Epidemiology and pathogenesis

For most patients who present with metastatic disease, routine examination and investigation will quickly disclose the underlying primary tumour. Occasionally, the primary tumour may be more elusive, and a number of clinical, histopathological and serological clues may help to establish its site. For 3–5% of patients, however, the primary site remains undisclosed because it is too small to be detected or has regressed. The usual histological diagnosis in these patients with a cancer of unknown primary (CUP) site is adenocarcinoma or poorly differentiated carcinoma. The benefits of establishing the primary site include:

• 
  

  diagnosing treatable disease (Table 37.1)

  
  
• avoiding overtreating unresponsive disease and hence iatrogenic morbidity in resistant disease
  
• preventing complications that relate to occult primary disease, such as bowel obstruction
  
• clarifying the prognosis

In 2010, a total of 9762 people were diagnosed with CUP and 10,812 people died of CUP. That more people died of CUP than were diagnosed with it is chiefly a consequence of the vagaries of data recording. Although CUP accounts for 3% of cancers diagnosed in the United Kingdom, it causes nearly 7% of cancer deaths. Over the last decade, the incidence of CUP has declined markedly – by 34% in women and 39% in men. This probably, in part, reflects improvements in imaging and immunohistochemical staining to establish a primary tumour site. The incidence of CUP rises with age and whilst it accounts for 3% of cancers overall, 7% of cancers in those over 85 years old are CUP.

Clinical sites of metastatic spread

Different tumours follow different patterns of metastatic spread. This may be related to chemokine and chemokine receptor expression by tumours and stromal cells (see Box 1.4 and Box 2.2). The most common sites of metastases are shown in Table 37.2 and Figure 37.1.

Bone metastases

Bone metastases are a major source of morbidity in patients with cancer and often have a prolonged course. Bone metastases cause pain, reduced mobility, pathological fractures, hypercalcaemia, myelosuppression and nerve compression syndromes. The tumours that commonly metastasize to bone are lung, breast, prostate, renal and thyroid tumours and sarcomas. Metastases usually occur in the axial skeleton, femur or humerus. If they are found elsewhere, then renal cancer and melanoma should be considered as possible primary tumour sites. Most bone metastases are lucent, lytic lesions; occasionally dense, sclerotic deposits are seen in prostate, breast, carcinoid tumours and Hodgkin’s disease. The diagnosis of bone metastases is rarely complicated. The differential diagnosis is outlined in Table 37.3 (Figures 3.4, 3.6, 5.6, 7.3, 12.1, 14.3, 14.4, 14.5, 26.4, 31.2, 31.5, 37.1, 40.6d, 40.7, 40.8 and 40.9).

Diagnosis	Pain	Site	Age	X-ray	Bone scan, CT/MRI	Biochemistry
Metastases	Common	Axial skeleton	Any	Discrete lesions, pathological fracture, loss of vertebral pedicles	Soft tissue extension on MRI/CT	Raised ALP and Ca
Degenerative disease	Common	Limbs	Old	Symmetrical	Symmetrical uptake on bone scan	Normal
Osteoporosis	Painless (unless pathological fracture)	Vertebrae	Old (female)	Osteopenia	Normal bone scan/MRI	Normal
Paget’s disease	Painless	Skull (often)	Old	Expanded sclerotic bones	Diffusely hot bone scan	Raised ALP and urinary hydroxyproline
Traumatic fracture	Always	Ribs	Any	Fracture	Intense linear uptake on bone scan	Normal
ALP, alkaline phosphatase; Ca, calcium; CT, computed tomography; MRI, magnetic resonance imaging.

Clinical CUP syndromes

Five highly treatable subsets of unknown primary sites have been identified, which have more favourable outcomes and require distinct management:

1. Women with isolated axillary lymphadenopathy (adenocarcinoma or undifferentiated carcinoma) usually have an occult breast primary and should be managed as stage II breast cancer. They have a similar prognosis (5-year survival is 70%).
   
2. Women with peritoneal carcinomatosis (often papillary carcinoma with elevated serum CA-125) should be managed as stage III ovarian cancer.
   
