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(Chest. 2003;123:1868-1877.)
© 2003 American College of Chest Physicians

Clinical Characteristics of Pneumonic-Type Adenocarcinoma of the Lung*

Marie Wislez, MD; Marie-Ange Massiani, MD; Bernard Milleron, MD, FCCP; Abdelkader Souidi, MD; Marie-France Carette, MD; Martine Antoine, MD and Jacques Cadranel, MD, PhD

* From Laboratoire de Biologie Cellulaire et d’Immunopathologie Pulmonaire (Drs. Wislez, Milleron, and Cadranel), UPRES EA 3493, Université Paris VI, UFR Saint-Antoine, Paris; and Services de Pneumologie et de Réanimation Respiratoire (Dr. Massiani and Souidi), et de Radiologie (Dr. Carette), et d’Anatomie Pathologique (Dr. Antoine), AP-HP, Hôpital Tenon, Paris, France.

Correspondence to: Jacques Cadranel, MD, PhD, Service de Pneumologie et de Réanimation Respiratoire, Hôpital Tenon, 4 rue de la chine, 75020 Paris, France; e-mail: jacques.cadranel{at}tnn.ap-hop-paris.fr


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Purpose: To analyze diagnostic approaches, survival predictors, and treatment efficacy in pneumonic-type adenocarcinoma (P-ADC).

Patients and methods: Fifty-two patients with P-ADC diagnosed between January 1986 and December 2000 were studied. P-ADC was defined as histologically or cytologically proven pulmonary adenocarcinoma with a pneumonia-like consolidation, in a patient with no prior diagnosis of thoracic or extrathoracic adenocarcinoma.

Results: Sixty percent of the patients were men (n = 31), and 65% (n = 34) were current or former smokers. Mean (± SD) age at diagnosis was 66 ± 1.4 years. P-ADC was diagnosed by routine chest radiography in 17% of cases (n = 9). Bronchorrhea was present in 31% of cases (n = 16), and crepitant rales in 58% (n = 30). The primary tumor appeared as consolidations, which could not be assessed and were thus classified Tx, in 83% of the patients (n = 43). Ten percent of the patients (n = 5) had a satellite tumor within the lobe containing the primary tumor (T4), and 63% (n = 33) had a satellite tumor in another lobe (M1). Extrathoracic metastases were present in 5% of cases (n = 3). Bronchial biopsy, transbronchial biopsy, bronchial aspiration, and BAL were positive in 21%, 80%, 44%, and 66% of cases, respectively. The median survival time after diagnosis was 10.5 months (range, 1 to 150 months). The outcome of patients treated by lobectomy or bilobectomy was significantly better than that of patients treated with pneumonectomy, chemotherapy, or best supportive care (p < 0.01). Bronchorrhea and crepitant rales were independent predictors of shorter survival when the treatment modality (surgery vs no surgery) was not entered as a risk factor.

Conclusions: P-ADC is characterized by aerogenous propagation, as emphasized by the results of multivariate analysis showing that bronchorrhea and crepitant rales were the only two independent factors of shorter survival. Surgery remains the most effective treatment in P-ADC, especially when lobectomy is feasible. As CT is not sensitive enough to detect multifocal lesions, new tools are required to evaluate pulmonary involvement and thereby to refine the surgical strategy.

Key Words: adenocarcinoma • aerogenous progression • consolidation


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Lung cancer is the most common fatal malignancy worldwide. Approximately 80 to 90% of cases involve non-small cell carcinoma. Non-small cell carcinoma is subdivided into several histologic types, including squamous cell carcinoma, adenocarcinoma, and large cell undifferentiated carcinoma. Changes in smoking habits have influenced not only the incidence and mortality of lung cancer, but also the frequency of the different histologic types, with an increase in adenocarcinoma and a decrease in squamous cell carcinoma. Atypical adenomatous hyperplasia is thought to be a precursor of well-differentiated adenocarcinoma.1 It consists of focal peripheral proliferation of atypical epithelial cells that replace the preexisting normal alveolar or bronchioloalveolar epithelium, reflecting the aerogenous component of adenocarcinoma progression. This pattern of progression is also the main feature of bronchioloalveolar carcinoma (BAC), one of the four recognized adenocarcinoma subtypes.

