Updated: 18 August 2005
2.1 Clinico-pathologic Considerations
- Multiple invasive investigations are to be avoided since the diagnostic yield is low, but where indicated, tests should be directed to diagnosing potentially curable diseases including germ cell tumours, lymphomas and small cell anaplastic carcinoma of the lung.
- Contrast studies of the bowel should specifically be avoided unless the patient has symptoms referable to the site or positive occult bloods
- Because of the potential for high grade palliation, an effort should be made to identify patients where the occult primary tumour is located in the breast, prostate, thyroid, ovary or endometrium.
With the above in mind, all patients should have a careful history taken and thorough physical examination performed. The latter should include examination of all node-bearing areas, rectal examination with examination of the prostate and testes in males and a breast and pelvic examination in females.
Most patients should have a panel of relevant tumour markers performed to include CEA, ß-HCG, alphafetoprotein (AFP), prostatic specific antigen (PSA) in males, CA-125 and CA-15-3 in females (looking for gynecological and breast primary tumours respectively). All patients should have a chest X-ray as well as a complete blood count, renal and liver function tests. If breast cancer is a possibility, mammograms should be done. Abdominal and pelvic CT scan is a good screen for intra-abdominal and retroperitoneal primary tumours when these are felt to be likely and when such a finding may assist management. Bone scan with X-rays of areas of positive uptake is useful if the patient has bone pain. Fecal occult bloods should be performed for patients with symptoms or intra-abdominal adenocarcinomas. Other special studies should be done only if suggested by specific symptoms or clinical situations.
2.2 Diagnostic Pathology – Biopsy Considerations
When there is a need for pathologic assessment it is important that the physician decides upon the type of information required prior to biopsy. A variety of biopsy techniques are available including needle aspiration cytology, core biopsy or open biopsy. The choice of technique depends upon the clinical problem and differential diagnosis as well as the need for additional studies such as analysis of estrogen and progesterone receptors. Fresh, unfixed tissue is required for estrogen and progesterone receptor studies and is also preferred for analysis of DNA status, oncogene rearrangement and chromosomal studies. Fresh material and special fixatives are required for analysis of malignant lymphomas and are of particular importance in small cell, undifferentiated malignant tumours in children.
Core biopsy or open biopsy are the current standard techniques for obtaining tissue for pathological assessment. Preferably the material should be sent fresh to the laboratory with a brief outline of the clinical problem. This is particularly important when the biopsy is removing a solitary metastasis and no further tissue would be readily available. Submission of a small fragment of tissue for frozen section may be of assistance in confirming the presence of tumour. However, it is not advised to submit the tissue only for frozen section as this distorts morphology and may complicate interpretation. Fine needle aspiration cytology can also be very useful in confirming the diagnosis of malignancy as well as providing material for special stains or DNA analysis.
2.3 Tumour Markers and Pathology
While tumour markers may be performed on tissue, the immunological stains used to analyze these markers are not always reliable. In many instances the measurement of tumour markers on the patient's serum are more useful. As these markers may disappear from the patient's blood within a short time after removal of the tumour, it is important to obtain a blood sample prior to surgery in cases in which the tissue removed represents the major portion of the bulk of the patient's disease. The serum can be frozen and processed later as needed. Post-operative serum tumour markers may also be helpful, if elevated pre-op.
A careful pathologic assessment of the tumour can be helpful in narrowing the differential diagnosis. In some instances the likely site of origin can be suggested by the pathologist and may direct further diagnostic procedures. For example, the pathologic findings may point in the direction of an infradiaphragmatic primary lesion and suggest the need for an abdominal CT scan. Another example is nodal disease in the neck, which pathologically may be interpreted as suggesting nasopharyngeal carcinoma again suggesting diagnostic procedures directed to that site. New immunohistochemical stains may assist in pinpointing the primary origin: TTF-1; CSX-2; Hepar-1; GCDFP-16, etc. Newer molecular markers could be considered in some cases where molecular therapy is being contemplated: He-2neu, c-kit, EGFR.
In many instances the pathology interpretation carried out at the referring hospital is straightforward. However, particularly when the pathology has been interpreted as showing "malignancy - subtype undetermined," "carcinoma of unknown type," or "poorly differentiated or anaplastic carcinoma," then a pathology review should be carried out at the BC Cancer Agency. Advances in immunocytochemical techniques may make it possible to narrow down tumour sites quite considerably. When requesting a pathology review at BCCA, it is preferable to send a representative paraffin block from the biopsy together with the slides. Occasionally, it will be possible to reclassify poorly differentiated lesions as small cell anaplastic carcinoma, lymphoma or germ cell tumours, which would dictate a different treatment approach.