What are the etiologic and staging classifications of lymphedema?

Classification of Lymphedema

Etiologic Classification

Lymphedema is classified into two fundamental etiologic categories: primary lymphedema, which results from congenital abnormalities of the lymphatic system, and secondary lymphedema, which develops from acquired damage or obstruction to previously normal lymphatic structures. 1

Primary Lymphedema

Primary lymphedema stems from intrinsic developmental abnormalities of the lymphatic system and can be further subdivided by age of onset and anatomical defects 1, 2:

• Congenital lymphedema presents at birth or within the first two years of life 2, 3
• Lymphedema praecox manifests between ages 2-35 years, most commonly during puberty 2, 3
• Lymphedema tarda develops after age 35 years 2, 3

Known functional abnormalities in primary lymphedema include 2:

• Large vessel abnormalities such as congenital aplasia of the thoracic duct or cisterna chyli
• Congenital lymphatic valvular incompetence or aplasia
• Lymph node fibrosis
• Obliterated or reduced number of lymphatics (most common finding on lymphography)

Primary lymphedema may occur as an isolated finding or as part of genetic syndromes such as Turner syndrome and Noonan syndrome 4.

Secondary Lymphedema

Secondary lymphedema develops from disruption or obstruction of previously normal lymphatic pathways due to external insults. 1, 3

The most common causes in Western countries are 1, 5:

• Post-surgical lymph node dissection, particularly axillary dissection for breast cancer (most frequent cause in France and Western nations) or pelvic dissection for gynecologic, urologic, or melanoma malignancies 1, 6, 5
• Radiation therapy to lymph node regions, especially supraclavicular or axillary fields for breast cancer, or pelvic radiation for prostate, bladder, cervical, or uterine cancer 1, 6, 5
• Malignant obstruction from breast cancer, prostate cancer, Kaposi's sarcoma, or other neoplasms 3, 5
• Recurrent infections, particularly cellulitis in Western countries 1, 3
• Filariasis (the leading worldwide cause, predominantly in tropical regions) 3, 5

Less common secondary causes include 5:

• Rheumatoid arthritis and other rheumatic diseases
• Retroperitoneal fibrosis
• Immunosuppressive agents (e.g., sirolimus)
• Pathomimetic (factitious) lymphedema

A critical pitfall is failing to exclude deep venous thrombosis and recurrent malignancy at lymphedema onset, as these require urgent intervention. 5

Staging Classification

The International Society of Lymphology (ISL) staging system categorizes lymphedema severity from Stage 0 (subclinical) through Stage III (lymphostatic elephantiasis), providing a framework for disease progression and treatment planning. 1, 6

ISL Staging System

Stage 0 (Latent/Subclinical) 1, 6:

• Lymphatic transport impairment is present but no visible or palpable swelling exists
• May be detected by bioimpedance analysis before clinical manifestations appear
• Patients may report heaviness, tightness, or numbness despite absence of visible swelling

Stage I (Early/Reversible) 1:

• Visible swelling develops with accumulation of protein-rich fluid
• Pitting edema is present
• Swelling subsides with limb elevation
• Tissue is still relatively soft without significant fibrosis

Stage II (Moderate/Spontaneously Irreversible) 1:

• Limb elevation alone rarely reduces swelling
• Pitting may or may not be present as tissue fibrosis develops
• Progressive fibroadipose tissue deposition occurs
• Skin changes begin to appear

Stage III (Severe/Lymphostatic Elephantiasis) 1:

• Massive limb enlargement with extensive fibroadipose tissue
• Non-pitting due to severe fibrosis
• Skin changes include papillomatosis, hyperkeratosis, and warty overgrowths
• Significantly increased risk of cellulitis and functional disability

Clinical Grading by Interlimb Discrepancy

The Common Terminology Criteria for Adverse Events (CTCAE) provides an alternative grading system based on limb volume differences 7:

• Grade 1: 5-10% interlimb discrepancy
• Grade 2: >10-30% interlimb discrepancy
• Grade 3: >30% interlimb discrepancy

Diagnostic Features Distinguishing Lymphedema from Other Edema

Lymphedema exhibits specific clinical characteristics that differentiate it from cardiac, renal, or venous edema. 1

Key distinguishing features include 1, 8:

• Positive Stemmer sign (inability to pinch and lift the skin fold at the base of the second toe or finger) reflects dermal thickening and subcutaneous fibrosis unique to lymphedema
• Unilateral or asymmetric distribution (though primary forms may be bilateral) versus the bilateral symmetric pattern of cardiac edema
• Non-pitting quality in advanced stages due to fibrosis, versus persistent pitting in cardiac/venous edema
• No response to limb elevation or diuretics, unlike cardiac or venous edema which improves with these measures
• Progressive worsening if untreated, with increased cellulitis risk

A critical pitfall is using diuretics for lymphedema management—they are physiologically unsound and ineffective because lymphedema involves protein-rich fluid and fibroadipose tissue accumulation, not simple hydrostatic fluid overload. 1, 6