisk). H&E. Magnification 200 × . f) Signet ring carcinoma: neoplastic cells characterized by a large round cytoplasm vacuole displacing thenucleus. H&E. Magnification 200 × . Fig. 3.  Histological features observed in canine prostatic carcinomas. a) Sarcomatoid transformation: fascicles of neoplastic cells with a spindle-like morphology. H&E. Mag-nification 200 × . b) Perineurial invasion: circumferential encircling of nerve fibers by neoplastic glands. H&E. Magnification 200 × . c) Collagenous micronodules: acellularhyalinized stroma (arrows) admixed with neoplastic cells. H&E. Magnification 400 × . d) Urothelial differentiation: aggregate of neoplastic cells with abundant pale eosino-philic, occasionally vacuolated, cytoplasm. H&E. Magnification 200 × . e) Palisading of neoplastic cells around blood vessels. H&E. Magnification 200 × .571 C. Palmieri et al./Research in Veterinary Science 97 (2014) 568–573  The most common growth pattern associated with metas-tases was the mixed type (6 out of 12), followed by the solid (3 outof 12), cribriform (2 out of 12) and small acinar/ductal (1 out of 12)carcinomas.  3.3. Bacteriology Bacteriological examination was available in 6 out of 11 casesof suppurative prostatitis and revealed the isolation of hemolyticEscherichia coli (3), Pseudomonas aeruginosa (1) and Klebsiellapneumoniae (1), while in 1 case no aerobic or anaerobic bacterialgrowth were evidenced. 4. Discussion Other authors have attempted to classify prostate cancer (Bellet al., 1991; Cornell et al., 2000), although most of the morpholog- icalgrowthpatterns,exceptthewell-knownacinarandalveolar,havebeen simply categorized as poorly differentiated or undifferenti-ated.Ourstudy,togetherwiththedescriptionproposedbyLaietal.(2008), represents a comprehensive characterization of the differ-ent histological subtypes of canine prostate cancer, thus reflectingthe mixture of growth patterns and cell morphologies expressedbyneoplasticprostaticcells.Moreover,wehavedescribedothersub-types, such as signet ring and mucinous carcinomas, which shouldbe considered in the overall classification system of thiscondition.The diagnosis of mucinous carcinoma may be difficult becausetheamountof tissueobtainedbybiopsymaynotberepresentativeof the entire tumor. Moreover, one should exclude other mucinoustumors of non-prostatic srcin based on morphology and immu-nohistochemistry, and if necessary using clinical information. Onthe other hand, signet ring carcinoma should be diagnosed whenthepercentageofthetumortobesignetringcellsismorethan25%(Epstein et al., 2005).The pathological evaluation of primary tumors from our dogsrevealedconsiderablemorphologicheterogeneity.Themixedpatternof differentiationseeninmanycasessuggeststhatintratumoralhet-erogeneity,thehallmarkoflethalmalignancies,isaprevalentfeatureof spontaneous prostate cancer with the propensity of neoplasticcellstoproceedalongdivergentpathwaysofdifferentiation.Itismostlikely that tumors of mixed morphology represent a more biologi-cally aggressive variant of canine prostatic carcinoma as evidencedby the increased metastatic frequency associated with this growthpattern.Althoughthereisnocurrentlyawell-definedgradingscoringsystem for the canine prostate cancer, the majority of clinically di-agnosed cases would probably be graded highly malignant.Differences in the morphological appearance of androgen-sensitiveandandrogen-refractoryprostatecancerhavebeenreportedin human prostate. Kondo et al. (1997) have classified the glandu-lar, micro-glandular and cribriform growth patterns as androgen-sensitive, while fused glands, medullary/solid and columnar/trabecular patterns were classified as androgen-refractorycomponents. However, the relationship between androgen sensi-tivity,biologicalbehaviorandhistologicalpatternsarenotcurrentlyavailable for the canine counterpart.In our study, we have described additional histological fea-tures that are considered specific for prostate cancer in men, buthave not, to date, been reported in dogs: mucinous fibroplasiaandperineuralinvasion(Baisdenetal.,1999).Thesehistologicalfea- turesarereportedin1–2%(Thorsonetal.,1998)and22%(Humphrey, 2003) of prostate cancer biopsies in men, respectively. Collag-enous micronodules are not associated with mucin; therefore,the term mucinous fibroplasia may not be accurate. Ultrastructur-ally, they are composed of fragmented