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Japanese Journal of Clinical Oncology Pages 63-66

Temporal Relationship between Cancers of the Lung and Upper Aerodigestive Tract
Introduction
Patients and Methods
Results
Discussion
References

Temporal Relationship between Cancers of the Lung and Upper Aerodigestive Tract

Temporal Relationship between Cancers of the Lung and Upper Aerodigestive Tract Wei-Chung Hsieh, Yuh-Min Chen and Reury-Perng Perng

Chest Department,Veterans General Hospital-Taipei, Taipei, Taiwan

We retrospectively reviewed the chart records at the Veterans General Hospital-Taipei for the period between January 1985 and December 1994 to examine the temporal relationship between cancers of the lung and upper aerodigestive tract. A total of 56 patients (54 males, 2 females) with histocytologically proven double primary cancers, with either lung cancer or upper aerodigestive tract cancers appearing first, were found. Squamous cell carcinoma was the most frequent histologic type of lung cancer (squamous 57%, adenocarcinoma 27%, poorly differentiated carcinoma 9%, small cell lung cancer 7%). The incidence of lung cancer patients with upper aerodigestive tract cancer was 0.9% (56/6412). There was no significant difference in the occurrence of upper aerodigestive tract cancer between non-small cell and small cell lung cancer (P >0.05). However, the incidence of squamous cell lung cancer with upper aerodigestive tract cancer was higher than that of non-squamous cell lung cancer (P<0.05). With regard to the location of lung cancer, the right lung was more commonly affected than the left (P< 0.001). The locations of upper aerodigestive tract cancers in these lung cancer patients were as follows: larynx 24, nasopharynx 11, esophagus 10, hypopharynx 4, pharyngeal tonsils 2, oral cavity 5. Most upper aerodigestive tract cancers were diagnosed before lung cancer (36/56, 64%), and lung cancer was diagnosed within 3 years in more than half of cases after the diagnosis of upper aerodigestive tract cancer (58.3%). Most lung cancers that preceded upper aerodigestive tract cancer were at an early stage at diagnosis (stage I 4, stage IIIa 1), whereas the others, appearing either synchronously or after the diagnosis of upper aerodigestive tract cancer, were mostly at the late stage. There was no difference in survival between lung cancer patients with upper aerodigestive tract cancer and those without (P >0.05).

Key words: upper aerodigestive tract cancer - multiple primary neoplasia - field squamous cancerization - non-small cell lung cancer - small cell lung cancer

Introduction

Second primary tumor is a well-described risk associated with cancers of the upper aerodigestive tract (UADT). Nearly two thirds of second primary tumors occur within the UADT, including the head, neck, esophagus, larynx and oral cavity (1). It has been found that solitary pulmonary lesions occuring in combination with, or after treatment of, head and neck cancers are more likely to be primary bronchogenic cancers than isolated metastases from head and neck cancers (2-4). This affinity has been construed as reflecting the phenomenon of `field squamous cancerization', defined by Slaughter et al. in their review of the pathology of oral neoplasia (5). The incidence of second primary tumors among head and neck cancers is about 4-5% per year in patients who have been successfully treated (6). In previous reports, the incidence of primary lung cancer associated with second primary tumor at sites other than the lung has ranged from 3.2% to 8.6% (7,8). The incidence of second primary tumors in the head and neck area is 1-2% (7-10). However, the incidence and temporal relationship between lung cancer and UADT cancers and detailed survival data have rarely been analyzed by previous investigators. We therefore carried out a retrospective review to investigate these aspects.

Patients and Methods

We retrospectively reviewed the chart records at Veterans General Hospital-Taipei covering the period between January 1985 and December 1994, when there were 6412 patients with primary lung cancer. Fifty-six of these patients (54 males, 2 females) also had another primary tumor in the UADT. All 56 patients had histocytologically proven primary lung cancer and a second primary UADT cancer, with either the lung cancer or the UADT cancer occurring first. UADT cancers included head, neck, lip, oral and esophageal cancers. The criteria used (11,12) to diagnose multiple primary neoplasia are that the neoplasm must be clearly malignant as determined by histologic evaluation, each neoplasm must be geographically separate and distinct, and the possibility that the second neoplasm represents a metastasis should be excluded. The lesions were considered synchronous if they occurred within six months of each other and metachronous if they were separated by a greater time interval (9,13). Lung lesions were judged to be primary based on endobronchial origin, histologic findings showing evidence of histologic changes in the adjacent mucosa, and a clinical history of lung tumor. The statistical analyses used in this study were Pearson's [chi]2 test for incidence analysis and the log-rank test for survival analysis.


