What is regression in melanoma?

What is Regression in Melanoma

Regression in melanoma is the histological replacement of tumor cells by fibrosis, lymphocytic inflammation, melanophages, and neovascularization—representing an immune-mediated attack on the primary tumor that must be documented in pathology reports as a mandatory prognostic parameter. 1

Histological Definition and Criteria

Regression is defined as segmental replacement of melanoma by fibrosis, which is the most reproducible criterion with less observer variation compared to other descriptive terms. 1 The College of American Pathologists defines it more specifically as replacement of tumor cells by:

• Lymphocytic inflammation with attenuation of the epidermis 2
• Non-laminated dermal fibrosis with inflammatory cells 2
• Melanophagocytosis (pigment-laden macrophages) 2
• Telangiectasia (neovascularization) 2

Stages and Extent of Regression

Regression can be classified by extent and stage:

By Extent:

• Complete regression: Total disappearance of the primary tumor (rare, occurring sporadically) 3, 4
• Partial regression: Incomplete tumor replacement 5, 2
• Segmental regression: Focal areas of replacement 1, 2

By Stage:

• Early: Predominantly tumor-infiltrating lymphocytes (TILs) attacking tumor cells 2, 6
• Intermediate: Mixed inflammation and early fibrosis 2
• Late: Predominantly fibrosis with melanophages and minimal inflammation 2

Frequency and Pathogenesis

Between 10-35% of all melanomas show histological regression. 5 The mechanism involves the host's immune system attacking primary melanocytic tumor cells via tumor-infiltrating lymphocytes, resulting in progressive fibrosis. 2 The immunological mechanisms driving complete versus partial regression may vary. 2

Mandatory Reporting Requirements

The presence and extent of regression must be included in every melanoma pathology report as mandated by the NIH consensus conference of 1992 and French Consensus Conference of 1995. 1 This is a standard requirement, not optional. 1 The report should document:

• Whether regression is present or absent 1
• If present, the extent (complete, partial, or segmental) 2
• The stage (early, intermediate, or late) when identifiable 2

Prognostic Implications: A Complex Picture

The prognostic significance of regression remains controversial with inconsistent findings. 5 The most recent high-quality evidence (2021) from a large cohort of 8,693 patients provides important nuance:

Favorable Prognosis Scenario:

When regression occurs WITH tumor-infiltrating lymphocytes (TILs), it independently predicts:

• Negative sentinel lymph node biopsy (OR 0.33) 6
• Lowest risk of death from melanoma (HR 0.69) 6
• Lowest rate of disease recurrence (HR 0.71) 6
• Highest 10-year overall survival (65%), melanoma-specific survival (85%), and recurrence-free survival (60%) 6

Unfavorable Prognosis Scenario:

In Stage III melanoma patients (node-positive disease), regression predicts worse outcomes:

• Lowest overall survival 6
• Lowest recurrence-free survival 6
• May be a marker of more aggressive disease 6

Complete Regression Warning:

Complete regression of the primary lesion is associated with metastatic disease. 3, 4 Both documented cases of complete regression in one series had identified metastatic disease, suggesting this represents a poor outcome. 4

Clinical Pitfalls to Avoid

• Do not perform partial biopsies of melanocytic lesions, as regression can lead to sampling error and make accurate staging impossible. 1, 7
• Use scalpel excision, not laser or electro-coagulation, to prevent tissue destruction that compromises assessment of regression and other prognostic factors. 1, 7
• Do not ignore regression in pathology reports—it affects sentinel node prediction and survival outcomes, particularly when combined with TIL status. 6
• Recognize that regression without TILs may have different prognostic implications than regression with TILs. 6
• In Stage III disease, regression should heighten concern rather than provide reassurance. 6