Bronchioloalveolar carcinoma
Synonyms and keywords: Adenocarcinoma in situ (AIS); Bronchioloalveolar carcinoma (BAC)

# Overview
Bronchioloalveolar carcinoma (BAC) is a rare type of lung cancer which more frequently among never-smokers, women and Asians( particularly Eastern-Asian). In the new WHO classification of lung adenocarcinoma's, changes were made as proposed by the 2011 IASLC/ATS/ERS and bronchioloalveloar carcinoma (BAC) is now classified as a subtype of lung adenoacarcinoma and the term BAC is no longer in use. It is also known as "lepidic predominant adenocarcinoma" due to its progression along the alveolar walls without invading stromal, pleural or vascular tissue. By definition, BAC is not an invasive tumor. Therefore, pathologists classify it as a form of carcinoma in situ (CIS). However, unlike other forms of CIS, its behavior is malignant, often lethal. Major surgery, either a lobectomy or a pneumonectomy, is needed to control it, and recurrences are frequent. For this reason, oncologists classify it among the other malignant tumors, which are invasive tumors.

# Historical prespective
- John George Adami, MD, professor of pathology used the term lepidic in an address to the Toronto Pathological Society on January 4, 1902, for tumors that were derived from surface lining cells.
- Bronchioloalveolar carcinoma was first discovered by Dr. Averill Liebow, in the year of 1960.
- In 1999, the World Health Organization has given the term 'Pure BAC' as a subtype of adenocarcinoma that doesnt Invade.
- There have been recent changes in pathologic classification of lung cancer by (IASLC/ATS/ERS) as compared to previous WHO classification and bronchioloalveolar carcinoma is now described as adenocarcinoma in situ or AIS (previously known as solitary or pure BAC)

# Classification
According to the current criteria, bronchioloalveolar carcinoma is defined as a sub-type of lung adenocarcinoma and the lesions are now described under categories adenocarcinoma in Situ (AIS) and minimally invasive adenocarcinoma (MIA).
However it is distinct from other lung adenocarcinomas by different clinical features, prognosis and response to treatment.
IASLC/ATS/ERS Classification of Lung Adenocarcinoma in Resection Specimens describes BAC in following subheadings:

## Adenocarcinoma in situ (AIS) - Previously Known as solitary BAC
- Less than or equal to 3 cm
- Can be either mucinous or serous
- No stromal, lymphatic, or pleural invasion
- No necrosis
- No other growth pattern other than along the airways (lepidic)

## Minimally invasive adenocarcinoma (MIA)
- Less than or equal to 3 cm
- Less than or equal to 5 mm area of stromal invasion or another type of growth patterns (in comparison with the lepidic pattern of growth)
- Can be mucinous, non-mucinous or mixed

## Invasive adenocarcinoma
- Presence of stromal invasion or patterns of growth other than lepidic
- Lepidic predominant - Type of invasive adenocarcinoma with more than 5 mm invasion (Previously known as Non-Mucinous BAC with invasion)
- Invasive mucinous adenocarcinoma - Previously known as mucinous BAC
The two different sub-types of BAC depending on the cellular cytology are described as follows;

## Mucinous BAC:
- Less common
- More often seen in non-smokers
- Develop from bronchiolar epithelial metaplasia
- Present often as pneumonia-like infiltrate
- Frequently associated with a K-Ras mutation

## Non-Mucinous BAC:
- More common
- More often seen in smokers
- Originate from the terminal respiratory cells, type II pneumocytes, and Clara cells
- Presents usually as a ground glass opacity
- Frequently associated with EFGR mutations

# Pathophysiology
Bronchioloalveolar carcinoma is also known as "lepidic predominant adenocarcinoma" due to its progression along the alveolar walls without invading stromal, pleural or vascular tissue. The pattern of BAC can range from slow growing indolent tumor to rapidly growing fatal tumor. The mucinous type of bronchioloalveolar cancer is frequently associated with a K-Ras mutations and develop from bronchiolar epithelial metaplasia, is often seen in non-smokers and present usually as a pneumonia-like infiltrate. Non mucinous BAC develops in the cells near the alveoli (including type II pneumocytes and Clara cells) in the terminal or outer portion of the lungs and is frequently associated with EFGR mutations.It is more common in smokers and presents as ground glass opacity on radiograph. BAC can present as a solitary nodule or as multifocal lung nodules but there is no final answer to whether multiple lung nodules are due to disseminated malignant cells from primary focus or synchronous development of independent foci. Type-I cystic adenomatoid malformation (CAM) has been described as a precursor lesion for the development of mucinous AIS (adenocarcinoma in situ)recently due to its intramucinous cluster of cells resembling mucinous BAC and frequent K-Ras mutations in these lesions, but these cases are uncommon. The pathogenesis of BAC is poorly understood and hypothesized as a part of multi step carcinogenesis from atypical adenomatous hyperplasia (AAH) through bronchioloalveolar carcinoma (BAC) to invasive adenocarcinoma (AC), but there has been no formal demonstration of this phenomena so far.

