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Metastatic carcinoma in the cervical lymph nodes from an occult primary: a conservative approach to the role of radiotherapy
hr. f. Rodiamn Oncology Bid Phys., Vol. Printed in the U.S.A. All rights reserved.
18,pp.289-294
0360-3016/90 $3.00 + .oO Copyright 0 1990 Pergamon Press plc
??Original Contribution
METASTATIC: CARCINOMA IN THE CERVICAL LYMPH NODES FROM AN OCCULT PRIMARY: A CONSERVATIVE APPROACH TO THE ROLE OF RADIOTHERAPY ROBERT G. T. GLYNNE-JONES, MRCP, FRCR,* ANIL K. ANAND, M.D.,+ TERESA E. YOUNG, B.Sc.# AND ROGER J. BERRY, M.D., D.PHIL, FRCP, FRCR” The Meyerstein Institute of Radiotherapy and Oncology, The Middlesex and University College Hospital Medical School, London W 1N 8AA, U.K. This retrospective study examines the results of treatment for cervical lymph node metastases from an unknown primary epithelial cancer of squamous cell or anaplastic histology. The analysis covers a series of 87 consecutive unselected patients at the Middlesex Hospital, London, in the years between 1954 and 1986. Fifty-eight patients received radiation therapy with a view to cure, 25 patients were treated with radiotherapy to a palliative dose, 1 patient only had a radical neck dissection, and 3 patients received no treatment apart from excision biopsy. In contrast to common practice in the United States, only a single patient received prophylactic radiation to the nasopharynx as part of the initial therapy. Overall actuarial survival for all patients (87) at 2 years was 43% and at 5 years 33%, amd in the radically treated group (58) it was 52% and 40%, respectively. Only 6 of the 87 patients (7%) subsequently revealed a primary tumor above the clavicles. Overall disease control above the clavicles was achieved in 53% (46/87), but was 64% (37/58) in the radically treated group. Guidelines for radiation therapy are discussed in view of these results. Cervical metastases,
Unknown primary, Radiotherapy. METHODS
INTRODUCTION
AND
MATERIALS
In the majority of patients presenting with metastatic carcinoma in the cervical lymph nodes a primary lesion is identified on thorough otolaryngologic examination and biopsy ( 1), but the prima.ry site may remain undiscovered in up to 10% of cases (6, 14, 20, 21). A report as early as 1946 recognized that the prognosis for these patients is far from hopeless ( 15). According to some authors (3, 19, 28), the outcome for patients with cervical metastases from an occult primary is improved by extending radiation fields to include the possible primary sites in the head and neck. However, few recent reports have been published on the role of limited irradiation of the cervical nodes alone, which has been the practice at our institution for many years. The present study is a retrospective analysis of all patients with cervical metastases from an unknown primary of squamous cell or anaplastic histology, who were referred for radiotherapy to this department between 1954 and December 1986.
We reviewed the case notes of 87 consecutive unselected patients with histologically confirmed squamous cell or anaplastic carcinoma in the cervical lymph nodes, where investigations had failed to reveal a primary lesion. Patients with prior skin cancers of the head and neck, and lymphadenopathy or metastatic disease below the clavicles at the time of diagnosis, were discounted from the analysis. There were 53 males and 34 females, with a mean age of 6 1 years and a range of 12-85 years. Median time to follow-up was 35 months with a range of 4-300 months. The majority of the patients (80) presented with enlarged lymph nodes on one side of the neck, but seven patients had bilateral cervical lymphadenopathy. The most common single site of involvement was the jugulodigastric node which was involved in 24 of the patients, followed by the middle deep cervical nodes in 12 and supraclavicular nodes in 9. For comparison with series from the United States, patients were re-staged according to the
* Lecturer in Radiotherapy and Oncology. + Visiting Radiation Oncologist, Honorary Registrar. * Research Assistant. * Professor of Radiation Oncology. Reprint requests to: Teresa Young, The Meyerstein Institute of Radiotherapy, The Middlesex Hospital, Mortimer Street, London W 1N 8AA U.K.
Acknowledgements-We
would like to thank Dr. A. M. Jelliffe, Dr. M. F. Spittle, and Dr. C. A. E. Coulter for allowing us to report on their patients. We would also like to thank the Special Trustees of the Middlesex Hospital for supporting Mrs. Teresa Young, and Ms. Jeanette Hutchinson for clerical skills. Accepted for publication 9 August 1989.
289
I. J. Radiation Oncology 0 Biology 0 Physics
290
Table 1. Characteristics of lymph node involvement Number of sites Number of patients Stage Number of patients Size of nodes (cm) Number of patients
1 51 Nl 7 1-3 18
2 23 N2 24 4-6 40
3 13 N3 52 >7 17
Nx 4 Unknown 12
Nl corresponds to the presence of a single, mobile node less than 3 cm in diameter, N2 is a single node more than 3 cm or multiple mobile ipsilateral nodes, and N3 is a unilateral fixed node or bilateral nodes. American Joint Committee on Cancer (AJCC) classification for nodal disease in the head and neck. Table 1
shows the number of sites of involved nodes in the neck, their size, and their stage. Histopathology Histopathological diagnosis was obtained in all patients. In addition to the 43 squamous cell carcinomas (10 well differentiated, 9 moderately well differentiated, and 24 poorly differentiated) 44 were described as anaplastic carcinomas. Histological review was not possible in all cases because many early specimens had been discarded. Investigations If thorough clinical and radiological investigative procedures failed to discover a primary site, we proceeded to bronchoscopy, oesophagoscopy and examination under anesthetic (EUA) to examine the naso-, oro- and hypopharynx and larynx. If all still appeared macroscopically normal, blind biopsies of the left and right postnasal space, tonsil, base of tongue and hypopharynx were obtained. In the present series 82/87 patients underwent EUA. The histopathological diagnosis was obtained in all patients, by trucut biopsy in 54, incisional biopsy in 8, and excisional biopsy in 25 cases. Radiation therapy Dose. Radiation formed the mainstay of treatment for 83 patients, of whom 58 were treated with a view to cure (arbitrarily defined as radiation therapy in excess of 50 Gy in daily fractions over 5 weeks or 45 Gy over 43 weeks in combination with macroscopic clearance of disease). In this radically treated group, 3 patients were implanted with radium needles and 3 1 received at least 60 Gy. A further 24 received between 45 Gy and 60 Gy, but doses were often more radical than the total dose would imply because of non-standard fractionation (45 Gy/l5 fractions/2 1 days, 50 Gy/20 fractions/28 days or 54 Gyf 18 fractions/42 days). Palliative doses were administered to 25 patients to relieve pain or prevent fungation. Field size. For those 58 patients who received a radical dose of radiation, the field encompassed the whole side of the neck in 34 patients, and both sides of the neck in 9 patients (4 of whom presented with bilateral lymphadenopathy). Small localized fields to the area of nodal
February 1990, Volume 18, Number 2 with a margin (1.5-2.0 cm) were used in 15 patients. Only a single patient was treated with radiation fields covering both nasopharynx and the neck. This patient had an anaplastic carcinoma, diagnosed by cervical lymph node biopsy. Mucosal irregularity near the Fossa of Rosenmuller had been noted at EUA, although biopsy of this area did not confirm a primary tumor.
