What is the approach to diagnose and manage paraneoplastic erythroderma, including steps to exclude underlying malignancy through clinical evaluation, laboratory investigations (Complete Blood Counts (CBC), Liver Function Tests (LFT), Kidney Function Tests (KFT)), and radiological procedures?

Approach to Paraneoplastic Erythroderma and Malignancy Exclusion

In patients presenting with erythroderma of unclear etiology, a systematic malignancy workup should be initiated immediately, prioritizing complete blood count with differential, comprehensive metabolic panel, liver and kidney function tests, chest imaging, and age-appropriate cancer screening including PSA in men and breast imaging in women, followed by CT chest/abdomen/pelvis if initial workup is unrevealing. 1

Initial Clinical Evaluation

History Taking

• Document medication history comprehensively over the preceding 2 months, including all prescription drugs, over-the-counter medications, and complementary/alternative therapies with exact dates of initiation 1
• Assess for constitutional symptoms including weight loss, night sweats, fever, asthenia, and chronic cough—these "B symptoms" strongly suggest underlying malignancy 2, 3
• Inquire about travel history, new medications, recurrent infections, and family history of hematologic disorders or malignancy 1
• Evaluate for prior history of skin conditions (psoriasis, eczema, drug reactions) to exclude non-malignant causes 1

Physical Examination

• Perform total body skin examination documenting the percentage of body surface area involved (erythroderma typically involves >90% BSA) and presence of scaling, desquamation, or specific lesion patterns 1, 4
• Examine all mucous membranes carefully to exclude Stevens-Johnson syndrome, toxic epidermal necrolysis, or paraneoplastic pemphigus 1
• Palpate for lymphadenopathy in cervical, axillary, inguinal, and supraclavicular regions—any palpable nodes warrant biopsy 1
• Assess for hepatosplenomegaly through abdominal palpation, as this suggests hematologic malignancy 1, 5
• Document vital signs including temperature, as fever may indicate lymphoma or infection 1

Essential Laboratory Investigations

First-Line Blood Work

• Complete blood count with differential to detect leukemia, lymphoma, or myeloproliferative disorders—look specifically for eosinophilia, monocytosis, circulating blasts, or dysplasia 1
• Comprehensive metabolic panel including electrolytes, glucose, calcium, and uric acid to assess for tumor lysis syndrome or hypercalcemia of malignancy 1, 5
• Liver function tests (AST, ALT, alkaline phosphatase, bilirubin) as hepatic involvement may indicate metastatic disease 1, 5
• Kidney function tests (creatinine, BUN, eGFR) to establish baseline and detect renal involvement 1
• Lactate dehydrogenase (LDH) as an important prognostic marker for lymphoma and indicator of cell turnover 5

Specialized Hematologic Testing

• Peripheral blood smear review by experienced hematopathologist to identify abnormal cells, dysplasia, or circulating lymphoma cells 1
• Serum protein electrophoresis to detect paraproteinemia suggesting multiple myeloma or lymphoproliferative disorder 5
• β2-microglobulin as a prognostic marker for hematologic malignancies 5
• Serum tryptase and vitamin B12 levels which are elevated in myeloproliferative variants, particularly with PDGFRA fusion genes 1, 5
• Flow cytometry of peripheral blood for immunophenotyping if lymphoproliferative disorder is suspected 1, 5

Cancer-Specific Biomarkers

• Prostate-specific antigen (PSA) in all men presenting with erythroderma, as prostate cancer is a documented cause of paraneoplastic erythroderma 6, 4
• Thyroid function tests as thyroid dysfunction can influence skin manifestations 5
• Quantitative immunoglobulin levels including IgE, which may be elevated in reactive conditions but also in certain lymphomas 1

Inflammatory Markers

• Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) to assess systemic inflammation 1
• Antinuclear antibodies (ANA) and antineutrophil cytoplasmic antibodies (ANCA) to exclude autoimmune causes 1

Skin Biopsy Protocol

Biopsy Technique

• Obtain two separate biopsies: one from lesional skin for routine histopathology with hematoxylin and eosin staining, and a second from perilesional skin sent unfixed for direct immunofluorescence 1
• Request immunohistochemistry panel including cytokeratin 20 (CK-20), CD117, CD25, tryptase, and pancytokeratins to exclude cutaneous lymphoma or leukemia cutis 1
• Ensure adequate tissue for flow cytometry if lymphoproliferative disorder is suspected, as cutaneous biopsies may not yield sufficient cells 1

