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CANCERUL CUTANAT ASOCIAT BOLILORHEMATOLOGICE MALIGNE – DOUÃ CAZURI CLINICE

SKIN CANCER ASSOCIATED TO MALIGNANTHAEMATOLOGICAL DISEASES – TWO CLINICAL CASES

ALEXANDRA GEORGIANA BOCÎRNEA*, VIRGIL PÃTRAªCU**

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* Clinica Dermatologie, Spitalul Clinic Judeþean de Urgenþã Craiova / Clinic of Dermatology, Emergency Clinical Hospital of Craiova.** U.M.F Craiova / University of Medicine and Pharmacy, Craiova.

Rezumat

Bolile hematologice maligne cuprind o serie de condiþiipatologice heterogene ce constau în proliferarea neoplazicãa celulelor mãduvei osoase ºi sistemului limfatic.Aproximativ 250.000 de persoane sunt diagnosticate culeucemie în fiecare an în lume, reprezentând 2,5% dincazurile de cancer.

Cancerele cutanate reprezintã aprox. 20% din cazurilenoi de neoplazii maligne. Incidenþa cancerului cutanat înRomânia, este de aprox. 10 la 100.000 locuitori.

Caz clinic I. Pacient în vârstã de 77 ani, cunoscut cuLMNH limfocitic difuz stadiul IV B din anul 2008, sespitalizeazã pentru douã formaþiuni tumorale situate lanivelul faciesului. Rezultatul examenului HP a fost destructurã microscopicã de carcinom mixt ºi structurãmicroscopicã de keratozã seboreicã tipul hiperkeratozic.Pacientul prezenta ºi multiple papule eritemato-violaceeacoperite de cruste hematice intens pruriginoase la nivelulmembrelor inferioare.

Caz clinic II. Pacientã în vârstã de 73 ani, cunoscutãcu Neoplasm mieloproliferativ mielodisplazic neclasificabil,din anul 2013, se spitalizeazã pentru o formaþiunetumoralã situatã la nivelul unghiului intern al ochiuluidrept. Rezultatul examenului HP a fost structurãmicroscopicã de carcinom bazocelular adenoid.

Pacienþii cu boli hematologice sunt mult maisusceptibili de a dezvolta tumori maligne secundare,cancerul de piele fiind cel mai frecvent. Acestademonstreazã agresivitate crescutã la pacienþii cu bolihematologice ºi este asociat cu rate mai mari de recidivã,risc crescut de metastaze regionale ºi chiar deces.

Summary

Malignant haematological diseases comprise a series ofheterogenous pathological conditions that consist in theneoplastic proliferation of the bone marrow and lymphaticsystem cells. Every year, about 250.000 persons arediagnosed with leukemia all over the world, representing2.5% of cancer cases.

Skin cancers represent about 20% of the new cases ofmalignant neoplasias. The incidence of skin cancer inRomania is about 10 in 100,000 inhabitants.

Clinical case I. A 77-year old patient, known with non-Hodgkin’s lymphoma (NHL) stage 4 B since 2008, isadmitted to hospital for two tumor formations at face level.The result of the HP examination was a microscopicstructure of mixt carcinoma and of seborrheic keratosishyperkeratotic type. The patient also presented multipleeritemato-violaceous papules covered by intenselypruriginous haematic scalls in the lower limbs.

Clinical case II. A 73-year old female patient, knownwith myelodysplastic myeloproliferative, unclassifiableneoplasm since 2013, is hospitalized for a tumor formationsituated in the right eye angle. The result of the HPexamination was a microscopic structure of adenoid basalcell carcinoma.

The patients with blood diseases are much moresusceptible to develop secondary malignant tumors, skincancer being the most frequent one. This fact shows a highseverity in the patients with blood diseases and it isassociated to higher rates of relapse, a high risk for regionalmetastases and even death.

CAZURI CLINICECLINICAL CASES

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DermatoVenerol. (Buc.), 60: 147-158

Bolile hematologice maligne cuprind o seriede condiþii patologice heterogene ce constau înproliferarea neoplazicã a celulelor mãduveiosoase ºi sistemului limfatic. Aproximativ250.000 de persoane sunt diagnosticate culeucemie în fiecare an în lume, reprezentând 2,5%din cazurile de cancer.

Cancerele cutanate reprezintã aproximativ20% din cazurile noi de neoplazii maligne.Incidenþa cancerului cutanat în România, este deaproximativ 10 la 100.000 locuitori.[1]

Caz clinic I

Pacient în vârstã de 77 ani din mediul rural,se spitalizeazã pentru o formaþiune tumoralãglobuloasã, roºieticã, de 0,5 cm cu telangiectaziipe suprafaþã, situatã la nivelul piramidei nazale(Fig. 1) ºi pentru o formaþiune keratozicã, cu bazãmicã de implantare ºi aspect clinic de corncutanat în miniaturã situatã suborbital drept (Fig.2). Pacientul prezenta ºi multiple papuleeritemato- violacee acoperite de cruste hematiceintens pruriginoase la nivelul membrelorinferioare (Fig. 3).

