Cervical lymphatic metastases from occult primary tumor. A nation-wide 20-year study from the Danish society of head and neck oncology

Grau C, Johansen LV, Jakobsen J, Geertsen PF, Andersen EV, Jensen BB.    Ugeskr Laeger 2001 Mar 5;163(10):1432-6

Arhus Universitetshospital, Arhus Kommunehospital, onkologisk afdeling. caigrau@dadlnet.dk

Of the 352 consecutive patients with squamous cell or undifferentiated tumours seen from 1975 to 1995, a total of 277 (79%) were treated with radical intent. Most patients received radiotherapy to both sides of the neck as well as elective irradiation of the mucosal sites in nasopharynx, oropharynx, hypopharynx and larynx (81%). Irradiation of the ipsilateral neck only was done in 26 patients (10%). Radical surgery was the only treatment in 23 N1-N2 patients (9%). RESULTS: The five-year estimates of neck control, disease-specific survival and overall survival for radically treated patients were 51%, 48% and 36%, respectively. The emergence of the occult primary was observed in 66 patients (19%). About half of the emerging primaries were within the head and neck region with oropharynx, hypopharynx and oral cavity being the most common sites. Emerging primaries outside the head and neck region were primarily located in the lung (19 patients) and oesophagus (five patients). The most important factor for neck control was nodal stage (5-year estimates 69% [N1], 58% [N2] and 30% [N3]). Other important parameters for neck control and disease-specific survival included haemoglobin, gender and overall treatment time. Patients treated with ipsilateral radiotherapy had a relative risk of recurrence in the head and neck region of 1.9 compared to patients treated at both neck and mucosa. At five years, the estimated control rates were 27% (ipsilateral) and 51% (bilateral; p = 0.05). The 5-year disease-specific survival estimates were 28% and 45%, respectively (p = 0.10). DISCUSSION: Extensive irradiation to both sides of the neck and the mucosa in the entire pharyngeal axis and larynx resulted in significantly fewer loco-regional failures compared to patients treated with ipsilateral techniques, but only a trend towards better survival. Determination of the optimal strategy in terms of loco-regional control, survival and morbidity requires a prospective randomized trial.

Oncologic rationale for bilateral tonsillectomy in head and neck squamous cell carcinoma of unknown primary source.

Koch WM, Bhatti N, Williams MF, Eisele DW.   Otolaryngol Head Neck Surg 2001 Mar;124(3):331-3

Johns Hopkins University, Department of Otolaryngology-Head and Neck Surgery.

OBJECTIVE: To demonstrate an oncologic basis for the recommendation to perform bilateral tonsillectomy as a routine measure in the search for a primary mucosal lesion in patients presenting with cervical nodal metastasis of squamous cell carcinoma (SCC). STUDY DESIGN: A case series of individuals selected from a 3-year period is reported. SETTING: Academic medical center. RESULTS: Each individual presented with metastatic squamous cell carcinoma in a cervical lymph node from an unknown primary source. In each case, the primary source was identified in a tonsillectomy specimen, either located contralateral to the node, or in both tonsils. CONCLUSIONS: The rate of contralateral spread of metastatic cancer from occult tonsil lesions appears to approach 10%. For this reason, bilateral tonsillectomy is recommended as a routine step in the search for the occult primary in patients presenting with cervical metastasis of SCC and palatine tonsils intact.

The management of metastatic squamous cell carcinoma in cervical lymph nodes from an unknown primary.

Medini E, Medini AM, Lee CK, Gapany M, Levitt SH.    Am J Clin Oncol 1998 Apr;21(2):121-5

Department of Radiation Oncology and Otolaryngology, University of Minnesota, and Veterans Administration Medical Center, Minneapolis 55417, USA.

