Diagnostic and therapeutic management of cancer of an unknown primary

Abstract

Metastatic Cancer of Unknown Primary Site (CUP) accounts for approximately 3% of all malignant neoplasms and is therefore one of the 10 most frequent cancer diagnoses in man. Patients with CUP present with metastatic disease for which the site of origin cannot be identified at the time of diagnosis. It is now accepted that CUP represents a heterogeneous group of malignancies that share a unique clinical behaviour and, presumably, unique biology. The following clinicopathological entities have been recognised: (i) metastatic CUP primarily to the liver or to multiple sites, (ii) metastatic CUP to lymph nodes including the sub-sets involving primarily the mediastinal–retroperitoneal, the axillary, the cervical or the inguinal nodes, (iii) metastatic CUP of peritoneal cavity including the peritoneal papillary serous carcinomatosis in females and the peritoneal non-papillary carcinomatosis in males or females, (iv) metastatic CUP to the lungs with parenchymal metastases or isolated malignant pleural effusion, (v) metastatic CUP to the bones, (vi) metastatic CUP to the brain, (vii) metastatic neuroendocrine carcinomas and (viii) metastatic melanoma of an unknown primary. Extensive work-up with specific pathology investigations (immunohistochemistry, electron microscopy, molecular diagnosis) and modern imaging technology (computed tomography (CT), mammography, Positron Emission Tomography (PET) scan) have resulted in some improvements in diagnosis; however, the primary site remains unknown in most patients, even on autopsy. The most frequently detected primaries are carcinomas hidden in the lung or pancreas. Several favourable sub-sets of CUP have been identified, which are responsive to systemic chemotherapy and/or locoregional treatment. Identification and treatment of these patients is of paramount importance. The considered responsive sub-sets to platinum-based chemotherapy are the poorly differentiated carcinomas involving the mediastinal-retroperitoneal nodes, the peritoneal papillary serous adenocarcinomatosis in females and the poorly differentiated neuroendocrine carcinomas. Other tumours successfully managed by locoregional treatment with surgery and/or irradiation are the metastatic adenocarcinoma of isolated axillary nodes, metastatic squamous cell carcinoma of cervical nodes, or any other single metastatic site. Empirical chemotherapy benefits some of the patients who do not fit into any favourable sub-set, and should be considered in patients with a good performance status.

Introduction

In a general medical oncology service, metastatic carcinoma of an unknown primary site may constitute as much as 3–5% of the referred solid tumour patients 1, 2, 3. These are patients who are assigned the diagnosis of Metastatic Cancer of Unknown Primary Site (CUP). CUP represents a heterogeneous group of metastatic tumours for which no primary site can be detected following a thorough medical history, careful clinical examination and extensive diagnostic work-up. The primary site may either have a slow growth rate or it may possibly involute; therefore, the primary site rarely becomes manifest during the clinical course 4, 5.

Several terms have been used as synonyms of CUP such as Unknown or Occult Primary Tumour, Carcinoma or Adenocarcinoma of Unknown Primary, Metastases of Unknown Origin, Metastases from Unknown Primary Tumours and Tumour of Unknown or Unidentified Origin. Currently, the most widely accepted comprehensive term in use is ‘Cancer of Unknown Primary’. Historically, the definition of CUP has varied over time according to the inclusion criteria used and to the evolution of diagnostic tools.

In the early 1970s, some researchers argued that the diagnosis of CUP could be made only if the primary tumour was not found at autopsy [6]. Today, the definition of CUP includes patients who present with histologically-confirmed metastatic cancer in whom a detailed medical history, complete physical examination including pelvic and rectal examination, full blood count and biochemistry, urinalysis and stool occult blood testing, histopathological review of biopsy material with the use of immunohistochemistry, chest radiography, computed tomography (CT) of the abdomen and pelvis and, in certain cases, mammography fail to identify the primary site 7, 8 (Table 1).

Despite the recent advances in molecular immunohistochemistry and imaging technology, the diagnosis and therapy of these patients remains a real dilemma for practising oncologists. Whereas the majority of CUP patients are relatively resistant to systemic therapy and have short survival times, certain clinicopathological sub-sets defined by either clinical or pathological features have been identified which respond to treatment and have a better prognosis.