Din antecedentele personale patologice reþinem:Limfom malign non-Hodgkin limfocitic difuzstadiu IV B (LMNH) din 2008, HTA primarã grad3 din 2007, Cardiopatie ischemicã cronicãdureroasã, Adenom de prostatã din 2011, Hernieinghinalã corectatã chirurgical în 1984 ºi sechelede TBC pulmonar.

Condiþiile de viaþã ºi muncã au relevat expu-nerea cronicã la soare ºi expunerea în mediu cutoxice.

Medicaþia de fond: Perindopril 10 mg 1cp/zi (1-0-0), Clorhidrat de oxibutinã 5 mg (Driptane)1cp/zi (0-0-1) ºi Tamsulosin 0.4 mg (Tamsol)1cp/zi (0-0-1).

Malignant haematological diseases comprisea series of heterogenous pathological conditionsthat consist in the neoplastic proliferation of thebone marrow and lymphatic system cells. Everyyear, about 250.000 persons are diagnosed withleukemia all over the world, representing 2.5% ofcancer cases.

Skin cancers represent about 20% of the newcases of malignant neoplasias. The incidence ofskin cancer in Romania is about 10 in 100,000inhabitants.[1]

Clinical Case I

A 77- year old patient, from the rural area, isadmitted to hospital for a red, globular tumorformation, of 0.5 cm, with surface telangiectasies,situated at nasal pyramid (Fig. 1) and also for akeratosic formation, with small implantationbasis and a clinical aspect of a miniature skinclavus located suborbital right (Fig. 2). Thepatient also presented multiple eritemato-vio-laceous papules covered by intensely pruriginoushaematic scalls in the lower limbs. (Fig. 3).

From the pathological personal history wehighlight: Non-Hodgkin malignant lymphomastage 4 B (NHL), since 2008, Essential hyper-tension stage 3, since 2007, painful chronicischemic cardiopathy, prostate adenoma since2011, inguinal hernia surgically adjusted in 1984and pulmonary TBC sequelae.

Life and work conditions showed chronic sunexposure and toxic environment exposure.

Medication: Perindoprilum 10 mg 1 cp/day(1-0-0), Oxybutynin hydrochloride 1 cp/zi (0-0-1)and Tamsulosinum 1cp/day (0-0-1).

Diferitele modalitãþi terapeutice utilizate pentrutratarea bolilor hematologice maligne ar putea accentua încontinuare imunosupresia prin epuizarea sistemuluiimunitar, favorizând astfel apariþia celei de-a doua neoplazii(cancer cutanat).

Cuvinte cheie: carcinom bazocelular, boli hematologicemaligne, imunosupresie.

The various therapeutical methods used for thetreatment of malignant blood diseases may continue toexacerbate immunodepression through the immune systemdepletion, thus favouring the emergence of a secondneoplasia (skin cancer).

Keywords: basal cell carcinoma, malignant haemato-logical diseases, immunosuppression.

Intrat în redacþie: 9.07.2015

Acceptat: 14.08.2015

Received: 9.07.2015

Accepted: 14.08.2015

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Fig. 1. Carcinom mixt- piramida nazalã.

Fig. 1. Mixt carcinoma- nasal pyramid.

Fig. 3. Leziuni de vasculitã la nivelul membrelor inferioare.

Fig. 3. Injury vasculitis of the lower limbs.

Fig. 2. Keratozã seboreicã tipul hiperkeratozic

– suborbital drept.

Fig. 2. Seborrheic keratosis hyperkeratotic type

– suborbital right.

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Istoricul bolii

Pacientul este cunoscut cu LMNH din anul2008, cu douã recãderi (2010 ºi 2012) pentru carede-a lungul timpului, a urmat tratamentchimioterapic (cu FC- Fludarabinã, Ciclofosfa-midã; CHOP- Ciclofosfamidã, Doxorubicinã,Vincristinã, Predinison; CVP- Ciclofosfamidã,Vincristinã, Prednison), vitamina B1 + B6, Alo-purinol, Amoxicilinã, Dexametazonã ºi radio-terapie 36 Gy la nivelul mediastinului, axilei ºisupraclavicular. Acesta afirmã apariþia forma-þiunii tumorale de la nivelul piramidei nazale înurmã cu aproximativ 3 luni ºi a celei de la nivelulregiunii geniene drepte în urmã cu aproximativ 5luni. Leziunile purpurice de la nivelul membrelorinferioare au apãrut în urmã cu 3 sãptãmâni fiindintens pruriginoase.

Examen clinic general: pacient cu staregeneralã bunã, supraponderal, cu tegumentepalide ºi cu dispnee la eforturi fizice mici.

Investigaþiile paraclinice modificate au fost:Creatinina = 1.31 mg/dl ºi VSH = 14/26, restulparametrilor biologici fiind normali.

