Practical Essentials of Intensity Modulated Radiation Therapy, 3 Ed.

11. Metastatic Carcinoma in Neck Node with Unknown Primary

Neha Sharma • Gokhan Ozyigit • K. S. Clifford Chao

Head and Neck Cancers of Unknown Primary – Highlights

Key Recent Clinical Studies

Chen et al. (IJROBP 2011) reported patients treated with IMRT were found to have significant improvements in xerostomia while having no difference in oncologic outcome when compared with conventional RT. (PMID 20421143)

Villeneuve et al. (IJROBP 2012) showed in their single institution experience 100% overall survival, disease-free survival, and locoregional control rates at 3 years using IMRT. Late toxicities were minimal. (PMID 21497452)

Sher et al. (IJROBP 2011) reported impressive overall survival and locoregional control rates of 92% and 100%, respectively, for patients treated with IMRT and concurrent chemotherapy. (PMID 21177045)

New Target Delineation Contours

FIGURE 11-3. CTV1, CTV2, and CTV3 delineation in a patient with unknown head and neck primary cancer with right neck mass TxN2bM0 who received definitive IMRT.


• Neck node metastasis of unknown primary comprises 3% to 9% of head and neck malignancies. Jugulodigastric and midjugular lymph nodes are the most frequent sites.1

• The most common histology is squamous cell carcinoma (SCC), representing 75% of cases, followed by undifferentiated carcinoma and adenocarcinoma.1,2

• The possible site of origin can be estimated from the histology of the neck node, although the biopsy often reveals a poorly differentiated neoplasm. Lymphoma should also be excluded by proper immunohistochemical staining.

• A solitary upper jugular chain is the most common site because most head and neck cancers spread to this area first. This metastasis site is uncommon for tumors below the clavicle.3

• A mass between the angle of the mandible and the tip of the mastoid suggests origin in the nasopharynx, oropharynx, parotid, occasionally malignant melanoma, or other skin cancers.

• The oral cavity, larynx, and hypopharynx should be included as likely sites for the mass in the subdigastric region.

• Bilateral upper neck nodes usually originate from the nasopharynx, base of tongue, soft palate, supraglottic larynx, and pyriform sinus.

• A solitary submandibular mass suggests a primary site of origin in the oral cavity, lip, or nasal vestibule, or a primary submandibular salivary gland tumor. A solitary submental node is rare.

• A mass in the mid-neck region suggests a primary site from the larynx or hypopharynx or, less commonly, from the thyroid or cervical esophagus, or a tumor originating below the clavicle.

• A solitary lower neck mass is commonly metastatic from the chest or abdomen. A solitary spinal accessory mass suggests a nasopharyngeal site. Squamous cell carcinoma in the parotid lymph nodes is always from a skin or parotid gland cancer.


• Physical examination and assessment under anesthesia conducted by an experienced otolaryngologist can elucidate a primary site in more than 50% of patients with cervical lymph node metastasis.4,5 In the absence of physical or radiographic suspicion, pan-endoscopy with biopsies yields a 17% detection rate.5

• Mendenhall et al.4 reported that the sites of primary tumor found through this process were at the tonsillar fossa and base of tongue in 82% of patients. Repeat pan-endoscopy did not seem to increase the detection rate.

2.1. Imaging

• Repeated examinations and contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) scans are essential for finding primary lesions. CT or MRI to look for a possible primary site follows a diagnosis of squamous cell carcinoma. If the biopsy is not definitive, CT or MRI may redirect the workup.

• The CT or MRI examination should be performed with at least 3-mm sections from the nasopharynx through the entire neck. MRI is used as a supplement for focused evaluation of suspicious regions, but not necessarily when the CT results are positive or normal.

