Cutaneous Infiltration as an Indicator of Systemic Disease Progression in Waldenström Macroglobulinemia

Waldenström macroglobulinemia (WM) is a lymphoplasmacytic lymphoma characterized by bone marrow infiltration and elevated serum monoclonal immunoglobulin M (IgM). WM accounts for 1%–2% of hematologic malignancies [1]. It usually follows an indolent course, and extranodal involvement is uncommon, including neurological, renal, and cutaneous manifestations [2]. However, the relationship between cutaneous manifestations and systemic progression remains insufficiently defined. A 60-year-old woman with a family history of a brother affected by WM was diagnosed with the disease in 2012 (negative for MYD88 and CXCR4) after the detection of an IgM monoclonal component and a bone marrow biopsy showing infiltrates of plasmacytoid lymphocytes with kappa light chain restriction, CD20 positivity, and CD5 negativity. She presented to the dermatology department in 2019 with asymptomatic lesions on the trunk with a > 1-year history. Clinical examination revealed multiple confluent erythematous–brownish macules mainly on the abdomen (Figure 1a). Laboratory tests showed hemoglobin of 10 g/dL and an IgM monoclonal spike of 5150 mg/dL. Several skin biopsies were performed, revealing a perivascular lymphoplasmacytic infiltrate CD20+ (Figure 2a–c) with positive clonal rearrangement for the IGH gene, establishing the diagnosis of cutaneous infiltration by WM. Progressive worsening of the cutaneous manifestations was associated with the development of multiple adenopathies confirmed clinically and on computed tomography. First-line treatment with rituximab–bortezomib–dexamethasone was initiated, achieving a very good partial response (defined as a > 90% reduction in the monoclonal component) and a notable attenuation of the cutaneous lesions (Figure 1b), despite early discontinuation due to peripheral neuropathy. A new skin biopsy of residual macules showed persistence of the lymphoplasmacytic infiltrate despite clinical improvement. At follow-up in 2023, the patient again presented with worsening of the abdominal cutaneous lesions, as well as nodules on the left thigh and the medial aspects of both forearms of several months' evolution. A skin biopsy of one of the nodular lesions demonstrated a perivascular lymphoplasmacytic infiltrate consistent with WM infiltration. Immunohistochemistry revealed positivity for CD20, CD79, and IgM; negativity for CD3 and CD5; focal positivity for CD23; and kappa light-chain restriction. This cutaneous relapse was followed months later by anemia and an increase in the monoclonal component, prompting initiation of second-line treatment with zanubrutinib. The patient remains on zanubrutinib with a partial systemic response, attenuation of cutaneous lesions, and disappearance of some nodules. WM is an uncommon indolent B-cell lymphoma typically diagnosed in older adults [1, 3]. Its most common manifestations include asthenia (often secondary to anemia), constitutional symptoms, adenopathy, and splenomegaly [1]. Cutaneous involvement is uncommon and variably reported and can be classified as neoplastic (direct infiltration by lymphoplasmacytic cells) or non-neoplastic (paraproteinemia-associated). Neoplastic cutaneous involvement may present with infiltrated plaques, papules, or tumors, with variable anatomic distribution [2]. Classic descriptions report red-brown papules and plaques with variable distribution [4]. In the published series, infiltrated plaques and nodules represented the predominant clinical patterns, although presentations were heterogeneous among patients [2]. In contrast, our patient exhibited brownish macules and subsequently indurated nodules without facial involvement, representing an atypical phenotype. Whether isolated cutaneous infiltration should lead to systemic treatment remains uncertain, as its prognostic value and relationship with systemic progression are not well established [2]. In the present case, however, cutaneous worsening consistently preceded systemic relapse, suggesting that skin involvement may act as an early clinical indicator of disease activity [5]. From a practical standpoint, cutaneous infiltration may therefore justify closer systemic monitoring, even in the absence of other signs of progression. Nevertheless, this observation should be viewed as hypothesis-generating, since cutaneous involvement has not been shown to be an independent prognostic factor in WM, despite similar skin–systemic associations reported in other indolent B-cell lymphoproliferative disorders [2, 4]. The authors have nothing to report. The authors declare no conflicts of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.