Dear Editor, We report a rare adult case of hemophagocytic lymphohistiocytosis (HLH), a life-threatening immune- mediated disorder characterized by non-specific and heterogeneous clinical manifestations. A 46-year-old apparently healthy man presented to the dermatology outpatient department with painful nodules on the trunk and extremities for two months, which began insidiously and progressively involved the entire body. During the preceding week, a few nodules developed fluid-filled lesions. He also reported intermittent low-grade fever with chills responsive to antipyretics, anorexia, weight loss, rectal bleeding for 15 days, and arthralgia involving the knee and metacarpophalangeal joints without morning stiffness. On examination, the patient appeared lethargic with stable vital signs. Cutaneous examination showed multiple tender erythematous papules and nodules, a few exhibiting pseudo-vesiculation and others with hemorrhagic adherent crusts, predominantly on the trunk and limbs. Several hyperpigmented patches were noted Figure 1a-c. Firm, tender right-sided inguinal lymphadenopathy was present, with no peripheral nerve thickening or tenderness.Figure 1: (a-c) Clinical picture showing multiple well-defined, erythematous papules and nodules with adherent hemorrhagic crust. Several hyperpigmented patches are also notedThe initial differential diagnoses included erythema nodosum, necrotic erythema nodosum leprosum, medium-vessel vasculitis, autoimmune panniculitis, Sweet’s syndrome, and rheumatoid nodule Table 1.Table 1: Comparison of differential diagnoses consideredRoutine investigations revealed progressive pancytopenia over one week (hemoglobin 12.4 to 10 g/dL, white blood cell count 3.5 to 1.6 × 103μL, platelets 1.34 to 1 × 105/μL). Liver function tests showed elevated aspartate aminotransferase (AST): 597 IU/L, alanine aminotransferase (ALT) :187 IU/L, and bilirubin (total 3.43 mg/dL; direct 3.01 mg/dL). Renal evaluation revealed 2+ proteinuria, and erythrocyte sedimentation rate (ESR) was raised (35 mm/hr). Fever profile, serology for hepatitis B, C and human immunodeficiency virus, antinuclear antibody (ANA), rheumatoid factor (RF), and Mantoux test were negative. Blood cultures were negative, while urine culture grew Enterococcus species sensitive to linezolid and fosfomycin. Lactate dehydrogenase (LDH) was elevated (933 IU/L), triglycerides were increased (415 mg/dL), and hyperferritinemia was noted (990 ng/mL). Skin biopsy showed necrotic keratinocytes with sub-epidermal clefting and lobular panniculitis characterized by adipocytes surrounded by lymphocytes Figure 2a-d. Ultrasonography of the abdomen and pelvis revealed a right inguinal lymph node measuring approximately 2 × 2 cm, with no hepatosplenomegaly. Fine needle aspiration cytology (FNAC) of the lymph node demonstrated acute suppurative lymphadenitis. In view of patient’s rapid clinical deterioration, a bone marrow biopsy was performed instead of a lymph node biopsy to corroborate FNAC findings and simultaneously rule out hematological malignancy.Figure 2: (a) Histopathology examination (HPE) (Hematoxylin and eosin stain, scanner view) of skin biopsy specimen, showing necrotic keratinocytes in epidermis (black arrow), subepidermal clefting (blue arrow), altered collagen with interstitial infiltrates in dermis (blue star), lymphocytic lobular panniculitis (red arrow). (b) HPE (Hematoxylin and eosin stain, 100x) of skin biopsy specimen, showing necrotic keratinocytes in epidermis (black arrow), subepidermal clefting (blue arrow), congested upper dermal capillaries (orange arrow). (c and d) HPE (Hematoxylin and eosin stain, 400x) of skin biopsy specimen, showing lymphocytic lobular panniculitis (black arrow), emperipolesis (encircled area)Bone marrow examination revealed normoblastic hypercellularity with megakaryocytes and hemophagocytes Figure 3a, 3b. The patient fulfilled six of the eight hemophagocytic lymphohistiocytosis (HLH-2004) diagnostic criteria - fever, pancytopenia, hypertriglyceridemia, hyperferritinemia, liver dysfunction, and hemophagocytosis. Despite aggressive treatment with intravenous corticosteroids and antibiotics, the patient succumbed to multiorgan dysfunction syndrome.Figure 3: (a) Bone marrow biopsy (Hematoxylin and eosin stain, scanner view) showing a hemophagocyte (encircled area) and normoblastic hypercellular marrow (red arrow). (b) Bone marrow biopsy (Hematoxylin and eosin stain, 100x) showing engulfed platelets and lymphocytes in a hemophagocyte (black arrow), normoblastic hypercellular marrow (red arrow)HLH is a rare, rapidly progressive, and potentially life-threatening disorder caused by excessive activation of histiocytes and lymphocytes. It presents with fever, hepatosplenomegaly, and pancytopenia, with cutaneous manifestations reported in up to 65% of patients.7 HLH may be primary (genetic) or secondary (reactive) to infections, malignancies, or autoimmune diseases. Cutaneous eruptions occur in 24-40% of familial and 6-65% of acquired HLH cases, manifesting as maculopapular erythema, erythroderma, violaceous macules, edema, panniculitis, morbilliform eruptions, petechiae, purpura, and Kawasaki-like changes.8 The HLH-2004 diagnostic criteria requires the presence of at least five of eight features: Fever >38.5°C, splenomegaly, cytopenia (affecting ≥2 lineages), hypertriglyceridemia and/or hypofibrinogenemia, hemophagocytosis, low NK cell activity, serum ferritin >500 μg/L, and soluble CD25 ≥2400 U/mL.8 Our patient fulfilled six criteria, confirming the diagnosis. Onset in adult age (common in the pediatric age group with no underlying associations) and atypical presentation (tender nodular lesions with pseudo-vesiculation, few having overlying hemorrhagic crusting with low-grade fever and no underlying associations) complicated this patient’s diagnosis. Rapid progression of disease can occur due to cytokine storm that can be alleviated if clinical clues are recognized early, specifically before a rise in inflammatory markers like LDH and ferritin. This case underscores the decisive role of time interval between presentation and diagnosis in HLH, particularly in patients with atypical cutaneous manifestations. Despite early evaluation with baseline investigations, ANA testing to exclude connective tissue disorders, and bone marrow examination to rule out hematological malignancy, the disease followed a fulminant course over just 15 days. Before further etiological evaluation including whole-body CT imaging for occult solid organ malignancy could be completed, the patient succumbed. These observations highlight the need for heightened clinical suspicion at initial presentation and rapid, co-ordinated multi-disciplinary assessment, as even a short duration of diagnostic delay can have fatal consequences in HLH. Owing to the rapidly progressive clinical course and the patient’s demise, advanced investigations, including flow cytometry, extended immunohistochemistry, and T-cell clonality studies, could not be performed on bone marrow or lymph node specimens. As a result, an underlying occult malignancy, particularly low-grade lymphoma, could not be definitively excluded. The absence of an autopsy further limited etiological confirmation. Authors’ contributions We confirm that all authors have read and approved the manuscript for submission. All authors meet authorship criteria, and the manuscript represents honest work. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and due efforts will be made to conceal his identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest. Use of artificial intelligence (AI) The preparation of this manuscript was carried out entirely by the authors without the use of artificial intelligence technologies.
Acharya et al. (Thu,) studied this question.