collagen fibrils surroundedby basement membrane material, most likely resulting from thedigestion by collagenase released by prostatic carcinoma cells(Arangelovich et al., 2003). Although perineurial indentation by benignprostaticglandshasbeenreported,theglandsinthesecasesappear totally benign and are present at only one edge of the nerveratherthancircumferentiallyinvolvingtheperineuralspace,asseenin carcinomas (Carstens, 1980; McIntire and Franzini, 1986). Giant cells have been observed in the exceptionally rare variantof pleomorphicgiantcelladenocarcinomawithfewerthan10casesreported in men (Lopez-Beltran et al., 2005; Parwani et al., 2006). Since our case may represent the first described so far, the authorsbelieve that the occurrence of these multinucleated cells is sug-gestive of the abnormal differentiation and replication pattern of the neoplastic cells rather than representing an additional histo-logical subtype, although in 4 cases of pleomorphic giant cellcarcinomadescribedbyParwanietal.(2006)thisabnormalcellpop-ulation occupied only 5% of the section, as in our case. We can ruleout that this bizarre giant cells are large giant stromal cells asdescribed in benign conditions such as BPH (Chang et al., 2003) orsecondary to treatment effects (Bostwick et al., 1982), since nuclearatypia and cellular pleomorphism are quite distinctive.BPH has been observed in 40.5% of cases, although the true fre-quency may even be much higher than that, because veterinarianstendtotreatthediseaseonthebasisofphysicalfindingsonly.Wherea clinical history was available, most animals did not exhibit clin-ical signs related to the hyperplastic growth, most likely due to theoutward expansion of the canine gland (McConnell, 1991) com-pared to the inward nodular growth causing compression of theurethrainmen(McNeal,1978).Inourstudy,BPH-affecteddogshad a clinical history of urinary dysfunction that is a consistent featureof other prostatic lesions (prostatitis, prostatic carcinoma) in thisspecies (LeRoy and Northrup, 2009). Characteristic clinical fea- turesofprostatecarcinoma–asobservedin16%ofdogsinthisstudy– are ataxia, hind limb pain and paresis that may be due to mul-tiple factors. Concurrent prostatitis may be present and cause painor, if metastases to lumbar vertebrae and pelvis are present, nerveroots or spinal cord may be impinged and /or pathological frac-tures of the bones may occur (LeRoy and Northrup, 2009). Neurological lesions associated with prostate cancer are also oneofthefactorsleadingtounderestimationofthiscondition,sincedogswith late-stage prostate cancer may be misdiagnosed with primaryneurologicaldiseaseorseverespondylosisdeformans(LeavandLing,1968). The significance of a biopsy that reveals just chronic, non-specific prostatitis remains unclear. In men, neoplasia may bediagnosed in as many as 45% of the individuals whose initial biopsywas consistent with chronic non-specific prostatitis (Kronz et al.,2001). In our cases, areas of chronic lymphoplasmacytic inflam-mation were most commonly associated with foci of PIA lesions.These atrophic lesions, which frequently merge with HGPIN inhuman prostatic samples, have some of the hallmark somaticgenome alterations found in prostate cancer and HGPIN and havebeen proposed as “risk factor lesions” for the development of pros-tate cancer, underlying the specific role of chronic inflammation inprostate cancer etiology (Sfanos and De Marzo, 2012). Our study suggests that PIN and HGPIN are not uncommon in canine pros-tates and they can be reasonably detected in a routine biopsyspecimen. These results probably represent an underestimate dueto sampling variation inherent in reviewing a single or few ran-domlyselectedsections,sothatfuturestudiesshouldincludeserialsectioning and total embedding of the prostate if available.In conclusion, the recognition of histological variants of pros-tatecancerindogsmaybeimportantifrelatedtoclinicalinformationand follow-up since some subtypes in men are associated with adifferent clinical outcome and might have a different therapeuticapproach. The awareness of the unusual patterns might be criticalin avoiding diagnostic misinterpretation. Future efforts should bedirected in determining the strength of association between PIA, 572  C. Palmieri et al./Research in Veterinary Science 97 (2014) 568–573
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