Clinical Features of Adenosquamous Lung Carcinoma in 127 Patients'?

KASI S. SRIDHAR, MICHAEL J. BOUNASSI, WILLIAM RAUB, JR., and STEPHEN P. RICHMAN

Introduction

Adenosquamous lung carcinoma is defined by the World Health Organization (WHO) as a malignant lung neoplasm showing malignant squamous and glandular components (1, 2). After the modification of the WHO classification of lung cancer in 1982, recognition of this histology at our cancer center increased (3, 4). Our earlier studies were based on data in the tumor registry. The current study was undertaken to supplement the information available in the tumor registry by reviewingthe charts of the patients with adenosquamous lung carcinoma. Our objective was to determine the presenting symptoms and the influence of initial treatment on survival. Methods Weidentified the patients in whom a diagnosis of adenosquamous lung carcinoma had been made between 1975 and 1988 in the Jackson Memorial Hospital and the University of Miami Hospital and Clinics. The patients included private (third party reimbursement, private insurance, Medicare, self-pay, and Medicaid), sponsored (reimbursed by a nonprofit organization such as LIGA Control el Cancer, Deed Club, and non-Dade County indigents sponsored by their county), and Dade County indigents (none of the above). The first antitumor therapy was defined as primary, the second antitumor therapy was defined as secondary, and the third was tertiary treatment. In our previous two studies (3, 4), we analyzed only "analytic" patients, those who had both diagnosis and primary therapy at our center between 1977and 1986. In the current study we included, in addition, patients who received only secondary or tertiary therapy at our cancer center. All the study patients had histopathologic or cytologic diagnosis of adenosquamous carcinoma of the lung established by one or more of the faculty of the Department of Pathology. The tumors defined as adenosquamous lung carcinomas showed well-defined squamous components and adenocomponents on routine microscopic examination using hematoxylineosin staining. Squamous cellcarcinoma demonstrating mucin on mucin-carmine staining was labeled adenosquamous carcinoma. How-

SUMMARY There has been Increased recognition of adenosquamous lung carcinoma since the 1982 modification of World Health Organization (WHO) histologic criteria. However, data on clinical features of this histologic subtype were nonexistent. Medical records of 127patients with adenosquamous lung carcinoma were reviewed to determine the clinical features, namely, age, race, sex, smokIng history, asbestos exposure, symptoms present at the time of diagnosis, stage, treatments, and survival. The age distribution was: < 40 yr, 3%; 40 to 49, 17%; 50 to 59, 28%; 60 to 69,32%; 70 to 79, 18%; ~ 80, 2%. Men constituted 72%, and 90% were smokers. Four smokers had documented asbestos exposure. The symptoms In order of decreasing frequency were cough, weight loss, expectoration, anorexia, chest pain, dyspnea, weakness, hemoptysis, pneumonia, fever, nausea, vomiting, dizziness, and chills. Stage could be ascertained in 120(95%) patients. Local stage constituted 10%, regional constituted 30%, and distant constituted 60%. Local stage had the best survival, with a projected 5-yr survival of 62%. Median survivals In regional and distant stages were 8 and 4 months, respectively. Symptoms of adenosquamous lung carcinoma were similar to other histologies. Most patients present In regional or distant stages. Local-stage patients had a good long-term survival after surgiAM REV RESPIR DIS 1990; 142:19-23 cal excision of the tumor.

ever, neither ultrastructural examination nor immunoperoxidase stainings were used to diagnose adenosquamous carcinoma. Definitions used by the tumor registry are reported here. Race: persons of mixed parentage were classified according to the nonwhite parent (Census Bureau definition). Tobacco use: referred to the patient's history of tobacco use at time of first contact with one of our institutions. The indicated levelof consumption based on the number of packs/day and the pack-years were noted whenever possible. Wearbitrarily divided smokers into light « 20 pack-years), moderate (20 to 80 packyears), and heavy (> 80 pack-years). The Mountain's staging introduced in 1986 was not used because the data used in this study was recorded from 1975. The older staging system of the Florida Cancer Data System, an adaptation of the Summary Staging Guide for the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) program was used by us. Stage: Local disease included a single tumor of any size> 2 em from the carina and confined to one lung and/or the main-stem bronchus, and multiple masses confined to one lung and/or the main-stem bronchus. Regional disease included regional extension into the visceral pleura, parietal pericardium, pulmonary ligament, carina, trachea, esophagus, nerve(s) (recurrent laryngeal, vagus, phrenic, and cervical sympathetic evidenced by Horner's syndrome), major blood vessel(s)(pulmonary artery, azygos vein, and superior vena cava); di-