involvement
Radical neck dissection Six patients underwent radical neck dissection (RND), four of them as a planned combined modality of radiation and surgery, one as the sole modality of treatment, and one for nodal recurrence in the treated area after radical radiation. Chemotherapy Only one patient, a male aged 12 years, received adjuvant chemotherapy in addition to radical radiation therapy and neck dissection. Palliative chemotherapy was administered to eight patients with advanced disease after radiation had failed, but was not felt to have altered their survival. No treatment Three patients received no further treatment after the initial excision biopsy. RESULTS
Overall actuarial survival of all patients in this series (Fig. 1) was 43% at 2 years and 33% at 5 years. For the 58 patients treated with radical radiation, 2-year and 5year survival was 52% and 40%, respectively, and 20% and 16% for the 25 who received palliative irradiation (Fig. 2). Patients lost to follow-up (6) or those who died of incidental causes but had remained disease-free (13), were censored at the time of loss, and contributed to actuarial survival and recurrence only up until the time of last information. Age and sex made no difference to survival. Poor actuarial survival occurred in those patients with supracla-
o’B’n 0
n 24
46
n
n”n 72
96
n”c 120
144
E 166
fi
n c a 192
216
Time (months) from date of 1st treatment
Fig. 1. Shows actuarial survival of all patients.
I’ 240
Carcinoma in cervical lymph nodes 0 R. G. T. GLYNNE-JONES
0
0
24
46
72
96
120
144
166
192
216
240
0
24
40
Time (mon:hs) from date of 1st treatment
291
et al.
72
96
120
144
168
192
216
240
Time (months) from date of 1st treatment
Fig. 2. Shows actuarial survival of patients. (a) Treated radically with radiation (58); (b) Treated palliatively with radiation (25). (Excludes 4 patients who received no radiation.)
Fig. 3. Shows actuarial survival of patients with (a) cervical (63); (b) supraclavicular nodes (20). (Excludes 4 patients who received no radiation.)
2, Fig. 3), and more than two sites (Table 3).
Detection of the primary tumor The primary tumor site was later discovered in 19 out of 87 patients (22%). The most common primary site was the lung (7); the other sites included nasopharynx (4), oesophagus (2) and a single lesion each in the breast, epiglottis, parotid, cervix, kidney, and stomach. All primaries above the clavicles occurred in areas outside the radiation portals. The mean time before the appearance of a head and neck primary was 7 months, with a range of 2-l 8 months. Of the six primary tumors above the clavicles, only two (both nasopharyngeal carcinoma) were successfully salvaged by radiotherapy, but both subsequently died from disease below the clavicles.
vicular nodes (Table of nodal involvement
Local control Overall in 46 patients
out of 87 (53%) disease was controlled above the clavicles, and in the radically treated group 37/58 (64%). Of these 58 patients treated with a view to cure (Table 4), 18 recurred in the neck (13 in the treated area, 4 with a marginal recurrence, and a single patient in the contralateral untreated upper deep cervical nodes). Localized irradiation proved unsatisfactory since 4 out of 15 (27%) patients relapsed outside the field in the adjacent ipsilateral neck. (supraclavicular nodes 2, middle deep cervical 1, upper dleep cervical 1). For all irradiated patients, the majority of the failures in the neck lay within the radiation portals (3 l/39). Of the four patients who received no radiation, two relapsed in the ipsilateral neck
and two remained disease-free above the clavicles. Local control was less easily obtained with progressive ‘N’ stage and size of involved nodes (Table 5a and b). In the radically treated group escalating doses appeared to have no significant effect on local control or survival.
Table 2. Actuarial survival according to modality of treatment
Cervical nodes Radical group (48) Palliative group (15) (Excludes two patients who received no radiation) Overall (63) Supraclavicular nodes Overall (20) (Excludes two patients who received no radiation)
2 Years %
5 vears %
57 13
51 13
48
41
30
9
Note: Figures in parenthesis indicate number of patients. Survival curves for cervical nodes and supraclavicular nodes are significantly different p = 0.02.
Metastatic disease Metastatic disease below the clavicles was later observed in 34187 patients, 8 in combination with recurrent or persistent disease in the neck; 11 followed the discovery of a primary tumor below the clavicles and 15 occurred as an isolated finding. Mean time to the development of metastases was 18 months, with a median of 11 months. Morbidity Xerostomia was unusual, because the majority of both parotid glands could be spared by confining the radiation portals to the neck. Dryness of the pharynx, laryngeal oedema, fibrosis of the neck and minor degrees of limitation of movement in the neck occurred rarely, and did not require treatment. A single patient developed radiation
Table 3. Actuarial survival according to number of sites involved Number of sites
2 years %
5 years %
One (51) One or two (74) Three or more ( 13)
53 49 12
45 38 0
p = 0.028.