Examenul CT de torace (2013): microadeno-patii în fereastra aorto-pulmonarã ºi adenopatiecentimetricã în hilul drept.

Examenul HP a relevat – structurã micro-scopicã de carcinom mixt (scuamos moderatdiferenþiat ºi bazocelular adenoid) invaziv înhipoderm (Fig. 4) ºi pentru a doua leziune,structurã microscopicã de keratozã seboreicãtipul hiperkeratozic ( Fig. 5).

Am stabilit diagnosticul: Carcinom mixtasociat cu Limfom malign non- Hodgkinlimfocitic difuz stadiu IV B.

Diagnosticele secundare au fost: Keratozaseboreicã tipul hiperkeratozic, Vasculitã membreinferioare, Onicomicozã picioare, HTA primarãgrad 3, Cardiopatie ischemicã cronicã dureroasã,sechele TBC pulmonar, Adenom de prostatã ºiSuprapondere.

Tratament: s-a practicat excizia celor douãformaþiuni tumorale situate la nivelul faciesului.

Evoluþia a fost favorabilã. (Fig. 6, 7)A urmat tratament general cu Metilpred-

nisolon 32 mg. (1/2 -1/2 - 0), Oxacilinã 500 mg1cp. la 6 h, Desloratadinã 5 mg (1-0-0), Esome-prazol 20 mg (0-1-0) iar la nivelul leziunilorpapuloase roºii-violacee de la nivelul membrelor

Disease history

The patient is known with non-Hodgkinlymphoma (NHL) since 2008, cu with tworelapses (2010 and 2012) for which, over time, hereceived a chemotherapeutical treatment (withFC- Fludarabine, Cyclophosphamide; CHOP –Cyclophosphamide, Doxorubicin, Vincristine,Prednisone; CVP – Cyclophosphamide, Vin-cristine, Prednisone), Vitamins B1 + B6, Allo-purinol, Amoxicillin, Dexametasone and 36 Gyradiotherapy at level of the mediastine, axilla andsupra clavicular region. This shows the tumorformation at nasal pyramid level, appeared 3months ago, and the one in the right genianregion, appeared 5 months ago. The purplelesions in the lower limbs appeared 3 weeks ago,being intensely pruriginous ones.

General clinical examination: patient with agood general state, overweight, with paleteguments and with low-effort dyspnea.

Paraclinical investigations were modified:Creatinine 1.31 mg/dl and erythrocyte sedi-mentation rate 14/26, the rest of the biologicalparameters being normal.

The abdomen CT scan (2013): microadeno-pathies in the arorta-pulmonary side andcentimetric adenopathy in the right hilum.

The HP examination highlighted: a micro-scopic strucure of mixt carcinoma (moderatelydiffereniated squamous and basal cell adenoidcarcinoma) invazive in the hypodermis (Fig. 4),and for the second lesion, a microscopic structureof seborrheic keratosis hyperkeratotic type (Fig. 5).

The following diagnosis was confirmed: Mixtcarcinoma associated to non-Hodgkin malignantlymphoma stage 4 B.

The secundary diagnoses were: Seborrheickeratosis hyperkeratotic type, Inferior limbvasculitis, Onychomycosis, Essential hyper-tension stage 3, painful chronic ischemic cardio-pathy, pulmonary TBC sequelae, prostateadenoma and overweight.

Treatment: there was performed the excisionof the two tumor formations situated at face level.

The evolution was favorable. (Fig. 6, 7)The patient received a general treatment with

Methylprednisolonum 32mg. (1/2 - 1/2 - 0),Oxacillin 500 mg 1cp./6h, Desloratadine 5 mg (1-0-0), Esomeprazole 20 mg (0-1-0), and on the red-purple papular lesions in the lower limbs there

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Fig. 4. Carcinom mixt- aspect histopatologic.

Fig. 4. Mixt carcinoma- histopathological aspect.

Fig. 5. Keratoza seboreicã tipul hiperkeratozic: aspect

histopatologic.

Fig. 5. Seborrheic keratosis hyperkeratotic type:

histopathological aspect.

Fig. 6. Evoluþia la o lunã de la externarea din spital.

Fig. 6. Evolution to a month of discharge from hospital.

Fig. 7. Evoluþia favorabilã a vasculitei de la nivelul

membrelor inferioare.

Fig. 7. The favorable evolution of vasculitis of the lower

limbs.

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inferioare s-a aplicat mixturã cu Menthol,Nistatin ºi Hidrocortizon acetat.

Caz clinic II

Pacientã în vârstã de 73 ani din mediul rural,se spitalizeazã pentru o formaþiune tumoralã,ovalarã cu dimensiuni de 1,5/2 cm ºi marginiperlate situatã la nivelul unghiului intern alochiului drept (Fig. 8, 9).