BAC is extremely heterogeneous, with patients presenting either with a nonspecific peripheral nodule or with a fairly specific pneumonic-type pattern.2 Most recent BAC series have involved patients who had solitary lesions amenable to complete resection and who had better survival prospects than patients with other types of adenocarcinoma.3 Little information is available on the clinical presentation and course of pneumonic-type BAC.4 5 6 7 8 In addition, few of the patients included in previous studies met the 1999 revised World Health Organization (WHO)/International Association for the Study of Lung Cancer (IASLC) diagnostic criteria for BAC, and Travis3 underlined the need to re-evaluate much of the BAC literature. Indeed, most pneumonic-type adenocarcinomas (P-ADCs) contained a mixture of BAC and other histologic subtypes, including an invasive component,9 and their diagnosis was mostly based on small bronchial, transbronchial, or transthoracic needle biopsy (the patients rarely underwent surgical resection).3 In this study, we examined clinical, radiologic, and BAL findings in P-ADC, regardless of the histologic subtype in a series of 52 patients, together with diagnostic procedures, treatment outcome, and survival predictors.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study Design
In December 2000, the physicians of the chest, radiology, and pathology departments of our institution were asked to collate all cases of P-ADC diagnosed since January 1986. P-ADC was defined as follows: (1) histologically or cytologically proven pulmonary adenocarcinoma,9 in the absence of a prior diagnosis of thoracic or extrathoracic adenocarcinoma; (2) evidence of a pneumonia-like consolidation (Fig 1 ), defined as an essentially homogenous opacity in the lung characterized by little or no loss of volume, effacement of blood vessel shadows and, sometimes, by the presence of an air bronchogram10 (according to the glossary of terms for thoracic radiology, this definition is applicable only when the opacity can be attributed to partial filling of alveolar spaces by tissue or fluids10 ); and (3) no concomitant bacterial pneumonia or obstructive pneumonia due to an exophytic lesion occluding the lumen of the main or lobar bronchi.



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  		Figure 1.. Chest radiograph (top, A) and CT images (center, B, and bottom, C) showing pneumonia-like consolidation (homogenous opacity) characterized by little or no loss of volume, effacement of blood-vessel shadows, and presence of an air bronchogram.

 
Cases were included after independent consensus evaluation of the initial chest radiograph and CT by three investigators (M.W., M-A.M., and J.C.) and after review of cytologic and pathologic material by one pulmonary pathologist (M.A.). A questionnaire was completed for each case by two clinicians (M.W. and M-A.M.), based on medical charts.

Collection of Patient Data
The following data were collected at the time of P-ADC diagnosis: epidemiologic data (age, sex, smoking history, medical history), symptoms and signs (cough, dyspnea, sputum, bronchorrhea, hemoptysis, chest pain, etc.), and the time between symptom onset and diagnosis. Bronchorrhea was defined according to its abundance (at least one 120-mL glass per day, as quantified by the patient). Clinical features of P-ADC included weight loss (> 10%), performance status (WHO), crepitant rales and hypertrophic osteoarthropathy. Laboratory data included total and differential blood cell counts, and plasma lactate dehydrogenase (LDH) levels (normal < 500 IU/mL).

All chest radiologic and CT findings were reviewed, and the number, location, and characteristics of consolidations were recorded. Consolidations were then classified as single or multiple, affecting one or more lobes, and as unilateral or bilateral. Pleural effusion and mediastinal lymphadenopathy were also noted. Previous chest radiographs were sought in order to determine the interval between the first radiologic abnormality and diagnosis.

Each patient was staged according to the current International TNM Classification System for Lung Cancer.11 Clinical TNM staging included CT of the chest, liver, and adrenal glands; CT of the brain; and abdominal sonography. Bone scans were obtained if there were osseous symptoms or a plasma calcium elevation.

