Bronchogenic Carcinoma in Chronic Lymphocytic Leukemia* David G. Amamoo, M.D.; Houshang Moayeri, M.D.; Hiroshi Takita, M.D.; and Tin Han, M.D.
Fourteen cases of bronchogenic carcinoma were found in 191 patients with chronic lymphocytic leukemia seen at the RosweU Park Memorial Institute, Buffalo, NY, from 1951 to 1976. Four of these were not diagnosed until the time of autopsy. There was an average lag of nine months
between the onset of symptoms and signs suggestive of bronchogenic carcinoma and its diagnosis. In patients with chronic lymphocytic leukemia, a high index of suspicion for bronchogenic carcinoma is necessary for its early detection.
There have been conflicting reports on the association of other malignant neoplasms with chronic lymphocytic leukemia. Whipham! first drew attention to this in 1878. While several investigators have reported similar findings in the last two decades.' the exact incidence of such an association remains unestablished. Cutaneous malignant neoplasms are the most commonly associated," Studies by Berg" and by Gunz and Angus" reported that except for a higher incidence of cutaneous malignant neoplasms associated with chronic lymphocytic leukemia, the incidence of other malignant disease was not significantly higher; however, Manusow and Weinerman'' could observe an increased incidence of other malignant disease after excluding cutaneous neoplasms, thus confirming Hyman's? findings. More recently, Moayeri and associates" have reported similar findings, with pulmonary malignant disease being the most commonly associated neoplasm next to cancer of the skin. In the communication, we report our experience of 14 cases of bronchogenic carcinoma in 191 patients with chronic lymphocytic leukemia.
Except for chronic interstitial changes and moderate emphysema, the chest x-ray film was essentially normal. Hematologic data were as follows: white blood cell count, 142,000/ cu mm; lymphocytes, 98 percent; hemoglobin level, 9.9 gm/l00 ml, and red blood cell count, 3,800,OOO/cu mm. Study of the bone marrow revealed hyperceIIularity, with 85 percent of the cells being mature lymphocytes, thus confirming the diagnosis of chronic lymphocytic leukemia. Chemotherapy consisting of chlorambucil and prednisone was instituted, with only transient response. Subsequently, the patient was treated with radioactive colloidal 32phosphorus, with remission until 18 months after his initial visit, when he developed sudden cough, hemoptysis, fever, and pain in the chest. A chest x-ray film at this time revealed a right hilar mass and an infiltrate in the middle lobe. This was attributed to middle lobe pneumonia, and the patient was treated with antibiotics for a month, without response. Bronchoscopic examination was unrevealing, but cytologic study of the sputum revealed malignant neoplasm. The patient died of respiratory insufficiency two weeks later. Autopsy revealed multiple malignant neoplasms, as follows: (1) small cell bronchogenic carcinoma of the right lung, with metastases to the mediastinal nodes, the liver, the adrenal glands, and the vertebrae; (2) chronic lymphocytic leukemia with leukemic infiltration of the liver, the spleen, and abdominal lymph nodes; and (3) medullary carcinoma of the thyroid.
CASE REPORTS CASE
1
A 60-year-old man was referred with the established diagnosis of chronic lymphocytic leukemia, which was discovered at previous hospitalization elsewhere a month before admission to the Roswell Park Memorial Institute, Buffalo, NY, for thrombophlebitis of the left calf. Prior to that time, the patient had maintained good health. He had smoked one pack of cigarettes per day for 40 years. Physical examination revealed generalized lymphadenopathy and hepatosplenomegaly. ·From the New York State Department of Health, Roswell Park Memorial Institute, Buffalo. Manuscript received September 16; revision accepted July 26.
