Metastatic Bronchioloalveolar Carcinoma and Metastatic Adenocarcinoma of the Lung: Comparison of Clinical Manifestations, Chemotherapeutic Responses, and Prognosis
EDWARD R. FELDMAN, M.D., * ROBERT T. EAGAN, M.D., Division ofMedical Oncology; DANIEL J. SCHAID, Ph.D., Cancer Center Statistics
Between 1975 and 1985,25 patients with metastatic bronchioloalveolar carcinoma and 223 patients with metastatic adenocarcinoma of the lung received experimental cisplatin-based chemotherapy at the Mayo Clinic. The chemotherapeutic response rates were 32% and 33%, respectively. The median times to progression of disease were identical (3 months in both groups). The median survival times were 4 months and 6 months, respectively. Metastatic bronchioloalveolar carcinoma is an aggressive disease that is associated with a poor prognosis, similar to metastatic adenocarcinoma of the lung.
Bronchioloalveolar carcinoma (BAC) is a controversial clinicopathologic entity. The pathogenesis of BAC is unclear, and the pathologic distinction from adenocarcinoma of the lung (ACA) is arbitrary. Nevertheless, BAC is generally considered a discrete entity. 1 Malassez- first described the solitary and multiple nodular types of BAC in 1876. In 1903, Musser' characterized the pneumonic variant. The antemortem diagnosis and surgical resection of BAC, accomplished in 1936, were subsequently reported by Skorpi1.4 In 1960, Liebow' defined BAC as a well-differentiated adenocarcinoma that originated peripherally in the pulmonary parenchyma, preserved the pulmonary interstitial structure, and disseminated by aerogenic and lymphatic pathways. Currently, the diagnostic criteria are as follows: the presence of no other primary adenocarcinoma, no central bronchial source, no disruption of the pulmonary interstitial structure, and growth of malignant cells lining the alveolar septum."
The cause of BAC is unknown. Commonly, BAC is associated with the formation of pulmonary scars related to tuberculosis, other infections, inflammations, and idiopathic fibrosis. Such formation of scars stimulates epithelial proliferation, which may initiate the malignant transformation.' Jaagsiekte, a contagious disease of sheep, is an interesting animal model" that is characterized initially by proliferation of alveolar cells and eventually by a malignant tumor identical to BAC. A retrovirus is the apparent cause. Transmission from animals to humans has not been demonstrated, but BAC has been detected in patients exposed to infected sheep." Although a virus has not been isolated from a human case, intranuclear inclusions have been noted. 10 The name BAC implies an uncertain origin. Origins from the type II pneumonocyte, Clara cell, and bronchiolar mucous cell have been hypothesized. II Perhaps the cell of origin is a bronchioloalveolar stem cell that is capable of forming the three aforementioned types of cells. 1 The multicentricity of BAC is also poorly understood. The multiple nodular variant of BAC is probably due to aerogenic and lymphatic dissemination.F In damaged lung tissue, multiple tumors may develop concomitantly." Pathologically, BAC may simulate metastatic cancer, particularly pancreatic cancer and other gastrointestinal cancers. Therefore, the presence of another primary adeno-
*Current address: Mercy Memorial Hospital, Monroe, Michigan. Address reprint requests to Dr. R. T. Eagan, Division of Medical Oncology, Mayo Clinic, Rochester, MN 55905. Mayo Clin Proc 67:27-32, 1992
27
28
METASTATIC BRONCmOLOALVEOLAR CARCINOMA
carcinoma must be excluded. BAC may also contain a glandular element morphologically indistinguishable from adenocarcinoma. For accurate identification, ultrastructural studies may be necessary. Although the distinction between HAC and ACA is arbitrary, it may be useful. Occasionally, HAC manifests as a slowly enlarging pulmonary nodule, perhaps suggesting a more indolent disease than other lung cancers. In this study, we compared the clinical manifestations, responses to cisplatin-based chemotherapy, and prognoses associated with metastatic HAC and metastatic ACA. PATIENTS AND METHODS Study Subjects.-Hetween 1975 and 1985,25 patients with metastatic HAC and 223 patients with metastatic ACA received experimental cisplatin-based chemotherapy at the Mayo Clinic. We reviewed the medical records of all these patients. Almost all the diagnoses had been substantiated by biopsy; the other diagnoses had been determined by sputum cytology. The adenocarcinomas were not further subclassified. The pathologic specimens were not reviewed. All the patients are now deceased. Chemotherapeutic Regimens.-"CAP" chemotherapy consisted of cyclophosphamide (400 mg/m-), doxorubicin hydrochloride (Adriamycin) (40 mg/m"), and cisplatin (40 or 60 mg/m') intravenously every 4 weeks. "MAP" chemotherapy consisted of mitomycin (8 mg/nr'), Adriamycin (40 mg/ m-), and cisplatin (60 mg/rrr') intravenously every 4 weeks. "CAPIMCM" chemotherapy consisted of alternating cyclophosphamide (400 mg/m-), Adriamycin (40 mg/m-), and cisplatin (60 mg/m-) intravenously every 8 weeks with mitomycin (7.5 mg/m? intravenously), lomustine [N-(2chloroethyl)-N'-cyclohexyl-N-nitrosourea or CCNU] (40 mg/m? orally), and methotrexate (7.5 mg/m- orally) on days 1, 4, 8, 11, and 15 every 8 weeks. "TCAP" chemotherapy consisted of triazinate (150 mg/nr') on days 1, 2, and 3, cyclophosphamide (400 mg/m-) on day 3, Adriamycin (40 mg/m") on day 2, and cisplatin (20 mg/m/) on days 1,2, and 3 intravenously every 4 weeks. "VCAP" chemotherapy consisted of VP-16 (125 mg/m'), cyclophosphamide (425 mg/m-), Adriamycin (42.5 mg/m-), and cisplatin (40 mg/m-) intravenously every 4 weeks. Previously published criteria for evaluating the response in metastatic lung cancer were applied. 14 Statistical Analyses.-The age distributions of the patients with metastatic HAC and the patients with metastatic ACA were compared with use of the Wilcoxon rank sum test. The distributions of the other patient characteristics, disease characteristics, and chemotherapeutic responses were compared by X2 analysis. If the expected frequencies were small, the distributions were compared by using the Fisher exact test. The distributions of the time to progression
Mayo Clin Proc, January 1992, Vol 67
Table I.-Comparison of Characteristics of Patients With Metastatic Bronchioloalveolar Carcinoma (BAC) and Metastatic Adenocarcinoma of the Lung (ACA) Who Received Cisplatin-Based Chemotherapy at the Mayo Clinic Between 1975 and 1985 Factor
HAC (N = 25)
Gender (%) Male Female
60 40
Age (yr) Median Range
ACA (N = 223)
P
value
66 34 .