• With negative routine clinical examination and CT, positron emission tomography (PET) detects carcinoma in 5% to 25% of patients, whereas ipsilateral tonsillectomy detects carcinoma in approximately 25% of patients. Laser-induced fluorescence imaging with pan-endoscopy and directed biopsies shows encouraging results but requires further investigation. PET has an overall staging accuracy of 69%.6

• The use of FDG-PET in the detection and radiotherapy planning for treatment of squamous cell carcinoma and other malignancies of unknown origin in the head and neck have recently been reviewed.710This has also involved the use of PET/CT imaging which gives a higher positive detection rate.11 Kwee et al.7 advise a confirming biopsy in the case of a PET/CT positive lesion.

2.2. Biopsies

• If thorough clinical and radiological exams are unable to detect a primary, patients should undergo direct laryngoscopy and exam under anesthesia. Directed biopsies should be performed including those of nasopharynx, base of tongue, supraglottic larynx, and pyriform sinuses, in addition to a bilateral tonsillectomy.

• In a study of 87 patients who presented with cervical node metastases from an unknown primary, 26% of patients were found to have tonsil primaries diagnosed with tonsillectomy.12 Tonsillectomy is particularly important in patients with biopsy samples positive for p16 due to the association of human papillomavirus (HPV) with oropharyngeal cancers.13

• Molecular markers are increasingly being used to assist in the identification of the origin of the disease. A recent study14 examined a wide panel of proteins related to carcinogenesis and tumor environment to assist in determining the origin of unknown primary cancers.

2.3. Staging

• In 2010, the American Joint Committee on Cancer issued its new (7th edition) TNM staging guidelines.15 The nodal staging for neck metastases are substantially similar to the previous (6th edition) guidelines. Readers are urged to consult the new guidelines for details.


3.1. Surgical Management

• Data from surgery alone series revealed a median nodal recurrence rate of approximately 34% and a 5-year overall survival rate of approximately 66%.5,1618 The crude mucosal carcinoma emergence rate was approximately 25% (30/121 patients).

• Selected patients, especially those with pathologic N1 disease with no extracapsular extension, can be treated adequately with surgery alone.17

3.2. Irradiation Alone

• Grau et al.5 reported a group of 213 patients treated with radiation alone. The 5-year actuarial mucosal carcinoma emergence rate was 16%, the nodal relapse rate was 50%, and the survival rate was 37%. It should be noted that series using radiation alone have more unfavorable prognostic factors.

3.3. Surgery and Irradiation

• Colletier et al.19 reported a series of 136 patients who received radiotherapy after nodal excision or neck dissection. The mucosal carcinoma emergence rate was 10%, the nodal failure rate was 9%, and the 5-year overall survival rate was 60%.

3.4. Radiotherapy to Ipsilateral Neck

• Weir et al.20 compared 85 patients who received radiation to the involved nodal region with 59 patients who received radiation to the bilateral neck and putative primary sites. Mucosal primary tumors emerged in 7% of patients who received involved nodal field irradiation compared with 1.7% of patients in the second group. In multivariate analysis, no difference in survival or cause-specific survival was found between these groups.

• Similarly, Marcial-Vega et al.21 did not show a significant difference of portal volume on mucosal emergence rate and 5-year overall survival in a study of 80 patients.

• In Grau et al.5 series, 26 patients received ipsilateral neck radiation. In multivariate analysis, there was no significant difference in the rates of mucosal emergence, nodal failure, disease-specific survival, and overall survival compared with bilateral neck radiation. However, when combining all relapses above the clavicle, unilateral neck radiation showed a relative risk of 1.9 (P = 0.05) compared with bilateral neck radiation.

• Table 11-1 summarizes the results of comprehensive and limited radiotherapy.

3.5. Chemotherapy

• No data have been found to support the benefit of chemotherapy.


4.1. Target Volume Determination

• Table 11-2 summarizes the suggested target volume determination for unknown primary carcinoma. (See also Table 4-5 in Chapter 4.)

• A recent study by Wallace et al.22 suggested that eliminating the larynx and hypopharynx from the RT portals did not compromise outcome and likely reduces treatment toxicity.

