Correspondence 446 S Hongeng1,2 1Division of Hematology/Oncology, draining ears, eczematoid dermatitis, and bloody diarrhea. S Pakakasama1,2 Department of Pediatrics, Pediatr 1954; 13: 133–139. P Hathirat1,2 3Division of Hematology, 3 Kwan S-P, Lehner T, Hagemann T et al. Localization of the W Chaisiripoomkere2,3 Department of Medicine and gene for Wiskott–Aldrich syndrome between two flanking A Ungkanont2,3 2Bone Marrow Transplant Program, markers TIMP and DXS255, on Xp11.22-Xp11.3. Genomics 1991; 10: 29–33. Ramathibodi Hospital, 4 Zhu Q, Watanabe C, Liu T et al. Wiskott–Aldrich Mahidal University syndrome/X-linked thrombocytopenia: WASP gene, Rama VI Rd, Bangkok 10400, Thailand mutations, protein expression, and phenotype. Blood 1997; 90: 2680–2689. 5 Parkman R, Rappeport J, Geha R et al. Complete correction of the Wiskott–Aldrich syndrome by allogeneic bone marrow transplantation. New Engl J Med 1978; 298: 921–927. References 6 Brochstein JA, Gillio AP, Ruggiero M. Marrow transplan- tation from human leukocyte antigen-identical or haploident- ical donors for correction of Wiskott–Aldrich syndrome. J 1 Wiskott A. Familiarer, angeborener Morbus Werholfii? Mon- Pediatr 1991; 119: 907–912. atschrift Kinderheilkunde 1937; 68: 212–216. 7 Ozsahin H, Deist FL, Benkerrou M et al. Bone marrow trans- 2 Aldrich RA, Steinberg AG, Campbell DC. Pedigree demon- plantation in 26 patients with Wiskott–Aldrich syndrome from strating a sex-linked recessive condition characterized by a single center. J Pediatr 1996; 129: 238–244.

Multifocal reversible epithelial dysplasia changes with highly atypical features such as enlarged mimicking carcinoma in situ after hyperchromatic nuclei. conditioning therapy with busulfan and Further patient work-up revealed multifocal epithelial changes diagnosed by histology and/or cytology. Moder- cyclophosphamide ate dysplasia and parakeratosis were demonstrated in a of the oral mucosa. The gastric and antral mucosa Prolonged treatment with alkylating agents may induce and mucosa of the colon displayed atrophic changes. A changes in both squamous and non-squamous epithelium biopsy of the duodenal mucosa showed normal epi- similar to those seen in spontaneous epithelial dysplasia and thelium, but irregular nuclear enlargement in Brunner’s carcinoma in situ.1,2 We report a patient who developed glands. These changes were classified as mild to moderate reversible multifocal epithelial cell changes after condition- dysplasia. Both squamous cells and ciliated cells produced ing therapy with busulfan and cyclophosphamide followed by bronchial alveolar lavage revealed severe dysplastic by autologous peripheral stem cell transplantation for changes. Biopsy of the bronchus showed atrophic mucosa AML. with severe atypia consistent with carcinoma in situ A 40-year-old woman was diagnosed with acute (Figure 1c, d). Urothelial cells evaluated by exfoliative myeloid leukemia, subtype M5. A total of three induction urinary cytology displayed changes such as enlarged and cycles including two with cytarabine, thioguanine and irregular nuclei which were regarded as dysplastic. daunorubicin and one with high-dose cytarabine and The diagnosis of a chemotherapy-induced wide-spread mitoxantrone were administered. Complete remission was epithelial dysplasia was made and the patient was followed- achieved after the first cycle. Cells for autologous stem up closely. cell transplantation were mobilized by a single dose of A control cervical smear 2 months after the cone biopsy cyclophosphamide (2500 mg/m2). Conditioning therapy showed regression of the cellular atypia with few remain- was busulfan (4 mg/kg for 4 days, total of 1250 mg), fol- ing dyskaryotic cells. Further cytological examinations of lowed by cyclophosphamide (50 mg/kg for another 4 days, cervical, urothelial and bronchial cells revealed no evi- total of 14.4 g). Thereafter, peripheral stem cell transplan- dence of dysplasia during a follow-up period of 2 years. tation was performed. Acute toxicity observed was WHO The first report of cytologic atypia following chemo- grade IV mucositis. As a complication of myelo-ablative therapy was published in 1955.3 Cytologic changes in therapy hepatic veno-occlusive disease occurred 2 weeks different locations varying from a ‘polychromatic and after transplantation and was successfully treated by pro- polymorphous smear type’4 to -mimicking alter- staglandin E1 infusion. ations5 have been described in patients after receiving Four months after cessation of chemotherapy, a routine alkylating substances. Changes described were enlarge- cervical smear revealed severe cytological changes ment of cells, marked nuclear enlargement and hyperch- which were interpreted as a high-grade squamous intra- romatism.2 epithelial lesion (PAP IVa; CIN III) of the cervix. Con- We now report for the first time, to the best of our secutively, a cone biopsy and a curettage were perfor- knowledge, the appearance of multifocal intraepithelial med. Sections of the cone biopsy showed histologic lesions mimicking carcinoma in situ after high-dose, changes consistent with intra-epithelial cervical neo- short-term treatment with busulfan and cyclophospham- plasia grade III without any evidence of invasion (Figure ide. Our finding suggests that it is not the duration 1a, b). The endometrial mucosa displayed severe atrophic of treatment, but the dose of the chemotherapeutic Correspondence 447 a b

