Cancer of Unknown Primary with Axillary Nodal Metastases

Cancer of unknown primary with axillary nodal metastases is metastatic carcinoma in axillary lymph nodes without an identified primary tumour after full evaluation. In women with adenocarcinoma the usual source is an occult breast cancer, and treatment follows the approach for node positive breast cancer, with excellent outcomes.

It forms 0.3% to 1% of breast cancers. Median age at diagnosis is 50 to 60, with women forming the large majority. Other primaries include lung, skin (squamous and melanoma), head and neck, gastrointestinal tract, thyroid, and lymphoma.

Risk factors match those for breast cancer (age, family history, BRCA variants, hormonal factors). A history of breast implants or breast surgery is relevant when a nodal metastasis is found.

Pathophysiology. A small breast primary (often under 1 cm or in dense tissue) with early nodal spread, or regression of the primary, is the usual explanation. Receptor patterns (oestrogen receptor, progesterone receptor, HER2) are similar to those of ordinary breast cancer, and a minority are triple negative.

Prognosis. Five year survival is about 70% to 85% for occult breast cancer given breast cancer therapy, comparable to stage II or III breast cancer. For other primaries the prognosis follows the tumour type.

• A firm, painless axillary lump, usually unilateral, sometimes fixed or matted.
• Arm swelling from lymphatic obstruction, with chest wall or breast changes in some.
• Systemic symptoms (weight loss, bone pain, cough) in advanced disease.

Red flags.

• Arm swelling with venous or lymphatic obstruction.
• Neurological symptoms from brachial plexus involvement.
• Rapidly enlarging nodes with fever (lymphoma).

• Clinical breast, nodal, skin and thyroid examination, with breast and axillary ultrasound and bilateral mammography.
• Breast MRI with contrast (detects an occult primary in about 60% to 70%). FDG-PET-CT for systemic staging and an occult primary.
• Ultrasound directed core biopsy of the node (preferred over fine needle aspiration, which does not allow receptor testing).
• Immunohistochemistry: oestrogen and progesterone receptors, HER2, Ki-67, GATA3, mammaglobin, GCDFP-15, TTF-1, p63, S100, SOX10, CK7 and CK20. Squamous histology prompts a search of head and neck, skin, lung and cervix.
• CT of the chest, abdomen and pelvis and bone scan or PET for staging. Germline testing (BRCA1, BRCA2, TP53, PALB2) in selected women.

Differential diagnosis.

• Occult breast carcinoma (including lobular)
• Metastatic melanoma, lung carcinoma and head and neck squamous carcinoma
• Lymphoma and reactive or infective lymphadenopathy
• Sarcoidosis, silicone lymphadenopathy and gastrointestinal or thyroid metastases

Management follows the approach for stage II or III breast cancer in women with receptor positive or negative adenocarcinoma, decided by a breast multidisciplinary team.

Local therapy.

• Axillary lymph node dissection, with whole breast radiotherapy (45 to 50 Gy in 25 fractions with or without a boost) as an alternative to mastectomy, or mastectomy when an MRI lesion or patient choice dictates. Regional nodal radiotherapy is given for higher nodal burden.

Systemic therapy.

• Chemotherapy (anthracycline then taxane) for most women with node positive disease, receptor negative or HER2-positive tumours:
  • Doxorubicin: 60 mg/m2 IV on day 1 every 3 weeks for 4 cycles (every 2 weeks with pegfilgrastim 6 mg subcutaneously 24 to 72 hours after each cycle is an option); maximum cumulative working ceiling 450 mg/m2; monitoring: echocardiography at baseline and after completion, FBC before each cycle; adjustment: bilirubin 20 to 51 micromol/L reduce by 50%, 53 to 85 micromol/L reduce by 75%, over 85 micromol/L avoid; consider reduction when eGFR is under 30 mL/min/1.73 m2.
  • Cyclophosphamide: 600 mg/m2 IV on day 1 with doxorubicin, on the same schedule, for 4 cycles; maximum 600 mg/m2 each cycle; monitoring: FBC, hydration, urinary symptoms (haemorrhagic cystitis); adjustment: reduce by about 25% to 50% when eGFR is under 30 mL/min/1.73 m2, reduce in severe hepatic impairment.
  • Paclitaxel (12 weeks after the anthracycline): 80 mg/m2 IV weekly for 12 weeks; maximum 80 mg/m2 each week; monitoring: FBC, liver tests, neuropathy at each visit; premedication with dexamethasone, an antihistamine and an H2 blocker; adjustment: reduce by about 25% in moderate hepatic impairment, avoid when bilirubin is over 5 times the upper limit, no renal adjustment.
• HER2-positive disease: trastuzumab 8 mg/kg IV over 90 minutes as a loading dose, then 6 mg/kg IV over 30 to 90 minutes every 3 weeks to complete 1 year (18 cycles in total), for HER2-positive disease; maximum cumulative course 1 year; monitoring: left ventricular ejection fraction at baseline, every 3 months during treatment and after completion, infusion reactions, FBC; adjustment: hold for a fall in ejection fraction of 10 points or more to under 50% and repeat in 3 to 4 weeks, stop for symptomatic heart failure, no renal or hepatic adjustment, use extra caution with prior anthracycline exposure
• Endocrine therapy for hormone receptor positive disease:
  • Tamoxifen (premenopausal women): 20 mg orally once daily for 5 years (up to 10 years in selected higher risk women); maximum 20 mg daily; monitoring: ask about abnormal vaginal bleeding at each visit, thromboembolic symptoms, annual gynaecological review; adjustment: no renal adjustment, avoid strong CYP2D6 inhibitors (paroxetine, fluoxetine, bupropion), avoid in severe hepatic impairment and pregnancy, caution with prior venous thromboembolism.
  • Anastrozole (postmenopausal women): 1 mg orally once daily for 5 years (letrozole 2.5 mg or exemestane 25 mg once daily are equivalent options); maximum 1 mg, 2.5 mg and 25 mg daily respectively; monitoring: bone mineral density at baseline then every 1 to 2 years, calcium and vitamin D, lipids, arthralgia; adjustment: none in mild to moderate renal or hepatic impairment, letrozole 2.5 mg every other day in severe hepatic impairment.

Non-breast primaries. Treatment follows the likely origin: melanoma by surgery with immunotherapy, squamous carcinoma by site directed radiotherapy and surgery, lymphoma by haematology referral.

Men. Treated with a similar approach when immunohistochemistry suggests a breast source, with tamoxifen for hormone receptor positive disease.

Supportive care. Lymphoedema prevention and physiotherapy, shoulder rehabilitation, bone health, and psychological support.

Monitoring. Clinical examination every 3 to 6 months for 2 years, then every 6 to 12 months. Annual mammography and breast MRI where the breast is conserved.

Referral and escalation.

• Urgent referral to a breast service for any new axillary mass.
• Same day assessment for arm swelling with pain or discolouration (thrombosis).

Special groups.

• Pregnancy: surgery in any trimester and chemotherapy from the second trimester, with endocrine therapy and radiotherapy deferred.
• BRCA carriers: genetic counselling and risk reducing options.
• Older or frail patients: endocrine therapy alone, with radiotherapy for local control.