Diagnostic Procedures
Macroscopic results of fiberoptic bronchoscopy, together with cytologic analysis of bronchial aspirates and BAL fluid, and pathologic analysis of bronchial (two to six specimens) and transbronchial biopsies (two to four specimens) were reviewed. Total and differential BAL cell counts were recorded. An infectious etiology was eliminated by direct microbiological analysis and culture of pulmonary samples. When bronchoscopic samples were not contributory, the results of other diagnostic procedures were recorded (transthoracic needle biopsy, pleural biopsy, mediastinoscopy, and open-lung biopsy [OLB]).

All surgical samples were reviewed by the same lung pathologist (M.A.). P-ADC was classified according to the 1999 revised WHO/IASLC diagnostic criteria as papillary, acinar, bronchioloalveolar, or solid with mucin formation.9 The cytologic subtype was noted as mucinous or nonmucinous. Pathologic TNM staging was done after surgical resection, according to the current International TNM Classification System for Lung Cancer,11 and the presence of an invasive component (pleural, stromal and lymphatic or vascular invasion) was recorded. Furthermore, to better understand the pathologic substrate of the pneumonic component we examined resected tumors for lepidic tumor growth, partial filling of airspaces by mucin, and/or tumor cell alveolar shedding, and/or inflammatory cell alveolitis, and interstitial thickening due to fibrosis or lymphocytic infiltration.

Treatment and Follow-up Data
Initial treatment was noted. Clinical and radiologic pulmonary responses were assessed 2 to 4 months after initiation of therapy, according to the usual criteria when possible.12 As most of the patients had nonmeasurable disease, a response was defined as the disappearance of the lesion in at least one segment of the involved lobe(s). Progression was defined as the appearance of at least one new lesion or extension of a preexisting lesion to at least one new segment.

The cutoff date for the survival analysis was May 2001. Follow-up data were recorded until the cutoff date or death. Median follow-up was 10.5 months (range, 1 to 150 months). Survival was defined from the date of pathologic diagnosis until the cutoff date or death. The cause of death and disease status at the time of death were also recorded.

Statistical Analysis
Survival rates were calculated with the Kaplan-Meier method, and survival curves were compared using the log-rank test. The threshold of significance was set at p < 0.05. Multivariate analysis was performed with the Cox multiple regression method. The lack of collinearity between disease parameters was verified by using the {chi}2 test. Variables with p values < 0.1 in the log-rank test were entered in the Cox model. Data were processed with StatView and Survival Tools 5.0 software (Abacus Concepts; Berkeley, CA).


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Fifty-two patients with P-ADC were included in this study, including 1 patient with a history of prostatic adenocarcinoma. Two other patients were not included because they had a history of primary lung adenocarcinoma.

Patient Characteristics
There were 31 men (60%) and 21 women (40%). Mean age at diagnosis was 66 ± 1.4 years (range, 42 to 87 years). Thirty-four patients (65%) were current or former smokers, with an estimated average consumption of 43 ± 4.1 pack-years (range, 15 to 120 pack-years).

Twenty patients had a history of pulmonary disease: pulmonary tuberculosis (n = 9), COPD (n = 5), pneumonia (n = 4), purulent pleuritis (n = 1), pneumoconiosis (n = 1), or pulmonary thromboembolism (n = 1). Three patients had a history of cancer: bladder cancer (n = 1), cutaneous basocellular epithelioma (n = 1), or prostatic cancer (n = 1). This latter patient had been treated surgically > 5 years previously, and had negative serum prostatic markers at P-ADC diagnosis.

In nine patients (17%), P-ADC was diagnosed when asymptomatic, during routine chest radiography. In the other patients, cough was the most common symptom (73%). One third of patients had dyspnea, and one third had bronchorrhea. The median interval between symptom onset and diagnosis was 4.4 months (range, 1.6 to 109 months). Ninety-nine percent of patients had a performance status of ≤ 2. Twenty-two percent had lost > 10% of their initial body weight. Fifty-seven percent had crepitant rales, and 13.5% had hypertrophic osteoarthropathy. The mean neutrophil count was 5,472 ± 297/µL (range, 1,930 to 13,114/µL), and the mean LDH plasma level was 505 ± 60 IU/mL (range, 150 to 1,583 IU/mL).