0.52
62 43-79
60 33-74
0.12
Weight loss (%) None slO% of body weight > 10% of body weight
44 36 20
50 29 21
0.77
ECOG* performance status (%) 0 1 2 3
16 48 32 4
21 56 20 3
0.20
*Eastem Cooperative Oncology Group.
of disease and the survival time were estimated by the Kaplan-Meier method" and then compared with use of the logrank test. 16 The associations of the clinical variables with the time to progression of disease and the survival time were evaluated by a Cox proportional hazards model. 17 The covariates for the multivariate model were determined by a stepwise forward selection procedure. The clinical variables considered were pathologic condition (HAC versus ACA), age (younger than 60 years versus 60 years or older), gender (male versus female), history of smoking (no versus yes), history of respiratory disease (no versus yes), previous therapy (no versus yes), weight loss (10% or less of total body weight versus more than 10% of total body weight), performance status (Eastern Cooperative Oncology Group stage 0 or 1 versus 2 or 3), and number of secondary sites (one versus more than one). Differences in these variables were considered significant if P values were 0.05 or less. RESULTS In our study group of 25 patients with metastatic HAC and 223 patients with metastatic ACA who had received experimental cisplatin-based chemotherapy, metastatic HAC constituted 10% of the metastatic ACA. In an assessment of the characteristics of the patients with metastatic HAC and those with metastatic ACA, the age and sex distributions were similar (P = 0.12 and P = 0.52, respectively) (Table 1). The
Mayo Clin Proc, January 1992,Vol67
Table 2.-Comparison of Medical History of Patients With Metastatic Bronchioloalveolar Carcinoma (BAC) and Metastatic Adenocarcinoma of the Lung (ACA) Who Received Cisplatin-Based Chemotherapy at the Mayo Clinic Between 1975 and 1985
Table 3.-Previous Treatment in Patients With Metastatic Bronchioloalveolar Carcinoma (BAC) and Metastatic Adenocarcinoma of the Lung (ACA) Who Received Cisplatin-Based Chemotherapy at the Mayo Clinic Between 1975 and 1985
% of patients Historical factor Smoking None ~60 pack-years >60 pack-years Respiratory disease None Obstructive disease Restrictive disease Asbestosis Exposure to tuberculosis or infection
29
METASTATIC BRONCHIOLOALVEOLAR CARCINOMA
BAC (N = 25)
ACA (N = 223)
32 64 4
I7 67 16
72
9 0 0
75 19 2 0.5
12
3
% of patients
p
value
0.09
0.32
weight loss and the performance status were also similar (P = 0.77 and P = 0.20, respectively). In a comparison of medical histories, more patients with metastatic HAC were nonsmokers, and more patients with metastatic ACA were heavy smokers (Table 2). A history of smoking, however, was not a statistically significant factor (P = 0.09). The histories of respiratory disease among patients with HAC and those with ACA were similar (P = 0.32), although the sample may underrepresent the incidence of obstructive disease associated with metastatic ACA. In comparison with the patients who had ACA, more patients with metastatic HAC had undergone previous potentially curative thoracic surgical procedures (Table 3). This finding perhaps reflects the indolent nature of earlier stage disease. The median intervals from operation to the diagnosis of metastatic disease, however, were similar (14 months for metastatic BAC and 11 months for metastatic ACA). More patients with metastatic ACA received no previous therapy, a fact that probably reflects the aggressive nature of the disease. The confounding variables that influence the previous therapies preclude a meaningful statistical analysis. At the time of initiation of the cisplatin-based chemotherapy, the patients with metastatic HAC and the patients with metastatic ACA were rarely asymptomatic (Table 4). Significantly more patients with metastatic HAC produced sputum (P = 0.009); otherwise, the symptoms were similar in the two groups of patients (P~0.20). The extent of disease at the time of initiation of the cisplatin-based chemotherapy in patients with metastatic HAC and those with metastatic ACA is compared in Table 5. Not surprisingly, lung metastatic lesions developed in more patients with metastatic HAC (P = 0.003), whereas pleural
Previous therapy Potentially curative thoracic operation Adjuvant radiation therapy Potentially curative radiation therapy Palliative chemotherapy None
HAC (N = 25)
ACA (N = 223)
44
9 2. 2 5 85
o
4 8 48
metastatic tumors (P = 0.03) and mediastinal nodal metastatic lesions (P = 0.007) developed in more patients with metastatic ACA. The incidences of metastatic involvement of other nodes were similar (P~O.1 0), as were the incidences of hepatic, adrenal, skeletal, and brain metastatic lesions (P~O.lO). Disseminated disease developed in more patients with metastatic ACA (P = 0.04), perhaps an indication of a more aggressive disease. The chemotherapeutic data for both groups of patients (those with metastatic HAC and those with metastatic ACA) are summarized in Table 6. More patients with metastatic HAC received VCAP chemotherapy. The response rates to the chemotherapeutic regimens were similar (data not presented). Cisplatin-based chemotherapy produced minimal morbidity and no mortality. Table 4.-Comparison of Manifestations of Disease in Patients With Metastatic Bronchioloalveolar Carcinoma (BAC) and Metastatic Adenocarcinoma of the Lung (ACA) at Time of Initiation of Cisplatin-Based Chemotherapy at the Mayo Clinic Between 1975 and 1985
