Lencastre, A

Pinheiro, R

English

Repositório do Centro Hospitalar de Lisboa Central, EPE

Corey Georgesen MD1Amin A. Hedayat MD2Travis J. Hollmann MD, PhD2Michael A. Marchetti MD1,3Klaus J. Busam MD1,2Anthony M. Rossi MD1,3Susan K. Seo MD1,4Alina Markova MD1,31Department of Dermatology, New York-Presbyterian Hospital/WeillCornell Medical Center, New York City, New York2Department of Pathology, Dermatopathology Service, Memorial SloanKettering Cancer Center, New York City, New York3Department of Medicine, Dermatology Service, Memorial SloanKettering Cancer Center, New York City, New York4Department of Medicine, Infectious Diseases Service, Memorial SloanKettering Cancer Center, New York City, New YorkEmail: markovaa@mskcc.orgDOI: 10.1111/cup.13453REFERENCES1. Justice SS, Hunstad DA, Cegelski L, Hultgren SJ. Morphological plasticityas a bacterial survival strategy. Nat Rev Microbiol. 2008;6(2):162-168.2. Justice SS, Harrison A, Becknell B, Mason KM. Bacterial differentiation,development, and disease: mechanisms for survival. FEMS MicrobiolLett. 2014;360(1):1-8.3. Sutton BJ, Parsons AC, Palavecino EL. Filamentous bacteria masquerad-ing as fungi: a diagnostic pitfall in direct smear interpretation withreport of two cases. J Clin Pathol. 2011;64(10):927-929.4. Lorian V, Ernst J, Amaral L. The post-antibiotic effect defined by bacte-rial morphology. J Antimicrob Chemother. 1989;23:485-491.5. Diver JM, Wise R. Morphological and biochemical changes in Escheri-chia coli after exposure to ciprofloxacin. J Antimicrob Chemother. 1986;18(Suppl D):31-41.6. Klein R, Luginbuhl GH. Ampicillin-induced morphological alterations ofHaemophilus influenzae type b. Antimicrob Agents Chemother. 1977;11(3):559-562.7. Suwantarat N, Jacobs MR. Photo quiz: positive blood culture in a patientwith sickle cell crisis. Answer: Klebsiella pneumoniae bacteremia showingfilamentous forms and spheroplasts due to the presence of subinhibitoryconcentrations of β-lactams. J Clin Microbiol. 2013;51(8):2475-2807.8. Miller C, Thomsen LE, Gaggero C, Mosseri R, Ingmer H, Cohen SN. SOSresponse induction by beta-lactams and bacterial defense against anti-biotic lethality. Science. 2004;305:1629-1631.Immunotherapy-related genital BCGitis: Case report and areview of histopathologyKEYWORDS : active immunotherapy, BCGitis, BCG vaccine, dermatopathology, granulomaImmunotherapy with bacillus Calmette-Guérin (BCG) is widely usedfor superficial urothelial cancer treatment. The resulting granuloma-tous inflammation probably leads to the concomitant destruction oftumor cells.1 BCG, an attenuated strain of Mycobacterium bovis,remains viable, hence a potential for serious life-threatening complica-tions exists.2 Most complications, however, are common, and includeminor reactions such as cystitis, hematuria, fever, and malaise.3,4Granulomatous inflammation of the penis with BCG intravesicaltherapy is reportedly rare.4 Clinical manifestations vary, as does theinterval between immunotherapy sessions and lesion appearance.Penile edema, yellowish papules, ulceration, and abscesses havebeen described, and regional lymphadenopathies are common.4The local inoculation of the BCG is the main causal factor due toimproper execution of the procedure (oftentimes citing trauma,FIGURE 1 Papules, pustules, and a hemorrhagic crust on the glans penis (A); a distinct suppurative granuloma, composed of layers of epithelioidhistiocytes without multinucleated giant cells, a central collection of