Cervical Lymph Nodes
Poorly Differentiated Carcinomas
Poorly Differentiated Neuroendocrine Carcinomas
Peritoneal Carcinomatosis
Isolated Axillary-Nodal Metastasis
Inguinal Node Metastasis
Melanoma (Melanotic or amelanotic) Occurring in a Single Nodal Site
Multiple Involvement
Current Clinical Trials

The overwhelming majority of patients presenting with carcinoma of unknown primary (CUP) have disseminated disease that is relatively chemoresistant. Potentially curative treatment can be delivered, however, in a few situations.

All patients should undergo a careful head, neck, and lung evaluation including coronal computed tomography and/or magnetic resonance imaging of the head and neck and directed biopsies of the nasopharynx and tongue base. In those patients with squamous cell or undifferentiated carcinoma, tonsillectomies have been recommended and should be considered if the tonsils have not been previously removed.[1] Fluorodeoxyglucose F 18-positron emission tomography scan may identify an occult primary site in the head and neck area.[2,3] If no primary site can be determined, the following approaches should be considered:

• Radical radiation therapy with curative intent to the cervical lymph nodes and possible sites of origin.[4]
• Preoperative radiation therapy followed by radical neck dissection.
• Radical neck dissection.
• Radical neck dissection followed by postoperative radiation therapy to possible sites of origin.[5]

(Refer to the PDQ summary on Metastatic Squamous Neck Cancer with Occult Primary Cancer Treatment for more information.)

Patients who have poorly differentiated carcinomas with or without serologic or histologic evidence of beta human chorionic gonadotropins or alpha-fetoprotein should be treated with intensive chemotherapy as used in the treatment of disseminated germ cell tumors.

In a series, more than 220 patients with excellent performance status were treated with aggressive combination chemotherapy. This chemotherapy generally consisted of vinblastine, bleomycin, and cisplatin; however, some patients received a doxorubicin-containing modification of this regimen and some received etoposide instead of vinblastine. The response rate was 63%, with a complete response rate of 26%, and a long-term disease-free survival of 16%.[6] Carboplatin-containing regimens were found to have equal activity.[7] A paclitaxel-based combination yielded a 48% response rate in 71 patients with various histologic types of carcinoma of unknown origin.[8]

In a series of 29 patients with poorly differentiated neuroendocrine carcinomas, 19 were treated with intensive cisplatin-based combination chemotherapy, and six additional patients received doxorubicin combinations. Six patients achieved complete response and four of these patients were alive 19 to 100 months after diagnosis.[9]

Women with peritoneal carcinomatosis of an adenocarcinoma serous histologic type have a favorable response to chemotherapy and improved prognosis. Response and survival rates in these patients approach those seen in ovarian cancer patients, and therapy appropriate for ovarian cancer should be used.[10,11] (Refer to the PDQ summary on Ovarian Epithelial Cancer Treatment for more information.)

The most common primary site for isolated axillary metastasis is the breast. Mammography should be performed in all patients with isolated axillary-nodal metastasis. After an adequate evaluation of the breast and lung to rule out these primary sites, the following treatment options should be considered:

• Lymph node dissection with or without mastectomy or radiation therapy to the breast with curative intent.[12]
• Lymph node dissection with or without mastectomy or radiation therapy to the breast with curative intent plus adjuvant chemotherapy with an accepted therapeutic adjuvant approach for breast cancer. This option should be considered especially if breast cancer is proven or if other lymph nodes show adenocarcinoma.[13]

Metastatic carcinoma in inguinal nodes from an unknown primary source occurs in approximately 1% to 3.5% of patients. A diagnostic excisional-node biopsy should be performed when no primary source of carcinoma can be found. The most common pathologic diagnosis in this instance is Hodgkin lymphoma or non-Hodgkin lymphoma, with CUP being less frequent.

Treatment options:

• Superficial groin dissection alone.
• Local excisional biopsy with or without radiation, inguinal node dissection, or chemotherapy.

In a small proportion of patients, local excision alone is sufficient therapy. Initial therapy with radiation may be used successfully in some patients, depending on extent of disease and individual patient characteristics. Isolated metastases also present in the central nervous system, liver, and genitourinary tract.[14] More information can be found in the PDQ summaries for these malignancies.

Approximately 5% of patients present with no detectable primary site.

Treatment option:

• Radical lymph node dissection. For patients who present with a single site of nodal metastasis, this treatment will yield a survival that is slightly better than that obtained in conventional stage II melanoma.