% of patients Symptom
HAC (N = 25)
ACA (N = 223)
value
None Production of sputum Cough Dyspnea Chest pain Hemoptysis Skeletal pain Neurologic symptoms Hoarseness Abdominal pain Mass Cutaneous lesion Dysphagia
4 68 60 56 40 16 16 8 0 0 0 0 0
1 39 55 43 42 13 13 15 5 5 4 2 1
0.27 0.009 0.59 0.22 0.87 0.63 0.75 0.55 0.26 0.61 0.60 1.00 1.00
P
30
METASTATIC BRONCHIOLOALVEOLAR CARCINOMA
Table 5.-Comparison of Extent of Disease in Patients With Metastatic Bronchioloalveolar Carcinoma (BAC) and Metastatic Adenocarcinoma of the Lung (ACA) at Time of Initiation of Cisplatln-Based Chemotherapy at the Mayo Clinic Between 1975 and 1985
Mayo Clin Proc, January 1992, Vol 67
Table 6.-Data on Cisplatin-Based Chemotherapy Received at the Mayo Clinic Between 1975 and 1985 by Patients With Metastatic Bronchioloalveolar Carcinoma (BAC) and Metastatic Adenocarcinoma of the Lung (ACA)
% of patients
% of patients
BAC (N =25) Secondary sites Lung Pleura Pericardium Hilar nodes Mediastinal nodes Supraclavicular nodes Other peripheral nodes Retroperitoneal nodes Liver Spleen Kidneys Adrenal gland Skin Skeleton Brain Number of secondary sites One More than one
72
8
o
4 4 20 4 4 4
o o
ACA (N =223)
29 28 5 17 28 25 6 4
10
OA
28 8
0.4 7 7 36 15
60 40
39 61
16
o
P value 0.003 0.03 0.61 0.14 0.007 0.81 0.65 1.00
OA8
1.00 1.00 0.11 0.38 0.51 0.55 0.04
The chemotherapeutic response rates were similar in patients with metastatic BAC and those with metastatic ACA (P = 0.94) (Table 7). Of the patients with metastatic BAC, 32% achieved a partial remission, and no patient achieved a complete remission. The corresponding findings in patients with metastatic ACA were 31% and 2%. All sites of disease involvement responded occasionally, but no site was particularly sensitive. The lung lesions of metastatic BAC and metastatic ACA apparently responded similarly, although the incomplete data precluded a meaningful statistical analysis. The durations of response were also similar. The median duration of response was 4 months for metastatic BAC and 5 months for metastatic ACA. For the five patients with metastatic ACA who achieved a complete remission, the median duration of response was 11 months (range, 7 to 24 months). The times to progression of disease were similar in the two groups of patients (p:=: 0.77) (Fig. 1). The median time to progression of metastatic BAC was 3 months (range, 1 to 25 months). The median time to progression of metastatic ACA was also 3 months (range, 0 to 44 months). For the five patients with metastatic ACA who achieved a complete remission, the median time to progression of ACA was 12 months (range, 8 to 25 months). The following factors were associated with a prolonged time to progression of disease:
Chemotherapy Regimen* CAP MAP CAPIMCM TCAP VCAP Toxic effects None Nadir leukocyte count :;;1,000/mm3 Vomiting that necessitated discontinuation of chemotherapy Neutropenic sepsis Nadir platelet count :;;20,000/mm3 Severe hemorrhage Death
BAC (N = 25)
ACA (N = 223)
40 8 4 24 24
51 13 17 13 6
88 8
85 9
4 4 0 0 0
4 0.5 4 0 0
*CAP =cyclophosphamide, doxorubicin hydrochloride (Adriamycin), and cisplatin; MAP = mitomycin, Adriamycin, and cisplatin; CAPIMCM = alternating cyclophosphamide, Adriamycin, and cisplatin with mitomycin, lomustine [N-(2-chloroethyl)-N'-cyclohexyl-V-nitrosourea or CCNU], and methotrexate; TCAP = triazinate, cyclophosphamide, Adriamycin, and cisplatin; VCAP = VP-16, cyclophosphamide, Adriamycin, and cisplatin. See text for specific dosages.
age 60 years or older (P :=: 0.007), female sex (P = 0.02), no history of respiratory disease (P = 0.02), weight loss of 10% or less oftotal body weight (P = 0.03), and only one secondary site of disease (P = 0.005). When the statistical comparison was adjusted for the significant covariates, the times to progression of disease were still similar (P :=: 0.95). The survival times of patients with metastatic BAC and those with metastatic AcA were also similar (P:=: 0.64) (Fig. 2). For patients with metastatic BAC, the median survival time was 4 months (range, 1 to 51 months). For patients with metastatic ACA, the median survival time was 6 months (range, 0 to 107 months). For the five patients with metastatic ACA who achieved a complete remission, the median survival time was 26 months (range, 12 to 107 months). Weight loss of 10% or less of total body weight (P = 0.001) and only one secondary site of disease (P = 0.004) were factors associated with a prolonged survival time. When the statistical comparison was adjusted for the significant covariates, the survival times were still similar (P = 0.62). The 2-year survival was 8.0% for patients with metastatic BAC and 8.5% for those with metastatic ACA. Only one patient
Mayo CUn Proc,January 1992, Vol 67
METASTATIC BRONCHIOLOALVEOLAR CARCINOMA
Table 7.-Responses in Patients With Metastatic Bronchioloalveolar Carcinoma (BAC) and Metastatic Adenocarcinoma of the Lung (ACA) to Cisplatin-Based Chemotherapy Received at the Mayo Clinic Between 1975 and 1985 Chemotherapeutic outcome
BAC (N = 25) % No.
