A 43-Year-Old Man With Isolated Cutaneous Lymphomatoid Granulomatosis Presenting as a Chronic Necrotizing Ulcer of the Upper Arm

Introduction

Lymphomatoid granulomatosis (LYG) is a rare Epstein-Barr virus (EBV)-associated angiocentric and angiodestructive lymphoproliferative disorder characterized by an atypical proliferation of EBV-infected B cells within a reactive T-cell background [1]. First described by Liebow in 1972, LYG is considered part of the spectrum of EBV-driven B-cell lymphoproliferative diseases, with potential for transformation to overt lymphoma if untreated [1]. The lungs are the most involved organ, presenting in over 90% of cases with bilateral nodular infiltrates; however, extra-pulmonary manifestations are well documented, particularly involving the central nervous system, skin, liver, and kidneys [1].

Cutaneous involvement is the most frequent extrapulmonary manifestation, occurring in up to 45% of cases and typically in association with pulmonary disease [1,2]. Skin lesions are generally nonspecific, most often presenting as papules, nodules, or indurated plaques and less commonly as ulcerative or necrotic plaques that can resemble infections, vasculitis, or other inflammatory dermatoses [2,3]. Due to its rarity and heterogeneous presentation, cutaneous LYG poses a diagnostic challenge, particularly when it presents with isolated or atypical skin findings in the absence of pulmonary symptoms [4,5]. Delayed recognition can lead to progression to higher-grade disease and systemic dissemination [6,7]. In this report, we present a rare case of LYG manifesting as a chronic, necrotizing, non-healing ulcer of the upper arm, with no pulmonary symptoms at presentation. This unusual isolated cutaneous manifestation highlights the need for heightened clinical suspicion and early histological evaluation in persistent ulcerative skin lesions of unclear etiology.

Case Report

A 43-year-old man with no significant past medical history presented to the emergency department with a 6-month history of non-healing, painful ulcers on the anterior and lateral aspect of the right upper arm. The lesions began as small papules, which progressively ulcerated with associated necrotic eschar and purulent discharge. He reported experiencing tiredness, low-grade fever, and nausea but denied prior trauma, insect bite, weight loss, chronic cough, or night sweats. His vital signs on admission were within normal limits except for elevated blood pressure of 143/81 mmHg. Physical examination revealed a deep, irregular ulcer with undermined edges and necrotic base measuring approximately 4×5 cm and 3×4 cm, surrounded by erythema, edema, and induration (Figure 1). He had mild ankle swelling and pale conjunctiva, while chest, cardiovascular, neurological, and abdominal examinations were unremarkable. No regional lymphadenopathy was noted. Initial differential diagnosis included pyoderma gangrenosum, deep fungal infection, cutaneous tuberculosis, and vasculitic ulcer.

Laboratory investigations showed mild leukopenia (white blood cells 3700 k/μL [reference range. 3.8–10.5k/uL]), normocytic anemia with hemoglobin level of 8.2 g/dL (reference, 13.9–16.3 gm/dL), elevated erythrocyte sedimentation rate of 40 mm/h (reference, <15 mm/h), and mildly elevated C-reactive protein level of 45 mg/L (reference, 5–10 mg/L). Blood urea nitrogen and creatinine were both elevated: blood urea nitrogen, 98 mg/dL (reference, 7–23 mg/dL); creatinine, 10.2 mg/dL (reference, 0.7–1.2mg/dL). The estimated glomerular filtration rate was 6 mL/min/1.72 m2 by CKD EPI (reference, >60 mL/min/1.72 m2). Serum calcium levels ranged from 8.5 to 8.9 mg/dL (reference, 8.4–10.5 mg/dL), serum phosphorus was elevated at 5.3 mg/dL (reference, 2.5–4.5 mg/dL), and parathyroid hormone levels were elevated at 393 pg/mL (reference, 10–65 pg/mL). Urinalysis showed greater than 300 mg/dL (negative) of protein, without red blood cells. He was admitted for possible acute on chronic kidney disease and was started on hemodialysis. Glycated hemoglobin was 5.8%, consistent with prediabetes, hepatitis B serology showed chronic hepatitis B, while HIV and hepatitis C serologies were negative. Autoimmune markers, including anti-neutrophil cytoplasmic antibodies, were all negative. Kidney ultrasound revealed bilateral shrunken kidneys with increased echogenicity. Hepatic panel showed hypoalbuminemia and hypoproteinemia. MRI of the right arm showed findings consistent with myonecrosis involving the brachial and brachioradialis muscles with possible cellulitis, but no evidence of osteomyelitis (Figure 2). He was started on intravenous ceftriaxone and linezolid for possible cellulitis. Based on his renal function test results, calciphylaxis was also considered as a differential.