rect extension into regional lymph nodes and the extrapulmonary mediastinal extension and/or the tumor in the following regional lymph nodes: intrapulmonary, hilar (bronchial, parabronchial, and pulmonary root), subcarinal, carinal, and mediastinal (paratracheobronchial, paratracheal, pericardial, paraesophageal, and supradiaphragmatic paraaortic). Distant stage included direct extension to the following: brachial plexus from superior sulcus or Pancoast tumor, contralateral lung and/or the main-stem bronchus, visceral pericardium, heart, parietal pleura, rib, sternum, vertebra, chest (thoracic) wall, skeletal muscle, skin of chest, diaphragm and/or distant lymph nodes (contralateral or bilateral hilar, mediastinal, supraclavicular, scalene, (Received in original form October 27, 1989 and in revised form January 22, 1990) 1 From the Departments of Oncology and Medicine, Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, the Jackson Memorial Hospital, and the Veterans Administration Medical Center, Miami, Florida. 2 Supported in part by Student Assistantship Grant No. 5-R 25-CAI7912-14 from the National Cancer lnsitutute, and by the Joan Levy Cancer Foundation, Miami, Florida. 3 Correspondence and requests for reprints should be addressed to Kasi S. Sridhar, M.D., FACP, FCCP, FRCP (C), Associate Professor, Departments of Oncology and Medicine, University of Miami School of Medicine, P.O. Box 106960 (084), Miami, FL 33101.

19

20

SRIDHAR, BOUNASSI, RAUB, AND RICHMAN

cervical, infradiaphragmatic para-aortic, and other distant sites, respectively, and/or hematogenous metastasis (bone, brain, liver, and other organs). Histology: WHO definition of adenosquamous carcinoma (a malignant lung neoplasm showing malignant squamous and glandular components) was used (1). Survival was calculated from the date of diagnosis to death or the date of last contact only in analytic patients because the followup data were incomplete in nonanalytic patients. Data wereanalyzed using the "survcalc" program (Wiley Professional Software; John Wiley & Sons, New York, NY). The survival analyses were calculated using the productlimit estimation method of Kaplan and Meier (5) and stratified by primary treatment modality and stage. The analyses included the relationship between sex, race, tobacco use, age, and symptoms. Comparisons of the survival curves werecarried out using the log rank test (6).

Results

The general characteristics of the study sample are shown in table 1. Adenosquamous lung carcinoma occurred in a broad age range (29 to 86 yr). However, it was uncommon below the age of 40 and over the age of 80. Nearly two-thirds of the patients were between 50 and 70 yr of age. The racial distribution was similar

TABLE 2 STAGE AND FINANCIAL STATUS IN ADENOSQUAMOUS LUNG CARCINOMA Indigent

Private Stage Local Regional Distant Unstaged Total •p

Sponsored

Unknown

Total

White

Black

White

Black

White

Black

White

Black

White

Black

8 13 18 0

1 3 6 2

1 7 22 0

1 8 12 2

1 3 9 0

0 2 1 0

0 0 4 3

0 0 0 0

10 23 53 3

2 13 19 4

3

7

0

89

38

*(39

*(30

12)*

23)*

13

< 0.03 by chi-square analysis. Comparisons are between private and

to that in lung cancer at our center and showed a white:black ratio of 2:1. Eight men (three white and five black) had prior antituberculosis therapy, 6 months to 17 yr prior to the diagnosis of cancer. One white woman had a prior history of a positive tuberculin test, but whether the patient had active tuberculosis and/or antituberculosis therapy was unknown. White patients were more likely to have private insurance than were black patients (table 2). Adenosquamous lung carcinoma occurred more often in men, with a male:female ratio of 5:2, and the tumor was located in the right lung more often than in the left lung, with a ratio of 2:1.

indigent patients irrespective of stage.

All patients were symptomatic. The symptoms in the 127 patients are shown in table 3. Most patients had multiple symptoms. Reflecting the limitations of a retrospective analysis, absence of many of the symptoms was not documented in a large number of patients. It is plausible that many of the symptoms may not have been documented either because of their absence or because of the failure of the patients to volunteer the symptom. Hemoptysis was a more common presenting symptom in men than in women (table 4). Weight loss was more frequent in men than in women, but this difference was not significant. The other symptoms were similar in men and in women.