31
!! i5
ACA (N = 223) No. %
~,
r
BAC ACA
iil
25
PATIENTS
223 PATIENTS
0
~
z
Rate of response Partial Complete Site of response Lung* Pleura Lymphnodes Liver Skin Skeleton Duration of response (mo) Median Range
8 0
32
6/25 1/2 0/8 1/1
24 50 100
2/7
29
69 5
31 2
58/223 5/62 14/113 2/22 1/16 3/81
26 8 12 9 6 4
4 1-23
5t 1-24
*Primary and secondary lesions. t In nine patients, the duration of response was unknown.
with metastatic ACA (0.4%) who achieved a complete remission survived more than 5 years.
DISCUSSION More than 1,000 cases of BAC have been reported in the literature." BAC constitutes about 4% oflung cancers'? and about 15% of ACA,20 The sex distribution for BAC is more equal than for the other lung cancers; the male:female ratio is approximately 3:2. Patients with BAC may be slightly older than those with other lung cancers. The peak incidence is in the sixth and seventh decades of life. Smoking may be a pathogenetic factor, although smokers and nonsmokers have a similar incidence.'? A history of respiratory disease is common, and BAC is often associated with formation of pulmonary scars. At the time of initial assessment, approximately 60% of patients with BAC are asymptomatic. About 70% of asymptomatic patients have pathologic stage I disease. The 5-year survival for patients with pathologic stage I disease is about 75%. Approximately 65% of symptomatic patients have stage III or IV disease. The 5-year survival for patients with stage IV disease is about 8%.19 Earlier reports suggested that metastatic BAC is resistant to radiation therapy and chemotherapy.i-" Only symptomatic and supportive care was recommended. A more recent report suggested that metastatic BAC may have a more favorable chemotherapeutic response than the other variants of adenocarcinoma." Cisplatin, however, was not a compo-
'-l
_.- .... 0.0
0.5
1.0
_._._._._. _._-_._._.-..,....._._._._.
1.5
2.5
2.0
3.0
Years from Randomization
Fig. 1. Time to progressionof disease in patients with metastatic bronchioloalveolar carcinoma (BAC) and patients with metastatic adenocarcinoma of the lung (ACA), all of whom had received cisplatin-based chemotherapy at the MayoClinicbetween1975and 1985. nent of the chemotherapeutic regimen that was used, the sample was small, and the difference in survival was not statistically significant. The current study shows that metastatic BAC and metastatic ACA have similar clinical manifestations, chemotherapeutic responses, and poor prognoses. Among our study subjects, more patients with metastatic BAC had production of sputum and development of metastatic lesions in the lung. In contrast, pleural metastatic tumors, mediastinal nodal metastatic lesions, and disseminated disease developed more
!! i5
:[ s
BAC ACA
25 PATIENTS 223 PATIENTS
V)
~
8'
~
~
0.0
0.5
1.0
1.5
2.0
2.5
3.0
Yearsfrom Randomization
Fig. 2. Survivaltime of patientswith metastatic bronchioloalveolar carcinoma (BAC) and patients with metastatic adenocarcinoma of the lung (ACA), all of whom had received cisplatin-based chemotherapy at the Mayo Clinic between 1975and 1985.
32
frequently in patients with metastatic ACA. Otherwise, the patient and disease characteristics were similar in the two groups. The overall chemotherapeutic response rates were 32% for metastatic BAC and 33% for metastatic ACA. The responses were usually limited. The median time to progression of disease was 3 months for both metastatic BAC and metastatic ACA. The median survival times were 4 months for metastatic BAC and 6 months for metastatic ACA. Weight loss of 10% or less of total body weight and only one secondary site of disease were factors associated with a prolonged survival time. Unfortunately, 2-year survival was uncommon, and 5-year survival was rare. CONCLUSION Although early-stage BAC may be an indolent disease that is associated with a relatively good prognosis, metastatic BAC is an aggressive disease that is associated with a poor prognosis, similar to metastatic ACA. REFERENCES 1.
Mayo Clin Proc, January 1992, Vol 67
MET ASTATIC BRONCHIOLOALVEOLAR CARCINOMA
Edwards CW: Alveolar carcinoma: a review. Thorax 39:166-174,1984 2. Malassez L: Examen histologique d'un cas de cancer encephaloide du poumon (epithelioma). Arch Physiol Norm Pathol 3:353-372, 1876 3. Musser JH: Primary cancer of the lung. Trans Assoc Am Physicians 18:625-636, 1903 4. Skorpil F: Beitrag zur Pathologie und Histologie des Alveolarepithelcarcinoms. Frankfurter Z Pathol 55:347-363, 1941 5. Liebow AA: Bronchiole-alveolar carcinoma. Adv Intern Med 10:329-358, 1960 6. Schraufnagel D, Poloquin A, Pare JAP, Wang N-S: Differentiating bronchioloalveolar carcinoma from adenocarcinoma. Am Rev Respir Dis 125:74-79,1982 7. Meyer EC, Liebow AA: Relationship of interstitial pneumonia honeycombing and atypical epithelial proliferation to cancer of the lung. Cancer 18:322-351, 1965 8. Nobel TA, Perk K: Bronchiolo-alveolar cell carcinoma. Am J Pathol 90:783-786, 1978
9. 10.
11. 12. 13. 14. 15. 16. 17. 18. 19. 20.
21. 22. 23.