292
I. J. Radiation Oncology 0 Biology 0 Physics Table 4. Pattern of initial failure by extent of radiation treatment: patients treated for cure Localized
Unilateral
Bilateral
Total
IS l/l5
34 24134
9’ 619
58 37
9 8
3 3 -
I8 I3 4
4
I 1 -
10 5 5
4
12 6
3 I
22 II
3
6
2
II
No. of patients Control above clavicle Site of failure Neck In field Adjacent Contralateral neck Primary site Above clavicle Below clavicle
6 2 4
-
3 2
Distant metastasis Alone In addition to Primary site or neck nodes
I
I 6 1
‘
7
* Includes the only patient in whom nasopharynx irradiated. Note: Two patients relapsed in cervical nodes and at a primary site.
myelitis of the cervical cord in 1954; in retrospect, the spinal cord had been treated beyond currently accepted tolerance.
DISCUSSION The management of metastatic carcinoma in the cervical lymph nodes from an occult primary remains controversial. Fortunately this clinico-pathological presentation is uncommon, and with the increasing use of CT scanning and Magnetic Resonance Imaging may become even more rare ( 17). Many authors have recently reviewed this subject (3, 7, 19) but there are few reports from the United Kingdom (1,6,23, 24). The prognosis and results appear to vary markedly, and 5-year survival in different centers ranges from 5%-70% (3, 6). The best reported results with radiation therapy used with curative intent (3) occur in the context of a number of highly favorable factors, for example 70/93 patients
Table 5a. Control above clavicles according to ‘N’ Stage radically treated group (58) Nl
N2
N3
NX
Failure Control
4
3 15
17 15
:
Total
414
15/18
15132
314
37158
Table 5b. Control above clavicles according to size radicallv treated croup (58) Size in cm. l-2.9
3-5.9
6-8.9
9+
Unknown
Failure Control
4
8 21
8 6
2 1
3 5
Total
414
21129
6114
113
518
37158
February 1990, Volume 18, Number 2
48/93 having a neck diswith a single nodal metastasis; section; an absence of primaries discovered below the clavicle; a separate analysis of the patients with supraclavicular lymph nodes; a large number of patients (26/93) with findings suggestive of nasopharyngeal carcinoma (lymphoepithelioma histology, involvement of posterior and spinal accessory nodes, and macroscopic abnormalities of the nasopharynx in the presence of a negative biopsy). Most authors agree that both adenocarcinoma (26) and supraclavicular nodal involvement have a very poor prognosis. Other studies (25) have reported similarly favorable results for Nl tumors after surgery alone. In contrast 52/87 (60%) of our patients in the present analysis were classified as N3 nodal staging, and only 7/ 87 as Nl. Only 6 patients had a RND, and 17 had complete macroscopic clearance of tumor prior to irradiation. Twenty had supraclavicular nodes. Only a single patient was felt to be a possible nasopharyngeal carcinoma. Radiotherapeutic practice in the United Kingdom has tended to be more conservative than in the U.S.A., where guidelines for management of cervical metastases from an unknown primary often recommend radiation fields which encompass naso-, hypo-, and oro-pharynx in addition to the neck (3, 19). In the present analysis the approach to management has remained remarkably consistent over the period of study, with only a single patient receiving prophylactic irradiation of the nasopharynx. It is encouraging that this conservative policy led to control of the disease above the clavicles in 53% overall (46/87). This result is comparable with many other series where radiation fields were more extensive and often covered the nasopharynx, tonsil, base of tongue, and hypopharynx (4, 19, 20, 21). A major criticism that can be levelled against the present study is our failure to review the histology. Indeed two patients treated palliatively survived for a prolonged period. A 5 1-year old man with a 5 cm middle deep cervical node was diagnosed by trucut biopsy as having an anaplastic carcinoma. He received 32 Gy in 8 fractions over 21 days to the whole left neck. He remained NED until lost to follow-up 39 months later. The second patient, a 58-year old man, also presented with an anaplastic carcinoma diagnosed by incisional biopsy of a 7 cm fixed confluent mass of nodes in the jugulodigastric area. He received 40 Gy in 16 fractions over 28 days to the whole left neck. Post mortem examination 78 months later confirmed death as a result of a myocardial infarction and no evidence of carcinoma. In retrospect, since the original biopsy specimens are not available for review, we suspect the true diagnosis may well have been a lymphoma in both these cases. However, as the results for squamous and anaplastic histologies (Table 6) are not significantly different, we do not believe that our failure to review the histology in all cases has led to the inclusion of many other patients with lymphoma in the anaplastic category. Subsequent identification of the primary site remains an exception rather than the rule in this and many other series, occurring in 19 patients (6 above and 13 below the
Carcinoma in cervical lymph nodes 0 R. G. T. GLYNNE-JONESet al.
Table 6. Actuarial survival according to histology Histology
2 years %
5 years %
Squamous cell carcinoma (43)
40 45
30 34
Anaplastic carcinoma (44)
Note: Figures in parenthesis indicate numbers of patients. Not statistically significant, p = 0.69.
