Elsevier

The Lancet

Volume 379, Issue 9824, 14–20 April 2012, Pages 1428-1435
The Lancet

Seminar
Cancer of unknown primary site

https://doi.org/10.1016/S0140-6736(11)61178-1Get rights and content

Summary

Cancer of unknown primary site (CUP) is a well recognised clinical disorder, accounting for 3–5% of all malignant epithelial tumours. CUP is clinically characterised as an aggressive disease with early dissemination. Diagnostic approaches to identify the primary site include detailed histopathological examination with specific immunohistochemistry and radiological assessment. Gene-profiling microarray diagnosis has high sensitivity, but further prospective study is necessary to establish whether patients' outcomes are improved by its clinical use. Metastatic adenocarcinoma is the most common CUP histopathology (80%). CUP patients are divided into subsets of favourable (20%) and unfavourable (80%) prognosis. Favourable subsets are mostly given locoregional treatment or systemic platinum-based chemotherapy. Responses and survival are similar to those of patients with relevant known primary tumours. Patients in unfavourable subsets are treated with empirical chemotherapy based on combination regimens of platinum or taxane, but responses and survival are generally poor.

Introduction

Patients diagnosed with cancer of unknown primary site (CUP) present with histologically confirmed metastatic cancer for which clinicians are unable to identify a primary tumour after a standard diagnostic approach (panel 1).1

CUP accounts for 3–5% of all human cancers, is reported to be the seventh to eighth most frequent malignant tumour, and is the fourth most common cause of cancer death in both sexes. The overall age-standardised incidence per 100 000 people per year is 7–12 cases in the USA, 18–19 in Australia, 5–7 in the Netherlands, and 4–6 in Switzerland.1 Median age at presentation is 65–90 years.2 The disorder is slightly more common in men than in women, and predominantly affects adults (less than 1% of patients with diagnosed solid CUP are children).2

Section snippets

Pathophysiology

Some investigators believe that biologically distinct CUP cases exist. Such cases are thought to have a peculiar and poorly understood biology and a metastasis-causing genetic signature independent of that of the primary tumour.1, 3 Here we review the evidence for the existence of such a distinct biology.

Hedley and colleagues4 reported that 106 (70%) of 152 patients with CUP had aneuploid tumour cells. Additionally, several investigators have used immunohistochemistry to study the oncogenes MYC

Clinical features and clinicopathological subsets

Whether the clinical course of CUP—especially for patients with untreatable subsets—differs substantially from that of known primary tumours is unclear. CUP has several fundamental characteristics: short history with symptoms and signs associated with metastatic sites, early dissemination in the absence of primary tumour, aggressive clinical course, and occasionally an unpredictable metastatic pattern (frequency and location of metastases different from those of known primary tumours).

Histopathology

Three rules are of paramount importance to the diagnosis of CUP. First, the pathologist should receive an adequate tumour tissue or properly processed cytological samples. Second, a stepwise algorithm with immunohistochemical staining should be applied to provide a final diagnosis. Third, close contact with the clinical oncologist to retrieve necessary clinical and laboratory information is pivotal. The immunochemistry of a CUP biopsy should establish three things: whether the cancer is

Favourable subsets

For the past 50 years, chemotherapy has been the basis of CUP treatment. Generally, treatment recommendations are based mainly on type 3 evidence, and therapeutic modalities are thought to be suitable for individual clinical or investigational use.

Women with serous papillary adenocarcinoma of the peritoneal cavity should be managed similarly to patients with stage III and IV ovarian cancer. Best possible treatment includes maximum surgical cytoreduction followed by chemotherapy with a

Future prospects and research needs

CUP is a heterogeneous group of metastatic cancers with a distinct biology. However, although our inability to identify a primary tumour is because of clinical or technological inefficiencies in a substantial proportion of patients, sometimes the primary tumour will regress or stay dormant and the malignant clone will metastasise early to several secondary sites. For this subgroup of genuine CUP, research should be focused on the multigene prometastatic signature of these tumours, which might

Search strategy and selection criteria

We searched Medline with the search terms “cancer”, “carcinoma”, or “adenocarcinoma”, in combination with “unknown primary” or “unknown origin”. We mostly selected publications from between 1981 and January, 2011, but did not exclude commonly referenced and highly regarded older reports. We also searched the reference lists of articles identified by this search strategy and selected those we judged relevant. Review articles and book chapters are cited to provide readers with more details and

References (48)

  • K Polyzoidis

    Miliaras G, Pavlidis N. Brain metastasis of unknown primary: a diagnostic and therapeutic dilemma

    Cancer Treat Rev

    (2005)
  • S Culine

    Prognostic factors in unknown primary cancer

    Semin Oncol

    (2009)
  • KA Oien

    Pathologic evaluation of unknown primary cancer

    Semin Oncol

    (2009)
  • DJ Sher et al.

    Efficacy and toxicity of chemoradiotherapy using intensity-modulated radiotherapy for unknown primary of head and neck

    Int J Radiat Oncol Biol Phys

    (2011)
  • GR Varadhachary et al.

    Carcinoma of unknown primary with a colon-cancer profile—changing paradigm and emerging definitions

    Lancet Oncol

    (2008)
  • GR Varadhachary et al.

    Overview of patient management and future directions in unknown primary carcinoma

    Semin Oncol

    (2009)
  • G Lazaridis et al.

    Liver metastases from cancer of unknown primary (CUPL): a retrospective analysis of presentation, management and prognosis in 49 patients and systematic review of the literature

    Cancer Treat Rev

    (2008)
  • V Golfinopoulos et al.

    Comparative survival with diverse chemotherapy regimens for cancer of unknown primary site: multiple-treatments meta-analysis

    Cancer Treat Rev

    (2009)
  • N Pavlidis et al.

    Cancer of unknown primary

    Crit Rev Oncol Hematol

    (2009)
  • G Pentheroudakis et al.

    Cancer of unknown primary site: missing primary or missing biology?

    Oncologist

    (2007)
  • GM Stella et al.

    MET mutations in cancers of unknown primary origin (CUPs)

    Hum Mutat

    (2011)
  • G Pentheroudakis et al.

    Circulating tumour cells in cancer of unknown primary site: correlation with clinicopathologic characteristics and prognosis

    Ann Oncol

    (2010)
  • G Pentheroudakis et al.

    Axillary nodal metastases from carcinoma of unknown primary (CUPAX): a systematic review of published evidence

    Breast Cancer Res Treat

    (2010)
  • N Pavlidis et al.

    Cervical lymph node metastases of squamous cell carcinoma from an unknown primary site: a favourable prognosis subset of patients with CUP

    Clin Transl Oncol

    (2009)
  • Cited by (425)

    View all citing articles on Scopus
    View full text