Cervical Lymph Nodes
Poorly Differentiated Carcinomas
Metastatic Melanoma to a Single Nodal Site
Isolated Axillary Metastasis
Inguinal Node Metastasis

Opinions are divergent concerning the value and extent of evaluation that should be performed to determine the primary tumor in patients who present with carcinoma of unknown primary (CUP). Clinical and pathological investigations to detect tumors that are potentially responsive to treatment (e.g., lymphoma, germ cell tumor, breast, or ovarian tumor) may be undertaken.

The chest radiograph has become an almost routine procedure in general medical practice. Although chest radiography is routinely performed, in the setting of CUP no distinguishing feature clearly separates primary from metastatic disease within the chest. The abdominal computed tomographic (CT) scan is the only radiographic test that may frequently be of value in defining the primary site, because of the inordinately high representation of pancreatic cancer in the CUP process.[1] With the exception of ovarian cancer, however, CT scans rarely identify treatable primary cancers.[2,3]

The clinical biology of the disease, the types of tumors most often encountered, and the high level of inaccuracy of unguided radiographic studies raise issues of cost effectiveness for intensive diagnostic work-up. Two studies have indicated that a large negative cost/benefit ratio exists for an extensive unguided clinical evaluation, with a single study citing a 9.5% increase in 1-year survival at a cost of 2 to 8 million dollars. The most reasonable approach is to develop a comprehensive knowledge of the manner in which CUP patients present and to remember that this presentation is associated with tremendous heterogeneity regarding outcome.[4-9]

A histologic diagnosis of metastatic carcinoma in cervical nodes requires a meticulous examination of the upper aerorespiratory tract. Histologically, these tumors are usually squamous cell carcinoma, but occasionally may be adenocarcinoma, melanoma, or anaplastic tumors. Metastatic adenocarcinoma is generally associated with a poor prognosis. Approximately 2% to 5% of patients with primary squamous cell carcinoma of the head and neck region will present with cervical adenopathy as the primary disease manifestation; about 10% of this group will present with bilateral adenopathy. The 3-year survival rate ranges from 35% to 59% when patients with squamous or undifferentiated tumors are treated with radical radiation therapy, surgery, or both.[10-12]

Investigators have defined a subpopulation of potentially curable patients with 1 or more of the following characteristics:

• Age younger than 50 years.
• Midline tumor distribution, multiple pulmonary nodules or lymph nodes, elevated serum levels of beta human chorionic gonadotropins (HCG) or alpha-fetoprotein (AFP).
• Cells positive for beta HCG or AFP by immunohistochemical stain.
• The presence of neuroendocrine granules.
• Clinical evidence for rapid tumor growth.
• Tumors that were very responsive to chemotherapy or radiation therapy.

In retrospective review, many of these patients, including some complete responders to chemotherapy, did not have any recognizable histopathologic features of germ cell tumors.[13-15] A single study has shown that the i(12p) marker chromosome may be used as a diagnostic tool in patients with suspected midline germ cell tumors.[16]

Approximately 5% of patients with malignant melanoma will present without a documented primary site. Special stains and electron microscopy may be important in establishing the diagnosis. Patients with this diagnosis should, like those with stage II melanoma, have a radical lymph node dissection. Survival is actually slightly better than that seen in patients with stage II melanoma with a documented primary site.[5,17-19] (Refer to the PDQ summary on Melanoma Treatment for more information.)

Most patients who present with nodal metastasis above the diaphragm ultimately are documented to have lung cancer, the most common supradiaphragmatic primary malignancy. The presence of isolated axillary metastasis in females, however, raises another possibility. A few studies involving a small number of patients have shown that approximately 50% of patients who present with isolated axillary metastasis of an adenocarcinoma will ultimately be shown to have breast cancer. Although some of these patients will have a positive mammogram after the initial evaluation, approximately 50% of the patients will not. When these patients are treated with local excision, or as having primary breast cancer, 2- to 10-year survival has been obtained in approximately 50% of patients. The availability of estrogen-receptor (ER) and progesterone-receptor (PR) assays may aid in this diagnosis, and these studies should be performed in this setting. If the clinical setting is consistent with breast cancer, and ER and/or PR levels are elevated, CUP with this distribution should be treated as breast cancer.[1,4,20] (Refer to the PDQ summary on Breast Cancer Treatment for more information.)

Squamous carcinoma detected in the inguinal lymph nodes is almost always metastatic from the genital or anal/rectal area. In females, careful examination of the vulva, vagina, and cervix is indicated, with biopsy of any suspicious areas. The penis of uncircumcised males should be carefully inspected. In both sexes, the anorectal area should be carefully examined, including biopsy of suspicious areas. Isolated metastases present in the central nervous system, the liver, and the genitourinary tract. Information about these presentations may be found in PDQ summaries that specifically detail their management.

In addition to the above situations, significant palliation can be achieved in certain instances in patients with CUP. Breast, prostate, ovarian, and thyroid cancers are all treatable malignancies, even when metastatic, and they represent approximately 15% of all CUP tumors. As with other CUP presentations, the pattern of spread of these malignancies is somewhat atypical. For instance, patients with prostate cancer who present with CUP have an inordinately high incidence of metastases to nonosseous sites such as lung (75%), liver (50%), and brain (25%). Bone metastases are also less common than lung metastases in thyroid cancer presenting as CUP.

References

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2. Abbruzzese JL, Abbruzzese MC, Lenzi R, et al.: Analysis of a diagnostic strategy for patients with suspected tumors of unknown origin. J Clin Oncol 13 (8): 2094-103, 1995.  [PUBMED Abstract]
   
   
3. Karsell PR, Sheedy PF 2nd, O'Connell MJ: Computed tomography in search of cancer of unknown origin. JAMA 248 (3): 340-3, 1982.  [PUBMED Abstract]
   
   
4. Patel J, Nemoto T, Rosner D, et al.: Axillary lymph node metastasis from an occult breast cancer. Cancer 47 (12): 2923-7, 1981.  [PUBMED Abstract]
   
   
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