A patient is diagnosed with an unknown primary of the head and neck when metastatic disease is present in the cervical lymph node or nodes and no primary lesion is detected by thorough physical examination, directed biopsies of suspicious or most likely primary sites, and imaging studies. The optimal management of patients who have this syndrome is still unclear and controversial. We report our results and analysis of the management of 24 patients with this syndrome. From 1976 through 1992, 24 patients who had metastatic squamous cell carcinoma in the cervical lymph nodes were seen in our medical center. A thorough search did not detect a primary lesion in any of them. Patients underwent radical neck dissection of the involved neck; 23 had unilateral and I had bilateral neck disease. Postoperative radiotherapy was delivered to both sides of the neck and to the potential primary mucosal and submucosal sites. The relation between clinical N stage, histologic findings of numerous involved lymph nodes, presence of extracapsular tumor extension, and survival were statistically analyzed. The Kaplan-Meier method was used for the survival analysis. The p values of log-rank test for the comparison of the two groups 1) N1 and N2 versus N3, and 2) presence of extracapsular tumor extension versus its absence are less than 0.005, with extracapsular tumor extension versus nonextracapsular tumor extension slightly smaller. The 5- and 10-year disease-free survival rate for the entire group was 54.2% (70.5% for N1 and N2, and 14.2% for N3). Three patients had locoregional failure, two in the primary sites, one in the nasopharynx, and the other in the oropharynx (the latter also had recurrent disease in the undissected neck). In 8 patients, distant metastases developed 7 to 38 months after radiotherapy. All 11 patients (45.8%) who had recurrent disease had advanced clinical N stage, microscopic findings of numerous involved lymph nodes, and prominent extracapsular tumor extension to the surrounding soft tissue and blood vessels. The high incidence of distant metastases shortly after treatment suggests a hematogenous spread before treatment in patients who had extensive nodal and extranodal disease. Our long-term disease-free survival beyond ten years seems to indicate combined treatment modalities, including radical neck dissection with postoperative radiotherapy of the neck, and the potential primary site in patients with N2 and N3 disease (our N1 group is too small for analysis). Further improvement of cure rate can be expected in the future with early detection and treatment.

Metastatic squamous cell carcinoma to cervical lymph nodes from unknown primary mucosal sites.

Nguyen C, Shenouda G, Black MJ, Vuong T, Donath D, Yassa M.    Head Neck 1994 Jan-Feb;16(1):58-63

Department of Oncology, McGill University, Montreal, Quebec, Canada.

Between 1978 and 1991, 54 patients with metastatic squamous cell or undifferentiated carcinoma to the cervical lymph nodes, with unknown primary mucosal sites, were treated with curative intent at McGill University teaching hospitals. The median age at diagnosis was 58 years with a male:female ratio of 6:1. All patients presented with a painless neck mass. Five patients (9%) presented with N1 disease, 28 (52%) with N2a disease, four (7%) with N2b disease, three (6%) with N2c disease, and 14 (26%) with N3 disease. Twenty-four patients (44%) underwent neck dissection, and 30 (56%) had only excisional lymph node biopsy. Fifty-three patients (98%) were treated with radiotherapy to a median dose of 60 Gy (range 38 to 66 Gy) in 30 fractions. With a median follow-up time of 49 months, the overall actuarial survival was 63% and 59% at 5 and 10 years, respectively. Three patients were found to have a subsequent primary head and neck tumor. The single most important prognostic factor was the N stage, which influences both neck control and long-term survival. There was no statistically significance difference in survival or local neck control rates between patients who had neck dissection or excisional lymph node biopsy (p > 0.05).

Cervical lymph node metastases from occult squamous cell carcinoma.

Nieder C, Ang KK.    Curr Treat Options Oncol 2002 Feb;3(1):33-40

Department of Radiation Oncology, Klinikum rechts der Isar, TU Munich, Ismaninger Str. 22, 81675 Munich, Germany. cnied@hotmail.com

Depending on patient and tumor characteristics, reported 5-year actuarial survival rates of patients with cervical nodal metastasis from an unknown primary carcinoma range from 18% to 63%. Prognostic factors for survival include N-stage, number of nodes, grading, extracapsular extension, and performance status. Retrospective studies suggest that neck relapse is more common than are distant metastases or emergence of mucosal primary tumors. The treatment options include neck dissection alone, radiation alone to the neck with or without the putative mucosal origin, and combination unilateral neck dissection plus limited or comprehensive radiotherapy. Combination of nodal dissection with comprehensive bilateral radiotherapy yielded most favorable results in local-regional disease control. However, its impact on the quality of life should be recognized. Also, the confounding effects of patient selection for various treatment modalities on therapeutic outcome cannot be quantified. Retrospective single-institution comparisons between comprehensive and unilateral neck radiotherapy did not show apparent differences in outcome. A randomized trial to compare the therapeutic value of comprehensive versus volume-limited radiotherapy is being planned. No data were found to support the benefit of chemotherapy for the treatment of this disease.

