Adenocarcinoma in situ of the lung

Classification

In WHO-2004, BACs are one of four specific histologic subtypes of lung adenocarcinoma, along with acinar adenocarcinoma, papillary adenocarcinoma, and solid adenocarcinoma with mucin production. However, approximately 80% of adenocarcinomas are found to contain two (or more) of these four subtypes. Multiphasic tumors such as these are classified into a fifth "subtype", termed adenocarcinoma with mixed subtypes.

There are other classification systems that have been proposed for lung cancers, including BACs and other forms of adenocarcinoma. The Noguchi classification system for small adenocarcinomas has received considerable attention, particularly in Japan, but has not been nearly as widely applied and recognized as the WHO system.

Like other forms of lung carcinoma, BAC possesses unique clinical and pathological features, prognosis, and responses to different treatments.

Diagnosis

The criteria for diagnosing BACs have changed since 1999. Under the new definition, BAC is defined as a tumor that grows in a lepidic (that is, a scaly covering) fashion along pre-existing airway structures, without detectable invasion or destruction of the underlying tissue, blood vessels, or lymphatics. Because invasion must be ruled out, BAC can be diagnosed only after complete sectioning and examination of the entire tumor, not using biopsy or cytology samples. BAC is considered a pre-invasive malignant lesion that, after further mutation and progression, eventually generates an invasive adenocarcinoma. Therefore, it is considered a form of carcinoma in situ (CIS).

Epidemiology

The criteria for diagnosing BAC have changed since 1999. Under the new definition, BAC is not considered to be an invasive tumor by pathologists, but as one form of carcinoma in situ (CIS). Like other forms of CIS, BAC may progress and become overtly invasive, exhibiting malignant, often lethal, behavior. Major surgery, either a lobectomy or a pneumonectomy, is usually needed to control it, and like other forms of non-small cell lung carcinoma, recurrences are frequent. Therefore, oncologists classify it among the other malignant tumors, which are invasive tumors.

Under the new, more restrictive WHO criteria for lung cancer classification, BAC is now diagnosed much less frequently than it was in the past. Recent studies suggest that BAC comprises between 3% and 5% of all lung carcinomas in the U.S.

Variants of BAC

BAC occurs in two major histopathological variants, mucinous BAC (m-BAC, 20–25% of cases) and non mucinous BAC (nm-BAC, 75–80% of cases). Very rarely, BAC can also occur as a "mixed mucinous and non-mucinous" (or "indeterminant") variant.

Incidence

The incidence of bronchiolo-alveolar carcinoma has been reported to vary from 4–24% of all lung cancer patients. An analysis of Surveillance epidemiology and End results registry ( SEER) by Read et al. revealed that although the incidence of BAC has increased over the past two decade it still constitutes less than 4% of NSCLC in every time interval. This difference in the incidence has been attributed to complex histopathology of cancer. While pure BAC is rare, the increase in incidence as seen in various studies can be due to unclear histological classification till WHO came up with its classification in 1999 and then in 2004. Another distinguishing feature about BAC is that it afflicts men and women in equal proportions, some recent studies even suggest slightly higher incidence among women.

Histogenesis

Nonmucinous BAC is thought to derive from a transformed cell in the distal airways and terminal respiratory units, and often shows features of club cell or Type II pneumocyte differentiation. Mucinous BAC, in contrast, probably derives from a transformed glandular cell in distal bronchioles.

Type-I cystic adenomatoid malformation (CAM) has recently been identified as a precursor lesion for the development of mucinous BAC, but these cases are rare.

Rarely, BAC may develop a rhabdoid morphology due to the development of dense perinuclear inclusions.

Genetics

The genes mutated in AIS differ based on exposure to tobacco smoke. Non-smokers with AIS commonly have mutations in EGFR (a driver) or HER2 (an important oncogene), or a gene fusion with ALK or ROS1 as one of the elements.

Tumorigenesis

A multi-step carcinogenesis hypothesis suggests a progression from pulmonary atypical adenomatous hyperplasia (AAH) through bronchioalveolar carcinoma (BAC) to invasive adenocarcinoma (AC), but to date this has not been formally demonstrated.

Treatment

The treatment of choice in any patient with BAC is complete surgical resection, typically via lobectomy or pneumonectomy, with concurrent ipsilateral lymphadenectomy.

Non-mucinous BACs are highly associated with classical EGFR mutations, and thus are often responsive to targeted chemotherapy with erlotinib and gefitinib. K-ras mutations are rare in nm-BAC.

Mucinous BAC, in contrast, is much more highly associated with K-ras mutations and wild-type EGFR, and are thus usually insensitive to the EGFR tyrosine kinase inhibitors. In fact, there is some evidence that suggests that the administration of EGFR-pathway inhibitors to patients with K-ras mutated BACs may even be harmful.

Recurrence

When BAC recurs after surgery, the recurrences are local in about three-quarters of cases, a rate higher than other forms of NSCLC, which tends to recur distantly.

Prognosis and survival

Taken as a class, long-term survival rates in BAC tend to be higher than those of other forms of NSCLC. BAC generally carries a better prognosis than other forms of NSCLC, which can be partially attributed to localized presentation of the disease. Though other factors might play a role. Prognosis of BAC depends upon the histological subtype and extent at presentation but are generally same as other NSCLC.

Recent research has made it clear that nonmucinous and mucinous BACs are very different types of lung cancer. Mucinous BAC is much more likely to present with multiple unilateral tumors and/or in a unilateral or bilateral pneumonic form than nonmucinous BAC. The overall prognosis for patients with mucinous BAC is significantly worse than patients with nonmucinous BAC.

Although data are scarce, some studies suggest that survival rates are even lower in the mixed mucinous/non-mucinous variant than in the monophasic forms.

In non-mucinous BAC, neither Clara cell nor Type II pneumocyte differentiation appears to affect survival or prognosis.

Additional images

Mucinous BAC

Non-mucinous BAC