Radiologic Features and TNM Stage
The median interval between the first radiologic abnormality and diagnosis was 5.5 months (range, 3.3 to 89 months) and 4.2 months (range, 0 to 60 months) in asymptomatic and symptomatic patients, respectively. CT scan of the chest was significantly more sensitive than chest radiography for detecting multiple and bilateral lesions. Multiple lesions were detected in 48% and 63% of patients by chest radiograph and CT, respectively (p < 0.05). Bilateral lesions were observed in 46% and 58% patients by chest radiograph and CT, respectively (p < 0.05). Multiple lesions were multilobular in 63% of CTs. Multilobular lesions were unilateral in only three CTs. CT showed an air bronchogram in 86% of cases and pleural effusion in 11%. No atelectasis was observed.

Forty-three patients (83%) had consolidations that could not be assessed, with no evidence of tumor or obstruction on imaging or bronchoscopy; these patients were classified Tx. Three patients had measurable consolidations and were classified T2. One patient had pericardial involvement (T3). Five patients had a satellite tumor within the primary tumor lobe (T4), and 33 patients had a satellite tumor in a nonprimary tumor lobe (M1). Two patients had hilar lymphadenopathy (N1), seven patients had ipsilateral mediastinal lymphadenopathy (N2), and four patients had contralateral mediastinal lymphadenopathy (N3). Thorough analysis of the mediastinum was not possible in two patients. Three patients had an extrathoracic metastasis (bone, n = 2; liver, n = 1), of whom two were already classified M1 because of lung metastases. None of the patients had cerebral or adrenal metastasis. Altogether, 17 patients were staged I-IIIA, 1 patient was stage IIIB, and 34 patients were stage IV according to the current International TNM Classification System for Lung Cancer.11

Diagnostic Procedures and Histologic Findings
Fiberoptic bronchoscopy was performed in every case (Fig 2 ). No endobronchial tumors were observed, and microbiological analysis of pulmonary samples (BAL and bronchial aspirates) was negative in all the patients.



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  		Figure 2.. Diagnostic procedures used for P-ADC. *Number of patients with positive results over the number of patients who underwent the procedure. BA = bronchial aspiration; BB = bronchial biopsy (two to six specimens); TBB = transbronchial biopsy (two to four specimens).

 
A definite diagnosis was obtained by fiberoptic bronchoscopy in 42 of the 52 patients (80.8%). Except for transbronchial biopsy, the type and number of sampling methods did not differ according to whether bronchoscopy was diagnostic or not. Bronchial biopsies were performed in 47 patients and had positive results in 21% of cases. None of the patients underwent bronchial biopsy as the sole diagnostic procedure, as endobronchial lesions consisting of submucosal infiltration of the segmental or subsegmental bronchial wall were moderate and not sufficiently specific. Transbronchial biopsies were performed in 25 patients and had positive results in 80% of cases. Tumor cells were detected in 44% of 41 patients undergoing bronchial aspiration, and in 66% of 47 patients undergoing BAL. The total BAL cell count was increased (760 ± 162/µL), mainly owing to a marked increase in total (313 ± 105/µL) and differential (33 ± 5%) neutrophil counts.

Transthoracic needle biopsy results were always positive. Transthoracic needle biopsy was performed in eight patients because bronchoscopy did not yield the diagnosis, and in four patients because the clinician requested diagnostic confirmation. Only two patients underwent OLB as the final diagnostic procedure. In one patient with diffuse and bilateral opacities, OLB was performed because bronchial aspiration, bronchial and transbronchial biopsy, and BAL were noncontributory. In the remaining patient, bronchial aspiration and bronchial biopsy did not yield the diagnosis; transbronchial and transthoracic needle biopsies were not performed, as the patient was receiving anticoagulant treatment. OLB was converted to lobectomy, and yielded a final diagnosis of mixed-subtype pathologic T1N0M0 adenocarcinoma. Pleural biopsy and mediastinoscopy were never used.

