Cancer with Unknown Primary (CUP)

Discuss CUP?

CUP is a cancer in which a complete diagnostic work-up detects only metastases, but no primary tumour. CUP accounts for 3–5% of all malignancies. Modern investigations identify the primary tumour in 10-20% of patients only. Even in post mortem series, a primary is found in only 50% to 75% of cases. The median survival of patients with the CUP syndrome is 3 to 6 months.

Discuss the diagnostic approach to CUP?

CUPs are by de?nition metastatic tumours. Thus the diagnostic approach should be to de?ne the extent of tumour dissemination and help identify a minority of CUP patients who can expect to bene?t from directed therapy. This must be achieved with a minimum of stress to the patient. It is recommended that all patients with CUP should have:

  • Thorough physical examination (including head and neck, rectal, pelvic and breast examination), basic blood and biochemistry survey, urinalysis, faecal occult blood test and CT scan of thorax, abdomen and pelvis.
  • Endoscopy should be sign or symptom guided.
  • Serum assessment of AFP, HCG and PSA is suggested in male patients to exclude potentially curable extragonadal germ-cell tumour and those amenable to hormone treatment for prostate cancer. Other tumour markers, such as CEA, CA125, CA19-9, or Ca 15-3, are of low specificity and can only be used to follow the course of the illness.
  • Mammography or breast MRI is recommended in female patient with axillary adenopathy.
  • PET is suggested in patients with head and neck CUP

Discuss the favourable sub groups of CUP?

CUP has a very poor prognosis. However 20-30% of patients with CUP have good prognosis and can have long-term survival or even cure. Identification of these subgroups with favourable prognosis is of vital importance for the therapy of patients with CUP syndrome. The first step is always to test whether a patient has one of these well characterized disease entities and then to plan the treatment accordingly. These CUP subgroups with favourable prognosis are rare. These subgroups are

  • Axillary lymph node metastasis of adenocarcinoma in a women
    All should undergo mammography or breast MRI. Immunohistology for hormone status and c-erb2 should be checked. These patients with compatible immunohistology and absence of a breast primary should be treated as breast cancer with lymph node involvement (stage II)
  • Papillary carcinomatosis of a serous papillary adenocarcinoma in women-usually originates in the ovary or peritoneum. Ca125 is often increased. Therapy is identical to that of metastatic ovarian carcinoma in stage FIGO III.
  • Cervical lymph node metastasis of squamous cell cancer-These patients should undergo CT and/or MRI of the neck. PET is recommended as it may pick up small metabolically active lesions that are not seen on CT or MRI. They should also have a through ENT examination with biopsies of any suspicious lesions. Treatment is as for metastatic ENT tumours with a known primary.
  • Inguinal lymph node metastasis of squamous cell carcinoma- a large majority will have a detectable primary site in the genital or anorectal area. So external genitalia should be carefully examined in both sexes. Digital rectal examination and proctoscopy should be performed in both sexes to exclude anorectal lesions. If no primary site is identified, lymphadenectomy with or without postoperative radiation therapy to the inguinal nodal region may result in long-term survival.

    • Undifferentiated neuroendocrine carcinoma- a platinum/etoposide based regimen as currently used for small cell lung cancer is generally used.

  • Poorly differentiated carcinoma with germ cell characteristics- these patients typically have some of the following features;
    • Young males (<50) with retroperitoneal and mediastinal lymph node metastasis.
    • Serum levels of HCG or AFP is markedly elevated.
    • They also have cytogenetic aberrations like presence of 12p chromosomal gain on molecular genetic analysis.

    • These tumours should be treated like poor prognosis germ cell tumours. The response to chemotherapy is excellent and some are cured

  • Solitary metastasis: A PET scan is suggested to rule out any additional unrecognized sites of metastatic disease prior to definitive local therapy. If the metastasis is truly solitary, resection or definitive local radiation therapy is indicated. Local treatment sometimes results in long disease-free intervals.

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