Din antecedentele personale patologice reþinem:Neoplasm mieloproliferativ mielodisplazic ne-clasificabil (2013), HTA primarã grad 2 (2009),Anginã pectoralã de efort (2009), Insuficienþãmitralã degenerativã grad I (2009), Apendi-cectomie (1965), Colecistectomie, Coxartrozãbilateralã.

Condiþiile de viaþã ºi muncã au relevat expu-nerea cronicã la soare.

Medicaþia de fond: Trimetazidinã 35mg (1-0-1),Acid acetilsalicilic 75mg (1-0-0), Perindopril 5mg(1-0-0).

Istoricul bolii

Pacienta este cunoscutã cu Neoplasmmieloproliferativ mielodisplazic neclasificabil dinanul 2013, tratat în Clinica Hematologie cuCitarabinã (Cytosar), vitamina B6, Acid folic,Alopurinol, Ramoplanin, Hidrocortizon hemi-succinat, Dexametazonã ºi substituþie de masãeritrocitarã. Aceasta afirmã apariþia formaþiuniitumorale de la nivelul unghiului intern al

was applied a mixture with Menthol, Nistatinand Hydrocortisone acetate.

Clinical case II

A 73-year female patient, from the rural area,is hospitalized for a ovalary tumor, of 1.5/2 cmand pearly margins, situated at right eye internalangle ( Fig. 8, 9).

From the personal medical history, we highlightthe following: unclassifiable myelodysplasticmyeloproliferative neoplasm (2013), Essentialhypertension stage 2 (2009), effort angina pectoris(2009), degenerative mitral failure stage 1 (2009),Appendicectomy (1965), Cholecystectomy, bi-lateral coxarthrosis.

Life and work conditions: highlights chronicsun exposure.

Medication: Trimetazidine 35 mg (1-0-1),Acetylsalicylic Acid 75mg (1-0-0), Perindopril5mg (1-0-0).

Disease history

The patient is known with an unclassifiablemyelodysplastic myeloproliferative neoplasmsince 2013, treated in the Clinic of Haematologywith Cytarabine, vitamin B6, Folic acid, Allo-purinol, Ramoplanin, Hydrocortisone SodiumSuccinate, Dexametasone and erythrocyte masssubstitution. This confirms the appearance of thetumor formation at right eye internal angle for 2

Fig. 8. Carcinom bazocelular adenoid – unghi intern ochi drept.

Fig. 8. Adenoid basal cell carcinoma –right eye internal angle.

Fig. 9. Marginile perlate ale tumorii.Fig. 9. Pearly margins of the tumors.

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ochiului drept în urmã cu aproximativ 2 ani.Tumora a crescut lent în dimensiuni, iar înianuarie 2014 a prezentat sângerãri locale.

Examenul clinic general: pacientã cu staregeneralã medie, supraponderalã cu tegumente ºimucoase palide. Aparat cardio-vascular: suflusistolic în focarul aortic ºi focarul mitral ºi pulsdiminuat la artera tibialã posterioarã ºi pedioasãbilateral. Ficat cu marginea inferioarã la 2 cm subrebordul costal.

Examenele paraclinice aratã VSH = 60/85 mm,Leucocite = 14.850/mmc, Creatinina sericã= 1.08mg/dl ºi frotiu cu anizocitozã uºoarã.

Biopsia osteo-medularã (mãduvã hemato-genã uºor hipercelularã prin hiperplazie eritro-megakariocitarã, frecvente grupuri de eritro-blaºti, diseritropoiezã – eritroblaºti cu conturneregulat, grupuri de eritroblaºti cu dispoziþieanormalã, raport G/E – 1/1, maturaþie granulo-citarã prezenþã redusã ºi rare segmentate).

Imunohistochimie: CD34 este pozitiv înaproximativ 14-15% din celulele dispersate ºigrupate interstiþial, nodulul limfoid are caracterreactiv cu CD20 pozitiv în limfocitele mici Baglomerate în centrul nodulului. Noduliimonocitoizi sunt formaþi din celule monocitoide,plasmocitoide pozitive pentru CD68/PGM1 ºipentru CD123; CD68 este pozitiv ºi în grupurilerelativ rare de monocite.

Examen HP: Fragment cu structurã micro-scopicã de carcinom bazocelular adenoid. (Fig. 10)

Fig. 10. Structurã microscopicã de carcinom bazocelular adenoid- aspect histopatologic.Fig. 10. Microscopic structure of adenoid basal cell carcinoma- histopathological aspect.

years. The tumor has progressively increased,and in January 2014, it presented local bleedings.

The general clinical examination shows a patientwith an average general state, overweight, withpale teguments and mucosa. Cardiovascularsystem: systolic murmur in the aortic and mitralfocci, and a diminished pulse in the posteriortibial artery and the bilateral pedious one. Liverwith the inferior margin 2 cm below the costalmargins.

The paraclinical tests showed erythrocytesedimentation rate 60/85 mm, Leukocytes14.850/mmc, seric creatinine 1.08 mg/dl andfrotium with mild anisocytosis.