neutrophils, and lymphocytes at the periphery H&E ×200 (B)462 BRIEF COMMUNICATIONSTABLE1Histologicalfindingsinpublishedcasesofimmunotherapy-relatedBCGitisREFEFERENCEDurationa(days)InflammatoryinfiltrateasdescribedNecrosisbGiantcellscOtherfeaturesMBstainsdCultureeNATsfCommentKonohana,19921514GranulomatousYLTNeutrophilsNeg(T)Neg-MYC(U);BK(T)–DiagnosedasprimarypenileTBRibera,19951017Tuberculoidgranulomas&denselymphocyticYLT–Neg(T)MTBC(T)MTBC(T)–Latini,200016–MixedandgranulomatousN–Granulationtissue;fibrosisNeg (UNSS)UNSisolate(U;E;T)–PenileshaftnodulesFrench,20015>17GranulomatousY–Neg(T)Neg-MYC(U;T)––Manikandan,200317–GranulomatousN–Fibrosis–Neg-MYC(U)–MbovisdetectedonchestwallabcessGemmel,200418>180GranulomatousandlooselymphocyticCaseousY–Pos(U;S)BCG(U;S)–Scrotalabcess;lungdiseaseYusuke,200611–GranulomatousYLT–Neg(T)––ProstatelesionsKureshi,2006630GranulomatousY–UlcerationNeg(T)Neg-MYC(T)–PenileshaftnodulesYates,20074–GranulomatousY––Neg(T)Neg-MYC(T)––Michelet,2008(A)9>90GranulomatousYYLymphocytesPos(T)Neg-MYC(T)––Michelet,2008(B)9>81GranulomatousY–––Neg-MYC(U;T)Neg-BK(U;T)–Yoshida,200819–Granulomatous&denselymphocyticYLT–Pos(T)Neg-BK(T)Neg-BK(T)–Hillyer,200920>30Granulomatous&chronicinflammatory–––Neg(T)Neg-BCG(U);Neg-BK(E;S)––Lestre,2011790Granulomatous–YPlasmacells;lymphocytesNeg(T)Neg-MYC(T)––Sharma,2011213Granulomatous–LT––BK(T)Neg-BCG&Neg-BK(T)Culture-positivelymphadenopathyAslan,2013222GranulomatousCaseousLT––Neg-MYC(U)Neg-BK(U)PubicalandpenileshaftlesionsBaldoví,2013232NeutrophilicNNNeutrophilsNeg(T)BK(T)––Chowdhury,201324–GranulomatousCaseousLTUlcerationNeg(T)ND––Linden-Castro,20148–GranulomatousCentral–Granulationtissue;fibrosis––––Shimura,201712–GranulomatousY–Neg(T)MYC(T)BCG(T)ScrotalnodulesonlyPresentcase4SuppurativegranulomaNNNeutrophilabscessNeg(T)Neg(T)Neg-MTBC(T)–aDurationisgivenintimepresumablyelapsedsincebeginningoflesionsandbiopsy,asdescribedintext.bNecrosis:Y,yes;N,notpresent;−,notmentioned.c Giantcells:LT,Langhans-type;Y,yes;N,notpresent;−,notmentioned.dMBstains,mycobacterialstains:Neg,negative;Pos,positive;E,exudate;S,sputum;T,tissue;U,urine;UNSS,unspecifiedspecimen.eCulture:MYC,Mycobacteriumspp.(oracid-alcoholresistantbacillus);MTBC,Mycobacteriumtuberculosiscomplex;BK,Mycobacteriumtuberculosis;BCG,Mycobacteriumbovis;UNSisolate,unspecifiedisolate.f NATs,nucleicacidtests:MTBC,Mycobacteriumtuberculosiscomplex;BK,Mycobacteriumtuberculosis;BCG,Mycobacteriumbovis.BRIEF COMMUNICATIONS 463spillage, or difficult catheterization).5–11 Inadvertent voidance of theinstilled bladder content on the surrounding skin has also beenimplicated.12In addition to a history of BCG instillation therapy, a local biopsyis often the sole procedure to collect evidence of the condition,before treatment initiation.We recently observed a patient with immunotherapy-related gen-ital BCGitis and decided to review the literature on its histologicalfindings.A 67-year-old Caucasian male patient was observed due to sev-eral papules on the glans penis, with 4 days duration. Owing to ahigh-grade, urothelial carcinoma in situ, he underwent transurethralbladder resection 4 months before presentation. He started BCGtherapy approximately 4 weeks after surgery with a total of sevensessions. On the third session, the nurse-performed catheterizationwas reported as difficult and uncomfortable, and resulted in trauma tothe urethral meatus. The patient subsequently reported fever, malaise,shaking, and trembling which subsided during the following week. Sixweeks