Wound swabs were positive for Staphylococcus hemolyticus, but negative for fungal and mycobacterial organisms. During hospitalization, blood and fungal cultures were negative, and wound biopsy tissue cultures showed no growth of bacteria, acid-fast bacilli, or fungi. Consequently, intravenous antibiotics were discontinued, given the absence of evidence for bacterial infection. Histopathology of the wound biopsy revealed dense angiocentric and angiodestructive infiltrates of atypical lymphoid cells, with areas of necrosis consistent with advanced LYG (Figure 3). Immunohistochemistry showed polymorphic lymphoid infiltrate with small reactive T cells (CD2+, CD3+, CD5+, CD7+), predominantly CD4-positive T cells, and variable numbers of histiocytes, plasma cells, and large, atypical B cells expressing CD20 and PAX5, with variable CD30 positivity. EBV–encoded RNA (EBER) in situ hybridization demonstrated strong nuclear positivity in more than 50 cells per high-power field, confirming an EBV-positive lymphoproliferative process with tumor cells involving over 50% of nuclei in the sample, findings consistent with grade 3 LYG. Genomic testing revealed only a Tier III ATM variant of uncertain significance, with low tumor mutation burden, microsatellite stability, and no clinically relevant mutations detected in a broad lymphoma-associated gene panel (Figure 4). Tissue biopsy showed negative fungal (PAS, GMS), mycobacterial (acid-fast, Fite), spirochete, and Giemsa stains, excluding infectious mimics and reinforcing the diagnosis. EBV DNA was detected in blood by PCR at 274 IU/mL (log 2.44), indicating low-level viremia. In conjunction with EBER-positive histology, EBV viremia supported the diagnosis of an EBV-driven lymphoproliferative disorder.

Computed tomography of the chest demonstrated a solitary 5-mm pulmonary nodule in the right middle lobe without associated lymphadenopathy. Given its isolated, sub-centimeter, and nonspecific appearance, this finding was not considered radiographically consistent with pulmonary involvement by LYG, which characteristically manifests as multiple bilateral nodules (Figure 5). Computed tomography of the abdomen and head revealed no additional abnormalities. Testing for tuberculosis using the QuantiFERON assay returned a negative result. End-stage kidney disease (CKD G5D) was diagnosed, characterized by a persistent glomerular filtration rate of less than 15 mL/min/1.73 m2 and initiation of maintenance dialysis during hospitalization. After a 4-week hospitalization, the patient was discharged with plans for an outpatient whole-body PET scan to assess the extent and distribution of disease, along with scheduled oncology and nephrology follow-up. The patient was lost to follow-up after discharge.

Discussion

LYG is a rare, EBV-driven B-cell lymphoproliferative disorder characterized by angiocentric and angiodestructive infiltrates, predominantly affecting extranodal sites such as the lungs, skin, and central nervous system [1]. Initially described by Liebow in 1972, the disorder has since been classified by the World Health Organization as a distinct entity within the group of EBV-positive B-cell lymphoproliferative disorders, with disease grading from I to III based on the degree of cytologic atypia and necrosis [1,8].

The pathogenesis of LYG centers on the proliferation of EBV-infected B cells within a reactive background of reactive T lymphocytes [9]. Under normal circumstances, host immune surveillance contains EBV-infected cells, but failure of this mechanism, often from immunodeficiency, allows uncontrolled proliferation of infected B cells [9,10]. The angiocentric and angiodestructive nature of the disease leads to vascular compromise, tissue necrosis, and variable organ involvement [9,11–13]. Immunodeficient states, including those associated with HIV, post-transplant immunosuppression, and autoimmune conditions such as systemic lupus erythematosus or rheumatoid arthritis, have been identified as risk factors for disease development [14]. Epidemiologically, LYG is extremely rare with exact incidence unknown. It typically affects middle-aged adults between the ages of 40 and 60 years and exhibits a notable male predominance, with a male-to-female ratio of approximately 2: 1 [1,9,14,15].

Clinically, LYG most commonly presents with pulmonary symptoms, due to its predilection for the lungs in over 90% of patients [1,9,12]. Patients mostly develop respiratory symptoms, such as cough, dyspnea, hemoptysis, or constitutional symptoms, including fever, night sweats, and weight loss [9,14]. Only about one-to two-thirds of patients develop significant respiratory symptoms that prompt imaging, while the rest are diagnosed incidentally through abnormal pulmonary findings on imaging [1,9]. Extrapulmonary manifestations are also well documented and include involvement of the central nervous system, skin, liver, and kidneys [1,9]. However, extrapulmonary-only presentations are rare [16,17].