Radiological Investigations

Initial Imaging

• Chest X-ray as mandatory first-line imaging to detect lung masses, mediastinal lymphadenopathy, or hilar enlargement 1, 2
• Right upper quadrant abdominal ultrasound to assess liver and spleen size, texture, and detect focal lesions 5

Advanced Imaging When Indicated

• CT chest/abdomen/pelvis with contrast if chest X-ray is abnormal, constitutional symptoms are present, or lymphadenopathy is detected on examination 1, 2
• PET/CT scan if lymphoma is suspected based on lymphadenopathy or elevated LDH, as this provides whole-body staging 1
• Breast imaging (mammography and/or ultrasound) in women as breast cancer rarely presents with paraneoplastic erythroderma 7

Bone Marrow Evaluation

Indications for Bone Marrow Biopsy

• Perform bone marrow aspirate and biopsy when peripheral blood shows cytopenias, unexplained eosinophilia, circulating blasts, or abnormal immunophenotype 1, 5
• Include immunohistochemistry for CD117, CD25, tryptase, and reticulin/collagen stains for fibrosis 1
• Obtain conventional cytogenetics with karyotyping and fluorescence in situ hybridization (FISH) to detect chromosomal abnormalities 1
• Request molecular testing including next-generation sequencing for myeloid mutation panels and detection of tyrosine kinase fusion gene rearrangements 1

Algorithmic Approach to Malignancy Workup

Step 1: Immediate Exclusion of Drug Reactions

• Discontinue all non-essential medications and observe for improvement over 2-4 weeks 1
• If improvement occurs, diagnosis is likely drug-induced erythroderma rather than paraneoplastic

Step 2: Screen for Common Solid Tumors

• Men: PSA testing and digital rectal examination 6, 4
• Women: Breast examination and mammography 7
• All patients: Chest imaging for lung cancer 2

Step 3: Evaluate for Hematologic Malignancy

• If CBC shows abnormalities (cytopenias, leukocytosis, eosinophilia): proceed directly to bone marrow biopsy and flow cytometry 1
• If peripheral blood is normal but LDH elevated or lymphadenopathy present: obtain PET/CT and consider lymph node biopsy 1
• If serum protein electrophoresis shows monoclonal protein: evaluate for multiple myeloma or lymphoproliferative disorder 5

Step 4: Extended Workup if Initial Tests Negative

• CT chest/abdomen/pelvis with contrast to detect occult malignancy 1
• Consider age-appropriate cancer screening: colonoscopy if not up to date, as gastrointestinal malignancies can rarely cause paraneoplastic syndromes
• Testicular ultrasound in men if testicular examination is abnormal 1

Critical Pitfalls to Avoid

• Do not attribute erythroderma solely to benign causes (psoriasis, eczema) without completing malignancy workup, especially in patients over 50 years or with constitutional symptoms 4, 2
• Do not delay PSA testing in men—prostate cancer is a well-documented cause of paraneoplastic erythroderma and early detection improves outcomes 6, 4
• Do not overlook hematologic malignancies by focusing only on solid tumors—lymphomas and leukemias are more common causes of paraneoplastic erythroderma 1, 3
• Do not accept normal peripheral blood as excluding hematologic malignancy—bone marrow involvement may be present without peripheral manifestations initially 1
• Do not miss paraneoplastic pemphigus by failing to examine mucous membranes or obtain direct immunofluorescence on skin biopsy 1

Management During Workup

• Initiate symptomatic treatment with emollients, topical corticosteroids (high-potency class 1 such as clobetasol), and oral antihistamines while investigations proceed 1
• Consider systemic corticosteroids (prednisone 0.5-1 mg/kg/day) for severe symptoms, but recognize that improvement with steroids does not exclude malignancy 1, 4
• Monitor closely with serial photography to document progression or improvement 1
• If malignancy is identified, definitive treatment of the underlying cancer typically results in resolution of erythroderma, as demonstrated in prostate cancer cases where radiotherapy led to complete remission without recurrence 6, 4