Management options for pulmonary nodules with cancer of unknown primary

Cancer of unknown primary (CUP) is defined as a cancer with a histological diagnosis suggestive of a metastasis and incompatible with that of the biopsy site. This means that metastatic cancer has been diagnosed but the primary site remains unknown. It represents 2–3% of all cancers and 10% of tumors with metastasis, with the location of the primary never found in 40–50% in spite of exhaustive investigations. This may be because the primary is very small and slow growing, making it outside the resolution of modern imaging techniques or because the body’s immune system has already destroyed the primary but not before haematological or lymphatic spread has occurred. Staging of CUP located in the lung of necessity does not follow the traditional TNM classification, with the TNM classification in this scenario being ambiguous and open to differing interpretations. This means that there may be diverging perspectives and viewpoints between surgeons, physicians and pathologists leading to different treatment pathways. It can result in the chance of potentially curative surgical resection of a lung lesion, if necessary by lobectomy, being missed in the belief that the lung mass in such CUP cases is by definition a metastasis. This perspective explores the diagnostic challenges of CUP, highlights the diverging opinions between different specialties in CUP and illustrates how knowledge of the different survival subsets that make up the diverse pathologies under CUP, together with informed surgical decision regarding tumour resectability should guide treatment choices. Patients with surgical resectable lung pathology fall into the 20% of CUP identified as having better prognosis; these carry a 15% 5-year survival and a median survival of 3 years, compared to the unfavorable subset that carries a dismal mean survival of 6 months. This suggests that surgery, when possible, remains a treatment of first choice.