Further autopsy findings: A small, ill-defined, cystic, mucinous tumor was found in the head of the pancreas. The tumor also involved a peripancreatic lymph node. Its appearance was identical to the tumor in the lung.

Final diagnosis: Mucinous adenocarcinoma of pancreas masquerading as bronchioloalveolar carcinoma of lung. Metastases to both lungs, a peripancreatic lymph node, and mediastinal lymph nodes.

Comment: A diagnosis of primary bronchioloalveolar carcinoma of the lung should not be made if there is an extrapulmonary primary tumor with a similar histologic appearance. In this case, the asymptomatic pancreatic tumor was not considered to be a metastasis because a local lymph node was involved. Other than the sites mentioned, no other tumor was found. The behavior of pulmonary bronchioloalveolar carcinoma will be examined below, but it is important to remember that the multicentric pattern (and occasionally the solitary pattern) may represent metastasis from another site, which can sometimes only be determined by a complete autopsy.


Bronchioloalveolar Carcinoma (BAC)

Introduction: BAC is a peripheral, primary lung cancer in which tumor cells grow along preformed alveolar walls with little or no distortion of the architecture. Two patterns occur: solitary and multifocal. Histologically, tumors may be mucinous or non-mucinous. Non-mucinous tumors have been divided into sclerotic types that show some alveolar septal fibrosis, and non-sclerotic types. Now classified by WHO as a subtype of adenocarcinoma (Table), BAC is separated from other adenocarcinomas because of its peculiar growth pattern and because of the unusual behavior and poor prognosis of the multifocal form.

Table. Classification of Adenocarcinoma

Epidemiology: In a review of histologically confirmed lung cancers at UCLA, BAC increased in frequency from 4% of all lung cancers in 1955 to 24% in 1990 [1]. Traditionally, however, lower values of 1-9% of all lung cancers have been published [2]; M : F = 1.4-0.7 : 1 [2-5]. About 25% are non-smokers and about 25% smoke less than 20 pack-years [2]. Mean (or median) age at diagnosis varies from 54 to 65 [2, 3, 6]. The mucinous form of BAC may accompany congenital cystic adenomatoid malformations (CCAM) (9 reported cases) that have mucous cells (type 1 with large cysts) [7, 8]. The low mean age of the patients (27 y (range 11-42)) suggests a causal relationship of the CCAM [7]. Prognosis is good, but one patient died of recurrent tumor 4 y after pneumonectomy [7, 9].

Clinical presentation: Solitary, nodular lesions tend to be asymptomatic, but patients with consolidations or bilateral lesions may present with cough, chest pain, dyspnea, hemoptysis, weight loss, or sputum production [3]. Excessive sputum is a sign of late disease and occurs in only about 5% [4]. A recent report describes a 49-y-old woman who initially produced 300 ml of clear, watery sputum a day. Over several months the quantity increased to 9 L a day shortly before death. High levels of tumor markers, CEA and CA19-9, were found in the sputum, but blood levels were normal [10].

Radiographic appearances: By plain chest films and CT, tumors can be classified as solitary, spiculated, peripheral nodules (43%), consolidations (30%), or multicentric, diffuse disease (27%) [11]. Solitary lesions may be stable radiographically for 2 to 7 y before diagnosis [12]. Rarely, the tumor grows over the pleura to resemble mesothelioma [13]. In two large series, solitary lesions (nodules and consolidations) varied from 58% to 83% of the total [2, 3]. Effusions are present in 32% and hilar or mediastinal adenopathy in 18% [11].

Characteristic features of the radiograph: Air bronchograms and "bubble" lucencies correspond to patent medium-sized and small airways, but cavitation is rare [11]. Mucin-containing, consolidated areas show a low attenuation by CT, and contrast enhanced CT, which accentuates pulmonary vessels, gives a so-called CT angiogram sign. While non-specific, this sign can suggest BAC as a cause of lung consolidation [14]. Another HRCT pattern that resembles the "crazy-paving" pattern seen in alveolar proteinosis with patchy areas of thickened interstitial lines in a ground-glass background has been described in one patient. The pattern was unusual for PAP in that it was primarily unilateral [15]. Finally, 18F-fluorodeoxyglucose PET scans are likely to be negative in BAC [16]. They show less uptake (score 3.5) than squamous carcinomas (score 11) or other adenocarcinomas (score 9) [17].

Diagnosis: The frequency of positive results of diagnostic procedures is listed in the table.

Table: Positive diagnostic procedures and yield [2]

Gross pathology: A solitary tumor appears as a tan, rounded, subpleural mass often with a pleural retraction over a central scar with black pigment. The edges may appear well- or poorly-defined. When a glistening, mucoid surface indicates mucin production, scar is usually absent. It is important to examine the apparently normal lung parenchyma visually and by palpation for evidence of multifocal tumor. Multifocal tumors appear as ill-defined consolidations without a difference in color from the surrounding lung or as uniform gray consolidations that resemble organizing pneumonia. Neither solitary nor multifocal tumor forms masses in visible airways.