TABLE 3 TABLE 1

SYMPTOMS IN THE 127 PATIENTS WITH ADENOSQUAMOUS LUNG CARCINOMA

ADENOSQUAMOUS LUNG CARCINOMA IN 127 PATIENTS

Patients with the Symptom

Patients Characteristics Age, yr < 40 40-49 50-59 60-69 70-79 ~ 80 Race White Black Sex Men Women Sex and Race White males Black males White females Black females Financial class Private Indigent Sponsored * Unknown Anatomic location of tumor Right lung Left lung Both lungs Not documented

(n)

(%)

4 22 35 41 23 2

3.1 17.3 27.6 32.3 18.1 1.6

90 37

70.9 29.1

92 35

72.4 27.6

63 29 27 8

49.6 22.8 21.3 6.3

51 53 16 7

40.2 41.7 12.6 5.5

Present

Not Documented

Absent

Symptoms

(n)

(%)

(n)

(%)

(n)

(%)

Cough Weight loss Expectoration Anorexia Chest pain Dyspnea Weakness Hemoptysis Pneumonia Fever Nausea Vomiting Dizziness Chills

68 54 49 45 41 38 38 30 16 16 13 9 8 6

54 43 39 35 32 30 30 24 13 13 10 7 6 5

18 25 17 10 29 17 3 37 4 46 18 11 6 42

14 20 13 8 23 13 2 29 3 36 14 9 5 33

42 48 61 72 57 72 86 60 107 65 96 107 113 79

32 38 48 57 45 57 68 47 84 51 76 84 89 62

TABLE 4 MANIFESTATIONS OF ADENOSQUAMOUS LUNG CARCINOMA IN MEN AND IN WOMEN Symptoms*

77 39 3 8

60.6 30.7 2.4 6.3

• Reimbursed by either a nonprofit organization or by another county sponsoring a non-Dade indigent.

Men

Women

Chi-square Test

Hemoptysis

Present Absent

25 24

4 13

P = 0.05

Weight loss

Present Absent

46 18

9

NS

8

• The other symptoms were identical in the two groups.

21

CLINICAL FEATURES OF ADENOSQUAMOUS WNG CARCINOMA

Symptoms were identical in white and in black patients. Patients younger than 60 yr of age had a greater but statistically insignificant incidence of anorexia than did patients 60 yr of age or older. Other symptoms were not different between the various age groups. Smoking history was available in 108 patients, 78 men and 30 women (figure 1). Ninety-two were cigarette smokers, three werecigarette and cigar smokers, two were cigar smokers, and 11 were nonsmokers. All cigar smokers were men. Most patients were moderate to heavy smokers (figure 2). Of the 11 reported nonsmokers, six were men and five were women. Ninety-two percent of men and 83070 of women were smokers, and the difference in smoking history between them was not significant. All four with a documented history of asbestos exposure were men and smokers. The stage distribution is shown in tables 2 and 5. Although the private patients constituted only approximately40% of the patients, 75% of the local stage patients were private. These data suggest an inverse relationship between early stage and lower socioeconomic status. lro,

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TABLE 5 PRIMARY ANTITUMOR THERAPY Radiation Therapy

Chemotherapy

Surgery

Local Regional Distant Unknown

1 13 38 3

0 7 10 0

10 9 5 3

Total

55

17

27

Stage

None

Unknown

1 3

Total

0

0 4 0 1

12 36 72 7

23

5

127

19

TABLE 6 TREATMENT OF ADENOSQUAMOUS LUNG CARCINOMA Primary Surgery Radialion therapy Chemotherapy No antitumor treatment Not documented Total

Secondary

Tertiary

9

23 5

11 14 0 0

3 0 2 0 0

38 66 33 23 5

127

34

5

165

27 55

17

The treatments receivedby the patients are shown in tables 5 and 6. Of the 12 local stage patients, 10 were treated by surgery, one by radiation therapy followed by surgery, and one died of respiratory failure caused by emphysema before receiving any therapy. Local stage in this patient was confirmed by an autopsy examination. Of the 10analytic patients with local stage, one did not receive any antitumor therapy and nine underwent thoracotomy. Survival for these patients is shown in figure 3. Five patients were alive, with a minimum follow-up of 36 months. In regional and distant stages, there were no significant differences in survival between the patients treated with surgery, chemotherapy, or radiation therapy as the primary treatment (figures 4 and 5). 'TWo patients, who survived 6 and 28 months, are excluded in figure 4 because antitumor therapy was not known. Because it is unusual for patients with distant stage to be treated by surgery as the primary therapeutic modality, we de-