Reprint requests: Dr. Takita, Roswell Park Memorial Institute, 666 Elm Street, Buffalo 14263
174 AMAMOO ET AL
CASE
2
A 62-year-old man was referred for investigation of rightsided pleural effusion, loss of weight, and dyspnea. The patient was known to have congestive heart failure for the last five years. He had smoked two packs of cigarettes per day for 35 years. The pertinent findings included dyspnea with reduced breath sounds over the right lung, cervical lymphadenopathy, hepatosplenomegaly, and pitting edema of the legs. The chest x-ray film revealed total opacification of the lower two-thirds of the right hemithorax, with increased markings in the right middle pulmonary field. Hematologic studies and biopsy of bone marrow disclosed chronic lymphocytic leukemia. Bronchoscopic examination revealed no endobronchial lesion. Differential diagnosis included bronchogenic carcinoma and pulmonary abscess, but the patient was treated for chronic lymphocytic leukemia and received chlor-
CHEST, 75: 2, FEBRUARY, 1979
ambucil and prednisone. Bronchial washing was later reported as showing malignant cells. The patient died two months later due to respiratory insufficiency. Autopsy revealed squamous cell carcinoma arising from the right upper lobe, with pleural and diaphragmatic involvement and metastases to the peribronchial lymph nodes and the vertebrae, in addition to leukemic infiltration of the abdominal lymph nodes, the spleen, the liver, and the bone marrow.
Table 2--..4dditiona' Malipan, Le.o,.. in 45 Pade.... "';th Chronic Lymplaoeytic: Leukemia
Site Skin Lung
The clinical course of 191 patients (133 men and 58 women) with chronic lymphocytic leukemia seen at the Roswell Park Memorial Institute between 1951 and 1976 was reviewed. The ages of the patients ranged from 36 to 89 years (average, 63 years).
Prostate gland
RESULTS
Miscellaneous
Therapy in the 151 patients (101 men and 50 women) with chronic lymphocytic leukemia varied considerably, ranging from treatment with a single drug to multiple drugs, with or without irradiation. Forty patients received no treabnent (Table 1). The duration of treatment ranged from eight months to seven years (average, 20 months) . Fifty-five new malignant neoplasms were found in 45 patients. Of these 55 neoplasms, 24 were found prior to or concomitant with the diagnosis of chronic lymphocytic leukemia. Twenty-eight additional neoplasms were found seven months to seven years ( average, 44 months) after the diagnosis of chronic lymphocytic leukemia. The most common lesions were cutaneous and pulmonary malignant neoplasms (Table 2). Fourteen patients were found to have bronchogenic carcinoma in addition to the chronic lymphocytic leukemia. Their ages ranged from 36 to 74 years (average, 63 years). All 14 patients were men and were found to be heavy cigarette smokers (one to two packs per day for more than 20 years). The most common symptoms were cough (nine patients ), dyspnea (eight patients), loss of weight (eight patients), and fever (eight patients); other symptoms included fatigue, anorexia, or malaise (four patients), hemoptysis ( three patients), Table I-Treated '"~ Nontrea'ed Patien,.lf1ith Chronic Lymphocytic Leukemia
Data
No. of Patients
Therapy for chronic lymphocytic leukemia*
151
101**
sot
40
31
8
191
133
58
No therapy Total
Women
*Cytotoxic agents, cortisone, uphosphorus, irradiation, and splenectomy (alone or combined). **Ages, 36 to 89 years (mean, 62 years). fAges, 46 to 85 years (mean, 64 years).
CHEST, 75: 2, FEBRUARY, 1979
5
Colon or rectum
MATERIALS AND METHODS
Men
ConcomiPrior to tant with After Therapy * Therapy* Therapy* Total
0
5
8
14
2
7
14
3
3
6
2
2
4
Malignant melanoma
0
2
Breast
0
2
Mycosis fungoides Total
0
9
0
2
2
5
5
11
17
29
55
*Therapy for chronic lymphocytic leukemia.
