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radiation portal at UF (IJROBP 2001;50:55)

Cancer Metastatic to Cervical Lymph Nodes
          from an Occult Primary

            see NCCN Guidelines, radiation port
            also see section on lymph nodes
            see abstracts of studies on treatment of occult cancers

            read   review here

Many patients often present with a neck mass and are found to have squamous cell carcinoma in a cervical lymph node but the source of the cancer cannot be found. Common hidden sites include the nasopharynx, base of tongue, tonsil and pyriform sinus. There are two approaches: one is to do neck surgery only and watch the patient closely, the other approach is to do a neck dissection then radiate the rest of the neck and throat to try to eradicate the hidden cancer and prevent a relapse in the neck.
 The 5 year cure rate with either approach is 37 to 66%. The recent study from UF (IJROBP 2001;50:55) used a dose of radiation (56.7Gy) or 65Gy if no neck dissection and had a 67% 5 year survival rate. An older study from MDA Anderson reported a DFS/3y rate: surgery alone (57%), radiation alone (48%) and surg + radiation (46%.) They noted the ability to control the disease in the neck as below:

Relapse Rate in the Neck (Cancer 1973:31:854)
Stage Surgery Radiation Surg + Radiation
Nx - N1 13% 17% 0%
N2-N3 32% 22% 18%


see discussion of treatment techniques
Cervical lymph node metastases from occult squamous cell carcinoma: cut down a tree to get an apple? Carsten Nieder, Vincent Gregoire, K. Kian Ang International Journal of Radiation Oncology.Biology.Physics, 50:3 : 727-733

Positron emission tomography (PET) has an overall staging accuracy of 69%, with a positive predictive value of 56% and negative predictive value of 86%. With negative routine clinical examination and computerized tomography (CT) or magnetic resonance imaging (MRI), PET detected primary tumors in 5–25% of patients, whereas ipsilateral tonsillectomy discovered carcinoma in about 25% of patients. Laser-induced fluorescence imaging with panendoscopy and directed biopsies showed some encouraging preliminary results and warrants further study. All together, the reported mucosal carcinoma emergence rates were 2–13% (median, 9.5%) after comprehensive radiotherapy and 5–44% (median, 8%) after unilateral neck irradiation. The corresponding nodal relapse rates were 8–45% (median, 19%) and 31–63% (median, 51.5%), and 5-year survival rates were 34–63% (median, 50%) and 22–41% (median, 36.5%), respectively. Retrospective single-institution comparisons between comprehensive and unilateral neck radiotherapy did not show apparent differences in outcome. Grau et al. recently reported a series of 277 patients treated with radical intent in 5 cancer centers in Denmark Therapy consisted of radical surgery as the only treatment in 23 (9%), irradiation of the ipsilateral neck in 26 (10%), and radiotherapy to both sides of the neck and the mucosa in 224 patients (81%). The incidence of emerging primary in the head and neck was significantly higher in patients treated with surgery alone than those treated with radiotherapy (5-year actuarial risks of 54 1% as opposed to 15 3%, p < 0.0001). However, the cause-specific and overall survival rates of patients undergoing surgery alone were not significantly worse than those receiving combined therapy, most likely due to selection of patients with more favorable nodal stage for surgery alone and those with more advanced nodal disease for adjunctive radiotherapy.Combining data of surgery alone from four available series however, revealed a crude mucosal carcinoma emergence rate of about 25% (30 of 121 patients), a median nodal recurrence rate of around 34%, and a 5-year overall survival rate of approximately 66%. These data suggest that selected patients, particularly those with pN1 neck disease with no extracapsular extension, can be treated adequately with surgery alone. No data were found to support the benefit of chemotherapy in this disease.

A recent retrospective analysis by Mendenhall and colleagues on 130 patients with confirmed cervical lymph node metastases from clinically occult SCC showed that in the absence of physical or radiographic suspicion panendoscopy with biopsies yielded a 17% detection rate. The yield rate increased to 52–56% if either clinical examination or imaging was suggestive and to 65% if both were suggestive. Repeat panendoscopy did not appear to increase the detection rate. The sites of primary tumors found through endoscopy and biopsy were tonsillar fossa and base of tongue in 82% of patients. This finding is in contrast to a previous report of high likelihood of finding nasopharyngeal or hypopharyngeal cancers (20–40% for each site) (1). Tonsillectomy was performed in 10 patients without and 24 patients with clinical suspicion and revealed SCC in 1 and 10 (42%) patients, respectively. Two other groups found tonsillar carcinoma in 9 of 37 (24%) patients (13) and 23 of 87 (26%) patients (14) and also advocated ipsilateral tonsillectomy in the absence of suspicious lesions.
  unilateral XRT comprehensive XRT surgery alone
primary emerging 8% (5-44%) 9.5% (2-13%) 25- 54%
neck relapse 51.5% (31-63%) 19% (8-49%) 34%
distant mets 38% 19% (11-23% na
survival/5y 36.5% (22-41%) 50% (34-63%) 66%