clavicle). However, note that computerized axial tomography was not available in our institution until 1978. The
radiation technique commonly used in this institution involves anterior and posterior opposed portals to the involved side of the neck. either shielding or avoiding the spinal cord. Hence the ipsilateral oropharynx, larynx and hypopharynx may well have received a sufficient dose to sterilize small unrecognized primaries in these areas. The poor beam definition of 6oCo may well have contributed to this. The nasopharynx was found to be the primary site in only four cases. Note that in the series by Carlson et al. (3) of the subgroup of 20 patients who received neck irradiation alone, no patient subsequently developed a nasopharyngeal primary. Many authors feel the incidence of the nasopharynx as a site of the primary tumor is decreasing (4, 10). More aggressive investigative techniques, the use of the fiberoptic nasoendoscope, frequent blind biopsies of the nasopha.rynx, and increasing use of CT and MRI scan may account for this. In addition distant metastases developed in 34 patients (soon after discovery of the primary tumor in 11). In total 39 out of 87 patients (451%)demonstrated disease outside the head and neck area. An overview of 23 prior studies (2- 11, 13, 14, 16, 18, 19-25, 27, 28) of various treatments for cervical metastases from an unknown primary between 1963 and 1986 highlights the fact that of 1726 patients at risk, a total of only 203 (12%) primary tumors above the clavicles were eventually identified. The nasopharynx was the most common site of origin, and occurred in 56 patients (3%). For this reason, we do not recommend routine irradiation of the nasopharynx in this department, unless there is strong suspicion of a.primary nasopharyngeal carcinoma-namely the involvement of posterior cervical nodes, especially if bilaieral; the histology of lymphoep-
293
ithelioma; the clinical appearances of the nasopharynx in spite of a negative biopsy; Chinese ethnic origin; patients under 30 years; raised Epstein-Barr Virus (EBV) capsid antibody titres to IgA and IgG ( 12), or positive staining in biopsy material to EBV nuclear antigen (EBNA) (29). Moreover, the inclusion of the nasopharynx in the radiation field cannot confidently prevent the subsequent appearance of a primary at this site. In a series by Leipzig et al. ( 16) 4 out of 48 patients (8%) with cervical metastases from an occult primary, treated with wide field radiotherapy, demonstrated a primary tumor in the nasopharynx at a later date. The same authors ( 16) suggested that a 50% 5-year survival may be achieved for nodes larger than 3 cm after RND alone. Our experience with RND (56% 5-year survival) suggests the necessity of combining radiation with neck dissection to achieve the best results for bulky nodal masses, since planned combined treatment with RND and irradiation prevented relapse in the neck, whereas RND alone did not. Similar experience is shared by other authors (25). However, comparisons of surgery and radiotherapy are difficult to evaluate because in general irradiation is prescribed for more advanced disease (4). Patients with the histology of adenocarcinoma seem to have a different natural history from patients with the more common squamous-anaplastic histologies, and pursue a rapid downhill course irrespective of the mode of treatment (26). It is suggested that the optimal treatment is the delivery of a radical dose of radiation of at least 60 Gy in daily fractions over 6 weeks, or equivalent, to the ipsilateral neck (with RND in selected cases). Local control will be achieved in the majority of patients. We advise regular and careful follow-up for the first 2 years, if salvage is to be feasible for a primary tumor which may later appear above the clavicles, and for lymph nodes in the contralateral neck. We conclude that acceptable results which compare with many other series can be obtained from a conservative approach to the treatment of cervical lymph node metastases originating from an occult primary tumor. Many patients will ultimately die of disease below the clavicles, but they will have been spared the morbidity of wide field radiotherapy which includes the naso-oro-hypopharynx.
REFERENCES Barakat, M.; Flood, L. M.; Oswal, V. H.; Ruckley, R. W. The management of a neck mass: presenting feature of an asymptomatic head and neck primary malignancy? Ann. R. Coil. Surg. Engl. 69:181-184; 1987. Barrie, J. R.; Knapper, H.; Stony, E. W. Cervical nodal metastases of unknown origin. Am. J. Surg. 120:466-470; 1970. Carlson, L. S.; Fletcher, G. H.; Oswald, M. J. Guidelines for radiotherapeutic techniques for cervical metastases from an unknown primary. Int. J. Radiat. Oncol. Biol. Phys. 12: 2101-2110; 1986.
Coker, D. D.; Casterline, P. F.; Chambers, R. G.; Jaques, D. A. Metastases to lymph nodes of the head and neck from an unknown primary site. Am. J. Surg. 134:517-522; 1977. Dissing, I. Metastasis from an unknown tumour. Acta Radiol. (Ther.) 15:117-128; 1976. Fermont, D. C. Malignant cervical lymphadenopathy due to an unknown primary. Clin. Radiol. 31:355-358; 1980. 7. Fitzpatrick, P. J.; Keane, T. J. Cervical lymph node metastases from an unknown primary tumour: the place of radiotherapy. Head Neck Cancer 1:291-298; 1985. 8. Fitzpatrick, P. J.; Kotalik, J. F. Cervical metastases from
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1. J. Radiation Oncology ?? Biology 0 Physics an unknown primary tumour. Radiology 110:659-663; 1974. France, C. J.; Lucas, R. The management and prognosis of metastatic neoplasms in the neck with an unknown primary. Am. J. Surg. 106:835-839; 1963. Fried, M. P.; Diehl, W. H.; Brownson, R. J.; Sessions, D. G.; Ogura, J. H. Cervical metastases from an unknown primary lesion. Ann. Otol. Rhinol. Laryngol. 84: 152- 157; 1975. Greenberg, B. E. Cervical lymph node metastasis from unknown primary sites. Cancer 19:1091-1095; 1966. Ho, J. C.; Ng, M. H.; Kwan, H. C.; Chau, J. C. W. Epstein Barr Virus Specific IgA and IgG serum antibodies in nasopharyngeal carcinoma. Br. J. Cancer 34:655-660; 1976. Jesse, R. H.; Perez, C. A.; Fletcher, G. H. Cervical lymph node metastasis: unknown primary cancer. Cancer 3 1:854859; 1973. Jose, B.; Bosch, A.; Caldwell, W. L.; Frias, Z. Metastasis to neck from unknown primary tumour. Acta Radiol. (Oncol.) 18:161-170; 1979. Lampe, I.; Santin, G. Metastatic carcinoma in neck of unknown primary site; salvage by radiation treatment. Univ. Hosp. Bull. Ann Arbor 12: 106; 1946. Leipzig, B.; Winter, M. L.; Hokanson, J. A. Cervical nodal metastasis of unknown origin. Laryngoscope 9 1:593-597; 1981. Mancuso, A. A. Cervical lymph node metastases: oncologic imaging and diagnosis. Int. J. Radiat. Oncol. Biol. Phys. 10: 41 l-423; 1984. Marchetta, F. C.; Murphy, W. T.; Kovaric, J. J. Carcinoma of the neck. Am. J. Surg. 106:974-979; 1963. McCunniff, A. J.; Raben, M. Metastatic carcinoma of the