after, he progressively developed four painless erythematouspapulo-pustules, on the surface of the glans (Figure 1A). No lymph-adenopathies were present. The patient denied any systemic symp-toms and other genito-urinary signs. Skin biopsy showed a nodularinfiltrate of histiocytes with a central neutrophilic abscess (Figure 1B).Detection of acid-alcohol-resistant bacilli and culture were negative,and polymerase chain reaction (PCR) for mycobacteria was not per-formed. A diagnosis of penile BCGitis was made.BCG immunotherapy was interrupted and the patient was treatedwith isoniazid 300 mg/day, rifampicin 600 mg/day and ethambutol1200 mg/day (for 6 months). Residual hyperpigmentation remainedon a follow-up visit 1 month later. No relapses have been observedafter 12 months.A literature search using PubMed (with the keywords: BCGitis,glans, penis, genital, and immunotherapy) rendered 21 papers. Twowere excluded for lacking description of histology.13,14 The remainingaddress 20 different cases, to which we add our own (Table 1).Almost all cases mentioned lesions on the glans or balanoprepu-tial sulcum. Lymphadenopathy was very common. Involvement ofother neighboring sites was mentioned in three cases, and disease atdistant sites on the skin or on other organs in three cases.Immunotherapy-related BCGitis diagnosis was made based on clinicalfeatures supported by histology of skin lesions (n = 21); culture of tis-sue (n = 14), urine (n = 7), exudate (n = 2) or sputum (n = 2); andnucleic acid tests (NATs) of tissue (n = 6) or urine (n = 2).Regarding histology, specimens were from the penile mucosa orskin in 20 cases, and from scrotal lesions in one case.25 Twenty (95%)cases reported granulomatous inflammation. Eighteen casesaddressed the presence of necrosis, described as caseous in three andabsent in the remaining three cases. Ten cases mentioned giant cells,eight of which described some as Langhans-type. Other features wereoccasionally referenced, such as neutrophils and plasma cells, fibrosis,granulation tissue, or necrosis. Besides our current observation, onlyone other25 mentioned a relevant neutrophilic infiltrate. Staining withZiehl-Neelsen or auramine-rhodamine stains was mentioned in16 instances, where positivity was found in penile tissue biopsy inonly two occasions (12.5%).Culture was inconsistently described in terms of cultured speci-mens, bacterial isolation, especially growth media used, and notmentioned or not performed in three instances. In 18 cases, cul-tured specimens were: tissue in 14 cases, urine in seven cases, andexudate and sputum in two cases, each. Isolation was possible inseven cases.Finally, NATs were performed in seven instances (tissue, in sixcases, and urine, in two cases). Positivity for Mycobacterium tuberculo-sis complex and for BCG was found in one case, each.This study highlights that genital M bovis-related inflammation isgranulomatous in nature, with an infiltrate that is predominantly his-tiocytic and with frequent giant cells of Langhans type, as is commonfor tuberculous mycobacterial infections.26,27 Despite being fre-quently reported on, caseous necrosis may be absent. The presenceof a significant neutrophilic infiltrate is possible, and we postulate thatit may be related to lesion duration as part of the initial response tothe inoculate.28 We tried to support this hypothesis by examininglesion duration at the time of biopsy, but this clearly insufficient num-ber of cases precluded us from