Ivana Ilić

Lack of prognostic significance of the germinal-center phenotype in diffuse large B-cell lymphoma patients treated with CHOP-like chemotherapy with and without rituximab

The influence of the germinal-center B-cell (GCB) and the non-GCB phenotypes of diffuse large B-cell lymphoma (DLBCL) on the outcome of 92 patients treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP-like chemotherapy, with or without rituximab was determined in this study. The differentiation between the GCB and non-GCB types was arrived at by immunohistochemistry using previously published criteria. Thirty-nine patients had the GCB and 53 had the non-GCB type of DLBCL. Forty-nine patients were treated with rituximab and chemotherapy; 43 were treated with chemotherapy alone. The GCB and non-GCB group did not differ in their international prognostic index factors and score, presence of bulky disease, or frequency of rituximab treatment. Median follow-up of the surviving patients was carried out for 37 months. There was no difference between the GCB and non-GCB groups in both overall response rates (67 vs. 70%, respectively) and estimated rates of 3-year event-free (46 vs. 49%, respectively) and overall (54 vs. 56%, respectively) survival. In addition, no differences of the outcomes were observed between the subgroups treated with or without rituximab. The patients of this study with immunohistochemically determined GCB-type DLBCL did not have an improved prognosis, irrespective of whether they had received rituximab or not.

Prognostic significance of survivin and caspase-3 immunohistochemical expression in patients with diffuse large B-cell lymphoma treated with rituximab and CHOP.

Survivin is an inhibitor of apoptosis whose expression may be associated with inferior outcome in patients with diffuse large B-cell lymphoma (DLBCL) treated without rituximab. Caspase-3 is the final caspase of the apoptotic cascade and its pattern of expression may also be related to patients’ outcome. In this study we investigated immunohistochemical expression of survivin and caspase-3 (CPP32) in 57 patients with DLBCL treated with rituximab and CHOP (R-CHOP). According to previously published criteria, we separately analyzed correlation of different types of survivin expression with patients’ outcome. Nuclear survivin was expressed in only 26% of cases, cytoplasmic survivin was expressed in 81% of cases while application of immunoreactivity scoring system yielded 58% of survivin positive cases. Caspase-3 was expressed in 77% of cases. There were no significant correlations between any type of survivin expression and response to treatment or survival of the patients. The expression of caspase-3 was also not associated with patients’ outcome. We conclude that survivin and caspase-3 have no significant prognostic significance in patients with DLBCL treated with R-CHOP.

High frequency of cutaneous manifestations including vitiligo and alopecia areata in a prospective cohort of patients with chronic graft-vs-host disease.

Aim To determine the frequency and the characteristics of cutaneous manifestations, especially vitiligo and alopecia areata, in patients with chronic graft-vs-host disease (cGVHD). Methods 50 patients with cGVHD were prospectively enrolled in the observational study protocol and evaluated by an experienced dermatologist. The evaluation was focused on the clinical spectrum of skin and adnexal involvement, and the cutaneous GVHD score was determined according to National Institutes of Health (NIH) Consensus criteria. The presence of vitiligo, alopecia, xerosis, nail changes, and dyspigmentation was also assessed. Results Out of 50 cGVHD patients, 28 (56%) had skin involvement, and 27 of them (96%) had hypo and/or hyperpigmentations. 11 patients (39%) had a mild cutaneous NIH cGVHD score, 22% moderate, and 39% severe. 15 (30%) patients had nail changes and 10 (20%) had vitiligo or alopecia areata. Univariate analysis showed that patients with vitiligo/alopecia areata received more lines of prior systemic immunosuppressive therapy (P = 0.043), had lower Karnofsky performance status (P = 0.028), and had a higher B-cell number (P = 0.005), platelet count (P = 0.022), and total protein (P = 0.024). Vitiligo and alopecia areata were associated with higher NIH skin score (P = 0.001), higher intensity of immunosuppressive treatment (P = 0.020), and total body irradiation conditioning (P = 0.040). Multivariate regression model showed that patients with higher NIH skin scoring were 3.67 times more likely to have alopecia and/or vitiligo (odds ratio 3.67; 95% confidence interval 1.26-10.73), controlled for all other factors in the model (age at study entry, number of B-cells, platelet count, and global NIH score). Conclusion These data indicate that vitiligo and alopecia areata occur more frequently in cGVHD than previously reported.