The osteo-medullar biopsy showed a heamto-genous bone marrow, slightly hypercellulsthrough erytrhoid-megakariocyte hyperplasia,frequent groups of erythroblasts, dysery-thropoiesis – erythroblasts with an unevenmargin, groups of abnormally placed erythro-blasts, G/E ratio – 1/1, granulocyte maturation –reduced presence and rarely segmental.

Immunohistochemistry: CD34 is positive inabout 14-15% of the dispersed cells and groupedinterstitially, the lymphoid nodule has a reactivecharacteristic with positive CD20 in B smalllymphocytes agglomerated in the nodule center.The monocytoid nodules are formed from mono-cytoid cells, positively plasmocytoid for CD68/PGM1 and for CD123; CD68 is also positive in therelatively rare groups of monocytes.

HP examination: Fragment with a microscopicstructure of adenoid basal cell carcinoma (Fig.10).

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Am stabilit diagnosticul de Carcinom bazo-celular adenoid asociat cu Neoplasm mielo-proliferativ mielodisplazic neclasificabil.

Diagnosticele secundare au fost: HTA pri-marã grad 2, Anginã pectoralã de efort, Insufi-cienþã mitralã degenerativã grad I, Coxartrozãbilateralã, Suprapondere, Hepatomegalie.

Tratament: s-a practicat excizia formaþiuniitumorale de la nivelul unghiului intern al ochiu-lui drept.

Recomandãrile dermatologice au fost: evi-tarea expunerii la soare în anotimpurile însorite ºifotoprotecþie solarã.

Prognosticul în cazul celor 2 pacienþi esterezervat datoritã prezenþei bolilor hematologice,a vârstei înaintate ºi a imunosupresiei asociate.

Discuþii

Pacienþii cu boli hematologice sunt mult maisusceptibili de a dezvolta tumori malignesecundare, cancerul de piele fiind cel mai frec-vent. Tipurile de cancer de piele care predominãla pacienþii cu Limfoame maligne non- Hodgkin(LMNH) includ: melanomul, carcinomul cucelule scuamoase (CSC), carcinomul bazocelular(CBC) ºi carcinomul cu celule Merkel.

Multe tipuri de cancer de piele demonstreazãagresivitate crescutã la pacienþii cu LMNH ºi suntasociate cu rate mai mari de recidivã, risc crescutde metastaze regionale ºi chiar deces.

O asociere intrigantã între LMNH ºi tumorilemaligne cutanate este faptul cã fiecare este ceamai comunã tumorã malignã secundarã dupãdezvoltarea celuilalt.[2,3]

În cazul pacienþilor cu LMNH ºi cancercutanat este de multe ori identificat în jurul sau înapropierea tumorii un infiltrat limfocitic dens,care a fost gãsit la 36% din pacienþii cu Leucemielimfaticã cronicã (LLC) ºi conþine celule B leuce-mice în 75% din cazuri. Prezenþa infiltratuluileucemic poate influenþa capacitatea de a vedeaclar marginile reale ale tumorii ºi creºte riscul demetastazare ºi recidivã datoritã unor factoriimunosupresori eliberaþi de celulele B leucemicecu inhibarea rãspunsului imunologic anti-tumoral. [4]

În Statele Unite, o analizã retrospectivã dinperioada 1955-1974 efectuatã de cãtre Manusowºi Weinerman pe 102 pacienþi cu LLC, a

We confirmed the diagnosis of adenoid basalcell carcinoma associated to unclassifiable myelo-dysplastic myeloproliferative neoplasm.

Secundary diagnoses were: Essential hyper-tension stage 2, effort angina pectoris, dege-nerative mitral failure stage 1, bilateral cox-arthrosis, overweight, hepatomegalia.

Treatment: there was performed the excisionof the tumor formation at the right eye internalangle.

Dermatological recommendations: avoidingsun exposure during sunny seasons and sunprotection.

The prognosis for both patients is a reservedone, due to the presence of malignant blooddiseases, old age and associated immuno-supression.

Discussions

The patients with blood diseases are muchmore susceptible to develop secundary malig-nant tumors, skin cancer being the most frequentone. The types of skin cancers that prevail in thepatients with non-Hodgkin lymphoma (NHL)include: melanoma, squamous cell carcinoma(SCC), basal cell carcinoma (BCC) and Merkel cellcarcinoma.

Lots of skin cancer types show a high aggres-sivity in the NHL patients and are associated tohigh rates of relapse, a high risk for regionalmetastases and even death.