Heimann HL, Samuel E: Pulmonary adenomatosis: case report. S Afr Med J 27:934-935, 1953 Stinson JC, Leibovitz A, Brindley GV Jr, Hayward RH, Turner RA, McCombs WB III: Filamentous particles in human alveolar carcinomas: electron microscopy studies of six cases (preliminary report). J Nat! Cancer Inst 49:14831487, 1972 Greenberg SD, Smith MN, Spjut HJ: Bronchiolo-alveolar carcinoma-eell of origin. Am J Clin Pathol 63:153-167, 1975 Storey CF, Knudtson KP, Lawrence BJ: Bronchiolar ("alveolar cell") carcinoma of the lung. J Thorac Surg 26:331-403, 1953 Fraire AE, Greenberg SD: Carcinoma and diffuse interstitial fibrosis of lung. Cancer 31: 1078-1086, 1973 Eagan RT, Fleming TR, Schoonover V: Evaluation of response criteria in advanced lung cancer. Cancer 44:11251128, 1979 Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958 Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50:163-170,1966 Cox DR: Regression models and life-tables (with discussion). J R Stat Soc [B] 34:187-220, 1972 Edgerton F, Rao D, Takita H, Vincent RG: Bronchio-alveolar carcinoma: a clinical overview and bibliography. Oncology 38:269-273, 1981 Greco RJ, Steiner RM, Goldman S, Cotler H, Patchefsky A, Cohn HE: Bronchoalveolar cell carcinoma of the lung. Ann Thorac Surg 41:652-656, 1986 Grover FL, Piantadosi S, Lung Cancer Study Group: Recurrence and survival following resection of bronchioloalveolar carcinoma of the lung-the Lung Cancer Study Group experience. Ann Surg 209:779-790, 1989 Delarue NC, Anderson W, Sanders D, Starr J: Bronchioloalveolar carcinoma: a reappraisal after 24 years. Cancer 29:90-97, 1972 Ludington LG, Verska Jf, Howard T, Kypridakis G, Brewer LA III: Bronchiolar carcinoma (alveolar cell), another great imitator: a review of 41 cases. Chest 61:622-628, 1972 Serensen JB, Hirsch FR, Olsen J: The prognostic implication of histopathologic subtyping of pulmonary adenocarcinoma according to the classification of the World Health Organization: an analysis of 259 consecutive patients with advanced disease. Cancer 62:361-367,1988
EDWARD R. FELDMAN, M.D., * ROBERT T. EAGAN, M.D., Division ofMedical Oncology; DANIEL J. SCHAID, Ph.D., Cancer Center Statistics
Between 1975 and 1985,25 patients with metastatic bronchioloalveolar carcinoma and 223 patients with metastatic adenocarcinoma of the lung received experimental cisplatin-based chemotherapy at the Mayo Clinic. The chemotherapeutic response rates were 32% and 33%, respectively. The median times to progression of disease were identical (3 months in both groups). The median survival times were 4 months and 6 months, respectively. Metastatic bronchioloalveolar carcinoma is an aggressive disease that is associated with a poor prognosis, similar to metastatic adenocarcinoma of the lung.
Bronchioloalveolar carcinoma (BAC) is a controversial clinicopathologic entity. The pathogenesis of BAC is unclear, and the pathologic distinction from adenocarcinoma of the lung (ACA) is arbitrary. Nevertheless, BAC is generally considered a discrete entity. 1 Malassez- first described the solitary and multiple nodular types of BAC in 1876. In 1903, Musser' characterized the pneumonic variant. The antemortem diagnosis and surgical resection of BAC, accomplished in 1936, were subsequently reported by Skorpi1.4 In 1960, Liebow' defined BAC as a well-differentiated adenocarcinoma that originated peripherally in the pulmonary parenchyma, preserved the pulmonary interstitial structure, and disseminated by aerogenic and lymphatic pathways. Currently, the diagnostic criteria are as follows: the presence of no other primary adenocarcinoma, no central bronchial source, no disruption of the pulmonary interstitial structure, and growth of malignant cells lining the alveolar septum."
The cause of BAC is unknown. Commonly, BAC is associated with the formation of pulmonary scars related to tuberculosis, other infections, inflammations, and idiopathic fibrosis. Such formation of scars stimulates epithelial proliferation, which may initiate the malignant transformation.' Jaagsiekte, a contagious disease of sheep, is an interesting animal model" that is characterized initially by proliferation of alveolar cells and eventually by a malignant tumor identical to BAC. A retrovirus is the apparent cause. Transmission from animals to humans has not been demonstrated, but BAC has been detected in patients exposed to infected sheep." Although a virus has not been isolated from a human case, intranuclear inclusions have been noted. 10 The name BAC implies an uncertain origin. Origins from the type II pneumonocyte, Clara cell, and bronchiolar mucous cell have been hypothesized. II Perhaps the cell of origin is a bronchioloalveolar stem cell that is capable of forming the three aforementioned types of cells. 1 The multicentricity of BAC is also poorly understood. The multiple nodular variant of BAC is probably due to aerogenic and lymphatic dissemination.F In damaged lung tissue, multiple tumors may develop concomitantly." Pathologically, BAC may simulate metastatic cancer, particularly pancreatic cancer and other gastrointestinal cancers. Therefore, the presence of another primary adeno-
*Current address: Mercy Memorial Hospital, Monroe, Michigan. Address reprint requests to Dr. R. T. Eagan, Division of Medical Oncology, Mayo Clinic, Rochester, MN 55905. Mayo Clin Proc 67:27-32, 1992
27
28
METASTATIC BRONCmOLOALVEOLAR CARCINOMA