hoarseness (two patients), and cyanosis (one patient). In the 14 patients with bronchogenic carcinoma, chronic lymphocytic leukemia was diagnosed incidentally in five patients referred for investigation of a coin lesion or pleural effusion found on a routine chest x-ray film. Nine patients who were receiving treatment for chronic lymphocytic leukemia developed radiologic changes in their chest x-ray films, thus demanding further investigation. The types of treatment in the 14 men with bronchogenic carcinoma were as follows: cyclophosphamide (Cytoxan ), prednisone, chlorambucil, and irradiation, one patient; chlorambucil, prednisone, and splenectomy, one patient; radioactive 32phosphorus, one patient; 32phosphorus, prednisone, and chlorambucil, one patient; irradiation alone, one patient; irradiation plus prednisone, one patient; chlorambucil alone, three patients; and no treatment, five patients. In the patients with bronchogenic carcinoma, cytologic study of sputum revealed malignant neoplasm in six patients. Ten patients underwent bronchoscopic examination, with seven having abnormal findings (three patients with intrinsic tumor and four with abnormal bronchial washings). Diagnosis of bronchogenic carcinoma was made before death in ten patients with chronic lymphocytic leukemia. Autopsies revealed four additional cases which had been undetected previously. There were seven cases of squamous cell carcinoma, four cases of small cell (oat cell) carcinoma, and five cases of adenocarcinoma. Three patients had other malignant neoplasms in addition to the bronchogenic carcinoma; one patient had medullary carcinoma of the thyroid gland, the second had basal cell carcinoma of the nose, and the third had adenocarcinoma of the prostate gland.
BRONCHOGENIC CARCINOMA IN CHRONIC LYMPHOCYTIC LEUKEMIA 175
°
There was a time lag of to 48 months (average, nine months) between the time when attention was drawn to the symptoms of bronchogenic carcinoma and its diagnosis, and there was a lag of 19 months from the initial diagnosis of chronic lymphocytic leukemia. Survival after diagnosis ranged from zero to seven years (average, eight months). Four patients underwent pulmonary resection for bronchogenic carcinoma. In these the survival ranged from one month to seven years (average, 33 months). DISCUSSION
Several neoplastic diseases have been reported in association with chronic lymphocytic leukemia.v" Of the 191 patients studied, 14 patients (7 percent) were found to have bronchogenic carcinoma. The reported incidence of bronchogenic carcinoma in the United States in the group aged 60 to 64 years was 160/100,000 in 1974.9 It seems, therefore, that the incidence of bronchogenic carcinoma in patients with chronic lymphocytic leukemia is 11 times higher than in the general population. The average period of observation of our 191 patients was four years; thus, the incidence of bronchogenic carcinoma per year is 14/4 years or 3.5 per 191 patients, which is equivalent to 1,830/100,000. Chronic lymphocytic leukemia was an incidental finding in five patients with diagnosed bronchogenic carcinoma, but in the remaining nine patients, the diagnosis of leukemia preceded that of bronchogenic carcinoma. These patients developed signs and symptoms suggestive of bronchogenic carcinoma at the same time or soon after the diagnosis of chronic lymphocytic leukemia had been made. There was usually a nine-month delay before the accurate diagnosis of bronchogenic carcinoma could be made. In the two cases presented, the symptoms suggestive of bronchogenic carcinoma were present at the time when the diagnosis of leukemia was made. These were erroneously attributed to manifestations of chronic lymphocytic leukemia. This supports the findings of Moertel and Hagedorn: 10 "Any sign or symptoms suggestive of focal malignancy in a patient with leukemia or lymphoma should be regarded as representing a primary lesion until pathologically proved otherwise." Patients with organ transplants who are receiving long-term immunosuppressive therapy have a 5 to 6 percent incidence of new malignant neoplasms within the first few years after transplantation.'! Patients with chronic lymphocytic leukemia are also known to have impaired immunity; 12 they are therefore at a higher risk of developing cancer, as seen in our review of 191 patients. Of the 151 patients who received various forms of antileukemic
178 AMAMOO ET AL