## Microscopic Pathology

# Causes

## Smoking:
- Smoking has not been thought to be associated with BAC generally
- Almost 30 percent patients of BAC are never smokers as compared to adenocarcinoma's (15 percent are never smokers) and squamous cell cancers (only 5 percent are never smokers)
- However some recent pooled studies have shown a two-fold increased risk of BAC in smokers as compared to never-smokers and higher risk with increasing and prolonged consumption with risk decreasing in years following the smoking cessation
- Still, the magnitude of the relationship between smoking and adenocarcinoma in situ (BAC) is much smaller than other lung cancers and further studies are needed on this

## Genetics:
- Mucinous BAC are frequently associated with K-Ras mutations
- Non-mucinous BAC are frequently associated with EFGR mutations

## Hypothesis regarding JSRV:
- Jaagsiekte Sheep Retrovirus (JSRV) is a highly infectious retrovirus in sheep that causes low grade tumors in sheep resembling BAC
- This led to the hypothesis that same virus might be responsible for the similar cancer in humans
- However, no molecular study has confirmed this hypothesis so far

# Differentiating Bronchioloalveolar carcinoma (Adenocarcinoma in situ) from other Diseases
- BAC must be differentiated from other diseases that cause cough, sputum, shortness of breath, and weight loss, such as:
Cryptogenic Organizing Pneumonia (COP)
Pneumonia
Sarcoidosis
Tuberculosis
Pulmonary edema
Atypical adenomatous hyperplasia-can be a precursor to adenocarcinoma in situ (BAC)
- Cryptogenic Organizing Pneumonia (COP)
- Pneumonia
- Sarcoidosis
- Tuberculosis
- Pulmonary edema
- Atypical adenomatous hyperplasia-can be a precursor to adenocarcinoma in situ (BAC)

# Epidemiology and Demographics
- BAC is a rare form of lung cancer that comprises less than 4 percent of total cases of lung cancers
- Age adjusted Incidence rates were found to be between 1 or 2 per 100,000 in USA (1970's-1980's)
- Rising incidence has been suggested by some studies in later years, however no marked increased in incidence rate was confirmed or reported to SEER database in the next 2 decades (after 1980's)
- However, adding BAC along to mixed adenocarcinoma sub-types having a BAC component, the cummulative incidence is increased up to the 20 percent of total lung cancers

## Age
- BAC or AIS is thought to be more commonly seen in younger population, yet no evidence of such a pattern has been found in the studies and different studies have shown different results
- According to SEER database, mean age at diagnosis for BAC (years) is 66.99 +/- 10.66 which is very similar to other NSCLC and only 6.06 percent patients were found to be below 50 years of age

## Gender
- Women are more commonly affected by BAC than males.

## Race
- BAC usually affects individuals of the Asians( particularly Eastern-Asian) ethnicity.
- White individuals are less likely to develop BAC or AIS.

# Risk Factors
- Risk factors for development of BAC are poorly understood due to rarity of the type of cancer and recent change in WHO definition and classification
- Some common risk factors that can be considered in the development of BAC are smoking (not a confirmed risk factor) and genetic supectibility in certain ethnicities.
- Some single nucleotide polymorphism's (SNPs) are thought to be associated with adenocarcinoma in situ in certain ethnicities (asian) and non smokers for example TERT-CLPMT1L region on Chr5p15 was found to be linked with adenocarcinoma risk in non-smoking asian women, however no study showed particular relation of genetic supceptibility to BAC.

