Carcinoma of Unknown Primary
Summary of Key Points
Evaluation
• No universal agreement exists on the extent of evaluation to search for a primary cancer.
• “Adequate,” early biopsy of a metastatic site is recommended to establish the diagnosis and help direct further workup.
• Basic evaluation includes the following:
• Comprehensive history and physical examination (including breast and pelvic examinations in women and testis and prostate examinations in men).
• Routine laboratory tests, chest-abdominal-pelvic computed tomographic scan, and mammography in women.
• Directed invasive tests based on symptomatology and pathological evaluation of the tumor tissue.
• Judicious pathological assessment of the metastatic tumor sample including directed immunohistochemical markers. Additional molecular markers that have a therapeutic intent are based on clinicopathological evaluation (including KRAS mutational status, Her2 (ERBB2) expression, and epidermal growth factor receptor (EGFR) mutation studies).
• The diagnostic utility of positron emission tomography (PET) is poorly defined; it is beneficial in selected patients.
• The role of tissue of origin molecular profiling assays continues to evolve; these tests are beneficial in selected patients.
Therapy
• Empiric combination cytotoxic therapy and the “one treatment fits all” approach are no longer emphasized.
• Where possible, individualized therapy for the metastatic cancer “profile” is based on detailed clinicopathological evaluation.
• When pathological evaluation falls short (large differential), empiric platinum-based combination therapies are usually selected.
• Taxane, gemcitabine, fluoropyrimidine + platinum doublet is a common “broad spectrum” first-line regimen in good performance status patients.
• Additional lines of therapy depend on performance status, pathological “profile,” and response to first-line therapy.
1. A 59-year-old man is referred to you for evaluation of a metastatic poorly differentiated squamous cell carcinoma found on excisional biopsy of a 3.4-cm subdigastric lymph node. He first noticed the lump 3 months ago and it has grown slowly over time. The patient has a history of chewing tobacco for 15 years and quit 5 years ago. He has minimal alcohol intake and is currently asymptomatic. Physical examination of the oral cavity reveals no lesions and that of the neck reveals a well-healed scar with no evidence of lymphadenopathy. Ear, nose, and throat evaluation with triple (pan) endoscopy does not reveal a primary tumor. Appropriate management would include:
2. What percentage of carcinoma of unknown primary is adenocarcinoma on light microscopy?
3. A 39-year-old man is evaluated for symptoms of anorexia, weight loss (16 lbs), and nausea. His medical history is unremarkable. Physical examination reveals mild tenderness in the epigastrium with no hepatosplenomegaly or lymphadenopathy. Complete blood cell count and chemistry profile are normal. CT of the abdomen reveals thickening of the antrum with celiac lymph node enlargement (~2. 7 cm). Upper endoscopy reveals mild erythema in the distal stomach and antrum region. Gastric biopsies disclose anaplastic submucosal tumor consistent with poorly differentiated carcinoma. The most appropriate next step in the management of this patient is:
1. Answer: E. Most patients with cervical squamous cell cancer carcinoma of unknown primary (CUP) presentation benefit from a PET CT scan in addition to baseline CT imaging. Occasionally, the primary cancer is seated deep in the crypts of the tonsil(s) and staging bilateral tonsillectomies is standard of care. Thorough evaluation of the primary cancer in this setting helps focus ipsilateral radiation and minimizes the risk of significant xerostomia as well as helps with future surveillance.
2. Answer: A. The majority of patients are seen with adenocarcinoma and this is a challenge given that it has a large differential diagnosis including lung, breast, gastrointestinal, ovarian, pancreaticobiliary, and other profiles.
3. Answer: C. It is essential to order appropriate immunohistochemistry to evaluate for treatable/curable cancers. In this patient, gastric lymphoma was mislabeled as poorly differentiated carcinoma.