The role of fluorodeoxyglucose positron emission tomography in cervical lymph node metastases from an unknown primary tumor
Kyle E. Rusthoven, Mary Koshy, Arnold C. Paulino  Cancer 2004;101:2641

The overall sensitivity, specificity, and accuracy rates of FDG-PET in detecting unknown primary tumors were 88.3%, 74.9%, and 78.8%, respectively. Furthermore, FDG-PET detected 24.5% of tumors that were not apparent after conventional workup. FDG-PET imaging also led to the detection of previously unrecognized metastases in 27.1% of patients (regional, 15.9%; distant, 11.2%). FDG-PET had notably low specificity and a high false-positive rate (39.3%) in the tonsils. In contrast, the false-positive rates for FDG-PET of the base of tongue and hypopharynx were only 21.4% and 8.3%, respectively. FDG-PET exhibited decreased sensitivity to tumors in the base of tongue (81.5%). The sensitivity of this technique at other sites was 90.5%.

The detection of primary tumors in patients with cervical lymph node metastases is important for several reasons, including target volume delineation and treatment-associated morbidity. Patients with known primaries in the head and neck receive site-specific treatment, whereas patients with persistent unknown primaries after conventional workup often undergo irradiation of mucosal sites, where primary tumors commonly occur. The mucosal sites that undergo elective irradiation vary according to distribution of involved lymph nodes but commonly include the nasopharynx, base of tongue, and hypopharynx. Because of the larger target volume involved, such panmucosal radiotherapy can cause additional morbidity when compared with the radiotherapy administered to treat a known primary tumor.

The rate of primary tumor detection by FDG-PET in the current series was slightly improved relative to the rate reported in the review by Fogarty  Those investigators found that FDG-PET correctly detected a primary tumor that had gone undetected by CT/MRI in 62 of 276 cases (22.5%). Our analysis suggests that FDG-PET provided additional information beyond conventional anatomic imaging in 24.5% of patients. More impressive was the difference in specificity between the current review (74.9%) and the reviews conducted by Fogarty et al. (65.3%) and Neider et al. (62%). The lower false-positive rate in the current series was attributable in part to the exclusion of data from FDG-SPECT. In addition, our analysis includes data from 4 studies and 125 patients who were not included in those previous reviews. The specificity of FDG-PET in these 4 studies was 74%, which is consistent with the data from the rest of our analysis. Despite this improvement, however, low specificity remains the most notable weakness of FDG-PET. Proposed reasons for the high false-positive rate include physiologic uptake in the tonsils, reactive lymph nodes, and muscles of mastication. Less commonly, FDG accumulation can occur in patients with sarcoidosis, granulomatous disease, and benign tumors of the salivary glands. Stokkel  have also suggested that recent mucosal biopsy in the workup of unknown primaries can cause a tissue repair reaction with a consequent increase in FDG uptake. Finally, Greven  suggested that the high false-positive rate also may be attributable to sampling error in PET-directed biopsies.

In the current series, FDG-PET exhibited high sensitivity (88%) in the detection of primary tumors. Neider et al. reported a slightly lower sensitivity for this technique (82%). Kole have suggested several possible causes for false-negative results; disruption of the signal-to-noise ratio caused by high background uptake, especially in the brain, can disrupt the detection of a tumor, and in addition, well differentiated tumors have been shown to have a lower rate of FDG uptake. Kole and colleagues have also suggested that small tumors that are below the resolution of FDG-PET can lead to false-negative results. Nonetheless, the high sensitivity of FDG-PET in the current review can be attributed to the large number of true-negative results. In our analysis, 61.9% of patients (187 of 302) never had a primary tumor found, and FDG-PET yielded true-negative findings in 46.4% of all patients (140 of 302 patients). Some have speculated that the failure to detect a primary tumor after extensive workup may be the result of phenomena such as spontaneous regression or immune-mediated destruction of the primary lesion.

