What is the appropriate diagnostic and treatment approach for a patient with lymphadenopathy and microcytic anemia, characterized by low Mean Corpuscular Hemoglobin (MCH), low Mean Corpuscular Volume (MCV), and high Red Cell Distribution Width (RDW)?

Diagnostic and Treatment Approach for Lymphadenopathy with Microcytic Anemia

This patient requires immediate serum ferritin testing to confirm iron deficiency anemia, followed by mandatory gastrointestinal evaluation to identify the source of blood loss, while simultaneously investigating the lymphadenopathy for underlying malignancy or systemic disease.

Understanding the Laboratory Pattern

The combination of low MCH, low MCV, and high RDW creates a distinctive signature that strongly indicates iron deficiency anemia rather than thalassemia or anemia of chronic disease:

• High RDW (>14-16.9%) is the key discriminator, reflecting heterogeneous red cell populations as iron stores become progressively depleted, and this pattern has 91.4% accuracy for iron deficiency when combined with low MCV 1, 2
• RDW often appears before MCV changes become apparent, making it an early indicator of iron deficiency 1, 3
• Thalassemia typically presents with normal or only slightly elevated RDW, which helps distinguish it from iron deficiency 1, 3

The presence of lymphadenopathy alongside this anemia pattern raises critical concerns about underlying malignancy, particularly lymphoma, which can present with both iron deficiency and lymph node enlargement 4.

Immediate Diagnostic Workup

First-Line Laboratory Tests

Serum ferritin is the single most powerful test and must be obtained immediately 4, 1:

• Ferritin <30 μg/L confirms iron deficiency in the absence of inflammation 1, 2
• Ferritin <100 μg/L may still indicate iron deficiency if inflammation is present (elevated CRP) 1, 2
• Ferritin >100 μg/L makes iron deficiency almost certainly not present 4

Obtain these tests simultaneously with ferritin 1:

• Transferrin saturation (<30% supports iron deficiency) 4, 3
• CRP to identify concurrent inflammation that may falsely elevate ferritin 1, 3
• Complete blood count with reticulocyte count to assess bone marrow response 3

Critical Pitfall to Avoid

Serum ferritin can be falsely elevated in inflammatory conditions, chronic disease, malignancy, or liver disease, potentially masking iron deficiency 3. This is particularly relevant in a patient with lymphadenopathy who may have underlying malignancy or systemic inflammation. In such cases, ferritin up to 100 μg/L may still be consistent with iron deficiency 1, 3, 2.

Lymphadenopathy Evaluation

The lymphadenopathy requires parallel investigation while working up the anemia:

History and Physical Examination Specifics

Document these critical features 5:

• Lymph node location (epitrochlear or supraclavicular nodes particularly concerning for malignancy)
• Duration of lymphadenopathy (>4 weeks warrants imaging and biopsy)
• Systemic symptoms: fever, night sweats, unintentional weight loss (B symptoms suggesting lymphoma)
• Node characteristics: size >2 cm, hard consistency, or matted/fused nodes indicate malignancy or granulomatous disease

Imaging and Biopsy

If lymphadenopathy persists beyond four weeks or is accompanied by systemic symptoms, obtain imaging and proceed to biopsy 5:

• Fine-needle aspiration, core needle biopsy, or excisional biopsy depending on node accessibility 5
• Avoid corticosteroids as they can mask the histologic diagnosis of lymphoma 5

Mandatory Gastrointestinal Investigation

All adult men and post-menopausal women with confirmed iron deficiency require complete gastrointestinal evaluation, regardless of symptom presence 1, 2:

• Upper endoscopy with mandatory small bowel biopsies to screen for celiac disease (causes iron deficiency in 2-3% of cases) 2
• Colonoscopy or CT colonography to exclude colonic malignancy 1
• This presentation warrants investigation for malignancy, as gastrointestinal blood loss is the most common source in these populations 1

Common GI Causes to Consider

The differential includes 4:

• Occult GI blood loss: NSAID use, colonic cancer/polyps, gastric cancer, angiodysplasia
• Malabsorption: celiac disease (most frequent), bacterial overgrowth
• Lymphoma (particularly relevant given the lymphadenopathy)
• Document NSAID and aspirin use, as these cause occult bleeding 2

Special Consideration for Premenopausal Women

Even in premenopausal women with menstrual blood loss, gastrointestinal pathology should not be excluded if there are concerning features like lymphadenopathy 2.

Treatment Algorithm

If Ferritin Confirms Iron Deficiency (<30 μg/L)

Initiate oral iron supplementation immediately 1, 2:

• Ferrous sulfate 200 mg (65 mg elemental iron) three times daily 2
• Add ascorbic acid (vitamin C) to enhance iron absorption 2
• Continue for 3-6 months after hemoglobin normalizes to replete iron stores 1, 2

Monitoring Response

Hemoglobin should rise ≥10 g/L (≥1 g/dL) within 2 weeks, which confirms iron deficiency 2:

• If no response within 2-4 weeks, consider non-compliance, ongoing blood loss (most common causes), or malabsorption 2
• Switch to intravenous iron (iron sucrose or iron gluconate) if malabsorption is suspected, with expected hemoglobin increase of at least 2 g/dL within 4 weeks 2

Addressing the Underlying Cause

Treatment of the underlying cause will cure the anemia 4, 2:

• Address any identified GI pathology (malignancy, celiac disease, inflammatory bowel disease) 2
• If lymphoma is diagnosed, treatment of the lymphoma will resolve both the lymphadenopathy and the anemia 4
• Stop NSAIDs and aspirin if possible 4

Integrated Diagnostic Approach

The key clinical challenge is determining whether the lymphadenopathy and anemia are related or coincidental:

1. If lymphoma is found on lymph node biopsy, this explains both findings, as lymphoma can cause iron deficiency through GI involvement or chronic disease 4
2. If lymphadenopathy is reactive or benign, proceed with full GI evaluation for the iron deficiency 1, 2
3. If GI malignancy is found, this may explain both the iron deficiency and reactive lymphadenopathy 4, 1

The presence of both findings mandates aggressive investigation to exclude malignancy in both systems simultaneously rather than sequentially.