About 5% of patients with cancer have no discernable primary site. Of these:
- 70% are adenocarcinoma
- 20% are undifferentiated carcinoma
- 5% are undifferentiated neoplasm
- 1% are neuroendocrine carcinoma
- The remainder are squamous cell carcinoma
The majority of cases are incurable but identifying the primary site can often help with palliative treatments (eg. androgen deprivation for prostate cancer). Cure is also possible for some lymphomas or germ cell tumours.
Establishing Diagnosis
All patients should undergo a full history and physical examination. This may assist in localising the tumour (eg. GI symptoms in for colorectal tumour).
If the site is still not apparent, further investigations are warranted based on the histological type and pattern of metastases.
Immunohistochemistry is helpful in subdividing tumour types:
- Cytokeratins are usually positive in epithelial tumours
- Desmin/vimentin are positive in many sarcomas
- S100 and melan-A are positive in some melanomas
- Synaptophysin and chromogranin are positive in many neuroendocrine tumours
- Leukocyte Common Antigen (CD79a) is positive in most lymphomas
Adenocarcinoma
The sites of metastases is often helpful. CT abdomen and PET scan are able to detect the primary site in about 1/3rd of patients.
- Breast imaging is helpful in patients with axillary metastases
- Panendoscopy may be used for patients with GI symptoms or liver/retroperitoneal metastases
Specific tumour immunohistochemistry markers may be helpful:
- PSA for prostate cancer
- TTF1 for adenocarcinoma of the lung
- OR/PR for breast cancer
- The pattern of CK7 and CK20 staining can be helpful
- CK7+/CK20- tumours tend to arise in the lung, breast and pancreas
- CK7-/CK20+ tumours are often colorectal
- CK7-/CK20- may arise from the bladder or prostate
Squamous Cell Carcinoma
Squamous cell carcinoma is rarely of unknown primary. It is most commonly found in lymph nodes, which guide further investigations:
- Upper cervical lymphadenopathy may be due to a skin or mucosal primary.
- Lower cervical lymphadenopathy may represent lung cancer or advanced disease from another site
- Inguinal lymphadenopathy may reflect SCC of the skin, genitals or anal canal
Undifferentiated Carcinoma
This group is the second most common category but also the most difficult to identify a primary site. CT and PET scanning may be of help. The most essential test in this group are b-hCG and AFP - these may be positive in germ cell tumours which are potentially curable even if metastatic.
In addition to the usual immunohistochemistry tests, chromosomal tests may be performed. This may detect characteristic mutations but is a bit of a long shot.
Undifferentiated Neoplasms
Establishing a diagnosis may help guide further therapy and the standard immunohistochemistry panel and cytogenetics may be of help.
Neuroendocrine Carcinoma
These may be well differentiated (carcinoid) or poorly differentiated (small cell tumour).
- Well differentiated neuroendocrine tumours often arise in the gut and may lead to carcinoid syndrome.
Prognostic Factors for Adenocarcinoma
Adenocarcinoma is the most commonly diagnosed carcinoma of unknown primary site. There are several features associated with improved survival with empiric chemotherapy:
- Lymph node involvement as opposed to organ or bone involvement
- Limited sites of disease
- Female gender
- Good performance status
- Normal bloods (LDH, albumin, lymphocytes)
Treatment of ACUP with empiric platinum and taxol combinations is most promising currently, except in the special cases listed below.
Management
Adenocarcinoma of Unknown Primary
Primary sites are more readily identified with the use of PET scanning. IN some cases, the location of metastases can guide therapy.
Unilateral Axillary Lymphadenopathy
Women with unilateral axillary lymphadenopathy are potentially curable even in the absence of a breast primary lesion. Standard therapy should include axillary lymph node dissection and treatment of the breast. Standard therapy is a total mastectomy, although there is good data supporting radiotherapy alone to the breast for women who wish to preserve the breast.
Peritoneal Carcinomatosis
Women with adenocarcinoma diffusely involving the peritoneum are most likely suffering from ovarian cancer even in the absence of an overt ovarian malignancy. Treatment recommendations usually follow that for ovarian cancer (maximal tumour debulking, systemic therapy).
Bone Metastases in Men
Men with widespread bony metastases may be suffering from prostate cancer, especially if the tumour stains positively for PSA or they have elevated PSA levels. Even in the absence of this, a trial of androgen deprivation is warranted if no other site of disease is identified.
Colorectal cancer distribution
Patients with liver and retroperitoneal metastases are frequently treated with systemic therapy that matches that for colorectal primaries, particularly if immunochemistry is suggestive of a colorectal primary (CK7- CK20+).
Squamous Cell Carcinoma of Unknown Primary
In the neck, see the Unknown Primary in the Head and Neck topic. Radiotherapy is generally indicated for advanced lesions with surgery reserved for single metastatic deposits.
SCC in inguinal nodes typically reflects metastasis from an ano-genital primary and therapy should be directed as per the primary site if found. In cases of isolated inguinal lymphadenopathy, surgical resection and/or local radiotherapy.
SCC in other sites including the supraclavicular fossa or bony metastases suggests a lung primary in most cases and this should be sought.
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