treabnent over an average period of 20 months, only 14 patients (all men) developed bronchogenic carcinoma. In nine cases, these treatments included various combinations of chemotherapy, irradiation, and splenectomy. About a third of these 14 patients (five patients) received no treatment before the diagnosis of bronchogenic carcinoma was made. None of the 58 female patients who received similar antileukemic treatment developed bronchogenic carcinoma. It therefore seems unlikely that the agents used in the treatment of chronic lymphocytic leukemia were the cause or contributed to the development of bronchogenic carcinoma. Good and Catti'" found a high incidence of primary malignant neoplasms in several immunologic deficiency diseases. They reported incidences of 15 percent for lymphoreticulosarcoma in Wiskott-Aldrich syndrome, 10 percent for lymphoma in ataxia-telangiectasia, and 10 percent for acute lymphocytic leukemia in Burton's agammaglobulinemia." In most of these cases abnormalities of T and B lymphocytes were found and predisposed to the development of neoplasms. It is quite conceivable that similar factors present in the patient with chronic lymphocytic leukemia may be responsible for the high incidence of second malignant neoplasms. The overall survival was an average of eight months once bronchogenic carcinoma was diagnosed in this group of patients with chronic lymphocytic leukemia. In the four patients who underwent pulmonary resection for early bronchogenic carcinoma, the average survival was 33 months. These figures on survival are not much different from those in nonleukemic patients with bronchogenic carci-
noma. 14- 16 From these observations, we may conclude the following: (1) the incidence of bronchogenic carcinoma is increased among patients with chronic lymphocytic leukemia; (2) symptoms of bronchogenic carcinoma in patients with chronic lymphocytic leukemia are often overlooked or erroneously attributed to the original disease, causing delay in correct diagnosis; (3) overall survival of the patients with bronchogenic carcinoma and chronic lymphocytic leukemia does not seem to differ much from that of nonleukemic patients; and (4) in patients with chronic lymphocytic leukemia, a high index of suspicion for bronchogenic carcinoma is necessary for its early detection. REFERENCES
1 Whipham T: Splenic leukemia with carcinoma. Trans Pathol Soc London 29:313-319, 1878 2 Benvenisti DS, DeBellis RH: Carcinoma of the breast, chronic lymphocytic leukemia, macroglobulinemia, eosino-
CHEST, 75: 2, FEBRUARY, 1979
3 4
5 6
7 8 9
philic chloroma and myelosclerosis: A unique association. Cancer 23:1204-1209, 1969 Beresford OD: Chronic lymphocytic leukemia associated with malignant diseases. Br J Cancer 6:339-344, 1952 Berg JW: The incidence of multiple primary cancers: 1. The development of further cancers in patients with lymphoma, leukemias, and myeloma. J Nat! Cancer Inst 38:741-752, 1967 Gunz FW, Angus HB: Leukemia and cancer in the same patient. Cancer 18:145-152,1965 Manusow D, Weinerman BH: Subsequent neoplasia in chronic lymphocytic leukemia. JA MA 232:267-269, 1975 Hyman GA: Increased incidence of neoplasia in association with chronic lymphocytic leukemia. Scand J Haematol 6:99-104, 1969 Moayeri H, Han T, Stutzman L, et al: Second neoplasms with chronic lymphocytic leukemia. NY State J Med 76:378-382, 1976 Third National Cancer Survey Incidence Data. (monograph 41). Bethesda, National Cancer Institute, 1975, p 114
CHEST, 75: 2, FEBRUARY, 1979
10 Moertel CG, Hagedorn AB: Leukemia or lymphoma and coexistent primary malignant lesions: A review of the literature and a study of 120 cases. Blood 12:788-803, 1957 11 Stutman 0: Immunodepression and malignancy. Adv Cancer Res 22:261-422, 1975 12 Han T: Studies of correlation of lymphocyte response to phytohemagglutinin with the clinical and immunologic status in chronic lymphocytic leukemia. Cancer 31 :280285, 1973 13 Good R, Gatti R: Immunobiology of Cancer. In Najanian JS, Simmons RL (eds): Transplantation (sec 3). Philadelphia, Lea and Febiger, 1972, p 311 14 Takita H, Brugarolas A, Marabella PC, et al: Small cell carcinoma of the lung: Clinicopathological studies. J Thorac Cardiovasc Surg 66:472-477, 1973 15 Marabella PC, Takita H: Adenocarcinoma of the lung: Clinicopathological study. J Surg Oncol 7 :205-212, 1975 16 Marabella PC, Takita H, Lane WW: Squamous cell carcinoma of the lung: Clinicopathologic study. Chest 71:497-501, 1977
BRONCHOGENIC CARCINOMA IN CHRONIC LYMPHOCYTIC LEUKEMIA 177
Fourteen cases of bronchogenic carcinoma were found in 191 patients with chronic lymphocytic leukemia seen at the RosweU Park Memorial Institute, Buffalo, NY, from 1951 to 1976. Four of these were not diagnosed until the time of autopsy. There was an average lag of nine months
between the onset of symptoms and signs suggestive of bronchogenic carcinoma and its diagnosis. In patients with chronic lymphocytic leukemia, a high index of suspicion for bronchogenic carcinoma is necessary for its early detection.