Histologic changes: These tumors are well-differentiated adenocarcinomas that develop distal to the bronchi. They grow in a simple columnar to cuboid cell layer over existing walls and sometimes cause connective tissue to be deposited there. In solitary tumors there may be subpleural collapse and scar formation centrally (as in other adenocarcinomas), but the major part of the tumor lines alveolar walls. In multifocal tumors, the lung architecture remains preserved. Hemorrhage, necrosis, and cavitation are almost always absent [1].

Cell type: Three types of cells have been described: Clara cells, type II cells, and mucin-producing cells. In one ultrastructural study of 54 tumors, 43 (80%) had a single cell type--Clara cells in 32 (59%), type II cells in 1 (2%), and mucous cells in 10 (19%). Eleven tumors (20%) had a mixture of cell types. Rarely, ciliated cells are present. Non-mucin-producing tumors outnumber mucinous ones 2-3:1. There is no relationship between tumor cell type and radiographic presentation although mucinous tumors tend to be multicentric [5].

Non-mucinous tumors are composed of Clara cells and/or type II cells. The Clara cell is cuboid to columnar with a rounded protrusion of the apical surface above the cell junctions. Ultrastructurally, the Clara cell has characteristic electron dense, apical granules [5].

Type II cells, which react immunohistochemically with antibody to surfactant apoprotein, are more cuboid, and may contain lamellated bodies of surfactant protein. Eosinophilic nuclear inclusions that can be present in these cells show branching tubules by EM and have reactivity for a surfactant component [18]. These inclusions must be distinguished from similar appearing intranuclear inclusions that do not show these features [19]. Lymphoid tissue is common in the scant stroma of Clara cell and type II cell tumors, and Langerhans' cells have been described in the infiltrates [18].

The mucin-producing cell is tall columnar with a basal nucleus. The apical cytoplasm is vacuolated and stains for mucin with PAS after diastase digestion (PAS-D-positive). The PAS-D-positive air space mucin should not be mistaken for pulmonary alveolar proteinosis [20].

Growth pattern: In addition to growth along alveolar walls, some tumors have a distinct papillary component with growth of tumor over thin, fibrous projections. However, if this pattern predominates and the projections have a prominent fibrous core, the tumor should be designated a papillary adenocarcinoma [21]. At the edges of BAC, clusters of tumor cells can sometimes be seen arising abruptly from a normal alveolar wall. At other times, tumor cells blend in gradually with hyperplastic alveolar cells. There is subjectivity in separating some solitary bronchioloalveolar carcinomas from other adenocarcinomas; in BAC the predominant pattern should be tumor cells lining preformed alveolar walls. In some cases, minute precursor lesions--atypical alveolar hyperplasias--have been described in parenchyma surrounding the BAC.

Significance of multifocal disease: Compared to other types of lung cancer, BAC is more likely to be multifocal in the lung. Possible mechanisms of spread are via vessels, along alveoli, or aerogenously with implantation in other sites. Some evidence for a monoclonal origin of multifocal tumor is based on similar K-ras mutations in different tumor foci in 10 of 20 cases examined and loss of heterozygosity for p53 in 4 of 20 (overall, similar changes in different tumor foci were found in 11 of 20 cases) [22].

Differential diagnosis: Metastatic adenocarcinoma from the ovary, breast, or GI tract, including the pancreas, can produce a histologic pattern resembling multifocal BAC. Also, multifocal BAC may resemble pulmonary alveolar proteinosis, but the mucin in BAC stains with both PAS-D and alcian blue, whereas the surfactant material in PAP stains only with PAS-D. Bronchiolization in usual interstitial pneumonia should not be confused with BAC. Radiographically, multifocal disease may resemble infection, chronic eosinophilic pneumonia, cryptogenic organizing pneumonia, Wegener's granulomatosis, or lymphomatoid granulomatosis [20].

Treatment and outcome: The authors of a recent study reviewed the 5-year survival of patients in 5 large series and added 70 cases of their own. On review of the histology in their 70 cases, 20% of those originally diagnosed BAC were excluded from that category, indicating some difficulty with the histologic classification. Some of the large differences in survival (see table) may be attributed to misclassification of tumors. Survival by stage is similar to that of other non-small cell carcinomas, and diagnostic delay is common (ave 8 mo). There is controversy about whether mucinous tumors do worse than non-mucinous ones. Lack of symptoms, low TNM stage, and complete resection are good prognostic signs. Among the 70 cases, pulmonary recurrences were more frequent (n=26) than nodal (n=4) or extrapulmonary metastases (n=9), and they were more frequent with the pneumonic tumors [23]. Anecdotally, another report cites a 41-y-old woman who remained tumor-free 5.5 y following double lung transplant [24]. In another patient, massive bronchorrhea, which is rare, was treated successfully with low-dose radiation [25].

Percentage Survival by Stage in Multiple Series

5-year survival

Stage I

Stage II

Stage III

Diffuse

818 patients [23]

55-75%

20-66%

0-12%

0-36% (unilateral)

97 patients [12]

65%

16%

19%

25%

Ovine pulmonary carcinoma (Jaagsiekte) [26-27]: Human BAC resembles ovine pulmonary carcinoma, but there is no evidence that the human disease is caused by a virus.

Features of Ovine Pulmonary Carcinoma

References

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Clinical summary

Comments: mw6825@itsa.ucsf.edu

Table of Contents

Last revised 2/23/99

Copyright 1999 by Martha L. Warnock. All rights reserved.