What are the initial steps in a comprehensive diagnosis workup?

Initial Diagnostic Workup: A Systematic Approach

The initial diagnostic workup must begin with obtaining tissue diagnosis through excisional lymph node biopsy when lymphoma is suspected, or appropriate tissue sampling based on the clinical presentation, followed by comprehensive laboratory studies, imaging, and disease-specific staging procedures. 1

Core Components of Initial Workup

History and Physical Examination

Perform a thorough three-generation family history with pedigree analysis when evaluating neurodevelopmental disorders, as this guides targeted genetic testing and identifies familial patterns 2. For suspected malignancies, obtain complete medical history including B symptoms (fever, night sweats, weight loss), and conduct focused physical examination including all lymph node regions, head and neck, rectal, pelvic, and breast examination 2.

Tissue Diagnosis (When Applicable)

Excisional lymph node biopsy is mandatory for suspected lymphoma and should always be the first diagnostic step 2, 1. Core biopsies should only be performed when lymph nodes are not easily accessible (e.g., retroperitoneal masses) 2, 1. Fine-needle aspiration is inappropriate for reliable lymphoma diagnosis 2.

• Store fresh frozen tissue when possible to allow additional molecular analyses 2, 1
• Ensure histological diagnosis follows WHO classification 2, 1
• Confirm diagnosis with expert pathologist review 2

Laboratory Studies

Complete blood count with differential, comprehensive metabolic panel including liver function tests, lactate dehydrogenase, and uric acid constitute the minimal basic workup 2, 1.

Additional essential laboratory tests include:

• Disseminated intravascular coagulation panel (D-dimer, fibrinogen, PT/PTT) for suspected hematologic malignancies 2
• Tumor lysis syndrome panel (LDH, uric acid, potassium, phosphate, calcium) especially with high disease burden 2, 1
• HIV, hepatitis B and C screening 2, 1
• Serum protein immunofixation 2
• β2-microglobulin 2

For male patients with suspected malignancy, measure α-fetoprotein, β-HCG, and PSA to exclude germ cell tumors and prostate cancer 2.

Imaging Studies

CT scan of neck, thorax, abdomen, and pelvis represents the standard imaging workup 2, 1. Chest X-ray should be performed to detect mediastinal masses or pleural effusion 2.

PET/CT scanning is recommended to confirm localized stage I/II disease, identify areas of disease transformation, and establish baseline for response assessment 1. For suspected lymphoblastic lymphoma specifically, whole-body PET/CT is the recommended approach 2, 1.

Bone Marrow Assessment

Bone marrow aspirate and biopsy should be performed in all suspected lymphoma cases to determine disease extent 2, 1. This is essential for accurate staging and prognosis 2.

Disease-Specific Considerations

For Neurodevelopmental Disorders

When evaluating unexplained developmental delay, intellectual disability, or autism spectrum disorder, perform chromosomal microarray (CMA) and Fragile X testing as first-tier genetic tests 2.

• If family history suggests X-linked disorder, send X-linked ID panel and high-density X-CMA 2
• For females with unexplained ASD/DD, consider MECP2 sequencing and deletion/duplication analysis 2
• Exome sequencing (ES) or whole genome sequencing (WGS) should be first- or second-tier testing for unexplained DD/ID or congenital anomalies 2
• Consider metabolic testing when indicated by history and physical examination 2

For Suspected Malignancies

Evaluate for testicular involvement in males with suspected lymphoma using scrotal ultrasound as indicated 2, 1. For patients with neurologic symptoms, obtain CT/MRI of head with contrast to rule out CNS involvement 2, 1.

Perform gastrointestinal endoscopy when GI involvement is suspected, particularly in limited stage I/II disease 1. For gastric MALT lymphoma specifically, esophagogastroduodenoscopy with multiple biopsies from each gastric region, duodenum, and gastroesophageal junction is required 2.

For Chronic Spontaneous Urticaria

The diagnostic workup includes differential blood count, C-reactive protein/ESR, total IgE, and IgG-anti-thyroid peroxidase levels 2. A high ratio of IgG-anti-TPO to total IgE is currently the best surrogate marker for autoimmune CSU 2.

Risk Stratification and Staging

Stage according to the Ann Arbor classification system for lymphomas 2, 1. For follicular lymphoma, determine the Follicular Lymphoma-specific International Prognostic Index (FLIPI) incorporating >4 involved nodal sites, elevated LDH, age >60 years, stage III/IV, and hemoglobin <12 g/dL 2, 1.

Critical Pitfalls to Avoid

• Never rely on fine-needle aspiration alone for lymphoma diagnosis - it provides insufficient tissue architecture 2
• Do not perform extensive endoscopic evaluation without clinical indicators - endoscopies should be sign-, symptom-, or laboratory abnormality-guided 2
• Avoid delaying tissue diagnosis in favor of non-invasive testing - definitive pathologic diagnosis should be obtained early 2, 1
• Do not skip fertility counseling in pediatric/AYA patients before initiating cytotoxic therapy - refer to fertility preservation programs before starting treatment 2

Additional Evaluations Based on Clinical Context

For patients of childbearing potential, perform pregnancy testing before initiating any diagnostic procedures involving radiation or potentially teratogenic agents 2. Psychosocial assessment should be incorporated, particularly for adolescent and young adult patients 2.