An intriguing association between NHL andskin malignant tumors is that each of themrepresents the most common secundary malig-nant tumor after developing the other one. [2,3]

In the case of NHL patients and skin cancer,lots of times, around it or nearby the tumor, thereis identified a dense lymphocyte infiltrate, whichwas found in 36% of the patients with chroniclymphocytic leukemia (CLL), containing leu-kemia B cells in 75% of the cases. The presence ofthe leukemia infiltrate may influence theprobabilty of having a clear view of the realmargins of the tumor, also increasing the risk formetastases and relapse, due to some immuno-supressor factors released by leukemia B cellswith inhibiting the anti-tumor immunologicalresponse.[4]

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evidenþiat cã incidenþa celui de-al doilea tip decancer a fost ridicatã în comparaþie cu cea dinpopulaþia generalã de aceeaºi vârstã ºi sex. Risculpentru toate tipurile de cancer în curs dedezvoltare la pacienþii cu LLC, a fost dovedit a fide 8 ori mai mare pentru cancerul de piele ºi de 2ori mai mare pentru toate tipurile de cancer, cuexcepþia cancerului de piele.[5]

Aproximativ în acelaºi timp, Santoro ºi colab.la Institutul Naþional al Tumorilor din Milano, auraportat studii cu privire la incidenþa unui aldoilea neoplasm primar în 82 de cazuri conse-cutive de LLC. La 19,5% dintre pacienþi, unneoplasm asociat a fost diagnosticat ulterior sauconcomitent cu LLC. Carcinoamele localizate lacap ºi gât ºi cancerul de sân au avut cea mai mareincidenþã. Rezultatele acestui studiu susþin încontinuare ipoteza cã pacienþii cu LLC suntpredispuºi sã dezvolte cancere.[6]

Într-un alt studiu, Hartley ºi colab. audocumentat tendinþa mare de CSC cu recidivãlocalã ºi metastaze în ganglionii limfatici lapacienþii cu LLC. În acest studiu, 60% dintrepacienþi au avut mai multe carcinoame primare.[7]

Larsen ºi colab. au raportat un caz de CSC laun pacient cu LLC care a recidivat local dupãexcizie ºi ulterior a metastazat la distanþã întimpul tratamentului cu fludarabinã.[8]

Într-o altã serie de caz Weimar ºi colab. austudiat comportamentul a 4 CSC ºi 3 CBC la 7pacienþi cu LLC. Tumorile de piele au recidivat înmod repetat dupã tratamentul convenþional ºi aucrescut la dimensiuni mari. CSC a metastazat latoþi cei 4 pacienþi cu LLC.[9,10,11]

Mulþi alþi factori joacã de asemenea un rolimportant în imunosupresia din cadrul LLC,incluzând nivelurile scãzute ale complementului,modificarea complexului major de histocompa-tibilitate, hipogamaglobulinemia, insuficienþagranulocitarã, expresia alteratã a receptorilorgenelor regiunii variabile.

Este foarte posibil ca o mutaþie în anumitelocaþii, cum ar fi defecte ale cromozomului 17q, sãinfluenþeze agresivitatea nu numai a LLC, dar ºia cancerului de piele.

Alte ipoteze cu privire la asocierea canceruluide piele cu bolile hematologice includ anomaliilegenetice, variaþiile HLA, agenþii patogeni viralicare pot provoca aberaþii genetice comune ºi

In the United States, a retrospective analysisbetween 1955 and 1974, performed by Manusowand Weinerman on 102 patients with CLL,showed that the incidence of the second type ofcancer was high in comparison to the one in thegeneral population with the same age and sex.The risk for all types of developing cancer in theCLL patients was shown to be 8 times higher forskin cancer and 2 times higher for all types ofcancer, except for skin cancer. [5]

About the same time, Santoro et. al, at theNational Institute of Tumors in Milan, reportedstudies regarding the incidence of a secondprimary neoplasm in 82 consecutive cases ofCLL. In 19.5% of the patients, an associatedneoplasm was diagnosed subsequently or at thesame time as CLL. The carcinomas localized inthe head and neck and breast cancer had thehighest incidence. The results of this studycontinue to support the idea that CLL patients areprone to develop a type of cancer.[6]

In another study, Hartley et. al made someresearch upon the high tendency for SCC withlocal relapse and metastases in the lymphaticganglions in CLL patients. In this study, 60% ofthe patients had multiple primary carcinomas. [7]

Larsen et. al reported a case of SCC in a CLLpatient, which had a local relapse after excisionand it subsequently metastasized during theFludarabine treatment. [8]

In another case series, Weimar et. al studiedthe behaviour of 4 SCC and 3 BCC in 7 patientswith CLL. Skin tumors had repeated relapsesafter the conventional treatment and reachedlarge sizes. SCC metastasized in all the CLLpatients. [9,10,11]

Lots of factors also play an important part inimmunodepression within CLL, including com-plement low levels, changes of the histo-compatibility major complex, hypogamma-globulinemia, granulocyte failure, altered expres-sion of variable region gene receptors.

It is very probable that a mutation in certainlocations, such as 17q chromosome defects, mayinfluence not only the CLL aggressiveness, butalso that of skin cancer.

Other hypotheses regarding the associationof skin cancer to malignant blood diseasesinclude genetic abnormalities, HLA variations,viral pathogenic agents that may cause common

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predispun individul atât la boli hematologice câtºi la cancer de piele.