When patients present with widespread metastatic disease and special studies reveal a probable primary tumor for which standard systemic therapy is available, such therapy should be administered. This may include hormonal therapy for prostate and breast cancer, I¹³¹ for thyroid cancer, or cytotoxic single-agent or combination chemotherapy for hormone-refractory breast and ovarian cancers. Standard approaches for such diseases are available in the specific PDQ summaries for each diagnosis.

The majority of patients will not have a definable primary source. For such patients, a variety of combination chemotherapy approaches have been tried with little success. No treatment can be considered standard at present. Therefore, such patients should be considered for available clinical trials.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with newly diagnosed carcinoma of unknown primary. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References

1. Righi PD, Sofferman RA: Screening unilateral tonsillectomy in the unknown primary. Laryngoscope 105 (5 Pt 1): 548-50, 1995.  [PUBMED Abstract]
   
   
2. Lassen U, Daugaard G, Eigtved A, et al.: 18F-FDG whole body positron emission tomography (PET) in patients with unknown primary tumours (UPT). Eur J Cancer 35 (7): 1076-82, 1999.  [PUBMED Abstract]
   
   
3. Rades D, Kühnel G, Wildfang I, et al.: Localised disease in cancer of unknown primary (CUP): the value of positron emission tomography (PET) for individual therapeutic management. Ann Oncol 12 (11): 1605-9, 2001.  [PUBMED Abstract]
   
   
4. Beldì D, Jereczek-Fossa BA, D'Onofrio A, et al.: Role of radiotherapy in the treatment of cervical lymph node metastases from an unknown primary site: retrospective analysis of 113 patients. Int J Radiat Oncol Biol Phys 69 (4): 1051-8, 2007.  [PUBMED Abstract]
   
   
5. Davidson BJ, Spiro RH, Patel S, et al.: Cervical metastases of occult origin: the impact of combined modality therapy. Am J Surg 168 (5): 395-9, 1994.  [PUBMED Abstract]
   
   
6. Hainsworth JD, Johnson DH, Greco FA: Cisplatin-based combination chemotherapy in the treatment of poorly differentiated carcinoma and poorly differentiated adenocarcinoma of unknown primary site: results of a 12-year experience. J Clin Oncol 10 (6): 912-22, 1992.  [PUBMED Abstract]
   
   
7. Pavlidis N, Kosmidis P, Skarlos D, et al.: Subsets of tumors responsive to cisplatin or carboplatin combinations in patients with carcinoma of unknown primary site. A Hellenic Cooperative Oncology Group Study. Ann Oncol 3 (8): 631-4, 1992.  [PUBMED Abstract]
   
   
8. Greco FA, Burris HA 3rd, Erland JB, et al.: Carcinoma of unknown primary site. Cancer 89 (12): 2655-60, 2000.  [PUBMED Abstract]
   
   
9. Garrow GC, Greco FA, Hainsworth JD: Poorly differentiated neuroendocrine carcinoma of unknown primary tumor site. Semin Oncol 20 (3): 287-91, 1993.  [PUBMED Abstract]
   
   
10. Strnad CM, Grosh WW, Baxter J, et al.: Peritoneal carcinomatosis of unknown primary site in women. A distinctive subset of adenocarcinoma. Ann Intern Med 111 (3): 213-7, 1989.  [PUBMED Abstract]
    
    
11. Dalrymple JC, Bannatyne P, Russell P, et al.: Extraovarian peritoneal serous papillary carcinoma. A clinicopathologic study of 31 cases. Cancer 64 (1): 110-5, 1989.  [PUBMED Abstract]
    
    
12. Merson M, Andreola S, Galimberti V, et al.: Breast carcinoma presenting as axillary metastases without evidence of a primary tumor. Cancer 70 (2): 504-8, 1992.  [PUBMED Abstract]
    
    
13. Ellerbroek N, Holmes F, Singletary E, et al.: Treatment of patients with isolated axillary nodal metastases from an occult primary carcinoma consistent with breast origin. Cancer 66 (7): 1461-7, 1990.  [PUBMED Abstract]
    
    
14. Guarischi A, Keane TJ, Elhakim T: Metastatic inguinal nodes from an unknown primary neoplasm. A review of 56 cases. Cancer 59 (3): 572-7, 1987.  [PUBMED Abstract]
    
    

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