3. Men with extragonadal germ cell syndrome or atypical teratoma present with features reminiscent of gonadal germ cell tumours. They occur predominantly in young men with pulmonary or lymph node metastases. Germ cell tumour markers (α-foetoprotein (AFP) and human chorionic gonadotrophin (HCG)) may be detected in the serum and in tissue by immunocytochemistry. Cytogenetic analysis for isochromosome 12p (see Box 1.4) is positive in 90% of cases. Empirical chemotherapy with cisplatin-based combinations yields response rates of over 50% and up to 30% long-term survival.
   
4. Patients with neuroendocrine carcinoma of an unknown primary site overlap with extrapulmonary small cell carcinoma, anaplastic islet cell carcinoma, Merkel cell tumours and paragangliomas. Immunocytochemical staining for chromogranin, neuron-specific enolase, synaptophysin and epithelial antigens (cytokeratins and epithelial membrane antigen) is usually positive. Patients often present with bone metastases and diffuse liver involvement. These tumours are frequently responsive to platinum-based combination chemotherapy. Patients with neuroendocrine cancers may have prolonged survival and their tumours mistakenly identified as adenocarcinomas.
   
5. Patients with high cervical lymphadenopathy containing squamous cell carcinoma may have occult head and neck tumours of the nasopharynx, oropharynx or hypopharynx. Radical neck dissection followed by extended field radiotherapy that includes these possible primary sites may yield 5-year survival rates of 30%. Adenocarcinoma in high cervical nodes and lower cervical adenopathy containing either histology, however, have a much worse prognosis and should not be treated in this aggressive fashion.

Unfortunately, the majority of unknown primary tumours do not fit into any of these subsets and the response rates to chemotherapy are below 20%. These responses are usually of brief duration, with limited impact on overall survival. The median survival is under 12 months. The exception to this rule is in the group of patients who are under 45 years old. In this group, treatment with BEP (bleomycin, etoposide and cisplatin) or a taxane combination is worthwhile. For this group of patients, 50% survive in excess of 2 years despite the fact that the tumours do not have the characteristics of germ cell cancers and do not stain positively for HCG or AFP.

Histopathological characterization

The histopathological characterization of unknown primaries to establish their origin includes a number of techniques: light microscopy, immunocytochemical staining (Table 37.4), immunophenotyping, electron microscopy, cytogenetics and molecular analysis. These are described in detail in Chapter 3. There are numerous studies investigating the role of molecular diagnostics, including microarray-based gene expression profiling of CUP tumours.

Use of tumour markers

Tumour markers are proteins produced by cancers that are detectable in the blood of patients. Ideally, serum tumour markers should be quick and cheap to measure, have high sensitivity (of more than 50%) and specificity (over 95%) and yield a high predictive value of positive (PPV) and negative (NPV) results. Under these circumstances, tumour markers may be used for population screening, diagnosis, as prognostic factors, for monitoring treatment, diagnosing remission and detecting relapse and for imaging metastases. A large number of serum tumour markers are available, and each may be valuable for any of screening, diagnosis, prognostication and monitoring treatment (Table 37.5).

Approach to investigation of metastatic disease to establish primary site

There is a worrying tendency to over-investigate patients with unknown primary cancer while at the same time ignoring their palliative care needs. So often the greater the eminence and number of consultants whose advice is sought, the larger the number of esoteric investigations ordered, and the less well the patient and their family are informed. Investigations should be restricted to those that will alter clinical management. It is estimated that in the absence of a localizing symptom, extensive radiological investigation leads to the identification of a primary site in less than 5% of all patients. The prognosis is generally poor, with a median survival of 3–4 months. Less than 25% of patients survive to 1 year and less than 10% are alive after 5 years. The site of the primary is usually on the same side of the diaphragm as the metastases, and 75% of tumours are infradiaphragmatic; of the 25% that arise above the diaphragm, nearly all arise from the lung. Where identified, the most common primary sites, in order of frequency, are lung, pancreas, liver, colorectal, stomach, kidney, prostate, ovary, breast, lymphoid and testis. A good performance status is the most important predictor of survival, while extensive weight loss and older age are adverse prognostic factors. With the exception of the five clinical syndromes listed above, treatment other than symptom palliation is rarely appropriate.

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