Total

termined the reason for surgery to be the following : resection of brain metastasis, resection of a primary lung tumor in absence of a diagnosis before a thoracotomy, and treatment of a critically placed lesion in a weight-bearing bone. Approximately 40% of all patients were treated with radiation therapy as either primary or secondary therapy. About 23070 of the patients receivedsurgery as primary treatment and about 20% of patients died without receiving any specific antitumor treatment. Overall survival of the 103 analytic patients is shown in figure 6. The median survival was 6 months. The 1-, 2-, and 5-yr survivals were 27, 17, and 9%, respectively. There were no 5-yr survivors in regional and distant stages (figure 7). Discussion

We had previously noted that in addition to the widely recognized increase in adenocarcinoma (7-9), there was also an increase in adenosquamous lung carcino-

Fig. 3. Survival of nine local stage patients who underwent the thoracotomy.

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SRIDHAR, BOUNASSI, RAUB, AND RICHMAN

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rna (3, 4). A review of the literature showed no data on the clinical features of adenosquamous subtype (1, 2, 10-15). The present study was undertaken to fill this void in our knowledge. Our study suggests that smoking was the predominant predisposing factor for adenosquamous lung carcinoma. Asbestos exposure was documented in four men who also had a positive smoking history. The sex, race, and age distributions and symptoms appear to be similar to other histologic types of lung cancer (16-18). In patients with adenosquamous lung carcinoma, symptoms were independent of age, sex, and race. However, race was related to financial status and stage at presentation. Local stage, the only stage associated with a good survival was two- to threefold more common in white than black patients and fivefold more common in private patients than in indigent patients. This may be related to either delay in access to the health care system by the indigent patients or to the referral of resectable local-stage private patients to our center (19). Our data (3) suggest that in local- and regional-stage lung cancer,

white patients have a better survival rate than do black patients, contrary to the data collected between 1955 and 1964(20) and consistent with more recent data collected between 1973 and 1976 (21). Our retrospective study of 127patients is the largest series and is the first study to report the clinical features, namely, symptoms, race, sex, and stage distributions, and smoking history in patients with adenosquamous lung carcinoma. Symptomatology in adenosquamous lung carcinoma is similar to other histologic subtypes of lung carcinoma. Smoking was the major predisposing factor. Our study suggests that although local stage

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References 1. The World Health Organization histological typing of lung tumors. 2nd ed. Am J Clin Pathol 1982; 77:123-36. 2. Hammar SP. Common neoplasms. In: Dail DH, Hammar SP, eds. Pulmonary pathology. lst ed. New York: Springer-Verlag, 1988; 727-845. 3. Sridhar KS, Raub W, Duncan RC, Hilsenbeck

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Acknowledgment The writers thank Dr. N. Love for sponsoring Mr. Bounassi, Ms. L. Vega for typing the manuscript, Ms. D. Vetromile for drawing the figures, and Ms. D. Smith of the Tumor Registry.

Fig. 6. In the 103 analytic patients, projected survival rates were: 1 yr, 30%; 2yr, 22%; 3yr, 13%; 4yr, 11%; and 5 yr, 9%, respectively.

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is uncommon at presentation, it was associated with good survival after surgery. There was a high prevalence of regional and distant stages. Survival was dismal in regional and distant stages, despite the trial of different therapies. There was no significant difference in survival between the various primary treatments, namely, surgery, radiation therapy, or chemotherapy. The survival in this histologic subtype is similar to that in adenocarcinomas and in large cell lung carcinomas (3). In the absence of data on therapy of adenosquamous lung carcinoma (22), it seems reasonable to treat this subtype in a fashion similar to other non-small cell lung carcinomas (23, 24).

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Fig. 7. Survival curve of 84 analytic patients who received antitumor therapy related to the stage is shown. Nine had local stage, 29 had regional stage, and 46 had distant stage.