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neck from an unknown primary. lnt. J. Radiat. Oncol. Biol. Phys. 12: 1849- 1852; 1986. Nordstrom, D. G.; Tewfik, H. H.; Latourette, H. B. Cervical lymph node metastases from an unknown primary. lnt. J. Radiat. Oncol. Biol. Phys. 5:73-76; 1979. Pacini, P.; Olmi, P.; Cellai, E.; Chiavacci, A. Cervical lymph node metastases from an unknown primary tumour. Acta Radiol. (Oncol.) 20:311-314; 1981. Pica, J.; Frias, Z.; Bosch, A. Cervical lymph node metastases from carcinoma of undetermined origin. Am. J. Roentgenol. 111:95-102; 1971. Probert, J. C. Secondary carcinoma in cervical lymph nodes with an occult primary tumour. A review of 61 patients including their response to radiotherapy. Clin. Radiol. 2 1: 211-218; 1970. Shaw, H. J. Metastatic carcinoma in cervical lymph nodes with occult primary tumour-diagnosis and treatment. J. Laryngol. Otol. 84:249-265; 1970. Spiro, R. H.; DeRose, G.; Strong, E. W. Cervical node metastasis of occult origin. Am. J. Surg. 146:441-446; 1983. Templer, J.; Pery, M. C.; Davis, W. E. Metastatic cervical adenocarcinoma from unknown primary tumour. Arch. Otolaryngol. 107:45-47; 198 1. Winegar, L. K.; Griffin, W.; Arbor, A. The occult primary tumour. Arch. Otolaryngol. 98: 159-l 63; 1973. Yang, Z. Y.; Hu, Y. H.; Yan, J. H.; Cai, W.; Qin, D. X.; Xu, G. Z.; Wu, X. L. Lymph node metastases in the neck from an unknown primary. Acta Radio]. (Oncol.) 22: 1722; 1983. Young, L. S.; Sixbey, J. W.; Clark, D.; Rickinson, A. B. Epstein-Barr virus receptors on human pharyngeal epithelia. Lancet i:240-242; 1986.
18,pp.289-294
0360-3016/90 $3.00 + .oO Copyright 0 1990 Pergamon Press plc
??Original Contribution
METASTATIC: CARCINOMA IN THE CERVICAL LYMPH NODES FROM AN OCCULT PRIMARY: A CONSERVATIVE APPROACH TO THE ROLE OF RADIOTHERAPY ROBERT G. T. GLYNNE-JONES, MRCP, FRCR,* ANIL K. ANAND, M.D.,+ TERESA E. YOUNG, B.Sc.# AND ROGER J. BERRY, M.D., D.PHIL, FRCP, FRCR” The Meyerstein Institute of Radiotherapy and Oncology, The Middlesex and University College Hospital Medical School, London W 1N 8AA, U.K. This retrospective study examines the results of treatment for cervical lymph node metastases from an unknown primary epithelial cancer of squamous cell or anaplastic histology. The analysis covers a series of 87 consecutive unselected patients at the Middlesex Hospital, London, in the years between 1954 and 1986. Fifty-eight patients received radiation therapy with a view to cure, 25 patients were treated with radiotherapy to a palliative dose, 1 patient only had a radical neck dissection, and 3 patients received no treatment apart from excision biopsy. In contrast to common practice in the United States, only a single patient received prophylactic radiation to the nasopharynx as part of the initial therapy. Overall actuarial survival for all patients (87) at 2 years was 43% and at 5 years 33%, amd in the radically treated group (58) it was 52% and 40%, respectively. Only 6 of the 87 patients (7%) subsequently revealed a primary tumor above the clavicles. Overall disease control above the clavicles was achieved in 53% (46/87), but was 64% (37/58) in the radically treated group. Guidelines for radiation therapy are discussed in view of these results. Cervical metastases,
Unknown primary, Radiotherapy. METHODS
INTRODUCTION
AND
MATERIALS
In the majority of patients presenting with metastatic carcinoma in the cervical lymph nodes a primary lesion is identified on thorough otolaryngologic examination and biopsy ( 1), but the prima.ry site may remain undiscovered in up to 10% of cases (6, 14, 20, 21). A report as early as 1946 recognized that the prognosis for these patients is far from hopeless ( 15). According to some authors (3, 19, 28), the outcome for patients with cervical metastases from an occult primary is improved by extending radiation fields to include the possible primary sites in the head and neck. However, few recent reports have been published on the role of limited irradiation of the cervical nodes alone, which has been the practice at our institution for many years. The present study is a retrospective analysis of all patients with cervical metastases from an unknown primary of squamous cell or anaplastic histology, who were referred for radiotherapy to this department between 1954 and December 1986.
We reviewed the case notes of 87 consecutive unselected patients with histologically confirmed squamous cell or anaplastic carcinoma in the cervical lymph nodes, where investigations had failed to reveal a primary lesion. Patients with prior skin cancers of the head and neck, and lymphadenopathy or metastatic disease below the clavicles at the time of diagnosis, were discounted from the analysis. There were 53 males and 34 females, with a mean age of 6 1 years and a range of 12-85 years. Median time to follow-up was 35 months with a range of 4-300 months. The majority of the patients (80) presented with enlarged lymph nodes on one side of the neck, but seven patients had bilateral cervical lymphadenopathy. The most common single site of involvement was the jugulodigastric node which was involved in 24 of the patients, followed by the middle deep cervical nodes in 12 and supraclavicular nodes in 9. For comparison with series from the United States, patients were re-staged according to the
* Lecturer in Radiotherapy and Oncology. + Visiting Radiation Oncologist, Honorary Registrar. * Research Assistant. * Professor of Radiation Oncology. Reprint requests to: Teresa Young, The Meyerstein Institute of Radiotherapy, The Middlesex Hospital, Mortimer Street, London W 1N 8AA U.K.