Histologic analysis of the 19 surgical specimens showed a uniform histologic pattern in 7 cases (BAC, n = 6; papillary, n = 1) and a mixed histology in 12 cases (papillary and acinar, n = 3; solid and papillary, n = 1; BAC and papillary, n = 6; BAC and acinar, n = 2) [Table 1 ]. Cytologic analysis showed a nonmucinous type in 10 tumors, a mucinous type in 5 tumors, and a combined mucinous/nonmucinous type in 4 tumors. An invasive component was identified in all the tumors, consisting of a stromal reaction (n = 18), and vascular or lymphatic (n = 8), pleural (n = 5) and nodal (n = 8) invasion (Tables 1 , 2 ).


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  		Table 1.. Pathologic Analysis of the 19 Patients With Surgical Resection*

 

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  		Table 2.. Pathologic Substrate of the Pneumonic Component in the 19 Patients With Surgical Resection

 
The pathologic substrate of the pneumonic component was also evaluated on the 19 surgical specimens (Table 2) . It resulted from a combination of lepidic tumor growth, partial filling of alveolar airspaces by mucin, tumor cell alveolar shedding and inflammatory cell alveolitis (macrophages and neutrophils), and interstitial thickening by fibrosis or inflammatory cell infiltration (lymphocytes, plasmocytes, and monocytes). In a few cases, partial alveolar collapse was due to architectural destruction with fibroblastic proliferation and foci of massive tumor proliferation.

Treatment
Nineteen patients underwent surgical resection, 19 patients received systemic chemotherapy, and 14 patients received best supportive care (Table 3 ). Among the 19 patients undergoing surgical resection, 8 patients underwent pneumonectomy, and 11 patients underwent lobectomy or bilobectomy. There were four postoperative deaths after pneumonectomy (massive pulmonary embolism, n = 1; myocardial infarction, n = 1; nosocomial pneumonia complicated by ARDS, n = 1; and bronchopleural fistula with empyema, n = 1) and none after lobectomy or bilobectomy. Among the four patients who survived pneumonectomy, three patients had recurrences within a median of 8 months (range, 3.9 to 23.7 months). Among the 11 patients with lobectomy or bilobectomy, 7 patients had recurrences within a median of 24 months (range, 3.3 months to 8.9 years). All the recurrences after surgical resection involved the lungs (lung, n = 5; lung, bone, and brain, n = 1; lung and pleura, n = 1; lung, pleura, and mediastinum, n = 1; lung and mediastinum, n = 2).


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  		Table 3.. Survival According to Treatment

 
Seventy-four percent of the 19 patients who received systemic chemotherapy were treated with cisplatin-based regimens. A partial response was observed in only 1 of the 16 patients evaluated 2 to 4 months after chemotherapy. Fourteen patients received best supportive care, for the following reasons: old age and/or poor performance status (n = 8), Alzheimer’s disease precluding informed consent (n = 2), left ventricular failure (n = 1), stroke (n = 1), and notoriously chemotherapy-resistant tumors (n = 2).

Factors Affecting Survival
None of the patients were unavailable for follow-up. Forty-one patients had died as of May 2001. The median survival time after diagnosis was 10.5 months (range, 1 to 150 months). The actuarial survival rates at 1 year, 2 years, and 5 years were 43%, 30%, and 13%, respectively. Median and actuarial survival rates are shown in Table 4 according to the treatment group (lobectomy or bilobectomy, pneumonectomy, chemotherapy, or best supportive care). The patients treated with lobectomy or bilobectomy fared significantly better than those treated with pneumonectomy, chemotherapy, or best supportive care (p < 0.01; Fig 3 ). Death was due to P-ADC progression in 83% of cases (respiratory failure in 90% of these patients). There were five iatrogenic deaths (four postoperative deaths and one case of fatal sepsis during chemotherapy-related neutropenia). The status of the 11 surviving patients was as follows: complete (n = 5) or partial remission (n = 1), no change (n = 2), or progression (n = 3).


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  		Table 4.. Factors Predictive of Survival (Univariate Analysis)

 


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  		Figure 3.. Survival curve according to treatment: lobectomy or bilobectomy (n = 11), pneumonectomy (n = 8), chemotherapy (n = 19), or best supportive care (n = 14). Patients treated with lobectomy or bilobectomy had significantly longer survival than the other patients (p < 0.05, log-rank test).