Figure 1. Temporal relationship of diagnosis of UADT cancer to lung cancer (time of diagnosis of lung cancer represented as 0)

Results

Among the 56 patients with histocytologically proven double primary cancers, 15 were found to have synchronous and 41 metachronous UADT cancers. There were 54 male and 2 female patients, all of whom were smokers (smoking index ranging from 300 to 1200 pack years) and some of whom had the habit of betel nut chewing (22/56). Of the lung cancers, squamous cell carcinoma was the most frequent histologic type (squamous 57%, adenocarcinoma 27%, poorly differentiated carcinoma 9%, small cell lung cancer 7%). Except for those presenting with moderate to severe upper airway obstruction, no obvious difference was found in the clinical characteristics of lung cancer patients with or without UADT cancer.

Table 1 Clinical characteristics of 56 patients with lung cancer and UADT cancer
Temporal Histology Total No. at each clinical stage
relationship     NSCLC SCLC
      I II IIIa IIIb IV Limited Extensive
Preceding

 NSCLC

 5

 4

 1

Synchronous

 NSCLC

 14

2

 7

 5

SCLC

 1

1

Following

 NSCLC

 33

2

 7

 9

 15

SCLC

 3

1

 2
UADT, upper aerodigestive tract; NSCLC, non-small cell lung cancer; SCLC, small cell lung cancer; Preceding, diagnosis of lung cancer preceding that of UADT cancer; Synchronous, both diagnosed at the same time; Following, diagnosis of lung cancer following that of UADT cancer.

The majority of the UADT cancers arose before lung cancer was diagnosed (36 patients, 64%). Primary lung cancer preceded UADT cancer in only 5 patients (9%). The remaining 15 patients had synchronous primary cancers (27%). More than half of the patients were diagnosed as having lung cancer within 3 years after the diagnosis of UADT cancer (58.3%). The detailed temporal relationship between the two tumor types is shown in Fig. 1.

Most of the lung cancers that preceded the diagnosis of UADT cancer were at the early stage when diagnosed (stage I 4, stage IIIa 1). All of the lung cancers synchronous with UADT cancers were at the late stage (stage IIIa 2, stage IIIb 7, stage IV 5, extensive stage 1). Lung cancers found after the diagnosis of UADT cancers showed a distribution similar to the synchronous ones (stage II 2, stage IIIa 7, stage IIIb 9, stage IV 15, limited stage 1, extensive stage 2). The detailed data are shown in Table 1.


Figure 2. Survival curves for lung cancer patients with and without UADT cancer. P = 0.1157

The incidence of lung cancer with a second primary cancer occurring in the UADT was 0.9% (56/6412). Among 5582 patients with non-small cell lung cancer (NSCLC), 52 also had UADT cancers (an incidence of 0.9%). The incidence of UADT cancers in patients with small cell lung cancer (SCLC) was 0.5%. There was no significant difference in the incidence of UADT cancers between the NSCLC and the SCLC groups (P >0.05). The results are shown in Table 2.


Table 2 Incidence of NSCLC and SCLC occuring with UADT cancer
Lung cancer Total patients With UADT cancers (%)
NSCLC 5582 52 (93)
SCLC 830 4 (7)
Total 6412 56  
NSCLC, non-small cell lung cancer; SCLC, small cell lung cancer; UADT, upper aerodigestive tract. (P > 0.05).


Table 3 . Incidence of squamous and non-squamous NSCLC with UADT cancer
NSCLC Total patients With UADT cancer (%)
Squamous 2208 32 (62)
Non-squamous 3374 20 (38)
Total 5582 52  
NSCLC, non-small cell lung cancer; UADT, upper aerodigestive tract. (P <0.05).


Table 4 . Locations of lung cancers combined with UADT cancer
Location Total No. of patients
Right lung 38  
Right upper lobe   18
Right middle lobe   6
Right lower lobe   12
Right main bronchus   2
Left lung 18  
Left upper lobe   9
Left lower lobe   7
Left main bronchus   2
UADT, upper aerodigestive tract.


Among the NSCLC group, the incidence of squamous cell lung cancer with UADT cancers was significantly greater than that of non-squamous cell lung cancer (1.4% vs 0.6%, P <0.05). The results are shown in Table 3.