4.2. Target Volume Delineation

• In patients receiving postoperative intensity-modulated radiation therapy (IMRT), clinical target volume (CTV) 1 encompasses the residual tumor and the region adjacent to it but not directly involved by the tumor, the surgical bed with soft tissue invasion by the tumor, or the extracapsular extension by metastatic neck nodes. CTV2 includes primarily the prophylactically treated neck.

• CTV1 and CTV2 delineation in a patient with a clinically TxN2bM0 squamous cell carcinoma of unknown primary who received definitive IMRT is shown in Figure 11-1. The patient had multiple level II lymph nodes, and a fine-needle biopsy taken from one of the nodes revealed squamous cell carcinoma. The patient underwent examination under anesthesia with biopsies at multiple sites, which were all negative. Both MRI and CT failed to show any primary disease.

• CTV1 and CTV2 delineation in a patient with a clinically TxN2bM0 squamous cell carcinoma of unknown primary who received postoperative IMRT is shown in Figure 11-2. The patient had multiple right level II lymph nodes and underwent a right supraomohyoid neck dissection. IMRT was given to all mucosal sites and to the involved and uninvolved neck.

• Figure 11-3 illustrates target delineation for a 67-year-old man with unknown head and neck primary cancer, with right neck mass, staged as TxN2bM0.

• Figure 11-4 illustrates target delineation for a 60-year-old man with unknown head and neck primary with two involved lymph nodes of the right level II neck. The patient’s status post right modified neck dissection was pTxN2bM0, with extranodal extension and lymphovascular invasion.

4.3. Suggested Target and Normal Tissue Doses

• See Chapter 4 for suggested target and normal tissue doses.

4.4. Intensity-Modulated Radiation Therapy Results

• Following these guidelines, we treated nine patients with unknown primary carcinoma by using IMRT between February 1997 and December 2000 at Washington University.23 The N stages were N1 (one patient), N2 (seven patients), and N3 (one patient). The median follow-up time was 34 months (range 10–55 months). We observed one locoregional recurrence, and none of the patients developed lung metastasis. All patients are alive, except one who died of recurrent disease.

• A gastrostomy tube was placed in one patient during the course of IMRT. We observed no grade 3 or 4 late complications in our patients who were treated with IMRT. Grade 1 xerostomia was observed in five patients, and grade 2 xerostomia developed in one patient as a late sequelae.

• A study of 22 patients with carcinomas of unknown primary was performed by Lu et al.24 using IMRT, definitive (6 patients) and postoperative (12 patients). Two-year overall survival and regional recurrence-free survival were 74.2% and 88.5%, respectively.

• A retrospective study of outcomes on 95 patients treated postoperatively between 1990 and 2007 showed that 3D CRT and IMRT gave better locoregional control and survival compared to 2D methods. The addition of chemotherapy had no survival benefit.25

FIGURE 11-1. Clinical target volume (CTV) delineation in a patient with TxN2b squamous cell carcinoma of unknown primary who is receiving definitive intensity-modulated radiation therapy (IMRT). CTV1 (light blue line); CTV2 (red line); CTV3 (dark blue line); oral cavity (OC) (magenta line); gross tumor volume (GTV) (yellow line); left parotid gland (P) (aqua line); right parotid gland (P) (rust line); and spinal cord (SC) (green line).

FIGURE 11-2. CTV delineation in a patient with TxN2bM0 squamous cell carcinoma of unknown primary who is receiving postoperative IMRT. Preoperative computed tomography (CT) (left); postoperative CT (right). CTV1 (red line); CTV2 (dark blue line); oral cavity (OC) (magenta line); left parotid gland (P) (aqua line); right parotid gland (P) (rust line); and spinal cord (SC) (green line).

FIGURE 11-3. Target delineation for a 67-year-old man with unknown head and neck primary cancer, with right neck mass, stage TxN2bM0. p, parotid gland.

• Frank et al.26 reported a retrospective study of 52 patients with squamous cell carcinoma of unknown primary treated with IMRT at MD Anderson. Five-year actuarial primary mucosal tumor control was 98% and corresponding overall survival was 88%, with only 2 patients experiencing a grade 3 toxicity.

