Etiology

Given the inherent variability in presentation, no specific etiologic factors are proven 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 behavior and, presumably, a unique biology. However, exact details of this biology have yet to be elucidated.

The prevailing hypothesis dictates that the primary tumor remains microscopic, thus evading detection, or disappears completely after seeding the metastasis, with some authors citing angiogenic incompetence within the primary tumor as a biologic rationale.[12][13]​​​ This scenario is difficult to test clinically, due to lack of a primary tumor focus to evaluate. Other authors suggest that metastases could occur very early in tumorigenesis in this disease, hypothesizing that these tumors 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 hematoxylin and eosin staining of tissue from the metastatic focus can distinguish those tumors 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 tumors, and neuroendocrine tumors.[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 workup 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 tumors

  • Neuroendocrine carcinoma.

European Society for Medical Oncology: classification of favorable 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 nonsupraclavicular 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 histologic and immunohistochemical profile (renal-like CUP).

Use of this content is subject to our disclaimer