safely drawing a definite conclusion.The overall results of our review highlight the importance of his-tologic examination for iatrogenic genital BCGitis diagnosis becauseculture and NATs yield inconsistent results. Detection of an infectiveagent is difficult (38% of cases in this literature series). Direct micro-scopical observation of bacilli was rare (9.5%). Culture results wereinconsistently described as isolates of mycobacteria. NATs werescarcely reported on, and were conclusive on already “culture-posi-tive” cases.Because culture and NATs are scarcely reported and apparentlyproduce inconsistent results, histology is also crucial for supportingthe diagnosis of iatrogenic BCGitis. Without a clear clinical history theclinical differential diagnoses could include mainly infective conditions(e.g., herpes virus, syphilis, candida, other mycobacteria), and rarelytuberculids, or other inflammatory conditions (e.g., psoriasis, pyo-derma, or Behçet disease). For most of these, a clear-cut granuloma-tous dermal inflammation will disfavor the diagnosis.In conclusion, iatrogenic penile BCGitis is mainly responsible for agranulomatous inflammation, although a predominantly or mixed neu-trophilic infiltrate is possible, as seen in this case. Clinical-pathologiccorrelation is of paramount importance, because microbiological testsmay be negative.ORCIDAndré Lencastre https://orcid.org/0000-0001-7378-7068André Lencastre MDRita R. Pinheiro MDDepartment of Dermatology, Centro Hospitalar de Lisboa Central,Lisbon, PortugalEmail: lencastre.derm@gmail.comDOI: 10.1111/cup.13458REFERENCES1. Morales A, Eidinger D, Bruce AW. Intracavitary bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J Urol. 1976;116(2):180-183.464 BRIEF COMMUNICATIONS2. Desmet M, Moubax K, Haerens M. Multiple organ failure and granulo-matous hepatitis following intravesical bacillus Calmette-Guérin instil-lation. Acta Clin Belg. 2012;67(5):367-369.3. Lamm DL, van der Meijden PM, Morales A, et al. Incidence and treat-ment of complications of bacillus Calmette-Guerin intravesical therapyin superficial bladder cancer. J Urol. 1992;147(3):596-600.4. Yates J, Stein B. Bladder and penile lesions with inguinal adenopathyafter intravesical bacillus Calmette-Guerin (BCG) treatment. Urology.2007;70(6):1223.e15-1223.e17.5. French CG, Hickey L, Bell DG. Caseating granulomas on the glanspenis as a complication of Bacille Calmette-Guérin intravesical ther-apy. Rev Urol. 2001;3(1):36-38.6. Kureshi F, Kalaaji AN, Halvorson L, Pittelkow MR, Davis MDP. Cuta-neous complications of intravesical treatments for bladder cancer:granulomatous inflammation of the penis following BCG therapy andpenile gangrene following mitomycin therapy. J Am Acad Dermatol.2006;55(2):328-331.7. Lestre SI, Gameiro CD, João A, Lopes MJ. Granulomas of the penis: arare complication of intravesical therapy with bacillus Calmette-Gue-rin. An Bras Dermatol. 2011;86(4):759-762.8. Linden-Castro E, Pelayo-Nieto M, Alias-Melgar A. Penile tuberculosisafter intravesical bacille Calmette-Guérin immunotherapy. Urology.2014;84(2):e3.9. Michelet N, Spenatto N, Viraben R, et al. BCG infection of the glanspenis after intravesical BCG therapy. Ann Dermatol Venereol. 2008;135(6–7):479-483.10. Ribera M, Bielsa J, Manterola JM, Fernández MT, Ferrándiz C. Myco-bacterium bovis-BCG infection of the glans penis: a complication ofintravesical administration of bacillus Calmette-Guerin. Br J Dermatol.1995;132(2):309-310.11. Yusuke H, Yoshinori H, Kenichi M, et al. Granulomatous balanoposthi-tis after intravesical bacillus-Calmette-Guerin instillation therapy. Int JUrol. 