There have been conflicting reports on the association of other malignant neoplasms with chronic lymphocytic leukemia. Whipham! first drew attention to this in 1878. While several investigators have reported similar findings in the last two decades.' the exact incidence of such an association remains unestablished. Cutaneous malignant neoplasms are the most commonly associated," Studies by Berg" and by Gunz and Angus" reported that except for a higher incidence of cutaneous malignant neoplasms associated with chronic lymphocytic leukemia, the incidence of other malignant disease was not significantly higher; however, Manusow and Weinerman'' could observe an increased incidence of other malignant disease after excluding cutaneous neoplasms, thus confirming Hyman's? findings. More recently, Moayeri and associates" have reported similar findings, with pulmonary malignant disease being the most commonly associated neoplasm next to cancer of the skin. In the communication, we report our experience of 14 cases of bronchogenic carcinoma in 191 patients with chronic lymphocytic leukemia.
Except for chronic interstitial changes and moderate emphysema, the chest x-ray film was essentially normal. Hematologic data were as follows: white blood cell count, 142,000/ cu mm; lymphocytes, 98 percent; hemoglobin level, 9.9 gm/l00 ml, and red blood cell count, 3,800,OOO/cu mm. Study of the bone marrow revealed hyperceIIularity, with 85 percent of the cells being mature lymphocytes, thus confirming the diagnosis of chronic lymphocytic leukemia. Chemotherapy consisting of chlorambucil and prednisone was instituted, with only transient response. Subsequently, the patient was treated with radioactive colloidal 32phosphorus, with remission until 18 months after his initial visit, when he developed sudden cough, hemoptysis, fever, and pain in the chest. A chest x-ray film at this time revealed a right hilar mass and an infiltrate in the middle lobe. This was attributed to middle lobe pneumonia, and the patient was treated with antibiotics for a month, without response. Bronchoscopic examination was unrevealing, but cytologic study of the sputum revealed malignant neoplasm. The patient died of respiratory insufficiency two weeks later. Autopsy revealed multiple malignant neoplasms, as follows: (1) small cell bronchogenic carcinoma of the right lung, with metastases to the mediastinal nodes, the liver, the adrenal glands, and the vertebrae; (2) chronic lymphocytic leukemia with leukemic infiltration of the liver, the spleen, and abdominal lymph nodes; and (3) medullary carcinoma of the thyroid.
CASE REPORTS CASE
1
A 60-year-old man was referred with the established diagnosis of chronic lymphocytic leukemia, which was discovered at previous hospitalization elsewhere a month before admission to the Roswell Park Memorial Institute, Buffalo, NY, for thrombophlebitis of the left calf. Prior to that time, the patient had maintained good health. He had smoked one pack of cigarettes per day for 40 years. Physical examination revealed generalized lymphadenopathy and hepatosplenomegaly. ·From the New York State Department of Health, Roswell Park Memorial Institute, Buffalo. Manuscript received September 16; revision accepted July 26.
