Rapidly Progressive Cutaneous Nodules in an Elderly Woman

An 83-year-old woman previously diagnosed with ulcerative colitis presented to our department with a 1-year history of a progressively enlarging lesion localised to the left lower extremity. Initially, the lesion appeared as a poorly demarcated, non-tender erythematous plaque. She underwent multiple courses of antibiotic therapy under the clinical suspicion of cellulitis; however, no clinical improvement was observed. In the 3 months preceding consultation, the lesion evolved into multiple firm, non-tender nodules, progressively increasing in size and number, ultimately impairing her ability to ambulate. She reported unintentional weight loss over the past year and denied the presence of any other systemic symptoms. Physical examination revealed multiple well-circumscribed, indurated nodules with smooth surfaces distributed over the left lower extremity. Some nodules exhibited superficial ulceration with an erythematous and hyperpigmented base (Figure 1). An excisional biopsy of a nodule was performed. Immunohistochemical staining demonstrated positivity for CD20, MUM1 and PAX5, with nuclear c-MYC expression in approximately 30% of tumour cells (Figure 2). The neoplastic cells were negative for CD3, CD30 and CD138. Complete blood count revealed normocytic anaemia, with a haemoglobin level of 10.3 g/dL, haematocrit of 32.1%, and a reduced red blood cell count of 3.41 M/µL. Platelet count was mildly decreased at 128 K/µL. Serum chemistry analysis showed hypercalcemia, with a serum calcium level of 14.9 mg/dL, and elevated lactate dehydrogenase at 391 U/L. The remaining laboratory parameters were unremarkable. Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT). PCDLBCL-LT accounts for approximately 11% of all primary cutaneous B-cell lymphomas (CBCLs) and predominantly affects elderly women [1, 2]. It is characterised by aggressive behaviour, rapid progression, frequent extracutaneous dissemination, and resistance to conventional therapies. The 5-year disease-specific survival rate is approximately 66% [2, 3]. Poor prognostic factors include localisation to the lower extremities, multiple lesions, and age over 75 years [1, 4]. Spontaneous regression is exceedingly rare [5]. Clinically, PCDLBCL-LT presents as rapidly enlarging papules, nodules, or plaques, typically reddish, brownish, or violaceous, and frequently ulcerated. Although initially described on the lower limbs, involvement of the scalp, neck and face has also been reported [2-4]. Histopathologically, it is characterised by a dense, diffuse infiltrate of large atypical lymphoid cells involving the dermis and subcutaneous tissue. The neoplastic population predominantly consists of centroblasts and immunoblasts, exhibiting round nuclei and frequent mitotic figures, with minimal admixture of reactive T cells [3, 4, 6]. Immunophenotypically, these lymphomas express pan–B-cell markers such as CD20, CD79a and PAX5, with strong expression of MUM1/IRF4, frequently accompanied by BCL-2 and FOXP1 positivity, supporting a post–germinal centre (activated B-cell–like) phenotype [1, 2, 4]. The Ki-67 proliferation index is typically high, consistent with the aggressive biological behaviour of this entity. In situ hybridisation for Epstein–Barr virus–encoded RNA is consistently negative, helping to exclude EBV-associated systemic diffuse large B-cell lymphoma with secondary cutaneous involvement [2, 4, 5]. At the molecular level, multiple genetic alterations underlie the aggressive nature of PCDLBCL-LT. MYC protein expression is detected in 65%–80% of cases and is associated with poor prognosis. MYD88 gene mutations, particularly the L265P variant, are present in up to 60% of cases and serve as independent predictors of adverse outcomes [2, 4, 5]. Additional alterations include CDKN2A gene inactivation and mutations affecting B-cell receptor signalling components, such as CD79A/B and CARD11, which contribute to therapeutic resistance and unfavourable prognosis [2, 6]. In routine practice, immunohistochemical evaluation may include additional markers, such as BCL-2 and Ki-67, to further refine subtype classification and prognostic stratification; in the present case, assessment focused on key diagnostic markers. The main clinically relevant differential diagnoses include primary cutaneous follicle centre lymphoma (PCFCL) and secondary cutaneous involvement by systemic diffuse large B-cell lymphoma. PCFCL was considered less likely given the exclusive involvement of the lower extremity, the aggressive clinical course, the presence of multiple rapidly enlarging nodules, and the strong expression of MUM1 with partial MYC positivity, features favouring PCDLBCL-LT over a germinal centre–derived lymphoma. A detailed comparison with other primary cutaneous B-cell lymphomas is provided in Table 1. First-line therapy typically involves combination chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus rituximab (R-CHOP) [1, 3]. The presence of MYD88 mutations and MYC rearrangements not only provides diagnostic utility but also offers potential therapeutic targets [2]. Emerging therapies targeting the NF-κB signalling pathway hold promise in selected cases [1, 2]. Extracutaneous dissemination commonly involves the central nervous system (CNS), bone marrow, and visceral organs, contributing to poor prognosis; therefore, comprehensive systemic evaluation at diagnosis is essential [2, 3, 6]. In our patient, however, the disease progressed rapidly, with CNS involvement identified shortly after biopsy. Due to the fulminant clinical course, comprehensive systemic staging studies could not be performed, and the patient ultimately died during hospitalisation. This case underscores the dismal prognosis associated with PCDLBCL-LT, particularly in elderly patients with extensive disease, and highlights the importance of early recognition, comprehensive molecular profiling, and the development of novel therapeutic strategies to improve patient outcomes. Valeria Olvera-Rodríguez and Gerardo González-Martínez were responsible for patient care and data collection. Valeria Olvera-Rodríguez, Gerardo González-Martínez and Marion Carolina Alemán-Jiménez drafted the initial version of the manuscript. Minerva Gómez-Flores, Jorge Ocampo-Candiani and Lucía T. Fernández critically reviewed and revised the manuscript for important intellectual content. All authors reviewed and approved the final version of the manuscript. The authors received no specific funding for this work. All patients in this manuscript have given written informed consent for participation in the study and the use of their de-identified, anonymized, aggregated data and their case details (including photographs) for publication. Ethical approval: Not applicable. The authors declare no conflicts of interest. Data sharing is not applicable to this article as no datasets were generated or analysed during the current study. The data that support the findings of this study are available from the corresponding author upon reasonable request.