Cutaneous involvement occurs in approximately 40% to 50% of cases and may precede, accompany, or follow pulmonary disease [1,14]. The range of skin lesions is broad, including erythematous papules, nodules, and plaques, as well as less commonly, ulcerated or necrotic lesions, which are frequently disseminated across the entire body [2,9,18,19]. However, isolated cutaneous presentations, particularly necrotizing ulcers confined to the extremities, trunk, or head and neck, are uncommon and may result in diagnostic delay, as they can mimic a wide range of more prevalent dermatologic and infectious conditions, thereby permitting progression to higher-grade disease with systemic dissemination [9,19,20]. In the present case, the patient presented with a chronic necrotizing ulcer of the upper arm accompanied by malaise and low-grade fever, without pulmonary involvement. In contrast, reported cases and literature reviews of cutaneous LYG most commonly describe maculopapular eruptions or subcutaneous nodules without ulceration or drainage, often with widespread distribution [7,19]. This atypical presentation highlights the diagnostic challenge of LYG, particularly in the absence of characteristic pulmonary and cutaneous manifestations. The differential diagnoses for such cutaneous ulcers are broad and include pyoderma gangrenosum, cutaneous tuberculosis, deep fungal infections, atypical mycobacterial infections, leukocytoclastic vasculitis, and cutaneous manifestations of systemic lymphomas [21]. In our patient, the isolation of Staphylococcus hemolyticus from the wound swab was most consistent with secondary colonization rather than the primary etiology, as both the tissue and blood cultures showed no evidence of infection. Calciphylaxis was considered in the context of the patient’s end-stage renal disease. However, it was considered unlikely due to the absence of lesions in adipose-predominant regions and the lack of vascular or soft-tissue calcifications on histopathologic evaluation [21]. Instead, biopsy revealed EBV-positive angiocentric lymphoid infiltrates, establishing the diagnosis of LYG.

Computed tomography revealed a solitary 5-mm pulmonary nodule that was considered nonspecific and not radiographically characteristic of pulmonary LYG, which typically manifests as multiple bilateral peribronchovascular or subpleural nodules, frequently cavitary, with surrounding ground-glass opacities and a relapsing–remitting pattern [22,23]. The patient had no respiratory symptoms or other evidence of pulmonary involvement. Given the small size and low-risk imaging features, a biopsy was not performed. Our patient was also diagnosed with end-stage kidney disease at presentation. Although LYG lesions are frequently identified in the kidneys at autopsy, clinically significant renal disease is rare, as these lesions are typically silent and remain asymptomatic during life [24].

Histopathologic evaluation remains the cornerstone of diagnosis, with classic features including angiocentric and angiodestructive infiltrates, extensive necrosis, and the presence of EBV- positive large B cells amid a dense reactive T-cell background [22]. Immunohistochemistry and in situ hybridization for EBER are essential for confirming the diagnosis [13,22,25]. LYG is histologically graded into 3 categories (grades 1 to 3) based on the number of EBV-positive large atypical B cells and the degree of necrosis, which correlates with clinical aggressiveness and prognosis [8,13]. Grade 1 lesions contain few EBV-positive large B cells scattered within a dense background of reactive T lymphocytes, with minimal necrosis; grade 2 shows an intermediate number of EBV-positive large B cells with more conspicuous cytologic atypia and focal necrosis; and grade 3 is characterized by numerous EBV-positive large atypical B cells forming sheets with extensive necrosis, often indistinguishable from diffuse large B-cell lymphoma [8,13].

Management of LYG is guided by histologic grade and clinical severity. Patients with low-grade disease (grade 1 to 2) may respond to immunomodulatory therapies, including interferon-alpha or monoclonal anti-CD20 therapy with rituximab [4,26,27]. In contrast, high-grade disease (grade 3), which resembles diffuse large B-cell lymphoma, typically requires systemic chemotherapy. The most used regimen is R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) [9,28]. Central nervous system involvement can necessitate the addition of high-dose methotrexate or intrathecal therapy, and autologous hematopoietic stem cell transplantation may be considered in refractory cases [29,30]. Our patient was diagnosed with grade 3 LYG based on histologic features, with EBER in situ hybridization demonstrating strong nuclear staining in numerous atypical large B cells, exceeding 50 cells per high-power field, and was being worked up prior to R-CHOP chemotherapy. However, he was lost to outpatient follow-up with the oncologist. Prognosis in LYG is variable and often depends on disease grade, organ involvement, and the timeliness of treatment. Early diagnosis and prompt initiation of appropriate therapy significantly improve outcomes, whereas untreated or delayed cases can progress to overt high-grade lymphoma or result in multiorgan failure [22].

Conclusions

This case highlights an uncommon presentation of LYG manifesting as isolated, chronic necrotizing cutaneous ulcers in the absence of overt pulmonary involvement. Given the rarity and protean clinical features of cutaneous LYG, particularly when presenting without respiratory symptoms, diagnosis is frequently delayed. LYG should be considered in patients with persistent, unexplained necrotizing skin lesions after exclusion of common infectious and noninfectious causes. Early histopathologic assessment with immunohistochemistry and EBV testing is essential for accurate diagnosis, appropriate grading, and timely initiation of therapy, which are critical determinants of prognosis. Failure to recognize the condition early can result in disease progression with subsequent systemic dissemination.