c d

Figure 1 (a) The cervical smear displays severe dysplastic changes. The nuclei show irregularities of their outline and chromatin condensation (PAP- stain, 40×). (b) Photomicrograph of the cervical cone biopsy showing the loss of polarity in the epithelium. Nuclear abnormality within the epithelium can be seen. No features suggestive of papilloma virus infection are present. This lesion was classified as a high grade intra-epithelial neoplasia (H&E stain, 10×). (c) This group of cells produced by bronchial alveolar lavage has a high nucleocytoplasmatic ratio and hyperchromatic nuclei. Those changes were interpreted as dysplastic (PAS-stain, 40×). (d) The tissue of this bronchus biopsy shows highly atypical cellular changes. These dysplastic cells correlate with the predominant cells in the bronchial alveolar lavage (PAS-stain, 40×).

drug used which is responsible for the development of EC Obermann11Institute of and dysplasia. N Meidenbauer22Department of Hematology and Another important observation is the complete reversi- R Zeltner2 Oncology, University of Regensburg, bility of the dysplastic changes in this patient. None of R Andreesen2 Franz-Josef-Strauss-Allee 11, the epithelial dysplasias persisted or progressed into A Reichle2 93053 Regensburg, Germany invasive forms of cancer. Furthermore, the dysplastic 1 Hughes RG, Colquhoun M, Alloub M et al. Cervical changes subsided within a few months after diagnosis. intraepithelial neoplasia in patients with breast cancer: However, prospective clinical studies are necessary to a cytological and colposcopic study. Br J Cancer 1993; determine if such early lesions are indicators of an 67: 1082–1085. increased risk for the development of secondary malig- 2 Stella F, Battistelli S, Marcheggiani F et al. Urothelial nancies in the long term. cell changes due to busulfan and cyclophosphamide We suggest keeping the possibility of chemotherapy- treatment in bone marrow transplantation. Acta Cytol induced changes in mind if dysplastic alterations of the 1990; 34: 885–890. epithelium are seen in patients who have received 3 Weston JT, Guin GH. Epithelial atypias with chemo- alkylating substances, even for a short time. According therapy in 100 acute childhood leukemias. Cancer to our experience, close monitoring is adequate to follow 1955; 8: 179–186. such dysplastic changes. In order to differentiate between 4 Kraus H, Schuhmann R, Ganal M, Geier G. Cytological chemotherapy-induced dysplasia and pre-existing dys- findings in vaginal smears from patients under treatment plasia, cytological examination of cervical, bronchial and with cyclophosphamide. Acta Cytol 1977; 21: 726–730. urothelial cells should routinely be performed prior to 5 Forni AM, Koss LG, Geller W. Cytological study of treatment. the effect of cyclophosphamide on the epithelium of the urinary bladder in man. Cancer 1964; 17: 1348–1355.