Borelli, S.

Herr, D.

Kempf, W.

Trojan, A.

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and differentiate them from other conditions in order toinstitute the appropriate treatment, if this is possible.V. Garipidou1, S. Vakalopoulou1, E. Zafiriadou2,K. Tziomalos1* & V. Perifanis11Haematology Section, Second Propedeutic Department of InternalMedicine, Aristotelian University of Thessaloniki, Ippokration GeneralHospital, Thessaloniki; 2First Radiology Department, IppokrationGeneral Hospital, Thessaloniki; 3Department of Pathology,Aristotelian University of Thessaloniki, Thessaloniki, Greece(* E-mail: ktziomalos@yahoo.com)References1. Jules-Elysee K, White DA. Bleomycin-induced pulmonary toxicity.Clin Chest Med 1990; 11: 1–20.2. Onuma T, Holland JF, Masuda H et al. Microbiological assay of bleo-mycin: inactivation, tissue distribution, and clearance. Cancer 1974;33: 1230–1238.3. Harrison JH Jr, Hoyt DG, Lazo JS. Acute pulmonary toxicity of bleo-mycin: DNA scission and matrix protein mRNA levels in bleomycin-sensitive and -resistant strains of mice. Mol Pharmacol 1989; 36:231–238.4. Sleijfer S. Bleomycin-induced pneumonitis. Chest 2001; 120:617–624.5. Rossi SE, Erasmus JJ, McAdams HP et al. Pulmonary drug toxicity:radiologic and pathologic manifestations. Radiographics 2000; 20:1245–1259.doi:10.1093/annonc/mdi073Published online 24 January 2005Fludarabine: risk factor foraggressive behaviour of squamouscell carcinoma of the skin?Fludarabine, a purine analogue, is effective in the therapy oflow-grade non-Hodgkin’s lymphomas. Side-effects includefever, peripheral neuropathy, pulmonary toxicity and signifi-cant depletion of T-lymphocyte populations. In addition, flareup and aggressive behaviour of squamous cell carcinoma(SCC) during fludarabine therapy has been observed [1].We report on a 65-year-old patient with a lymphocytic B-cell lymphoma (stage IVA) diagnosed in 1997. Owing to anexcess of blasts he was treated according to the German con-sensus protocol for aggressive non-Hodgkin’s lymphoma.However, three cycles of CHOEP (cyclophosphamide, doxoru-bicin, vincristine, etoposide and prednisone) chemotherapyand two cycles of salvage therapy with holoxane, cytosar andvepeside did not produce a response, and led to complicationssuch as Candida esophagitis and generalised herpes zosterinfection. Owing to progressive lymphadenopathy andlymphocytosis, the patient was treated with four cycles ofchlorambucil and prednisone, showing again minimalresponse. In 2001, six cycles of fludarabine led to a nearcomplete remission with reduction of all lymph node manifes-tations and normalisation of peripheral lymphocyte counts.Since the patient’s disease progressed again, a combinedimmunochemotherapy with rituximab and fludarabine wasinitiated in autumn 2002. Again, a near complete clinicalremission was achieved. However, within 2 weeks of thefourth therapy cycle, the patient developed a well-circum-scribed nodule on the right cheek. The tumour impressed witha diameter of 1 cm and a centrally located horn plug.Histology showed a well demarcated invasive proliferationof epithelial cells with squamous differentiation, extendinginto the dermis, a perineural invasion by tumour cells andlymphohistiocytic infiltration at the margins of the neoplasm.Immunohistochemistry revealed that the majority of the infil-trating lymphocytes were CD3+ CD4+ T-helper cells, whereasa few cells expressed CD8 antigen. Complete excision of thelesion was conducted and confirmed by micrographic work-upof the specimen. Two months later the patient presented withregrowth of the tumour. Again, total excision was performedresulting in two further recurrences within the following 3months. Nine months after local consolidating radiotherapy(51 Gy) no further recurrence had occurred.Although differential diagnosis of keratoacanthoma wasconsidered initially, the histological features of perineuralinvasion and infiltrative tumour strands, as well as repeatedtumour recurrence, strongly suggested the diagnosis of SCC[2, 3]. However, aggressive behaviour of the tumour led tothe question of whether in this immunocompromised patienthuman papilloma viruses (HPV), especially HPV 5 and 8,might be involved in the development and unusual clinicalcourse of skin cancer [4]. Accordingly, we performed anested PCR, but did not detect the suspected HPV-specificsequences in the biopsy tissue. Non-Hodgkin’s lymphomason their own or fludarabine may be responsible for theincreased incidence and aggressive behaviour of SCC inthese patients [5]. Thus, we assume that the altered immunestatus in this patient was aggravated by concomitant fludara-bine-induced T-lymphocyte depletion, which thereby facili-tated the growth and aggressive behaviour of this secondarymalignancy [6]. Careful examination of patients at risk willbe warranted in order to detect secondary malignanciesearly