Cervical lymph node metastases from occult squamous cell carcinoma: cut down a tree to get an apple?

Nieder C, Gregoire V, Ang KK.   Int J Radiat Oncol Biol Phys 2001 Jul 1;50(3):727-33

Department of Radiation Oncology, Klinikum rechts der Isar, TU Munich, Munich, Germany. cnied@hotmail.com

PURPOSE: To review the value of extended diagnostic work-up procedures and to compare the results of comprehensive or volume-restricted radiotherapy in patients presenting with cervical lymph node metastases from clinically undetectable squamous cell carcinoma. METHODS AND MATERIALS: A systematic review was undertaken of published papers up to May 2000. RESULTS: 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. Prognostic determinants for survival are the N stage, number of nodes, extracapsular extension, and histologic grade. No data were found to support the benefit of chemotherapy in this disease. CONCLUSION: Physical examination, CT or MRI, and panendoscopy with biopsies remain the standard work-up for these patients. Routine use of PET or laser-induced fluorescence imaging cannot be firmly advocated based on presently available data. Although combination of nodal dissection with comprehensive radiotherapy yielded most favorable results, its impact on the quality of life should be recognized, and the confounding effects of patient selection for various treatment modalities on therapeutic outcome cannot be ruled out. A randomized trial comparing the therapeutic value of comprehensive vs. volume-limited radiotherapy is being considered.

Metastatic carcinoma in the cervical lymph nodes from an unknown primary site: results of bilateral neck plus mucosal irradiation vs. ipsilateral neck irradiation.

Reddy SP, Marks JE.  Int J Radiat Oncol Biol Phys 1997 Mar 1;37(4):797-802

Loyola University Chicago, Loyola-Hines Department of Radiotherapy, Maywood, IL, USA.

PURPOSE: To compare the outcome for patients with squamous cell carcinoma of cervical lymph nodes metastatic from an unknown primary site who were irradiated to both sides of the neck and potential mucosal sites with opposed photon beams, and for those irradiated to the ipsilateral side of the neck alone with an electron beam. METHODS AND MATERIALS: Fifty-two patients with squamous cell carcinoma metastatic to cervical lymph nodes from an unknown primary site were irradiated by two different methods. Thirty-six were irradiated with a bilateral technique (BT), i.e., to both sides of the neck, including the naso-oro-hypopharyngeal mucosa, and 16 were irradiated with an electron beam (EB) to the ipsilateral side of the neck alone. Twenty patients of the BT group and 11 of the EB group had cervical lymph node dissections, and the remaining 21 patients had lymph node biopsies, prior to radiotherapy. RESULTS: Tumor control in the ipsilateral side of the neck did not differ for either radiation technique, but was significantly higher after lymph node dissection than after biopsy (90 vs. 48%; p = 0.0004). Control of subclinical metastases in the contralateral cervical lymph nodes was higher for patients irradiated with BT than for patients irradiated with EB (86 vs. 56%; p = 0.03). The occult primary was later discovered in 8% of the patients in the BT group and 44% of the EB group (p = 0.0005). The disease-free survival rate at 5 years for patients who had lymph node dissection prior to irradiation was 61%, and was 37% for those who had biopsy (p = 0.05). Only 20% of patients who subsequently developed an occult primary were salvaged and survived for 5 years after salvage treatment. CONCLUSION: Bilateral neck and mucosal irradiation is superior to ipsilateral neck irradiation in preventing contralateral cervical lymph node metastases and the subsequent appearance of an occult primary cancer. Both techniques combined with cervical lymph node dissection were equally effective in controlling the ipsilateral neck disease.

Cervical nodal metastases from occult primary: undifferentiated carcinoma versus squamous cell carcinoma.

