What is the likelihood of recurrence in a post-menopausal woman with a history of stage 2B Invasive Lobular Carcinoma (ILC), 3 years post-surgery, on Letrozole (aromatase inhibitor), with a supraclavicular lymph node that has increased in size from 6mm to 8mm over one year?

Risk of Recurrence in Enlarging Supraclavicular Lymph Node

An 8mm supraclavicular lymph node that has increased from 6mm over one year in a patient 3 years post-surgery for stage 2B ILC on letrozole requires tissue diagnosis, as this represents a concerning finding that could indicate locoregional recurrence, which occurs in approximately 4-8% of patients with node-positive disease despite adjuvant endocrine therapy. 1

Understanding the Clinical Context

Baseline Recurrence Risk for Stage 2B ILC

• Stage 2B breast cancer (T2N1 or T3N0) with 1-3 positive lymph nodes carries a substantial risk of locoregional recurrence even with appropriate adjuvant therapy 2
• Extended adjuvant letrozole therapy reduces the risk of breast cancer recurrence by approximately 25% (HR 0.75) compared to no extended therapy, but recurrences still occur 1
• In the MA-17 trial of extended letrozole therapy, disease-free survival events occurred in 13.3% of patients on letrozole at median follow-up of 62 months, with breast cancer recurrence (including locoregional) occurring in approximately 8% 1

Specific Concerns with Supraclavicular Involvement

• Supraclavicular lymph node involvement represents N3c disease in breast cancer staging, which significantly impacts prognosis and indicates advanced locoregional disease 3
• The supraclavicular region is a recognized site of locoregional recurrence, particularly in patients who had positive axillary nodes at initial diagnosis 2
• An enlarging lymph node (from 6mm to 8mm over one year) is more concerning than a stable node and warrants immediate investigation 4

Differential Diagnosis to Consider

Most Likely: Locoregional Recurrence

• Given the patient's stage 2B disease with presumed nodal involvement at diagnosis, locoregional recurrence is the primary concern 4
• ILC has unique metastatic patterns and can present with late recurrences, even beyond 5 years 5
• The supraclavicular region should have been included in radiation fields if the patient had 1-3 positive nodes, but recurrence can still occur 2

Alternative Considerations

• Radiation-induced fibrosis is possible if the patient received supraclavicular radiation, though this typically presents as stable rather than progressively enlarging nodes 4
• Second primary malignancy is a rare but possible differential diagnosis in previously irradiated fields 4
• Reactive lymphadenopathy from infection or other benign causes

Immediate Diagnostic Approach

Tissue Diagnosis is Mandatory

• Biopsy of the supraclavicular lymph node is essential, as clinical assessment alone cannot distinguish between recurrence, second primary malignancy, or benign pathology 4, 3
• Fine needle aspiration (FNA) or core needle biopsy should be performed promptly
• If confirmed as ILC recurrence, this represents N3c disease requiring aggressive multimodal therapy 3

Additional Staging if Recurrence Confirmed

• Complete restaging with imaging (CT chest/abdomen/pelvis or PET-CT) to evaluate for distant metastases
• Assessment of hormone receptor and HER2 status on the recurrent disease, as these can change from the primary tumor

Prognostic Implications

If Confirmed as Isolated Locoregional Recurrence

• Isolated locoregional recurrence may be amenable to aggressive local therapy (surgery and/or radiation) plus systemic therapy, which can provide long-term disease control in selected patients 4
• However, supraclavicular recurrence often indicates more aggressive disease biology and higher risk of subsequent distant metastases

ILC-Specific Considerations

• ILC is less chemosensitive than invasive ductal carcinoma but responds well to endocrine therapy 6, 7, 5
• Response rates to letrozole in ER-positive ILC are high, with mean tumor volume reductions of 60-70% in neoadjuvant studies 6
• However, ILC has worse long-term outcomes compared to stage-matched invasive ductal carcinoma, with higher rates of late recurrence 5
• The molecular changes in ILC in response to endocrine therapy show downregulation of proliferation genes, but resistance can develop over time 8

Treatment Implications if Recurrence Confirmed

Systemic Therapy Modification

• Switch to alternative endocrine therapy (different aromatase inhibitor, fulvestrant, or tamoxifen if not previously used)
• Consider adding CDK4/6 inhibitor to endocrine therapy for hormone receptor-positive recurrent disease
• Chemotherapy is less effective in ILC but may be considered for rapidly progressive disease 7, 5

Local Therapy Considerations

• Regional nodal irradiation including supraclavicular field if not previously irradiated 3
• Surgical excision may be considered for isolated, resectable disease in combination with systemic therapy 9
• Standard radiation dose is 50 Gy in fractions of 1.8-2.0 Gy 3

Critical Next Steps

The patient requires immediate biopsy of the enlarging supraclavicular node—do not delay with imaging surveillance alone. The 2mm increase over one year, while seemingly modest, represents a 33% size increase and cannot be dismissed as stable disease. If biopsy confirms recurrence, this fundamentally changes the treatment paradigm from adjuvant to treatment of recurrent/metastatic disease, requiring comprehensive restaging and modification of systemic therapy beyond letrozole monotherapy.