Juvenile Onset Hypopigmented Mycosis Fungoides: A Case Series Of 3 Patients

Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma (CTCL). Primary cutaneous lymphomas (PCLs) are exceedingly rare in children and adolescents, with mycosis fungoides (MF) being the most frequent PCL diagnosed in childhood. The incidence of MF is 6.4 per 1, 000, 000 per year in adults, but the occurrence in children and young adults is rare and has not been well established yet. Hypopigmented mycosis fungoides (HMF) is an atypical and rare subtype of MF characterized by solely hypopigmented patches or in combination with erythematous patches or plaques. There are no criteria that define a typical case of HMF. We present three cases of juvenileonset HMF at Department of Dermatology and Venereology, University Hospital Center Zagreb between November 2014 and January 2015. Patients were between 9 and 12 years old at the time of diagnosis. The diagnosis was reached based on clinical, histopathological and immunohistochemical correlation. All patients were investigated at the time of diagnosis with complete blood count, peripheral smear, ultrasonography of abdomen and pelvis, and chest X-ray. They were all without extracutaneous progression of disease. Narrowband UVB (311nm) phototherapy and/or potent topical steroids were used as a first- line treatment. HMF is rare in Caucasians and with only few cases described in children. Juvenile-onset MF is often misdiagnosed at early stages as benign condition. HMF may simulate atopic dermatitis, pityriasis alba, pityriasis lichenoides, tinea versicolor, vitiligo, postinflammatory hyperpigmentation or leprosy (Hansen? disease). Although HMF has good prognosis, it is a malignant skin lymphoma and should always be treated as such. Treatment modalities for juvenile MF are based on general strategies for adults according to disease stage.

Burkitt lymphomas failing dose-adjusted R-EPOCH (DA-R-EPOCH)

Dear Editor, Adults with Burkitt lymphoma/leukemia (BL) are usually treated with high-dose methotrexate-based chemotherapy and rituximab (R-HD-MTX)-containing regimens. While exact drug combinations and schedules vary, all contain HD-MTX and all result in similar outcomes [1–7]. Survival (OS) ranges from 70 to 90 % and treatment-related mortality (TRM) is 10–20 %. Recently, excellent results with doseadjusted R-EPOCH (DA-R-EPOCH) have been reported with 100 % OS and 0 % TRM [8]. We therefore tried DAR-EPOCH in patients with BL and high risk of complications but were unable to obtain comparable results. DA-R-EPOCH was administered in hospital in accordance with published guidelines [9]. HIV-infected patients were continued on highly active antiretroviral therapy (HAART). Our first patient was a 39-year-old woman admitted to another hospital. After 1 month, a diagnosis of BL stage IVB was made and the patient transferred to us. She was in poor condition with massive intra-abdominal disease, bone marrow infiltration, hypercalcemia, and kidney failure. One cycle of DA-R-EPOCH resulted in tumor regression. Blood counts normalized after 2 weeks, but pulmonary and neurological dysfunction progressed and she died within a month from multiorgan failure. The second patient was a 34-year-old man who presented with ophthalmoplegia. An epipharyngeal tumor and HIV infection were found. Diagnostic evaluation showed stage IVB BL with involvement of lymph nodes, epipharynx, liver, and bone marrow. He achieved complete remission (CR) after three DA-R-EPOCH cycles. Dose escalations were continued for five cycles, and a dose reduction was necessary in the sixth. The epipharynx was irradiated. Five months after the end of immunochemotherapy, he relapsed with a submandibular nodal mass. The patient received four cycles of our R-HD-MTX-based regimen [7], achieved CR, and was autografted. He is well and free of disease 3 months after transplantation and 18 months after diagnosis. The third patient was a 37-year-old man with AIDS responding to HAART. He had stage IVB BL with a large intra-abdominal mass, abdominal wall, and small bowel involvement. CR was achieved after three cycles of DA-REPOCH. Dose escalations were continued for four cycles. Two weeks after the end of sixth cycle, he relapsed with a large intra-abdominal mass. He failed to respond to multiple lines of chemotherapy, including our standard regimen, and radiotherapy and died 1 year after diagnosis. After this, we switched back to using R-HD-MTX in all patients with BL and did not have any failures since. Our limited experience with DA-R-EPOCH is different from the originally reported [8]. DA-R-EPOCH is less toxic and easier to administer than R-HD-MTX but might not be without TRM and as effective as described. These discrepancies are probably caused by differences in referral patterns. The first patient, who was referred too late, serves to illustrate that in such instances, toxic deaths will occur I. Aurer (*) : S. Basic-Kinda : I. Radman Division of Hematology, Department of Internal Medicine, University Hospital Centre Zagreb, Kispaticeva 12, 10000, Zagreb, Croatia e-mail: aurer@mef.hr

Neonatal hyperimmune T-cell reaction mimicking T-cell non-Hodgkin's lymphoma following BCG and hepatitis B co-vaccination

We describe a case of a 2-week-old male infant who presented with a rapidly enlarging inguinal mass after having received both the bacille Calmette–Guérin (BCG) and hepatitis B vaccines at birth. The clinical picture raised suspicion of a neoplasm, and an excision biopsy was performed. It showed complete effacement of the lymph node architecture by a diffuse proliferation of monomorphic, mitotically active, and medium-sized T-cell blasts with strong expression of CD99. Coalescent necrotizing granulomas were also seen. The lymph node culture was negative for BCG. Upon expert review and additional molecular diagnostics, the initial pathological diagnosis of lymphoblastic T-cell lymphoma was changed to ectopic BCG lymphadenitis and hyperimmune post-vaccinal reaction. The atypical T-cell proliferation was most likely a result of the adjuvant effects of the co-administered vaccines. Post-vaccinal reactions usually involve the injection site or result in localized lymph node enlargements in the areas draining the inoculation site. This case highlights the importance of the clinical context for accurate interpretation of the pathological findings. In the setting of post-vaccinal lymphadenopathy, a biopsy is rarely needed but, when performed, should be interpreted with great caution.