Distal Limb Infiltration by Transformed Lymphoplasmacytoid Lymphoma.
Authors: Cavet James , Wiseman Daniel 
Published: October 2019

Abstract
We report 2 cases of lymphoplasmacytoid lymphoma (LPCL) with aggressive, high-grade transformation accompanied by extensive distal lower limb skeletal disease.
Case 1: a 26-year-old man with stage IVA anaplastic Ki-1+ NHL achieved durable CR1 with VAPEC-B induction, AC consolidation & mediastinal radiotherapy. In 1997 he re-presented with lymphadenopathy: biopsy & marrow showed small CD20+CD79a+ B lymphocytes with IgM(κ) light chain restriction & increased mature plasma cells, but no evidence of anaplastic NHL. He received VAD (×6) & autologous PBSCT (melphalan 200mg/m2) to CR1. Relapse in 2004 was treated with cyclophosphamide & dexamethasone, then fludarabine (×4). Ten months later he presented with B symptoms & painful right tibial swelling. MR showed multiple medullary lesions in proximal femoral shafts, tibiae & upper fibulae. CT confirmed widespread lymphadenopathy & bilateral renal deposits. Marrow had dense infiltrate of CD20+CD79a+ small lymphoid cells with additional immature CD20+CD79a+ blasts, consistent with transformation to high-grade DLBCL. New complex cytogenetics included XXY with t(14;22) (IGH rearrangement), add(1q), del(6q), del(9p) & trisomy 3. He received R-mini-BEAM (×2) & 2nd PBSCT (R-BEAM conditioning) in 2006 using residual 1997 PBSCH, acheiving CR4 with bony regression on MRI. Four months later B symptoms & right tibial pain recurred & the disease is currently being held by rituximab & steroid.
Case 2 was diagnosed with WM/LPCL in 1996, aged 54, following 8 years history of IgM MGUS. He received chlorambucil (1996), CVP (×6) (1997), fludarabine (×5) (1999/2000), chlorambucil (2001) rituximab (×8), further fludarabine (×3) (June 2003) & repeated R-CVP (2004/5). In Sept 2005 he presented with lower limb & right heel pain. MR revealed diffuse abnormality within tibiae, fibulae & distal femorae: a soft tissue mass infiltrated the right talus bone, & left calcaneus, talus & anterior malleolus showed patchy involvement. Biopsy of right talus yielded small lymphocytes, lymphoplasmacytoid cells & plasma cells, strongly CD20+ & κ light chain restricted (with smaller % CD138+ cells), in keeping with lymphoplasmocytic lymphoma. Bisphosphonate exacerbated the pain & single fraction of radiotherapy had no effect. He received salvage R-CVP (×6), reducing paraprotein from 6.9 to 2.7g/L. Nevertheless, the bone deposits continue to cause significant discomfort.
Transformation of WM/LPCL to high-grade lymphoma is rare but well-described. Lin et al. describe DLBCL transformation in 13% cases, at median 44 months after diagnosis & associated with poor outcome. Seven of the 12 cases had received cladrabine. Purine analogues have been implicated in pathogenesis of Richter’s syndrome, in which CLL transforms to aggressive NHL (estimated <3% CLL patients). MRI reliably demonstrates marrow involvement in WM/LPCL but changes are diffuse. In contrast to MM, focal skeletal MR abnormalities are not observed in WM/LPCL.
We present 2 cases of LPCL with focal distal lower limb bone involvement. The focal nature of skeletal involvement in sites not active in adult haemopoeisis (& atypical for LPCL or MM involvement), with B symptoms & rapidly progressive NHL are unusual features. Other features include >10year disease course, multiple lines of therapy (incl. purine analogues) & high-grade transformation/behaviour. Involvement of distal bones (e.g. talus) is rare in NHL, & we could find no previous reports of focal distal lower limb LPCL. We observe that LPCL can undergo high-grade transformation (analogous to Richter’s syndrome) with distinct trophic phenotype, & postulate that purine analogues may be implicated in selecting for this behaviour.