Acknowledgements-We
would like to thank Dr. A. M. Jelliffe, Dr. M. F. Spittle, and Dr. C. A. E. Coulter for allowing us to report on their patients. We would also like to thank the Special Trustees of the Middlesex Hospital for supporting Mrs. Teresa Young, and Ms. Jeanette Hutchinson for clerical skills. Accepted for publication 9 August 1989.
289
I. J. Radiation Oncology 0 Biology 0 Physics
290
Table 1. Characteristics of lymph node involvement Number of sites Number of patients Stage Number of patients Size of nodes (cm) Number of patients
1 51 Nl 7 1-3 18
2 23 N2 24 4-6 40
3 13 N3 52 >7 17
Nx 4 Unknown 12
Nl corresponds to the presence of a single, mobile node less than 3 cm in diameter, N2 is a single node more than 3 cm or multiple mobile ipsilateral nodes, and N3 is a unilateral fixed node or bilateral nodes. American Joint Committee on Cancer (AJCC) classification for nodal disease in the head and neck. Table 1
shows the number of sites of involved nodes in the neck, their size, and their stage. Histopathology Histopathological diagnosis was obtained in all patients. In addition to the 43 squamous cell carcinomas (10 well differentiated, 9 moderately well differentiated, and 24 poorly differentiated) 44 were described as anaplastic carcinomas. Histological review was not possible in all cases because many early specimens had been discarded. Investigations If thorough clinical and radiological investigative procedures failed to discover a primary site, we proceeded to bronchoscopy, oesophagoscopy and examination under anesthetic (EUA) to examine the naso-, oro- and hypopharynx and larynx. If all still appeared macroscopically normal, blind biopsies of the left and right postnasal space, tonsil, base of tongue and hypopharynx were obtained. In the present series 82/87 patients underwent EUA. The histopathological diagnosis was obtained in all patients, by trucut biopsy in 54, incisional biopsy in 8, and excisional biopsy in 25 cases. Radiation therapy Dose. Radiation formed the mainstay of treatment for 83 patients, of whom 58 were treated with a view to cure (arbitrarily defined as radiation therapy in excess of 50 Gy in daily fractions over 5 weeks or 45 Gy over 43 weeks in combination with macroscopic clearance of disease). In this radically treated group, 3 patients were implanted with radium needles and 3 1 received at least 60 Gy. A further 24 received between 45 Gy and 60 Gy, but doses were often more radical than the total dose would imply because of non-standard fractionation (45 Gy/l5 fractions/2 1 days, 50 Gy/20 fractions/28 days or 54 Gyf 18 fractions/42 days). Palliative doses were administered to 25 patients to relieve pain or prevent fungation. Field size. For those 58 patients who received a radical dose of radiation, the field encompassed the whole side of the neck in 34 patients, and both sides of the neck in 9 patients (4 of whom presented with bilateral lymphadenopathy). Small localized fields to the area of nodal
February 1990, Volume 18, Number 2 with a margin (1.5-2.0 cm) were used in 15 patients. Only a single patient was treated with radiation fields covering both nasopharynx and the neck. This patient had an anaplastic carcinoma, diagnosed by cervical lymph node biopsy. Mucosal irregularity near the Fossa of Rosenmuller had been noted at EUA, although biopsy of this area did not confirm a primary tumor.
involvement
Radical neck dissection Six patients underwent radical neck dissection (RND), four of them as a planned combined modality of radiation and surgery, one as the sole modality of treatment, and one for nodal recurrence in the treated area after radical radiation. Chemotherapy Only one patient, a male aged 12 years, received adjuvant chemotherapy in addition to radical radiation therapy and neck dissection. Palliative chemotherapy was administered to eight patients with advanced disease after radiation had failed, but was not felt to have altered their survival. No treatment Three patients received no further treatment after the initial excision biopsy. RESULTS
Overall actuarial survival of all patients in this series (Fig. 1) was 43% at 2 years and 33% at 5 years. For the 58 patients treated with radical radiation, 2-year and 5year survival was 52% and 40%, respectively, and 20% and 16% for the 25 who received palliative irradiation (Fig. 2). Patients lost to follow-up (6) or those who died of incidental causes but had remained disease-free (13), were censored at the time of loss, and contributed to actuarial survival and recurrence only up until the time of last information. Age and sex made no difference to survival. Poor actuarial survival occurred in those patients with supracla-
o’B’n 0
n 24
46
n
n”n 72
96
n”c 120
144
E 166
fi
n c a 192
216
Time (months) from date of 1st treatment
Fig. 1. Shows actuarial survival of all patients.
I’ 240
Carcinoma in cervical lymph nodes 0 R. G. T. GLYNNE-JONES
0
0
24
46
72
96
120
144
166
192
216
240
0
24
40
Time (mon:hs) from date of 1st treatment
291
et al.
72
96
120
144
168
192
216
240
Time (months) from date of 1st treatment
Fig. 2. Shows actuarial survival of patients. (a) Treated radically with radiation (58); (b) Treated palliatively with radiation (25). (Excludes 4 patients who received no radiation.)
Fig. 3. Shows actuarial survival of patients with (a) cervical (63); (b) supraclavicular nodes (20). (Excludes 4 patients who received no radiation.)
2, Fig. 3), and more than two sites (Table 3).
