Comprehensive Biological and Molecular Characterization of a RARE Case of Cutaneous Richter Syndrome

BACKGROUND

Richter syndrome (RS) is associated with unmutated VHIG status, VHIG 4 -39 sequences, stereotyped B-cell receptors and expression of ZAP70, CD38 and CD49d, as well as with a frequent disruption of TP53, ATM and CDKN2A, and mutational activation of NOTCH1. RS presents with extranodal involvement including gastrointestinal tract, lung, kidney, eye, testis, central nervous system, and skin. Extranodal RS presenting as skin lesion is extremely rare with only few cases reported and a biological and molecular characterization of these cases is still lacking. On the basis of these observations, we undertook a comprehensive characterization of a rare cutaneous RS transformation of CLL to DLBCL and investigated prognostic biological implications.

CASE

A 59 year-old woman affected by CLL, stage III/B, 13q14 and 11q23 deletion, presenting massive splenomegaly and pleural effusion underwent treatment with fludarabine-cyclophosphamide and rituximab (FCR). Third cycle was complicated by prolonged neutropenia, and chemotherapy was discontinuated. CT scan documented complete remission and bone marrow (BM) biopsy showed initial myelodysplastic features and presence of 7q deletion. Complete remission (CR) with incomplete recovery was achieved, and patient continued follow-up. As persistent neutropenia was observed, subsequent BM evaluation was performed showing unchanged morphology and normal cytogenetic. No signs of CLL relapse were present.

Eight years later, the patient presented edema of the right foot, rapidly worsened until prevent independent walking. Numerous hard papules and plaques appeared and multiple nodules were appreciable in subcutaneous tissue of both thighs and legs. B symptoms were absent.

CBC count showed persistent mild leucopenia and LDH levels were not increased,

Ultrasound of foot soft tissues revealed an organized anechoic nodal mass. Hystological examination documented a diffuse proliferation of large lymphoid cells, with a centroblastic morphology infiltrating the subcutaneous soft tissues displaying the following immunophenotype: CD20+, CD3-, CD5+, CD23+/-, cyclinD1-, bcl2+, CD10- bcl6-, MUM1+/-, EBV-, ZAP70-, p53 -, Ki67 40-50%.

11q23 deletion was also observed by FISH on formalin-fixed, paraffin embedded section suggesting that cutaneous lymphoma and leukemia arose from the same clone.

Furthermore, NOTCH1 hotspot mutation (c.7544_7545delCT) was absent both on foot soft tissues sample and on cryopreserved peripheral blood of CLL diagnosis.

CT scan was normal except for mild splenomegaly, while Positron Emission Tomography (PET) showed intense uptake on right ankle, multiple nodular in subcutaneous tissue of lower limbs and feet.

Cutaneous DLBCL consistent with RS was diagnosed and patient received 6 courses of R-CHOP. PET after 3 cycles of treatment show reduction of uptake and an evaluation at the end of therapy confirmed CR of RS that continued after 12 months of follow-up.

CONCLUSION

Cutaneous RS is exceptionally rare with only few reports or small case series described in literature In this study, we present a case of cutaneous RS occurred in patient in CR after chemo-immunotherapy for CLL. To the best of our knowledge, this is the first investigation assessing a comprehensive biological and molecular characterization of cutaneous RS case. Finally, we pointed out as the present case is interesting since it may represent a model of RS that diverges in prognosis from nodal involvement.