# Natural History, Complications and Prognosis
- The patients with BAC may remain asymptomatic for years
- Once symptomatic, patients deteriorate rapidly
- Common clinical features include cough, sputum and shortness of breath.
- If left untreated, diffuse disease usually leads to death within the 3 years
- Prognosis is generally good, especially in case of localized disease in early stages
- One study showed a 5 year prognosis of 100 percent after surgery in patients with tumors 3 cm or less
- However, the prognosis vary according to stage of disease at the time of diagnosis

## Prognostic Subgroups
- Low grade
100 percent 5 year disease free survival
Includes adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA)
- 100 percent 5 year disease free survival
- Includes adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA)
- Intermediate grade
Non-mucinous lepidic predominant - 90 percent 5 year disease free survival
Papillary predominant - 83 percent 5 year disease free survival
Acinar predominant - 84 percent 5 year disease free survival
- Non-mucinous lepidic predominant - 90 percent 5 year disease free survival
- Papillary predominant - 83 percent 5 year disease free survival
- Acinar predominant - 84 percent 5 year disease free survival
- High grade
Invasive mucinous adenocarcinoma - 75 percent 5-year disease-free survival
Colloid predominant - 71 percent 5-year disease-free survival
Solid predominant - 70 percent 5-year disease-free survival
Micropapillary predominant - 67 percent 5-year disease-free survival
- Invasive mucinous adenocarcinoma - 75 percent 5-year disease-free survival
- Colloid predominant - 71 percent 5-year disease-free survival
- Solid predominant - 70 percent 5-year disease-free survival
- Micropapillary predominant - 67 percent 5-year disease-free survival

# Diagnosis

## Diagnostic Criteria

## Symptoms
- Most patients are asymptomatic and BAC is discovered upon biopsy of an incidentally found solitary pulmonary nodule
- Others may presents with symptoms raging from cough, sputum, shortness of breath, hemoptysis, fever to bronchorrea which may lead to electrolyte imbalance
- Below are the percentage of symptoms seen in different patients:

## Physical Examination
- Patients with BAC usually appear normal in early stages of the disease.
- Physical examination is usually normal for all systems including lungs in most cases
- However exam may be remarkable for:
Fever
Lung findings consistent with consolidation ( dullness on percussion, increased vocal fremitus and increased vocal resonance) may be seen although not present in all cases
- Fever
- Lung findings consistent with consolidation ( dullness on percussion, increased vocal fremitus and increased vocal resonance) may be seen although not present in all cases

## Laboratory Findings
- There are no specific laboratory findings associated with BAC.

## Imaging Findings
- CT scan is the imaging modality of choice for BAC.
- X-Ray findings can range anywhere from single or multiple ground glass opacities ( with or without solid components) to consolidation and nodules
- CT scan may demonstrate ground glass opacities with or without consolidation often along with a bubble like low attenuation areas and open bronchus sign, air bronchograms or bronchiolograms, irregular or ill-defined margins and pleural tails

## Other Diagnostic Studies
- FDG-PET may also be used for diagnosis however it is less reliable in BAC as compared to the diagnosis of other NSCLC (Non small cell lung cancer).
- CT guided needle aspiration biopsy is very useful to confirm the diagnosis and for histological grading of the tumor

# Treatment

## Medical Therapy
- Treatment for BAC is primarily surgical in localized cases along with the fact that BAC is believed to be less responsive to chemotherapy as compared to other non small cell lung cancers
- However, in case of a large number of nodules or foci are found in lungs, chemotherapy is generally considered
- Initial treatment may be with standard cytotoxic platinum doublet chemotherapeutic regimen containing cisplatin or carboplatin
- Epidermal growth factor receptor tyrosine kinase inhibitors (EFGR-TKIs) like Gefitinib and Afanitib are currently used in treatment of advanced or recurrent disease with failed response to cytotoxic chemotherapy
- Some studies advocate the use of bortezomib as a therapeutic method especially those who progressed with an EFGR-TKIs treatment but more data is needed on that

## Surgery
- Surgery is the mainstay of therapy for localized bronchioloalveolar cancer.
- Lobectomy in conjunction with mediastinal lymph node dissection is the most common approach to the treatment of localized BAC
- Pneumonic form of BAC ( rare variant with lobar consolidation and filling of alveoli with mucinous adenocarcinoma) has a very poor prognosis despite surgical resection

## Prevention
- There are no primary preventive measures available for BAC. Role of smoking as a causative factor for BAC is controversial, however, smoking cessation helps in decreasing risk of most of the lung cancers in general
- Follow-up of solitary pulmonary nodules or ground glass opacities discovered incidentally on X-ray may lead to early identification of the disease
- Once diagnosed and successfully treated, patients with early stage BAC have high disease free survival rates as compared to similar stage adenocarcinoma
- Follow-up testing includes X-ray or HR-CT scan