Detection of the primary tumor The primary tumor site was later discovered in 19 out of 87 patients (22%). The most common primary site was the lung (7); the other sites included nasopharynx (4), oesophagus (2) and a single lesion each in the breast, epiglottis, parotid, cervix, kidney, and stomach. All primaries above the clavicles occurred in areas outside the radiation portals. The mean time before the appearance of a head and neck primary was 7 months, with a range of 2-l 8 months. Of the six primary tumors above the clavicles, only two (both nasopharyngeal carcinoma) were successfully salvaged by radiotherapy, but both subsequently died from disease below the clavicles.
vicular nodes (Table of nodal involvement
Local control Overall in 46 patients
out of 87 (53%) disease was controlled above the clavicles, and in the radically treated group 37/58 (64%). Of these 58 patients treated with a view to cure (Table 4), 18 recurred in the neck (13 in the treated area, 4 with a marginal recurrence, and a single patient in the contralateral untreated upper deep cervical nodes). Localized irradiation proved unsatisfactory since 4 out of 15 (27%) patients relapsed outside the field in the adjacent ipsilateral neck. (supraclavicular nodes 2, middle deep cervical 1, upper dleep cervical 1). For all irradiated patients, the majority of the failures in the neck lay within the radiation portals (3 l/39). Of the four patients who received no radiation, two relapsed in the ipsilateral neck
and two remained disease-free above the clavicles. Local control was less easily obtained with progressive ‘N’ stage and size of involved nodes (Table 5a and b). In the radically treated group escalating doses appeared to have no significant effect on local control or survival.
Table 2. Actuarial survival according to modality of treatment
Cervical nodes Radical group (48) Palliative group (15) (Excludes two patients who received no radiation) Overall (63) Supraclavicular nodes Overall (20) (Excludes two patients who received no radiation)
2 Years %
5 vears %
57 13
51 13
48
41
30
9
Note: Figures in parenthesis indicate number of patients. Survival curves for cervical nodes and supraclavicular nodes are significantly different p = 0.02.
Metastatic disease Metastatic disease below the clavicles was later observed in 34187 patients, 8 in combination with recurrent or persistent disease in the neck; 11 followed the discovery of a primary tumor below the clavicles and 15 occurred as an isolated finding. Mean time to the development of metastases was 18 months, with a median of 11 months. Morbidity Xerostomia was unusual, because the majority of both parotid glands could be spared by confining the radiation portals to the neck. Dryness of the pharynx, laryngeal oedema, fibrosis of the neck and minor degrees of limitation of movement in the neck occurred rarely, and did not require treatment. A single patient developed radiation
Table 3. Actuarial survival according to number of sites involved Number of sites
2 years %
5 years %
One (51) One or two (74) Three or more ( 13)
53 49 12
45 38 0
p = 0.028.
292
I. J. Radiation Oncology 0 Biology 0 Physics Table 4. Pattern of initial failure by extent of radiation treatment: patients treated for cure Localized
Unilateral
Bilateral
Total
IS l/l5
34 24134
9’ 619
58 37
9 8
3 3 -
I8 I3 4
4
I 1 -
10 5 5
4
12 6
3 I
22 II
3
6
2
II
No. of patients Control above clavicle Site of failure Neck In field Adjacent Contralateral neck Primary site Above clavicle Below clavicle
6 2 4
-
3 2
Distant metastasis Alone In addition to Primary site or neck nodes
I
I 6 1
‘
7
* Includes the only patient in whom nasopharynx irradiated. Note: Two patients relapsed in cervical nodes and at a primary site.
myelitis of the cervical cord in 1954; in retrospect, the spinal cord had been treated beyond currently accepted tolerance.
DISCUSSION The management of metastatic carcinoma in the cervical lymph nodes from an occult primary remains controversial. Fortunately this clinico-pathological presentation is uncommon, and with the increasing use of CT scanning and Magnetic Resonance Imaging may become even more rare ( 17). Many authors have recently reviewed this subject (3, 7, 19) but there are few reports from the United Kingdom (1,6,23, 24). The prognosis and results appear to vary markedly, and 5-year survival in different centers ranges from 5%-70% (3, 6). The best reported results with radiation therapy used with curative intent (3) occur in the context of a number of highly favorable factors, for example 70/93 patients
Table 5a. Control above clavicles according to ‘N’ Stage radically treated group (58) Nl
N2
N3
NX
Failure Control
4
3 15
17 15
:
Total
414
15/18
15132
314
37158
Table 5b. Control above clavicles according to size radicallv treated croup (58) Size in cm. l-2.9
3-5.9
6-8.9
9+
Unknown
Failure Control
4
8 21
8 6
2 1
3 5
Total
414
21129
6114
113
518
37158
February 1990, Volume 18, Number 2
48/93 having a neck diswith a single nodal metastasis; section; an absence of primaries discovered below the clavicle; a separate analysis of the patients with supraclavicular lymph nodes; a large number of patients (26/93) with findings suggestive of nasopharyngeal carcinoma (lymphoepithelioma histology, involvement of posterior and spinal accessory nodes, and macroscopic abnormalities of the nasopharynx in the presence of a negative biopsy). Most authors agree that both adenocarcinoma (26) and supraclavicular nodal involvement have a very poor prognosis. Other studies (25) have reported similarly favorable results for Nl tumors after surgery alone. In contrast 52/87 (60%) of our patients in the present analysis were classified as N3 nodal staging, and only 7/ 87 as Nl. Only 6 patients had a RND, and 17 had complete macroscopic clearance of tumor prior to irradiation. Twenty had supraclavicular nodes. Only a single patient was felt to be a possible nasopharyngeal carcinoma. Radiotherapeutic practice in the United Kingdom has tended to be more conservative than in the U.S.A., where guidelines for management of cervical metastases from an unknown primary often recommend radiation fields which encompass naso-, hypo-, and oro-pharynx in addition to the neck (3, 19). In the present analysis the approach to management has remained remarkably consistent over the period of study, with only a single patient receiving prophylactic irradiation of the nasopharynx. It is encouraging that this conservative policy led to control of the disease above the clavicles in 53% overall (46/87). This result is comparable with many other series where radiation fields were more extensive and often covered the nasopharynx, tonsil, base of tongue, and hypopharynx (4, 19, 20, 21). A major criticism that can be levelled against the present study is our failure to review the histology. Indeed two patients treated palliatively survived for a prolonged period. A 5 1-year old man with a 5 cm middle deep cervical node was diagnosed by trucut biopsy as having an anaplastic carcinoma. He received 32 Gy in 8 fractions over 21 days to the whole left neck. He remained NED until lost to follow-up 39 months later. The second patient, a 58-year old man, also presented with an anaplastic carcinoma diagnosed by incisional biopsy of a 7 cm fixed confluent mass of nodes in the jugulodigastric area. He received 40 Gy in 16 fractions over 28 days to the whole left neck. Post mortem examination 78 months later confirmed death as a result of a myocardial infarction and no evidence of carcinoma. In retrospect, since the original biopsy specimens are not available for review, we suspect the true diagnosis may well have been a lymphoma in both these cases. However, as the results for squamous and anaplastic histologies (Table 6) are not significantly different, we do not believe that our failure to review the histology in all cases has led to the inclusion of many other patients with lymphoma in the anaplastic category. Subsequent identification of the primary site remains an exception rather than the rule in this and many other series, occurring in 19 patients (6 above and 13 below the
Carcinoma in cervical lymph nodes 0 R. G. T. GLYNNE-JONESet al.