and to treat them extensively.D. Herr1, S. Borelli2, W. Kempf 3 & A. Trojan1*1Department of Oncology and 3Clinic of Dermatology, UniversityHospital, Ra¨mistrasse 100, 8091 Zurich; 2Clinic of Dermatology,Triemli Hosital, Zurich, Switzerland(* E-mail: andreas.trojan@usz.ch)References1. Davidovitz Y, Ballin A, Meytes D. Flare-up of squamous cell carci-noma of the skin following fludarabine therapy for chronic lymphocyticleukemia. Acta Haematol 1997; 98: 44–46.5152. Schwartz RA. Keratoacanthoma. J Am Acad Dermatol 1994; 30: 1–19.3. Cherpelis BS, Marcusen C, Lang PG. Prognostic factors for metastasisin squamous cell carcinoma of skin. Deramtol Surg 2002; 28:268–273.4. Meyer T, Arndt R, Nindl I et al. Association of human papillomavirusinfections with cutaneous tumors in immunosuppressed patients.Transpl Int 2003; 16: 146–153.5. Hartley BE, Searle AE, Breach NM et al. Aggressive cutaneous squa-mous cell carcinoma of the head and neck in patients with chronic lym-phocytic leukaemia. J Laryngol Otol 1996; 110: 694–695.6. Larsen CR, Hansen PB, Clausen NT. Aggressive growth of epithelialcarcinomas following treatment with nucleoside analogues. Am JHematol 2002; 70: 48–50.doi:10.1093/annonc/mdi074Published online 27 January 2005Can HER2 overexpression predictresponse to pegylated liposomaldoxorubicin in metastatic breastcancer patients?We conducted a phase II clinical trial to determine the clinicalefficacy and safety of pegylated liposomal doxorubicin incombination with gemcitabine as a first- or second-line treat-ment option in patients with metastatic breast cancer [1].Based on a previous phase II study [2], the recommendeddose was pegylated liposomal doxorubicin 25 mg/m2 intra-venously (i.v.) on day 1 and gemcitabine 800 mg/m2 i.v. ondays 1 and 8, every 21 days. A total of 41 patients wereentered into the study between February 2003 and April 2004.The demographic and baseline clinical characteristics of allpatients are listed in Table 1. Forty-one patients were assessa-ble for response. The overall objective response rate (ORR)was 51% [95% confidence interval (CI) 35.9% to 66.5%],with one complete response (CR) (2.5%) and 20 partialresponses (PRs) (48%). Eleven patients (27%) had evidence ofstable disease (SD), and the remaining nine patients had dis-ease progression (22%).Nineteen women had HER2-overexpressing (2+/3+; DakoHerceptest) breast tumors, while in the other 19 patients breastcancer did not overexpress HER2 (0/1+). HER2 overexpres-sion score 2+ showed amplification at the DNA level detectedby fluorescence in situ hybridization. In three patients HER2expression was not assessed. Concerning patients with HER2-positive tumors, 68% experienced a response (13 patients; oneCR and 12 PRs), while 15.7% had evidence of SD (threepatients) and 15.7% (three patients) had disease progression.Conversely, among women with HER2-negative tumors, theORR was half that observed in HER2-positive cases (31.5%,all PRs), with a rate of SD and PD of 42% (eight patients) and26% (five patients), respectively. Sixty-one per cent ofpatients with HER2-positive disease were endocrine responsive(estrogen receptor and/or progesterone receptor positivetumors). Among 13 women who achieved a response to pegy-lated liposomal doxorubicin plus gemcitabine combination,seven were chemotherapy naı¨ve for metastatic disease, whilesix had previously received chemotherapy. Responses werealso observed in six out of 13 patients with previous anthracy-cline exposure, with a PR rate of 46%.No data on the predictive value of HER2 expression regard-ing response to gemcitabine in breast cancer are currentlyavailable. It has been reported that the gemcitabine–cisplatininteraction is more active than the etoposide–cisplatin inter-action in lung cancer cells with high p185neu expression [3].Elevated levels of HER2 extracellular domain adversely affectthe efficacy of paclitaxel plus gemcitabine in advanced breastcarcinoma [4].Our findings seem to support, even considering the lownumber of patients recruited, a positive interaction betweenHER2 overexpression and sensitivity to pegylated liposomaldoxorubicin, substantially confirming the sensitivity ofTable 1. Characteristics of the patientsCharacteristicTotal patients 41Median age, years (range) 55 (33–71)Pre-/post-menopausal status 4/37Hormonal receptor statusER+/PgR+ 21ER/PgR 16ER+/PgR 3ER/PgR+ 1GradingGrade 1 6Grade 2 15Grade 3 20HER 2 (Dako Herceptest)0/1+ 19 (14/5)2+/3+ 19 (9a/10)Unknown 3Predominant metastatic sitesVisceral 34Bone/soft tissues 7No. of metastatic site1 30$2 11Previous anthracycline treatment 13Adjuvant 9Metastatic 4aAmplification at DNA level detected by fluorescence in situhybridization.ER, estrogen receptor; PgR, progesterone receptor.516

Fludarabine: risk factor for aggressive behaviour of squamous cell carcinoma of the skin?

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