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l.bths Fig. 5. Survival of 57 patients with distant stage related to the primary therapy is shown. Thirty-one received radiation therapy, eight surgery, and seven chemotherapy. Two patients were alive at 3 and 20 months after chemotherapy, and one was alive at 3 months with radiation therapy.

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CLINICAL FEATURES OF ADENOSQUAMOUS WNG CARCINOMA

S. Lung carcinoma in 1336 patients. Chest 1989; 96:271S. 4. Sridhar KS, Raub W, Duncan RC, Hilsenbeck S. Increasing recognition of adenosquamous carcinoma. Submitted to Cancer. 5. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53:457-81. 6. Fleming T, Harrington D. A class of rank test procedures for censored survival data. Biometrika 1982; 69:553-66. 7. Vincent RG, Pickren JW, Lane WW, et al. The changing histopathology of lung cancer: a review of 1682 cases. Cancer 1977; 39:1647-55. 8. Valaitis J, Warren S, Gamble D. Increasing incidence of adenocarcinoma of the lung. Cancer 1981; 47:1042-6. 9. Tsugane S, Watanabe S, Sugimura H, Urano Y, Matsubara S. Recent trends in different histological types of lung cancer in Tokyo based on pathological autopsy records. Jpn J Cancer Res 1987; 78:162-9. 10. Gould VE, Warren WHoEpithelial neoplasms of the lung. In: Roth JA, Ruckdeschel JC, Weisenburger TH, eds. Thoracic oncology. lst ed. Philadelphia: W.B. Saunders, 1989; 77-94. 11. Yesner R, Gerstl B, Auerbach O. Application

of World Health Organization classification of lung carcinoma to biopsy material. Ann Thorac Surg 1965; 1:29-33. 12. Kern WH, Jones JC, Chapman ND. Pathology of bronchogenic carcinoma in long term survivors. Cancer 1968; 21:772-80. 13. Auerbach 0, Frasca JM, Parks VR, et al. A comparison of World Health Organization (WHO) classification of lung tumors by light and electron microscopy. Cancer 1982; 50:2079-88. 14. Ashley DJ, Davies HD. Mixed glandular and squamous cell carcinoma of the bronchus. Thorax 1967; 22:431-6. 15. Fitzgibbons PL, Kern WHo Adenosquamous carcinoma of the lung: a clinical and pathologic study of seven cases. Hum Patho11985; 16:463-6. 16. Cromartie RS III, Parker EF, May JE, Metcalf JS, Bartles DM. Carcinoma of the lung. A clinical review. Ann Thorac Surg 1980; 30:30-5. 17. Green N, Kurohara SS, George FW, CrewsQE Jr. The biological behavior of lung cancer according to histologic type. Radiol Clin BioI 1972; 41: 160-70. 18. Doyle LA, Aisner J. Clinical presentation of lung cancer. In: Roth JA, Ruckdeschel JC, Weisenburger, eds. Thoracic oncology. 1st ed. Philadelphia: W.B. Saunders, 1989; 52-72.

23 19. Greenberg ER, Dain B, Freeman DH, Yates J, Korson R. Referral of lung cancer patients to university hospital cancer centers. Cancer 1988; 62:1647-52. 20. Page WF, Kuntz AJ. Racial and socioeconomic factors in cancer survival: a comparison of Veterans Administration results with selected studies. Cancer 1980; 45:1029-40. 21. Greenberg ER, Chute CG, Stukel T, et al. Social and economic factors in the choice of lung cancer treatment: a population-based study in two rural states. N Engl J Med 1988; 318:612-7. 22. Minna JD, Pass H, Glatstein E, Ihde DC. Cancer of the lung. In: DeVita VT, Helmman S, Rosenberg SA, eds. Cancer, principals and practice of oncology. 3rd ed. Philadelphia: J .B.Lippincott Co., 1989; 591-631. 23. Sridhar KS, Thurer R, Kim Y, et al. Multimodality treatment of non-small cell lung cancer: response to cisplatin, VP-16, and 5-FU chemotherapy and to surgery and radiation therapy. J Surg Oncol 1988; 38:193-215. 24. Sridhar KS, Varki J, Donnelly E, et al. Toxicity of FED chemotherapy in non -small celllung cancer. Am J Clin Oncol 1987; 10:499-506.

Clinical features of adenosquamous lung carcinoma in 127 patients.

There has been increased recognition of adenosquamous lung carcinoma since the 1982 modification of World Health Organization (WHO) histologic criteri...
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