Lung cancers associated with other UADT cancers were located predominantly in the right lung (68%, 38/56) with statistical significance (P < 0.05, Table 4).

The distribution of UADT cancers among these 56 patients was as follows: larynx (24), nasopharynx (11), esophagus (10), oral cavity (5), hypopharynx (4), pharyngeal tonsils (2). All of the UADT cancers were squamous cell carcinoma histologically. The majority of the synchronous UADT cancers were located in the esophagus (6 patients), followed by the larynx in 4, hypopharynx in 2, pharyngeal tonsil in 2 and oral cavity in 1. The UADT cancers that occurred after a diagnosis of primary lung cancer had been established were located in the esophagus in 2 patients, nasopharynx in 2, and larynx in 1. The two esophageal cancers were diagnosed 5 years and 14 years respectively after the diagnosis of primary lung cancer. UADT cancers that preceded lung cancer were laryngeal cancer in 19 patients, nasopharyngeal cancer in 9, oral cavity cancer in 4, hypopharyngeal cancer in 2 and esophageal cancer in 2. The distribution of the UADT cancers is shown in Table 5.

Table 5. Distribution of the 56 upper aerodigestive tract (UADT) cancers
Location GrI GrII GrIII No. of patients (%)
Larynx 4 1 19 24 (42.9)
Nasopharynx 0 2 9 11 (19.6)
Esophagus 6 2 2 10 (17.9)
Hypopharynx 2 0 2 4 (7.1)
Pharyngeal tonsils 2 0 0 2 (3.6)
Oral cavity 1 0 4 5 (8.9)
GrI, synchronous cancer; GrII, occurrence following lung cancer; GrIII, occurrence preceding lung cancer.

There was no significant difference in survival between patients with double primary cancers (lung and UADT) and patients with primary lung cancer alone (P >0.05). The survival curves for these two groups of patients are shown in Fig. 2.

Discussion

The first report of a multiple primary malignancy was that of Billroth in 1879 (11). Since then, many such cases have appeared in the literature. In 1955, Cahan (14) reported that 81 (3.2%) of 2502 patients with lung cancer had multiple malignancies. In 1962, Cahan and Montemayor (15) reported that the majority of other primary cancers occurring with lung cancer were located predominantly in the head and neck area, particularly the larynx. They found that 60 (62%) of 97 such head and neck primaries occurred in the larynx, which meant that 25% of lung cancer patients as a whole also had a second primary tumor in the larynx. In 1977, Sochocky (7) reported that 180 (8.6%) of 2059 patients with primary lung cancer had one or more second primaries, 24 (1.1%) of which were head and neck lesions. The incidence of multiple primary neoplasia of the head and neck and of the lung has been between 1% and 2% in previous retrospective studies. In our present study, the incidence of multiple primary neoplasia, including UADT and lung cancers, was 0.9%, and the majority of UADT cancers also involved the larynx (43%).

When the UADT cancer patients presented with multiple primary neoplasia, it was often of squamous cell histology, as has been reported for the majority of lung cancers associated with head and neck cancers (4,7,12,15). There are at least three hypotheses to explain the phenomenon of second primary tumors; these include common-carcinogen-induced multiple neoplasia in an exposed epithelial surface (field cancerization), induction of the second cancer by the treatment used against the first one, and the presence of hereditary factors that predispose individuals to multiple neoplasia (5,17,18). Michael et al. reported a shift from squamous toward non-squamous cell lung cancer in multiple primary neoplasia (16). In the present series, NSCLC was the major type of lung cancer associated with UADT cancers (93%), of which squamous cell carcinoma (62%) predominated over non-squamous carcinoma (38%).

The rarity of primary lung cancer preceding UADT cancer has been attributed to the relatively high mortality rate for lung cancer. Nevertheless, lung cancer, particularly that at an early stage, can occasionally precede UADT cancer, as reported elsewhere in the medical literature (4,14,15) as well as in our study where this sequence occurred in 9% of patients. All the lung cancers in our series which preceded UADT cancer were NSCLC. Patients who develop UADT cancer first, especially of the head and neck, are much more likely to survive long enough to develop a second primary tumor such as lung cancer. In this group, most of the lung cancers occurred in the first three years after the diagnosis of UADT cancer. This implies that intensive chemoprevention and a change in habit (smoking, betel nut chewing) are probably needed after curative treatment of the UADT cancer. Synchronous UADT cancers occurred mostly in the esophagus (40%), and made up 60% of the esophageal cancers in our series. Lung cancers associated with UADT cancer were located predominantly in the right lung (right:left = 2:1). This finding has not been reported previously.