Reprint requests: Dr. Takita, Roswell Park Memorial Institute, 666 Elm Street, Buffalo 14263
174 AMAMOO ET AL
CASE
2
A 62-year-old man was referred for investigation of rightsided pleural effusion, loss of weight, and dyspnea. The patient was known to have congestive heart failure for the last five years. He had smoked two packs of cigarettes per day for 35 years. The pertinent findings included dyspnea with reduced breath sounds over the right lung, cervical lymphadenopathy, hepatosplenomegaly, and pitting edema of the legs. The chest x-ray film revealed total opacification of the lower two-thirds of the right hemithorax, with increased markings in the right middle pulmonary field. Hematologic studies and biopsy of bone marrow disclosed chronic lymphocytic leukemia. Bronchoscopic examination revealed no endobronchial lesion. Differential diagnosis included bronchogenic carcinoma and pulmonary abscess, but the patient was treated for chronic lymphocytic leukemia and received chlor-
CHEST, 75: 2, FEBRUARY, 1979
ambucil and prednisone. Bronchial washing was later reported as showing malignant cells. The patient died two months later due to respiratory insufficiency. Autopsy revealed squamous cell carcinoma arising from the right upper lobe, with pleural and diaphragmatic involvement and metastases to the peribronchial lymph nodes and the vertebrae, in addition to leukemic infiltration of the abdominal lymph nodes, the spleen, the liver, and the bone marrow.
Table 2--..4dditiona' Malipan, Le.o,.. in 45 Pade.... "';th Chronic Lymplaoeytic: Leukemia
Site Skin Lung
The clinical course of 191 patients (133 men and 58 women) with chronic lymphocytic leukemia seen at the Roswell Park Memorial Institute between 1951 and 1976 was reviewed. The ages of the patients ranged from 36 to 89 years (average, 63 years).
Prostate gland
RESULTS
Miscellaneous
Therapy in the 151 patients (101 men and 50 women) with chronic lymphocytic leukemia varied considerably, ranging from treatment with a single drug to multiple drugs, with or without irradiation. Forty patients received no treabnent (Table 1). The duration of treatment ranged from eight months to seven years (average, 20 months) . Fifty-five new malignant neoplasms were found in 45 patients. Of these 55 neoplasms, 24 were found prior to or concomitant with the diagnosis of chronic lymphocytic leukemia. Twenty-eight additional neoplasms were found seven months to seven years ( average, 44 months) after the diagnosis of chronic lymphocytic leukemia. The most common lesions were cutaneous and pulmonary malignant neoplasms (Table 2). Fourteen patients were found to have bronchogenic carcinoma in addition to the chronic lymphocytic leukemia. Their ages ranged from 36 to 74 years (average, 63 years). All 14 patients were men and were found to be heavy cigarette smokers (one to two packs per day for more than 20 years). The most common symptoms were cough (nine patients ), dyspnea (eight patients), loss of weight (eight patients), and fever (eight patients); other symptoms included fatigue, anorexia, or malaise (four patients), hemoptysis ( three patients), Table I-Treated '"~ Nontrea'ed Patien,.lf1ith Chronic Lymphocytic Leukemia
Data
No. of Patients
Therapy for chronic lymphocytic leukemia*
151
101**
sot
40
31
8
191
133
58
No therapy Total
Women
*Cytotoxic agents, cortisone, uphosphorus, irradiation, and splenectomy (alone or combined). **Ages, 36 to 89 years (mean, 62 years). fAges, 46 to 85 years (mean, 64 years).
CHEST, 75: 2, FEBRUARY, 1979
5
Colon or rectum
MATERIALS AND METHODS
Men
ConcomiPrior to tant with After Therapy * Therapy* Therapy* Total
0
5
8
14
2
7
14
3
3
6
2
2
4
Malignant melanoma
0
2
Breast
0
2
Mycosis fungoides Total
0
9
0
2
2
5
5
11
17
29
55
*Therapy for chronic lymphocytic leukemia.