• Chen and coworkers27 at UC Davis compared results for 51 patients treated with CRT or IMRT for squamous cell carcinomas. No significant differences were seen in overall survival or locoregional control (86% and 89% at 2 years, respectively). However, IMRT gave better sparing of contralateral parotid gland, with severe xerostomia reduced from 58% to 11% (CRT vs IMRT).

• Sher et al.28 reported a retrospective study of 24 patients at Dana Farber treated with IMRT with concurrent chemotherapy for squamous cell carcinoma of unknown primary. Two-year actuarial overall survival and local control rates were 92% and 100%, respectively. Grade 2 xerostomia was limited to only 25%, but aggressively treated patients experienced a significant rate of esophageal stenosis.

FIGURE 11-4. Target delineation for a 60-year-old man with unknown head and neck primary with two involved lymph nodes of the right level II neck; status post right modified neck dissection was pTxN2bM0, with extranodal extension and lymphovascular invasion. p, parotid gland.

• Villeneuve et al.29 reported results on 25 patients in Montreal treated with IMRT for cervical lymph node metastases due to unknown primary disease. After 38 months of follow-up, there were no occurrences of primary cancer, and grade 2 xerostomia fell from 36% at 6 months to 8% (2 patients) at 24 months.

• These studies indicate that IMRT can provide high rates of local control for these diverse malignancies, with the advantage of significant reduction in toxicities and a better quality of life for the patient.


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8. Johansen J, Petersen H, Godballe C, Loft A, Grau C. FDG-PET/CT for detection of the unknown primary head and neck tumor. Q J Nucl Med Mol Imaging 2011;55(5):500–508.

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20. Weir L, Keane T, Cummings B, et al. Radiation treatment of cervical lymph node metastases from an unknown primary: an analysis of outcome by treatment volume and other prognostic factors. Radiother Oncol 1995;35(3):206–211.

21. Marcial-Vega VA, Cardenes H, Perez CA, et al. Cervical metastases from unknown primaries: radiotherapeutic management and appearance of subsequent primaries. Int J Radiat Oncol Biol Phys 1990;19(4):919–928.

22. Wallace A, Richards GM, Harari PM, et al. Head and neck squamous cell carcinoma from an unknown primary site. Am J Otolaryngol 2011;32(4):286–290.

23. Chao KSC, Ozyigit G, Tran BN, Cengiz M, Dempsey JF, Low DA. Patterns of failure in patients receiving definitive and postoperative IMRT for head-and-neck cancer. Int J Radiat Oncol Biol Phys 2003;55(2):312–321.

24. Lu HM, Yao M, Tan HM. Unknown primary head and neck cancer treated with intensity-modulated radiation therapy: to what extent the volume should be irradiated. Oral Oncol 2009;45(6):474–479.

25. Ligey A, Gentil J, Crehange G, et al. Impact of target volumes and radiation technique on loco-regional control and survival for patients with unilateral cervical lymph node metastases from an unknown primary. Radiother Oncol 2009;93(3):483–487.

26. Frank SJ, Rosenthal DI, Petsuksiri J, et al. Intensity-modulated radiotherapy for cervical node squamous cell carcinoma metastases from unknown head-and-neck primary site: M.D. Anderson cancer center outcomes and patterns of failure. Int J Radiat Oncol Biol Phys2010;78(4):1005–1010.

27. Chen AM, Li BQ, Farwell DG, Marsano J, Vijayakumar S, Purdy JA. Improved dosimetric and clinical outcomes with intensity-modulated radiotherapy for head-and-neck cancer of unknown primary origin. Int J Radiat Oncol Biol Phys 2011;79(3):756–762.

28. Sher DJ, Balboni TA, Haddad RI, 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;80(5):1405–1411.

29. Villeneuve H, Despres P, Fortin B, et al. Cervical lymph node metastases from unknown primary cancer: a single-institution experience with intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys 2012;82(5):1866–1871.