2006;13(10):1361-1363.12. Shimura H, Ihara T, Mitsui T, Takeda M. Tuberculous granuloma in thescrotal skin after Intravesical bacillus Calmette-Guerin therapy forbladder cancer: a case report. Urol Case Rep. 2017;11:4-6.13. Erol A, Ozgür S, Tahtali N, et al. Bacillus Calmette-Guerin (BCG) bala-nitis as a complication of intravesical BCG immunotherapy: a casereport. Int Urol Nephrol. 1995;27(3):307-310.14. Baniel J, Lev Z, Engelstein D, Servadio C. Penile edema and meatalulceration after intravesical instillation with bacillus Calmette-Guerin.Urology. 1996;47(6):932-934.15. Konohana A, Noda J, Shoji K, Hanyaku H. Primary tuberculosis of theglans penis. J Am Acad Dermatol. 1992;26(6):1002-1003.16. Latini JM, Wang DS, Forgacs P, Bihrle W 3rd. Tuberculosis of thepenis after intravesical bacillus Calmette-Guerin treatment. J Urol.2000;163(6):1870.17. Manikandan R, Srirangam S, Vickers D, O'Reilly PH, Brown SC. Peniletuberculosis after intravesical bacillus Calmette-Guérin instillation.BJU Int. 2003;92(Suppl 3):e16.18. Gemmel C, Jacek G, Lücking HC, et al. Abscess of the scrotum withswelling of the inguinal lymph nodes in an 86-year-old man. DtschMed Wochenschr. 2004;129:2032-2034.19. Yoshida R, Kawasaki H, Miyajima A, Amagai M, Ohyama M. Primarytuberculosis of the penis after intravesical bacillus Calmette-Guerin instil-lation therapy. J Eur Acad Dermatol Venereol. 2009 Jan;23(1):77-78.20. Hillyer S, Gulmi FA. Cutaneous BCG of the penis after intravesicaltherapy for bladder cancer: a case report in a 66-year-old male. Can JUrol. 2009;16(5):4866-4869.21. Sharma VK, Sethy PK, Dogra PN, Singh U, Das P. Primary tuberculosisof glans penis after intravesical bacillus Calmette Guerin immunother-apy. Indian J Dermatol Venereol Leprol. 2011;77:47-50.22. Aslan G, Sevinc C, Tuna B, Ozkal S, Yorukoglu K. Penile lesion withinguinal adenopathy after intravesical bacillus Calmette-Guerin instil-lation therapy. Indian J Urol. 2013;29:70-72.23. García Baldoví M, Pérez-Crespo M, Onrubia J, Moragón M. Balanitisgranulomatosa tras terapia intravesical con bacilo de Calmette-Guérin.Actas Dermosifiliogr. 2013;104:251-252.24. Chowdhury AR, Dey RK. Penile tuberculosis following intravesicalBacille Calmette-Guérin immunotherapy. Indian J Urol. 2013;29(1):64-66.25. García Baldoví M, Pérez-Crespo M, Onrubia J, Moragón M. Granulo-matous balanitis after intravesical Bacille Calmette-Guérin instillation.Actas Dermosifiliogr. 2013;104(3):251-252.26. Shah K, Pritt B, Alexander M. Histopathologic review of granuloma-tous inflammation. J Clin Tub Other Mycobact Dis. 2017;7:1-12.27. Saban MR, Simpson C, Davis C, et al. Discriminators of mouse bladderresponse to intravesical bacillus Calmette-Guerin (BCG). BMC Immu-nol. 2007;16(8):6.28. Pérez-Jacoiste AMA, Fernández-Ruiz M, López-Medrano F, et al.Bacillus Calmette-Guerin (BCG) infection following Intravesical BCGadministration as adjunctive therapy for bladder cancer incidence, riskfactors, and outcome in a single-institution series and review of the lit-erature. Medicine. 2014;93(17):236-254.BRIEF COMMUNICATIONS 465

Immunotherapy-Related Genital BCGitis: Case Report and a Review of Histopathology

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Immunotherapy-Related Genital BCGitis: Case Report and a Review of Histopathology

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