 
Bronchorrhea, crepitant rales, and multiple, bilateral, or multilobar disease, as shown by chest radiography (data not shown) or CT, were factors of poor prognosis, together with nonsurgical treatment (Table 4) . Age, gender, smoking history, weight loss, performance status, clinical TNM, blood neutrophil count, and LDH plasma levels did not influence survival. Among the BAL characteristics, an elevated total cell count, an elevated total and differential neutrophil count, and the presence of tumor cells were predictive of poor outcome (Table 4) . Total macrophage and lymphocyte counts did not influence survival. Bronchorrhea and crepitant rales were the only independent predictors of poor survival in multivariate analysis when the treatment modality, ie, surgery vs no surgery, was not considered as a risk factor (Table 5 ).


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  		Table 5.. Factors Affecting Survival*

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
P-ADC is not a WHO classification and is not commonly used; however, none of our patients could be classified as having BAC according to the 1999 revised WHO/IASLC classification (a final diagnosis of BAC must be based on a surgical resection specimen),3 and most of our patients did not undergo this procedure. Also, although transbronchial or transparietal needle biopsy showed adenocarcinoma with a lepidic growth pattern in almost all our patients, this aspect is only suggestive of BAC and cannot rule out invasive growth. Finally, pathologic study of surgical specimens clearly demonstrated the histologic heterogeneity of P-ADC and the presence of a desmoplastic fibrotic stromal reaction or of nodal, pleural, and vascular invasion, which are exclusion criteria for adenocarcinoma of the BAC subtype in the 1999 revised WHO/IASLC classification. Yet our study population was very homogeneous, being characterized by segmental, lobar, or lung consolidation resembling pneumonia and due to adenocarcinoma with a predominantly lepidic growth pattern. In addition, our patients differed strongly from the usual population of patients with lung adenocarcinoma, in terms of clinical and radiologic features, the diagnostic approach, and survival predictors.

The high frequency of bronchorrhea and crepitant rales, and the extensive pulmonary involvement at diagnosis in our series contrasts with reports of classical adenocarcinoma and surgically treated BAC.13 A significant relationship between presenting symptoms and advanced-stage and/or pneumonic-type BAC has previously been reported.7 14 15 16 17 18 As expected, chest CT was more sensitive than plain chest radiographic examination for detecting pulmonary extension, and showed that the lungs were extensively involved at diagnosis. However, the pathologic substrate of the pneumonic component was not only lepidic tumor growth with partial filling of alveolar airspaces by mucin or tumor cells, as in small adenocarcinomas of the BAC subtype,19 20 but also included inflammatory cell infiltration and a fibrotic stromal reaction, which appear to have prognostic significance.21 22 23 The lesions were already bilateral and multifocal in our patients, explaining the high proportion of stage M1 (64%). Only three patients had extrathoracic metastasis at diagnosis. This specific trend toward intrapulmonary spread and a lower frequency of extrathoracic metastasis is accompanied by limited regional node involvement, approximately 80% of P-ADC being N0 on CT evaluation.4 5 24 The use of particular diagnostic approaches in our patients was probably related to the pneumonic type of the adenocarcinoma. Bronchial biopsy during fiberoptic bronchoscopy contributed to the diagnosis in only 20% of cases, while transbronchial pulmonary biopsy and transthoracic pulmonary biopsy were contributory in 80% and 100% of cases, respectively. Tumor cells were detected in BAL fluid in 66% of cases, compared to only 30% of cases in previous series of peripheral adenocarcinoma.25 Together, BAL and bronchial, transbronchial, and/or transthoracic biopsy provided the diagnosis in all but two of our patients, thus avoiding diagnostic OLB in almost every case.