hoarseness (two patients), and cyanosis (one patient). In the 14 patients with bronchogenic carcinoma, chronic lymphocytic leukemia was diagnosed incidentally in five patients referred for investigation of a coin lesion or pleural effusion found on a routine chest x-ray film. Nine patients who were receiving treatment for chronic lymphocytic leukemia developed radiologic changes in their chest x-ray films, thus demanding further investigation. The types of treatment in the 14 men with bronchogenic carcinoma were as follows: cyclophosphamide (Cytoxan ), prednisone, chlorambucil, and irradiation, one patient; chlorambucil, prednisone, and splenectomy, one patient; radioactive 32phosphorus, one patient; 32phosphorus, prednisone, and chlorambucil, one patient; irradiation alone, one patient; irradiation plus prednisone, one patient; chlorambucil alone, three patients; and no treatment, five patients. In the patients with bronchogenic carcinoma, cytologic study of sputum revealed malignant neoplasm in six patients. Ten patients underwent bronchoscopic examination, with seven having abnormal findings (three patients with intrinsic tumor and four with abnormal bronchial washings). Diagnosis of bronchogenic carcinoma was made before death in ten patients with chronic lymphocytic leukemia. Autopsies revealed four additional cases which had been undetected previously. There were seven cases of squamous cell carcinoma, four cases of small cell (oat cell) carcinoma, and five cases of adenocarcinoma. Three patients had other malignant neoplasms in addition to the bronchogenic carcinoma; one patient had medullary carcinoma of the thyroid gland, the second had basal cell carcinoma of the nose, and the third had adenocarcinoma of the prostate gland.
BRONCHOGENIC CARCINOMA IN CHRONIC LYMPHOCYTIC LEUKEMIA 175
°
There was a time lag of to 48 months (average, nine months) between the time when attention was drawn to the symptoms of bronchogenic carcinoma and its diagnosis, and there was a lag of 19 months from the initial diagnosis of chronic lymphocytic leukemia. Survival after diagnosis ranged from zero to seven years (average, eight months). Four patients underwent pulmonary resection for bronchogenic carcinoma. In these the survival ranged from one month to seven years (average, 33 months). DISCUSSION
Several neoplastic diseases have been reported in association with chronic lymphocytic leukemia.v" Of the 191 patients studied, 14 patients (7 percent) were found to have bronchogenic carcinoma. The reported incidence of bronchogenic carcinoma in the United States in the group aged 60 to 64 years was 160/100,000 in 1974.9 It seems, therefore, that the incidence of bronchogenic carcinoma in patients with chronic lymphocytic leukemia is 11 times higher than in the general population. The average period of observation of our 191 patients was four years; thus, the incidence of bronchogenic carcinoma per year is 14/4 years or 3.5 per 191 patients, which is equivalent to 1,830/100,000. Chronic lymphocytic leukemia was an incidental finding in five patients with diagnosed bronchogenic carcinoma, but in the remaining nine patients, the diagnosis of leukemia preceded that of bronchogenic carcinoma. These patients developed signs and symptoms suggestive of bronchogenic carcinoma at the same time or soon after the diagnosis of chronic lymphocytic leukemia had been made. There was usually a nine-month delay before the accurate diagnosis of bronchogenic carcinoma could be made. In the two cases presented, the symptoms suggestive of bronchogenic carcinoma were present at the time when the diagnosis of leukemia was made. These were erroneously attributed to manifestations of chronic lymphocytic leukemia. This supports the findings of Moertel and Hagedorn: 10 "Any sign or symptoms suggestive of focal malignancy in a patient with leukemia or lymphoma should be regarded as representing a primary lesion until pathologically proved otherwise." Patients with organ transplants who are receiving long-term immunosuppressive therapy have a 5 to 6 percent incidence of new malignant neoplasms within the first few years after transplantation.'! Patients with chronic lymphocytic leukemia are also known to have impaired immunity; 12 they are therefore at a higher risk of developing cancer, as seen in our review of 191 patients. Of the 151 patients who received various forms of antileukemic
178 AMAMOO ET AL
