Aetiology

Given the inherent variability in presentation, no specific aetiological factors have been shown to underlie the pathogenesis of adenocarcinoma of unknown primary site (AUP). It is generally accepted that AUP represents a heterogeneous group of malignancies that share a unique clinical behaviour and, presumably, a unique biology. However, exact details of this biology have yet to be elucidated.

The prevailing hypothesis dictates that the primary tumour remains microscopic, thus evading detection, or disappears completely after seeding the metastasis, with some authors citing angiogenic incompetence within the primary tumour as a biological rationale.[12][13]​​ This scenario is difficult to test clinically, due to lack of primary tumour focus to evaluate. Other authors suggest that metastases could occur very early in tumourigenesis in this disease, hypothesising that these tumours are biologically aggressive from the outset.[14] This is clearly supported by the aggressive clinical nature of AUP and the overall poor prognosis.

Pathophysiology

The pathophysiology of the cells constituting this subtype is very similar to that of adenocarcinoma cells from known primary sites. Light microscopy and standard haematoxylin and eosin staining of tissue from the metastatic focus can distinguish those tumours with obvious gland formation (well-differentiated to moderately differentiated adenocarcinoma) from those with scant glandular structures, consistent with adenocarcinoma due to mucin production (poorly differentiated or undifferentiated adenocarcinoma). Immunohistochemical studies are essential to specify a likely site of origin of the metastatic cells, and only when these tests are unrevealing is a diagnosis of adenocarcinoma of unknown primary site (AUP) reached.

These modalities can generally differentiate AUP from other subtypes of cancers of unknown primary site, which include squamous cell carcinoma, undifferentiated carcinoma, germ cell tumours, and neuroendocrine tumours.[1]

Classification

Cancer of unknown primary site

There is no formal clinical classification of adenocarcinoma of unknown primary site, although numerous algorithms exist to direct the work-up and management of specific subgroups of patients. However, there are five broad categories of cancer of unknown primary site. These are:[1]

  • Adenocarcinoma

  • Undifferentiated carcinoma

  • Squamous cell cancer

  • Germ cell tumours

  • Neuroendocrine carcinoma.

European Society for Medical Oncology: classification of favourable cancer of unknown primary (CUP)[2]

  • Single metastatic deposit or oligometastatic disease amenable to local ablative treatment (single-site or oligometastatic CUP)

  • Women with isolated axillary lymph node metastases (breast-like CUP)

  • Women with peritoneal carcinomatosis of a serous papillary adenocarcinoma (ovarian-like CUP)

  • Squamous cell carcinoma involving non-supraclavicular cervical lymph nodes (head and neck-like CUP)

  • Men with blastic bone metastases and/or immunohistochemistry (IHC) or serum prostate-specific antigen (PSA) expression (prostate-like CUP)

  • Adenocarcinoma with colorectal IHC (CK7-negative, CK20-positive, CDX2-positive) or molecular profile (colon-like CUP)

  • Carcinoma with renal cell histological and immunohistochemical profile (renal-like CUP).

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