In 1989, Jay reported that the development of second primary tumors adversely affected subsequent survival in patients who had had their first cancer treated successfully (19). We found that there was no difference in survival between patients with or without a prior history of UADT cancer.

In summary, the incidence of lung cancer associated with UADT cancer was 0.9% in our series. Squamous cell carcinoma was the predominant histologic type of lung cancer, and the tumor was located in the right lung in most of these patients. Most of the lung cancers occurred within three years after the diagnosis of UADT cancer, and another second primary UADT cancer often occurred after curative treatment of an early lung cancer (stage I, II). Intensive chemoprevention and a change in habit (smoking, betel nut chewing) were necessary for these patients. The survival of lung cancer patients was not affected by the presence or absence of a prior history of UADT cancer.

References

1. Licciardello JTW, Spitz MR, Hong WK. Multiple primary cancer in patients with cancer of the head and neck, second cancer of the head and neck, esophagus and lung. Int. J Radiat Biol Phys 1989;17:467-76.

2. Laughead JR, Bushnell J. Metastasis of malignant tumors to the larynx. Laryngoscope 1954;64:50-2.

3. Wagenfeld DJH, Harwood AR, Bryce DP, Van Nostrand AW, De Boer G. Second primary respiratory tract malignancies in glottic carcinoma. Cancer 1980;46:1883-6.

4. Marks PM, Schechter FG. Multiple primary carcinomas of the head, neck and lung. Ann Thorac Surg 1982;33:324-32.

5. Slaughter DP, Southwick HW, Smajkal W. `Field cancerization' in oral stratified squamous epithelium. Cancer 1953;6:963-8.

6. Kirk HH, Scott ML. The incidence of second primary tumor in long-term survivors of small cell lung cancer. J Clin Oncol 1992;10:1519-24.

7. Sochocky S. Primary carcinoma of lung associated with primary malignancies in other systems. Br J Clin Pract 1977;31:52-6. MEDLINE Abstract

8. Peter HM, Frederick GS. Multiple primary carcinomas of the head, neck and lung. J Am Thorac Surg 1982;33:324-32.

9. Reynoid RD, Pajak TF. Lung cancer as a second primary cancer. Cancer 1978;42:2887-93.

10. Lyons MF, Redmond J. Multiple primary neoplasia of the head and neck and lung. Cancer 1986;57:2193-7. MEDLINE Abstract

11. Warren S, Gates D. Multiple primary malignant tumor: a survey of the literature and a statistical study. Am J Cancer 1932;51:1358-414.

12. Gluckman JC, Crissman JD, Donegan JD. Multicentric squamous carcinoma of the upper aerodigestive tract. Head Neck Surg 1980;3:90-6.

13. Thomas GW. The incidence and significance of multiple primary malignant tumors; a study of 2346 necropsies from a cancer research hospital. Am J Med Sci 1946;47:427-30.

14. Cahan WG. Lung cancer associated with cancer primary in other sites. Am J Surg 1955;89:494-514.

15. Cahan WG, Montemayor PB. Cancer of the larynx and lung in the same patient: a report of 60 cases. J Thorac Cardiovasc Surg 1962;44:305-18.

16. Michael FL. Multiple primary neoplasia of the head and neck and lung; the changing histopathology. Cancer 1986;57:2193-7.

17. Canellos GP, DeVita VT, Arseneau JC. Second malignancies complicating Hodgkin's disease in remission. Lancet 1975;1:947-9. MEDLINE Abstract

18. Knudsen AG. Hereditary cancer, oncogene and antioncogene. Cancer Res 1985;45:1437-43.

19. Jay S, Cooper JS, Thomas FP : Second malignancies in patients who have head and neck cancer: incidence, effect on survival and implication based on the RTOG experience. J Radiation Oncol Biol Phys 1989;17:449-56.

Received September 2, 1996; accepted November 21, 1996
For reprints and all correspondence: Wei-Chung Hsieh, Chest Department, Veterans General Hospital-Taipei, 201 Shih-pai Road, Sec.2, Taipei, Taiwan, ROC.
Abbreviations: UADT, upper aerodigestive tract; NSCLC, non-small cell lung cancer; SCLC, small cell lung cancer.

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