carcinoma must be excluded. BAC may also contain a glandular element morphologically indistinguishable from adenocarcinoma. For accurate identification, ultrastructural studies may be necessary. Although the distinction between HAC and ACA is arbitrary, it may be useful. Occasionally, HAC manifests as a slowly enlarging pulmonary nodule, perhaps suggesting a more indolent disease than other lung cancers. In this study, we compared the clinical manifestations, responses to cisplatin-based chemotherapy, and prognoses associated with metastatic HAC and metastatic ACA. PATIENTS AND METHODS Study Subjects.-Hetween 1975 and 1985,25 patients with metastatic HAC and 223 patients with metastatic ACA received experimental cisplatin-based chemotherapy at the Mayo Clinic. We reviewed the medical records of all these patients. Almost all the diagnoses had been substantiated by biopsy; the other diagnoses had been determined by sputum cytology. The adenocarcinomas were not further subclassified. The pathologic specimens were not reviewed. All the patients are now deceased. Chemotherapeutic Regimens.-"CAP" chemotherapy consisted of cyclophosphamide (400 mg/m-), doxorubicin hydrochloride (Adriamycin) (40 mg/m"), and cisplatin (40 or 60 mg/m') intravenously every 4 weeks. "MAP" chemotherapy consisted of mitomycin (8 mg/nr'), Adriamycin (40 mg/ m-), and cisplatin (60 mg/rrr') intravenously every 4 weeks. "CAPIMCM" chemotherapy consisted of alternating cyclophosphamide (400 mg/m-), Adriamycin (40 mg/m-), and cisplatin (60 mg/m-) intravenously every 8 weeks with mitomycin (7.5 mg/m? intravenously), lomustine [N-(2chloroethyl)-N'-cyclohexyl-N-nitrosourea or CCNU] (40 mg/m? orally), and methotrexate (7.5 mg/m- orally) on days 1, 4, 8, 11, and 15 every 8 weeks. "TCAP" chemotherapy consisted of triazinate (150 mg/nr') on days 1, 2, and 3, cyclophosphamide (400 mg/m-) on day 3, Adriamycin (40 mg/m") on day 2, and cisplatin (20 mg/m/) on days 1,2, and 3 intravenously every 4 weeks. "VCAP" chemotherapy consisted of VP-16 (125 mg/m'), cyclophosphamide (425 mg/m-), Adriamycin (42.5 mg/m-), and cisplatin (40 mg/m-) intravenously every 4 weeks. Previously published criteria for evaluating the response in metastatic lung cancer were applied. 14 Statistical Analyses.-The age distributions of the patients with metastatic HAC and the patients with metastatic ACA were compared with use of the Wilcoxon rank sum test. The distributions of the other patient characteristics, disease characteristics, and chemotherapeutic responses were compared by X2 analysis. If the expected frequencies were small, the distributions were compared by using the Fisher exact test. The distributions of the time to progression
Mayo Clin Proc, January 1992, Vol 67
Table I.-Comparison of Characteristics of Patients With Metastatic Bronchioloalveolar Carcinoma (BAC) and Metastatic Adenocarcinoma of the Lung (ACA) Who Received Cisplatin-Based Chemotherapy at the Mayo Clinic Between 1975 and 1985 Factor
HAC (N = 25)
Gender (%) Male Female
60 40
Age (yr) Median Range
ACA (N = 223)
P
value
66 34 .
0.52
62 43-79
60 33-74
0.12
Weight loss (%) None slO% of body weight > 10% of body weight
44 36 20
50 29 21
0.77
ECOG* performance status (%) 0 1 2 3
16 48 32 4
21 56 20 3
0.20
*Eastem Cooperative Oncology Group.
of disease and the survival time were estimated by the Kaplan-Meier method" and then compared with use of the logrank test. 16 The associations of the clinical variables with the time to progression of disease and the survival time were evaluated by a Cox proportional hazards model. 17 The covariates for the multivariate model were determined by a stepwise forward selection procedure. The clinical variables considered were pathologic condition (HAC versus ACA), age (younger than 60 years versus 60 years or older), gender (male versus female), history of smoking (no versus yes), history of respiratory disease (no versus yes), previous therapy (no versus yes), weight loss (10% or less of total body weight versus more than 10% of total body weight), performance status (Eastern Cooperative Oncology Group stage 0 or 1 versus 2 or 3), and number of secondary sites (one versus more than one). Differences in these variables were considered significant if P values were 0.05 or less. RESULTS In our study group of 25 patients with metastatic HAC and 223 patients with metastatic ACA who had received experimental cisplatin-based chemotherapy, metastatic HAC constituted 10% of the metastatic ACA. In an assessment of the characteristics of the patients with metastatic HAC and those with metastatic ACA, the age and sex distributions were similar (P = 0.12 and P = 0.52, respectively) (Table 1). The
Mayo Clin Proc, January 1992,Vol67
Table 2.-Comparison of Medical History of Patients With Metastatic Bronchioloalveolar Carcinoma (BAC) and Metastatic Adenocarcinoma of the Lung (ACA) Who Received Cisplatin-Based Chemotherapy at the Mayo Clinic Between 1975 and 1985
Table 3.-Previous Treatment in Patients With Metastatic Bronchioloalveolar Carcinoma (BAC) and Metastatic Adenocarcinoma of the Lung (ACA) Who Received Cisplatin-Based Chemotherapy at the Mayo Clinic Between 1975 and 1985
% of patients Historical factor Smoking None ~60 pack-years >60 pack-years Respiratory disease None Obstructive disease Restrictive disease Asbestosis Exposure to tuberculosis or infection
29
METASTATIC BRONCHIOLOALVEOLAR CARCINOMA
BAC (N = 25)
ACA (N = 223)
32 64 4
I7 67 16
72
9 0 0
75 19 2 0.5
12
3
% of patients
p
value
0.09
0.32
