Cancer of Unknown Primary

Cancer of unknown primary is a biopsy-proven metastatic malignancy in which standard investigation does not find the site of origin. It makes up 2 to 5% of cancers, with a median age of 60 to 70 years. The mechanism is thought to be early dissemination from a small, regressing or hidden primary, and metastases follow patterns of the tissue of origin. Autopsy finds a primary in about 70 to 80% of cases, most often lung, pancreas, hepatobiliary or colorectal.

Histology: well or moderately differentiated adenocarcinoma (about 50 to 60%), poorly differentiated carcinoma or adenocarcinoma (about 30%), squamous cell carcinoma (about 5%), and neuroendocrine carcinoma (about 2 to 5%).

Median survival is 6 to 10 months for unfavorable presentations, but several favorable subsets behave like their site of origin and have much longer survival:

• Women with adenocarcinoma in axillary nodes (treat as breast cancer)
• Women with serous papillary peritoneal carcinomatosis (treat as ovarian cancer)
• Squamous carcinoma in upper or mid-cervical nodes (treat as head and neck cancer)
• Squamous carcinoma in inguinal nodes (treat as anal or genital cancer)
• Men with blastic bone metastases and a high PSA (treat as prostate cancer)
• Poorly differentiated carcinoma with a midline distribution and young age (treat as germ cell tumor)
• Poorly differentiated neuroendocrine carcinoma
• A single metastasis that is resectable
• A colorectal-type profile (CK20 and CDX2 positive, CK7 negative)

Complications: rapid decline, brain and bone metastases, pleural and peritoneal effusion, thromboembolism and cachexia.

• Symptoms depend on the metastatic site: lymph node enlargement, liver pain and jaundice, bone pain, cough, dyspnea, ascites, neurological signs
• Weight loss, fatigue and anorexia
• Red flags: spinal cord compression, brain metastases, superior vena cava syndrome, hypercalcemia and rapid liver failure

A limited, targeted workup is recommended, and extensive repeated testing is avoided.

1. History and examination: breast, thyroid, lymph node basins, skin, genital and testicular, pelvic and rectal examination, and a drug and smoking history.
2. Laboratory tests: blood count, creatinine, liver tests, LDH, calcium. PSA in men, AFP and beta-hCG in young patients or with midline disease, CA 125 in women with peritoneal disease.
3. Imaging: CT of chest, abdomen and pelvis with contrast. Mammography and breast MRI for women with axillary nodes, testicular ultrasound in young men, and fluorodeoxyglucose PET-CT when there is a single site or a curative approach is considered.
4. Adequate tissue biopsy (core needle or excision) with immunohistochemistry: CK7, CK20, CDX2, TTF-1, napsin A, GATA3, PAX8, p40 or p63, PSA or NKX3.1, CD45, S100, SOX10, chromogranin and synaptophysin.
5. Molecular profiling: full genomic profiling for targetable alterations (EGFR, ALK, BRAF, NTRK, RET, HER2 and others), microsatellite instability and tumor mutational burden, and gene expression tissue-of-origin assays where available.
6. Endoscopy only for symptoms or a suggestive immunophenotype. Germline testing when features of a hereditary cancer are present.

Differentials: occult primary of breast, lung, pancreas, colon, ovary, prostate, kidney or thyroid, lymphoma, melanoma, germ cell tumor, sarcoma.

Management follows the subset, and treatment should begin once the workup is complete.

1. Favorable subsets: treat as the likely primary, for example axillary nodes in women with surgery, radiotherapy and systemic therapy for breast cancer, and platinum-based chemotherapy with cytoreductive surgery for ovarian-type disease. Cervical squamous nodes receive neck dissection with chemoradiotherapy (cisplatin 100 mg/m2 IV every 3 weeks for 3 doses with radiotherapy 66 to 70 Gy). Poorly differentiated midline carcinoma receives cisplatin 20 mg/m2 IV and etoposide 100 mg/m2 IV on days 1 to 5, with bleomycin 30 units on days 1, 8 and 15, every 21 days for 4 cycles. Isolated metastases can be resected or treated with radiotherapy.
2. Unfavorable subsets, empiric chemotherapy for performance status 0 to 2:
   • Carboplatin AUC 5 to 6 IV on day 1 with paclitaxel 175 to 200 mg/m2 IV on day 1, every 21 days for 4 to 6 cycles.
   • Cisplatin 75 mg/m2 IV on day 1 with gemcitabine 1000 mg/m2 IV on days 1 and 8, every 21 days.
   • FOLFOX: oxaliplatin 85 mg/m2, leucovorin 400 mg/m2 and fluorouracil 400 mg/m2 bolus then 2400 mg/m2 over 46 hours, every 14 days. Test for dihydropyrimidine dehydrogenase deficiency first.
3. Molecularly guided therapy: treat according to a predicted tissue of origin or a targetable alteration, for example site-specific therapy when a profile strongly points to a primary, and pembrolizumab 200 mg IV every 3 weeks for microsatellite-unstable or high mutational burden tumors. Use tumor-agnostic therapy for NTRK fusion (larotrectinib 100 mg orally twice daily) and BRAF V600E.
4. Local therapy: radiotherapy for symptomatic bone, brain and spinal metastases (8 Gy in 1 fraction for bone pain, or 20 Gy in 5 fractions), and stereotactic radiosurgery for brain metastases. Zoledronic acid 4 mg IV every 4 weeks for bone metastases.
5. Supportive care: antiemetics (ondansetron 8 mg with dexamethasone 8 mg), filgrastim 5 micrograms/kg SC daily for neutropenia, venous thromboembolism treatment with apixaban 10 mg orally twice daily for 7 days then 5 mg twice daily, early palliative care, nutrition and psychological support.
6. Poor performance status (3 or 4): best supportive care.

Follow-up: response assessment by CT every 2 to 3 cycles, with chemotherapy stopped for progression or intolerance. Counsel on uncertainty, prognosis and the patient's goals, and arrange early palliative care.