The most notable utility of FDG-PET imaging was its ability to detect new metastases. Three of the four studies that reported information on the detection of new metastases used whole-body FDG-PET. In the study by Fogarty  all three sites at which new distant metastases were found were located below the diaphragm. Braams et also comment on the possibility that both primary tumors and distant metastases could localize below the clavicle and advise that whole-body FDG-PET be used, especially when the metastases are located in the lower part of the neck. Overall, the data from the current review indicated that whole-body imaging was able to detect unsuspected regional or distant disease in 27% of all patients.

The detection of unknown distant metastases occurred in 11% of all patients reviewed. This finding is particularly important, because such information can lead to a change in the treatment objective from cure to palliation. Moreover, previously unrecognized regional disease, the detection of which could lead to inclusion of the contralateral neck in target delineation or to the administration of a higher radiotherapy dose to FDG-PET-positive lymph node sites, was found in 16% of patients. In the current review, data from FDG-PET scans led to changes in treatment in 24.7% of all patients in the 6 studies in which this endpoint was reported.

Our findings regarding primary tumor locations are consistent with those made in previous studies. In the current study, 24% of all primary tumors in patients with cervical lymph node metastases and unknown primaries were found below the clavicle. In their report, Jones  found that up to 40% of patients with malignant cervical lymph nodes had primary tumors outside of the head and neck (most commonly in the lungs). Among head and neck primaries, tumors of the tonsils and the base of the tongue were the most prevalent in the current analysis. Similarly, in the study by Mendenhall  tumors of the tonsils and the base of the tongue accounted for 43% and 39% of all primary tumors, respectively. Data from the current series also suggest a lower incidence of primary tumors of the nasopharynx (8.3%), hypopharynx (8.3%), and supraglottic larynx (5.3%) than has been previously reported in the literature on CUP.Mendenhall suggest that the decreased incidence of unknown tumors at these locations can, in all likelihood, be attributed to the increased sensitivity of fiberoptic endoscopes and anatomic imaging (CT/MRI) in the detection of primary tumors at these sites. In contrast, tumors of the tonsils and base of tongue can resemble lymphoid tissue and thus can be more difficult to detect with conventional workup.

In our audit, FDG-PET exhibited its highest accuracy for tumors of the hypopharynx and larynx. The high sensitivity (100%) and low false-positive rates (10%) that were observed indicate that FDG-PET is a valuable supplement to panendoscopy at these locations.

The most common site of false-negative FDG-PET findings in the current analysis was the base of tongue (sensitivity, 79.3%). The observed reduction in sensitivity can be attributed to the high baseline level of FDG uptake (as a result of speech and swallowing) at this site.[33] Consequently, FDG uptake by a tumor located at the base of the tongue can be misinterpreted as benign physiologic uptake. Because of the high false-negative rate, it is recommended that patients with negative FDG-PET findings at this site undergo further investigation, including panendoscopy and biopsy.

FDG-PET had a low false-positive rate for tumors located at the base of the tongue or in the hypopharynx. In the current series, there were only six false-positive diagnoses of tumors at the base of the tongue and only one false-positive diagnosis of a tumor in the hypopharynx. The low false-positive rate that was observed corresponds to a high specificity and positive predictive value for FDG-PET detection of tumors at these sites.

At anatomic locations other than the base of the tongue and the hypopharynx, false-positive rates were much higher. The tonsils were the most common site of false-positive FDG uptake (39.3%, compared with 28.3% for all other sites combined). The high rate of false-positive results and the low specificity of FDG-PET for tonsillar tumors can be attributed to FDG uptake caused by increased cellular metabolism in inflammatory lesions. Li  found that inflammatory lesions had a mean FDG standardized uptake value (SUV) of 2.58 (standard deviation, 0.77). Similarly, Adams et al.[37] found that inflamed lymphoid tissue had SUV values that ranged from 2.0 to 15.8. This enhanced FDG uptake by benign lesions in the tonsils overlaps with the range of uptake levels found in malignancies and can, therefore, lead to false-positive results. False-positive FDG-PET findings subject the patient to further diagnostic investigation and mucosal biopsy, which have associated costs and morbidities.

CONCLUSIONSFDG-PET detected primary tumors that went undetected by other modalities in approximately 25% of cases and was sensitive in the detection of previously unrecognized regional or distant metastases in 27% of cases. FDG-PET had low specificity for tonsillar tumors and low sensitivity for base-of-tongue malignancies