treabnent over an average period of 20 months, only 14 patients (all men) developed bronchogenic carcinoma. In nine cases, these treatments included various combinations of chemotherapy, irradiation, and splenectomy. About a third of these 14 patients (five patients) received no treatment before the diagnosis of bronchogenic carcinoma was made. None of the 58 female patients who received similar antileukemic treatment developed bronchogenic carcinoma. It therefore seems unlikely that the agents used in the treatment of chronic lymphocytic leukemia were the cause or contributed to the development of bronchogenic carcinoma. Good and Catti'" found a high incidence of primary malignant neoplasms in several immunologic deficiency diseases. They reported incidences of 15 percent for lymphoreticulosarcoma in Wiskott-Aldrich syndrome, 10 percent for lymphoma in ataxia-telangiectasia, and 10 percent for acute lymphocytic leukemia in Burton's agammaglobulinemia." In most of these cases abnormalities of T and B lymphocytes were found and predisposed to the development of neoplasms. It is quite conceivable that similar factors present in the patient with chronic lymphocytic leukemia may be responsible for the high incidence of second malignant neoplasms. The overall survival was an average of eight months once bronchogenic carcinoma was diagnosed in this group of patients with chronic lymphocytic leukemia. In the four patients who underwent pulmonary resection for early bronchogenic carcinoma, the average survival was 33 months. These figures on survival are not much different from those in nonleukemic patients with bronchogenic carci-
noma. 14- 16 From these observations, we may conclude the following: (1) the incidence of bronchogenic carcinoma is increased among patients with chronic lymphocytic leukemia; (2) symptoms of bronchogenic carcinoma in patients with chronic lymphocytic leukemia are often overlooked or erroneously attributed to the original disease, causing delay in correct diagnosis; (3) overall survival of the patients with bronchogenic carcinoma and chronic lymphocytic leukemia does not seem to differ much from that of nonleukemic patients; and (4) in patients with chronic lymphocytic leukemia, a high index of suspicion for bronchogenic carcinoma is necessary for its early detection. REFERENCES
1 Whipham T: Splenic leukemia with carcinoma. Trans Pathol Soc London 29:313-319, 1878 2 Benvenisti DS, DeBellis RH: Carcinoma of the breast, chronic lymphocytic leukemia, macroglobulinemia, eosino-
CHEST, 75: 2, FEBRUARY, 1979
3 4
5 6
7 8 9
philic chloroma and myelosclerosis: A unique association. Cancer 23:1204-1209, 1969 Beresford OD: Chronic lymphocytic leukemia associated with malignant diseases. Br J Cancer 6:339-344, 1952 Berg JW: The incidence of multiple primary cancers: 1. The development of further cancers in patients with lymphoma, leukemias, and myeloma. J Nat! Cancer Inst 38:741-752, 1967 Gunz FW, Angus HB: Leukemia and cancer in the same patient. Cancer 18:145-152,1965 Manusow D, Weinerman BH: Subsequent neoplasia in chronic lymphocytic leukemia. JA MA 232:267-269, 1975 Hyman GA: Increased incidence of neoplasia in association with chronic lymphocytic leukemia. Scand J Haematol 6:99-104, 1969 Moayeri H, Han T, Stutzman L, et al: Second neoplasms with chronic lymphocytic leukemia. NY State J Med 76:378-382, 1976 Third National Cancer Survey Incidence Data. (monograph 41). Bethesda, National Cancer Institute, 1975, p 114
CHEST, 75: 2, FEBRUARY, 1979
10 Moertel CG, Hagedorn AB: Leukemia or lymphoma and coexistent primary malignant lesions: A review of the literature and a study of 120 cases. Blood 12:788-803, 1957 11 Stutman 0: Immunodepression and malignancy. Adv Cancer Res 22:261-422, 1975 12 Han T: Studies of correlation of lymphocyte response to phytohemagglutinin with the clinical and immunologic status in chronic lymphocytic leukemia. Cancer 31 :280285, 1973 13 Good R, Gatti R: Immunobiology of Cancer. In Najanian JS, Simmons RL (eds): Transplantation (sec 3). Philadelphia, Lea and Febiger, 1972, p 311 14 Takita H, Brugarolas A, Marabella PC, et al: Small cell carcinoma of the lung: Clinicopathological studies. J Thorac Cardiovasc Surg 66:472-477, 1973 15 Marabella PC, Takita H: Adenocarcinoma of the lung: Clinicopathological study. J Surg Oncol 7 :205-212, 1975 16 Marabella PC, Takita H, Lane WW: Squamous cell carcinoma of the lung: Clinicopathologic study. Chest 71:497-501, 1977
BRONCHOGENIC CARCINOMA IN CHRONIC LYMPHOCYTIC LEUKEMIA 177