Mai mulþi factori pot influenþa reapariþia can-cerelor cutanate. Aceºtia includ comportamentulbiologic al tumorii, starea imunologicã a pacien-tului ºi tratamentul efectuat. Comportamentulbiologic al cancerului de piele este parþial de-pendent de modelul histologic al tumorii.

Sistemul imunitar al pacientului contribuie ºila capacitatea de apãrare a gazdei pentru a limitarecurenþele ºi metastazele cancerului de piele.

Rata de recurenþã a carcinomului bazocelular,chiar ºi dupã un tratament corect, este semni-ficativ mai mare la pacienþii cu un deficit alsistemului imunitar, cum ar fi pacienþii culeucemie mieloidã cronicã, comparativ cu per-soanele cu un sistem imunitar intact.

Existã unele sugestii în care agenþii dealchilare ºi analogii purinei pot fi asociaþi cu oincidenþã crescutã a tumorilor maligne secundareîn LLC. Tratamentul este cel al bolii hematologicede bazã.[12]

Referindu-ne la Carcinomul mixt ( scuamos ºibazocelular) sau metatipic, prezent ºi la cazulnostru, amintim cã existenþa de carcinoamebazocelulare cu caracteristici de carcinom cucelule scuamoase a fost postulatã pentru primadatã în 1922. Unii autori considerã cã reprezintã otranziþie de la carcinom bazocelular la carcinomcu celule scuamoase. Aceastã tumorã are oactivitate proliferativã mare, tendinþã dedistrugere la nivel local ºi potenþial pentrumetastaze precoce regionale ºi la distanþã,comportament care îl diferenþiazã de CBC.

Carcinomul metatipic sau mixt are oincidenþã de 3-4% ºi poate fi considerat ca o nouãentitate de cancer de piele, fiind o tipologieintermediarã între carcinoamele cu celule bazaleºi carcinoamele cu celule scuamoase.

Diagnosticul diferenþial include carcinomuladenoid chistic, carcinomul nediferenþiat cucelule mici, carcinomul bazocelular convenþionalºi carcinomul cu celule scuamoase.[13,14]

Leziunile cutanate apar la 25 % dintre pacienþiicu LLC. Acestea pot fi cauzate de infiltrareacutanatã cu celule leucemice (leukemia cutis) ºialte boli maligne sau tulburãri non-maligne.Prognosticul pacienþilor cu LLC ºi leukemia cutiseste bun, dupã unii autori care susþin cã aceastanu afecteazã în mod semnificativ supravieþuirea

genetical aberrations, predisposing theindividual both to blood diseases, as well as toskin cancer.

More factors may influence the relapse ofskin cancers. These include the tumor biologicalbehaviour, the patient’s immunological state andthe performed treatment. The biological behaviorof skin cancer is partially dependent on thehistological pattern of the tumor.

The patient’s immunitary system also contri-butes to the defence ability of the host, in order tolimit recurrences and metastases of skin cancer.

The recurrence rate of basal cell carcinoma,even after an accurate treatment, is significantlyhigher in the patients with an immunitary systemdeficit, such as patients with chronic myeloidleukemia, in comparison to the individualshaving an intact immunitary system.

There are some suggestions where the purineanalogues and alkylation agents may be asso-ciated to a high incidence of secundary malignanttumors in CLL. The treatment is the one per-formed in the basic blood disease. [12]

Referring to Mixt carcinoma (squamous andbasal cell), present in our case as well, we statethat the presence of basal cell carcinomas withcharacteristics of squamous cell carcinoma, wasfristly postulated in 1922. Some authors considerthat it represents a transition from basal cellcarcinoma to a squamous cell carcinoma. Thistumor has a high proliferative activity, a tendencyof local damaging and a potential for earlyregional and distance metastases, a behaviourthat differentiates it from BCC.

The mixt carcinoma has an incidence of 3-4%and may be considered a new entity of skincancer, representing an intermediary typebetween basal cell carcinomas and squamous cellcarcinomas.

The differential diagnosis includes cysticadenoid carcinoma, small cell non-differentiatedcarcinoma, conventional basal cell carcinoma andsquamous cell carcinoma.[13,14]

Skin lesions appear in 25% of the CLL patients.These may be caused by the skin infiltration withleukemia cells (leukemia cutis) and othermalignant diseases or non-malignant conditions.The prognosis of patients with CLL and leukemiacutis is a good one, according to some authorswho state that this does not significantly alter the

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pacienþilor. Alþi autori considerã prognosticul cafiind rezervat.[15]

Concluzii

1. Pacienþii imunodeprimaþi, cu boli hema-tologice ºi cancer de piele asociat, ar trebuisã fie trataþi prompt pentru a reduce risculde recidivã ºi metastazare.

2. Auto-examinarea regulatã a pielii, exa-menele dermatologice periodice ºifotoprotecþia sunt recomandate la aceºtipacienþi cu risc ridicat.