weight loss and the performance status were also similar (P = 0.77 and P = 0.20, respectively). In a comparison of medical histories, more patients with metastatic HAC were nonsmokers, and more patients with metastatic ACA were heavy smokers (Table 2). A history of smoking, however, was not a statistically significant factor (P = 0.09). The histories of respiratory disease among patients with HAC and those with ACA were similar (P = 0.32), although the sample may underrepresent the incidence of obstructive disease associated with metastatic ACA. In comparison with the patients who had ACA, more patients with metastatic HAC had undergone previous potentially curative thoracic surgical procedures (Table 3). This finding perhaps reflects the indolent nature of earlier stage disease. The median intervals from operation to the diagnosis of metastatic disease, however, were similar (14 months for metastatic BAC and 11 months for metastatic ACA). More patients with metastatic ACA received no previous therapy, a fact that probably reflects the aggressive nature of the disease. The confounding variables that influence the previous therapies preclude a meaningful statistical analysis. At the time of initiation of the cisplatin-based chemotherapy, the patients with metastatic HAC and the patients with metastatic ACA were rarely asymptomatic (Table 4). Significantly more patients with metastatic HAC produced sputum (P = 0.009); otherwise, the symptoms were similar in the two groups of patients (P~0.20). The extent of disease at the time of initiation of the cisplatin-based chemotherapy in patients with metastatic HAC and those with metastatic ACA is compared in Table 5. Not surprisingly, lung metastatic lesions developed in more patients with metastatic HAC (P = 0.003), whereas pleural
Previous therapy Potentially curative thoracic operation Adjuvant radiation therapy Potentially curative radiation therapy Palliative chemotherapy None
HAC (N = 25)
ACA (N = 223)
44
9 2. 2 5 85
o
4 8 48
metastatic tumors (P = 0.03) and mediastinal nodal metastatic lesions (P = 0.007) developed in more patients with metastatic ACA. The incidences of metastatic involvement of other nodes were similar (P~O.1 0), as were the incidences of hepatic, adrenal, skeletal, and brain metastatic lesions (P~O.lO). Disseminated disease developed in more patients with metastatic ACA (P = 0.04), perhaps an indication of a more aggressive disease. The chemotherapeutic data for both groups of patients (those with metastatic HAC and those with metastatic ACA) are summarized in Table 6. More patients with metastatic HAC received VCAP chemotherapy. The response rates to the chemotherapeutic regimens were similar (data not presented). Cisplatin-based chemotherapy produced minimal morbidity and no mortality. Table 4.-Comparison of Manifestations of Disease in Patients With Metastatic Bronchioloalveolar Carcinoma (BAC) and Metastatic Adenocarcinoma of the Lung (ACA) at Time of Initiation of Cisplatin-Based Chemotherapy at the Mayo Clinic Between 1975 and 1985
% of patients Symptom
HAC (N = 25)
ACA (N = 223)
value
None Production of sputum Cough Dyspnea Chest pain Hemoptysis Skeletal pain Neurologic symptoms Hoarseness Abdominal pain Mass Cutaneous lesion Dysphagia
4 68 60 56 40 16 16 8 0 0 0 0 0
1 39 55 43 42 13 13 15 5 5 4 2 1
0.27 0.009 0.59 0.22 0.87 0.63 0.75 0.55 0.26 0.61 0.60 1.00 1.00
P
30
METASTATIC BRONCHIOLOALVEOLAR CARCINOMA
Table 5.-Comparison of Extent of Disease in Patients With Metastatic Bronchioloalveolar Carcinoma (BAC) and Metastatic Adenocarcinoma of the Lung (ACA) at Time of Initiation of Cisplatln-Based Chemotherapy at the Mayo Clinic Between 1975 and 1985
Mayo Clin Proc, January 1992, Vol 67
Table 6.-Data on Cisplatin-Based Chemotherapy Received at the Mayo Clinic Between 1975 and 1985 by Patients With Metastatic Bronchioloalveolar Carcinoma (BAC) and Metastatic Adenocarcinoma of the Lung (ACA)
% of patients
% of patients
BAC (N =25) Secondary sites Lung Pleura Pericardium Hilar nodes Mediastinal nodes Supraclavicular nodes Other peripheral nodes Retroperitoneal nodes Liver Spleen Kidneys Adrenal gland Skin Skeleton Brain Number of secondary sites One More than one
72
8
o
4 4 20 4 4 4
o o
ACA (N =223)
29 28 5 17 28 25 6 4
10
OA
28 8
0.4 7 7 36 15
60 40
39 61
16
o
P value 0.003 0.03 0.61 0.14 0.007 0.81 0.65 1.00
OA8
1.00 1.00 0.11 0.38 0.51 0.55 0.04
The chemotherapeutic response rates were similar in patients with metastatic BAC and those with metastatic ACA (P = 0.94) (Table 7). Of the patients with metastatic BAC, 32% achieved a partial remission, and no patient achieved a complete remission. The corresponding findings in patients with metastatic ACA were 31% and 2%. All sites of disease involvement responded occasionally, but no site was particularly sensitive. The lung lesions of metastatic BAC and metastatic ACA apparently responded similarly, although the incomplete data precluded a meaningful statistical analysis. The durations of response were also similar. The median duration of response was 4 months for metastatic BAC and 5 months for metastatic ACA. For the five patients with metastatic ACA who achieved a complete remission, the median duration of response was 11 months (range, 7 to 24 months). The times to progression of disease were similar in the two groups of patients (p:=: 0.77) (Fig. 1). The median time to progression of metastatic BAC was 3 months (range, 1 to 25 months). The median time to progression of metastatic ACA was also 3 months (range, 0 to 44 months). For the five patients with metastatic ACA who achieved a complete remission, the median time to progression of ACA was 12 months (range, 8 to 25 months). The following factors were associated with a prolonged time to progression of disease:
Chemotherapy Regimen* CAP MAP CAPIMCM TCAP VCAP Toxic effects None Nadir leukocyte count :;;1,000/mm3 Vomiting that necessitated discontinuation of chemotherapy Neutropenic sepsis Nadir platelet count :;;20,000/mm3 Severe hemorrhage Death
BAC (N = 25)
ACA (N = 223)
40 8 4 24 24
51 13 17 13 6
88 8
85 9
4 4 0 0 0
4 0.5 4 0 0
*CAP =cyclophosphamide, doxorubicin hydrochloride (Adriamycin), and cisplatin; MAP = mitomycin, Adriamycin, and cisplatin; CAPIMCM = alternating cyclophosphamide, Adriamycin, and cisplatin with mitomycin, lomustine [N-(2-chloroethyl)-N'-cyclohexyl-V-nitrosourea or CCNU], and methotrexate; TCAP = triazinate, cyclophosphamide, Adriamycin, and cisplatin; VCAP = VP-16, cyclophosphamide, Adriamycin, and cisplatin. See text for specific dosages.