Good nutritional status despite extensive lung involvement has previously been reported in patients with BAC,14 and probably explains why performance status and weight loss were not predictive of survival in our series. Likewise, the TNM stage was not predictive of survival, probably because almost all the patients had consolidations that could not be further assessed, and because of the specific tendency for P-ADC to show intrapulmonary rather than nodal or extrathoracic spread. The only factors affecting survival in our series were clinical or radiologic signs of aerogenous spread, ie, crepitant rales, bronchorrhea, and multifocal, multilobar, or bilateral lesions. The results of the few previous studies focusing on BAC with a pneumonic-type presentation7 14 15 16 17 18 are in keeping with these findings, even though multivariate survival analysis was rarely performed.7 14 17 18 Interestingly, the detection of tumor cells and elevated total cell or neutrophil counts in BAL were also associated with poor outcome. We have demonstrated that neutrophils are recruited to and maintained in tumoral alveolar spaces by tumor-derived chemokines and antiapoptotic factors, respectively.21 26 We postulated that neutrophils might participate in the shedding and dispersion of tumor cells, through several mechanisms.21 The observation that bronchorrhea and crepitant rales were the only two independent factors of shorter survival in P-ADC emphasizes the responsibility of aerogenous propagation in fatal outcome. This is in keeping with the fact that 90% of P-ADC–related deaths were due to local pulmonary tumor progression and not to dissemination.

As in most previous BAC series,15 16 17 18 27 28 our patients with P-ADC treated by curative surgery had significantly longer survival than other patients (5-year survival, 36% vs 0%; p < 0.05) [Fig 3 ]. As a result, surgery was an independent survival factor, together with clinical signs of aerogenous spread, in multivariate analysis (see above). Likewise, patients treated with lobectomy or bilobectomy had a significantly longer survival time than those treated with pneumonectomy (5-year survival, 65% vs 0%; p < 0.05). This did not result only from the high postoperative mortality rate following pneumonectomy. Liu et al27 showed that the type of surgery (lobectomy or bilobectomy vs other surgical procedures, including pneumonectomy) also affected survival, independently of curative resection and the TNM stage. In accordance with Liu et al,27 we found evidence that lesions of the pneumonic type that extend beyond one lobe on CT are frequently associated with microscopic involvement of both lungs. A CT-pathologic correlation study of multifocal pulmonary adenocarcinoma showed that CT was unable to reveal multifocality in a high percentage of cases.29

We observed only one response to chemotherapy among 16 assessable patients. Response rates of 21 to 32% have been reported in patients with advanced BAC,4 5 30 and were either lower than or equal to the rates in patients with all types of adenocarcinoma. Heikkila24 observed no responses to chemotherapy, and Harpole et al31 found no survival difference among advanced-stage BAC patients according to whether or not they received systemic chemotherapy.

In summary, this series shows that diagnostic and extension-evaluation procedures, as well as prognostic criteria and treatment strategies, differ between P-ADC and classical adenocarcinoma, mainly because of the predominantly aerogenous spread of P-ADC. Because of this aerogenous spread, transbronchial biopsy and BAL are recommended diagnostic procedures. Multivariate analysis showed that crepitant rales and bronchorrhea were the only two independent predictors of shorter survival when the treatment modality (surgery vs no surgery) was not entered as a risk factor. It also showed that surgery was the most effective therapeutic strategy, especially when lobectomy was feasible. However, as CT does not seem sensitive enough to detect multifocal lesions, new tools are required to evaluate pulmonary involvement and thereby refine the surgical strategy.


   Acknowledgements
 
We thank Nathalie Rabbe, Virginie Isnel, and Lydie Fromont for technical assistance, and Antoine Flahaut (Service de Biostatistiques and INSERM U444, Université Paris VI, Paris, France) for helpful discussion of the biostatistic results.


   Footnotes
 
Abbreviations: BAC = bronchioloalveolar carcinoma; IASLC = International Association for the Study of Lung Cancer; LDH = lactate dehydrogenase; OLB = open-lung biopsy; P-ADC = pneumonic-type adenocarcinoma; WHO = World Health Organization

This study was supported by grants from Leg Poix.

Marie Wislez is a doctoral fellow of L’Académie de Médecine and La Ligue contre le Cancer.

Received for publication February 21, 2002. Accepted for publication December 19, 2002.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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