Tong CC, Luk MY, Chow SM, Ngan KC, Lau WH.   Head Neck 2002 Apr;24(4):361-9

Department of Clinical Oncology, Queen Elizabeth Hospital, 30 Gascoigne Road, Kowloon, Hong Kong. tccz01@hotmail.com

PURPOSE/OBJECTIVE: Controversy exists regarding the management of cervical lymph node metastases from occult primary. Oncologists face a major challenge in adopting an optimal approach. This study attempted to compare the clinical course of two different histologic findings of this disease entity. MATERIALS AND METHODS: A retrospective analysis was performed for all patients referred to our institution between 1988 and 1998 with cervical lymph node metastases from an unknown primary. Case records of consecutive unselected patients with histologically confirmed carcinoma in cervical lymph nodes were reviewed. Those with histologic findings other than squamous cell carcinoma (SCC) or undifferentiated carcinoma (UDC) and lymphadenopathies at the supraclavicular fossa alone or below the clavicles at the time of diagnosis were excluded. There were 45 patients identified with a mean follow-up of 36 months (range, 4-110 months). Thirty-seven were men and eight were women. The mean age was 57 (range, 29-91). There were 32 patients with SCC and 13 patients with UDC. Treatment modality included surgery (S) alone in 1 patient (2%), radiotherapy (RT) alone in 24 patients (53%), and combined modality in 20 patients (45%). (Twelve patients (27%) had combined S and RT, 8 patients (18%) had combined chemotherapy and RT.) Twenty-eight patients (62%) were treated with radical intent. For those patients treated by radical RT, the RT field covered both sides of the neck and the potential mucosal primary (PMP) sites, including the entire pharyngeal axis. The median radiation doses to the lymph nodes and the PMP were 65 Gy (range, 60-70 Gy) and 60 Gy (range, 40-70 Gy), respectively. RESULTS: At the time of analysis, ultimate control of disease above the clavicles according to N stage, treatment intent, and histologic type was as follows: N1s, 7 of 7 (100%); N2s, 15 of 26 (58%); N3s, 1 of 12 (8%); radical intent, 19 of 28 (68%); palliative intent, 3 of 17 (18%); UDC, 11 of 13 (85%); SCC,11 of 32 (34%). Eleven patients remained alive and disease free, with a median follow-up of 79 months (range, 27-110 months). The 5-year disease-specific survival (DSS) for the radical treatment group and the palliative treatment group were 67% and 18%, respectively (p =.0011). Significant difference in 5-year DSS was observed among the different N groups: 100% for N1s, 55% for N2s, and 0% for N3s, respectively (p =.0001). There was also a significant difference in the 5-year DSS between UDC and SCC: 81% for UDC vs 34% for SCC (p =.01). No significant difference in the 5-year DSS was observed on the basis of treatment modality in the radically treated group: 63% for RT alone vs 75% for S + RT (p =.711). CONCLUSIONS: UDC histologic findings in our series are associated with better locoregional control and DSS than SCC. Our results in local control, emergence of primary tumor, and DSS are comparable with other published data. However, disease control of advanced nodal stage remains poor; more aggressive treatment approaches, like the use of concurrent chemoradiation or altered fractionation scheme, should be explored.

Value of neck dissection in patients with squamous cell carcinoma of unknown primary.

Werner JA, Dunne AA.   Onkologie 2001 Feb;24(1):16-20

Klinik fur Hals-, Nasen- und Ohrenheilkunde der Philipps-Universitat Marburg. j.a.werner@mailer.uni-marburg.de

Lymph node metastases of cancer of an unknown primary (CUP syndrome) are responsible for 3-5% of the malignant diseases in the head and neck area. More than 70% of these patients show lymph node metastases of an unknown squamous cell carcinoma. The survival depends immediately on number and location of lymph node metastases. For a curative approach modified radical neck dissection combined with postoperative radiation therapy with or without chemotherapy should be considered in N1-N3 lymph node status. A radical neck dissection with postoperative radiation therapy should only be approved in cases of infiltration of the internal jugular vein, the accessory nerve and/or the sternocleidomastoid muscle. The different prognosis of patients with upper cervical and lower cervical lymph nodes should influence the indication and the extent of a neck dissection in the contralateral N0 neck.