age 60 years or older (P :=: 0.007), female sex (P = 0.02), no history of respiratory disease (P = 0.02), weight loss of 10% or less oftotal body weight (P = 0.03), and only one secondary site of disease (P = 0.005). When the statistical comparison was adjusted for the significant covariates, the times to progression of disease were still similar (P :=: 0.95). The survival times of patients with metastatic BAC and those with metastatic AcA were also similar (P:=: 0.64) (Fig. 2). For patients with metastatic BAC, the median survival time was 4 months (range, 1 to 51 months). For patients with metastatic ACA, the median survival time was 6 months (range, 0 to 107 months). For the five patients with metastatic ACA who achieved a complete remission, the median survival time was 26 months (range, 12 to 107 months). Weight loss of 10% or less of total body weight (P = 0.001) and only one secondary site of disease (P = 0.004) were factors associated with a prolonged survival time. When the statistical comparison was adjusted for the significant covariates, the survival times were still similar (P = 0.62). The 2-year survival was 8.0% for patients with metastatic BAC and 8.5% for those with metastatic ACA. Only one patient
Mayo CUn Proc,January 1992, Vol 67
METASTATIC BRONCHIOLOALVEOLAR CARCINOMA
Table 7.-Responses in Patients With Metastatic Bronchioloalveolar Carcinoma (BAC) and Metastatic Adenocarcinoma of the Lung (ACA) to Cisplatin-Based Chemotherapy Received at the Mayo Clinic Between 1975 and 1985 Chemotherapeutic outcome
BAC (N = 25) % No.
31
!! i5
ACA (N = 223) No. %
~,
r
BAC ACA
iil
25
PATIENTS
223 PATIENTS
0
~
z
Rate of response Partial Complete Site of response Lung* Pleura Lymphnodes Liver Skin Skeleton Duration of response (mo) Median Range
8 0
32
6/25 1/2 0/8 1/1
24 50 100
2/7
29
69 5
31 2
58/223 5/62 14/113 2/22 1/16 3/81
26 8 12 9 6 4
4 1-23
5t 1-24
*Primary and secondary lesions. t In nine patients, the duration of response was unknown.
with metastatic ACA (0.4%) who achieved a complete remission survived more than 5 years.
DISCUSSION More than 1,000 cases of BAC have been reported in the literature." BAC constitutes about 4% oflung cancers'? and about 15% of ACA,20 The sex distribution for BAC is more equal than for the other lung cancers; the male:female ratio is approximately 3:2. Patients with BAC may be slightly older than those with other lung cancers. The peak incidence is in the sixth and seventh decades of life. Smoking may be a pathogenetic factor, although smokers and nonsmokers have a similar incidence.'? A history of respiratory disease is common, and BAC is often associated with formation of pulmonary scars. At the time of initial assessment, approximately 60% of patients with BAC are asymptomatic. About 70% of asymptomatic patients have pathologic stage I disease. The 5-year survival for patients with pathologic stage I disease is about 75%. Approximately 65% of symptomatic patients have stage III or IV disease. The 5-year survival for patients with stage IV disease is about 8%.19 Earlier reports suggested that metastatic BAC is resistant to radiation therapy and chemotherapy.i-" Only symptomatic and supportive care was recommended. A more recent report suggested that metastatic BAC may have a more favorable chemotherapeutic response than the other variants of adenocarcinoma." Cisplatin, however, was not a compo-
'-l
_.- .... 0.0
0.5
1.0
_._._._._. _._-_._._.-..,....._._._._.
1.5
2.5
2.0
3.0
Years from Randomization
Fig. 1. Time to progressionof disease in patients with metastatic bronchioloalveolar carcinoma (BAC) and patients with metastatic adenocarcinoma of the lung (ACA), all of whom had received cisplatin-based chemotherapy at the MayoClinicbetween1975and 1985. nent of the chemotherapeutic regimen that was used, the sample was small, and the difference in survival was not statistically significant. The current study shows that metastatic BAC and metastatic ACA have similar clinical manifestations, chemotherapeutic responses, and poor prognoses. Among our study subjects, more patients with metastatic BAC had production of sputum and development of metastatic lesions in the lung. In contrast, pleural metastatic tumors, mediastinal nodal metastatic lesions, and disseminated disease developed more
!! i5
:[ s
BAC ACA
25 PATIENTS 223 PATIENTS
V)
~
8'
~
~
0.0
0.5
1.0
1.5
2.0
2.5
3.0
Yearsfrom Randomization
Fig. 2. Survivaltime of patientswith metastatic bronchioloalveolar carcinoma (BAC) and patients with metastatic adenocarcinoma of the lung (ACA), all of whom had received cisplatin-based chemotherapy at the Mayo Clinic between 1975and 1985.
32
frequently in patients with metastatic ACA. Otherwise, the patient and disease characteristics were similar in the two groups. The overall chemotherapeutic response rates were 32% for metastatic BAC and 33% for metastatic ACA. The responses were usually limited. The median time to progression of disease was 3 months for both metastatic BAC and metastatic ACA. The median survival times were 4 months for metastatic BAC and 6 months for metastatic ACA. Weight loss of 10% or less of total body weight and only one secondary site of disease were factors associated with a prolonged survival time. Unfortunately, 2-year survival was uncommon, and 5-year survival was rare. CONCLUSION Although early-stage BAC may be an indolent disease that is associated with a relatively good prognosis, metastatic BAC is an aggressive disease that is associated with a poor prognosis, similar to metastatic ACA. REFERENCES 1.
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MET ASTATIC BRONCHIOLOALVEOLAR CARCINOMA
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