3. Comunicarea regulatã între dermatologi ºihematologi va ajuta la identificareapacienþilor cu boli hematologice careprezintã un risc ridicat de a dezvolta adoua neoplazie (un cancer de piele).

4. Diferitele modalitãþi terapeutice utilizatepentru tratarea bolilor hematologicemaligne ar putea accentua în continuareimunosupresia prin epuizarea sistemuluiimunitar, favorizând astfel diverse boliinfecþioase ºi apariþia celei de-a douaneoplazii.

5. Creºterea gradului de conºtientizare aacestei asocieri este justificatã. Dezvol-tarea viitoare a strategiilor de supra-veghere poate fi necesarã pentru o popu-laþie tot mai mare de pacienþi care ausupravieþuit ºi care au risc pentru a douaneoplazie non-hematologicã.

patient’s survival. Other authors consider thatthe prognosis should remain a reserved one.[15]

Conclusions

1. The immunodepressed patients, withblood diseases and associated skin cancer,should be promptly treated in order toreduce the risk for relapse and metastases.

2. Frequent self-examination of the skin,periodical dermatological examinationsand sun-protection are recommended forthe patients with a higher risk.

3. Frequent communication between derma-tologists and haematologists will help toidentify the patients with blood diseasethat present a higher risk for developing asecond neoplasia (a skin cancer).

4. The various treatment methods used fortreating malignant blood diseases maycontinue to influence immunodepressionby depleting the immunitary system, thusfavouring various infectious diseases andemergence of a second neoplasia.

5. Improving the acknowledgment of thisassociation is a justified one. A futuredevelopment of monitoring strategiesmay be necessary for a larger populationof surviving patients, who have a risk fora second non-haematological neoplasia.

Bibliografie/ Bibliography

1. http://www.umfcv.ro/files/8/82304.pdf2. Travis LB, Curtis RE, Hankey BF, et al. Second cancers in patients with chronic lymphocytic leukemia. J Natl

Cancer Inst. 1992; 84:1422-1427. 3. Skin Cancer in Patients with Non-Hodgkin's Lymphoma. Jerry D Brewer, Expert Rev Dermatol. 2010;5(5):525-533.4. Smoller BR, Warnke RA. Cutaneous infiltrate of chronic lymphocytic leukemia and relationship to primary

cutaneous epithelial neoplasms. J Cutan Pathol. 1998;25:160-164.5. Manusow D, Weinerman BH. Subsequent neoplasia in chronic lymphocytic leukemia. JAMA. 1975;232:267-269.6. Santoro A, Rilke F, Franchi F, et al. Primary malignant neoplasms associated with chronic lymphocytic leukemia.

1980; 66:431-437. 7. Hartley BE, Searle AE, Breach NM, et al. Aggressive cutaneous squamous cell carcinoma of the head and neck in

patients with chronic lymphocytic leukaemia. J Laryngol Otol. 1996;110:694-695. 8. Larsen CR, Hansen PB, Clausen NT. Aggressive growth of epithelial carcinomas following treatment with

nucleoside analogues. Am J Hematol. 2002;70:48-50.

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9. Weimar VM, Ceilley RI, Goeken JA. Aggressive biologic behavior of basal- and squamous-cell cancers in patientswith chronic lymphocytic leukemia or chronic lymphocytic lymphoma. J Dermatol Surg Oncol. 1979;5:609-614.

10. Agnew KL, Ruchlemer R, Catovsky D, et al. Cutaneous findings in chronic lymphocytic leukemia. Br J Dermatol.2004;150:1129-1135.

11. Mehrany K, Weenig RH, Pittelkow MR, et al. High recurrence rates of basal cell carcinoma after Mohs surgery inpatients with chronic lymphocytic leukemia. Arch Dermatol. 2004;140:985-988.

12. Jerry D Brewer. Expert Rev Dermatol. 2010; 5 (5): 525-533. Skin Cancer in Patients with Non-Hodgkin'sLymphoma.

13. Journal of Experimental & Clinical Cancer Research 2008, 27:65 doi: 10.1186/1756-9966-27-6514. Philip R. Cohen, MD, Keith E. Schulze, MD, Bruce R. Nelson, MD. South Med Journal. 2005; 98(7):740-747.15. Robak E. Robak T. Leuk Limphoma 2007 May; 48(5):855-65.

Conflict de interese Conflict of interestNEDECLARATE NONE DECLARED

Adresa de corespondenþã: Prof univ. dr. Virgil Pãtraºcu, Universitatea de Medicinã ºi Farmacie din Craiova, Strada Petru Rareº, Nr. 2-4, 200345, Craiova, România, Tel: 004-0724273676, e-mail: [email protected]

Correspondance address: Virgil Pãtraºcu, MD, PhD, University of Medicine and Pharmacy from Craiova, Petru Rares Street, No 2-4, 200345, Craiova, Romania Phone: 004-0724273676,e-mail: [email protected]

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