Table 6. Actuarial survival according to histology Histology
2 years %
5 years %
Squamous cell carcinoma (43)
40 45
30 34
Anaplastic carcinoma (44)
Note: Figures in parenthesis indicate numbers of patients. Not statistically significant, p = 0.69.
clavicle). However, note that computerized axial tomography was not available in our institution until 1978. The
radiation technique commonly used in this institution involves anterior and posterior opposed portals to the involved side of the neck. either shielding or avoiding the spinal cord. Hence the ipsilateral oropharynx, larynx and hypopharynx may well have received a sufficient dose to sterilize small unrecognized primaries in these areas. The poor beam definition of 6oCo may well have contributed to this. The nasopharynx was found to be the primary site in only four cases. Note that in the series by Carlson et al. (3) of the subgroup of 20 patients who received neck irradiation alone, no patient subsequently developed a nasopharyngeal primary. Many authors feel the incidence of the nasopharynx as a site of the primary tumor is decreasing (4, 10). More aggressive investigative techniques, the use of the fiberoptic nasoendoscope, frequent blind biopsies of the nasopha.rynx, and increasing use of CT and MRI scan may account for this. In addition distant metastases developed in 34 patients (soon after discovery of the primary tumor in 11). In total 39 out of 87 patients (451%)demonstrated disease outside the head and neck area. An overview of 23 prior studies (2- 11, 13, 14, 16, 18, 19-25, 27, 28) of various treatments for cervical metastases from an unknown primary between 1963 and 1986 highlights the fact that of 1726 patients at risk, a total of only 203 (12%) primary tumors above the clavicles were eventually identified. The nasopharynx was the most common site of origin, and occurred in 56 patients (3%). For this reason, we do not recommend routine irradiation of the nasopharynx in this department, unless there is strong suspicion of a.primary nasopharyngeal carcinoma-namely the involvement of posterior cervical nodes, especially if bilaieral; the histology of lymphoep-
293
ithelioma; the clinical appearances of the nasopharynx in spite of a negative biopsy; Chinese ethnic origin; patients under 30 years; raised Epstein-Barr Virus (EBV) capsid antibody titres to IgA and IgG ( 12), or positive staining in biopsy material to EBV nuclear antigen (EBNA) (29). Moreover, the inclusion of the nasopharynx in the radiation field cannot confidently prevent the subsequent appearance of a primary at this site. In a series by Leipzig et al. ( 16) 4 out of 48 patients (8%) with cervical metastases from an occult primary, treated with wide field radiotherapy, demonstrated a primary tumor in the nasopharynx at a later date. The same authors ( 16) suggested that a 50% 5-year survival may be achieved for nodes larger than 3 cm after RND alone. Our experience with RND (56% 5-year survival) suggests the necessity of combining radiation with neck dissection to achieve the best results for bulky nodal masses, since planned combined treatment with RND and irradiation prevented relapse in the neck, whereas RND alone did not. Similar experience is shared by other authors (25). However, comparisons of surgery and radiotherapy are difficult to evaluate because in general irradiation is prescribed for more advanced disease (4). Patients with the histology of adenocarcinoma seem to have a different natural history from patients with the more common squamous-anaplastic histologies, and pursue a rapid downhill course irrespective of the mode of treatment (26). It is suggested that the optimal treatment is the delivery of a radical dose of radiation of at least 60 Gy in daily fractions over 6 weeks, or equivalent, to the ipsilateral neck (with RND in selected cases). Local control will be achieved in the majority of patients. We advise regular and careful follow-up for the first 2 years, if salvage is to be feasible for a primary tumor which may later appear above the clavicles, and for lymph nodes in the contralateral neck. We conclude that acceptable results which compare with many other series can be obtained from a conservative approach to the treatment of cervical lymph node metastases originating from an occult primary tumor. Many patients will ultimately die of disease below the clavicles, but they will have been spared the morbidity of wide field radiotherapy which includes the naso-oro-hypopharynx.
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Coker, D. D.; Casterline, P. F.; Chambers, R. G.; Jaques, D. A. Metastases to lymph nodes of the head and neck from an unknown primary site. Am. J. Surg. 134:517-522; 1977. Dissing, I. Metastasis from an unknown tumour. Acta Radiol. (Ther.) 15:117-128; 1976. Fermont, D. C. Malignant cervical lymphadenopathy due to an unknown primary. Clin. Radiol. 31:355-358; 1980. 7. Fitzpatrick, P. J.; Keane, T. J. Cervical lymph node metastases from an unknown primary tumour: the place of radiotherapy. Head Neck Cancer 1:291-298; 1985. 8. Fitzpatrick, P. J.; Kotalik, J. F. Cervical metastases from
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