Bronchioloalveolar carcinoma
Encyclopedia
Bronchioloalveolar carcinoma (BAC) is a term describing certain variants of lung cancer
Lung cancer
Lung cancer is a disease characterized by uncontrolled cell growth in tissues of the lung. If left untreated, this growth can spread beyond the lung in a process called metastasis into nearby tissue and, eventually, into other parts of the body. Most cancers that start in lung, known as primary...

 arising in the distal bronchioles or alveoli that initially exhibit a specific non-invasive growth pattern.

Classification

Lung cancers are an extremely heterogeneous family of malignant neoplasms, with well over 50 different histological variants recognized under the 2004 revision of the World Health Organization
World Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...

 ("WHO-2004") typing system, currently the most widely used lung cancer classification scheme. Because these variants can have widely differing genetic, biological, and clinical properties, including response to treatment, correct classification of lung cancer cases are necessary to assure that lung cancer patients receive optimum management.

Approximately 98% of lung cancers are carcinoma
Carcinoma
Carcinoma is the medical term for the most common type of cancer occurring in humans. Put simply, a carcinoma is a cancer that begins in a tissue that lines the inner or outer surfaces of the body, and that generally arises from cells originating in the endodermal or ectodermal germ layer during...

, which are tumors composed of cells with epithelial characteristics. 8 major groups of lung carcinomas are recognized in WHO-2004:
  • Squamous Cell Carcinoma
  • Small Cell Carcinoma
  • Adenocarcinoma
  • Large Cell Carcinoma
  • Adenosquamous Carcinoma
  • Sarcomatoid Carcinoma
  • Carcinoid Tumor
  • Salivary Gland-like Carcinoma


In WHO-2004, BAC's are one of four specific histologic subtypes of lung adenocarcinoma
Lung cancer
Lung cancer is a disease characterized by uncontrolled cell growth in tissues of the lung. If left untreated, this growth can spread beyond the lung in a process called metastasis into nearby tissue and, eventually, into other parts of the body. Most cancers that start in lung, known as primary...

, along with acinar adenocarcinoma
Acinar adenocarcinoma
Acinar adenocarcinoma is a histological subtype of gland-forming cancer that is diagnosed when cuboidal and/or columnar shaped malignant cells in the neoplastic tissue form acini and tubules...

, papillary adenocarcinoma
Papillary adenocarcinoma
Papillary adenocarcinoma is a histological form of lung cancer that is diagnosed when the malignant cells of the tumor form complex papillary structures and exhibit compressive, destructive growth that replaces the normal lung tissue.- External links :...

, 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 BAC's 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 BAC's 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
Malignant
Malignancy is the tendency of a medical condition, especially tumors, to become progressively worse and to potentially result in death. Malignancy in cancers is characterized by anaplasia, invasiveness, and metastasis...

 lesion
Lesion
A lesion is any abnormality in the tissue of an organism , usually caused by disease or trauma. Lesion is derived from the Latin word laesio which means injury.- Types :...

 that, after further mutation and progression, eventually generates an invasive adenocarcinoma
Adenocarcinoma
Adenocarcinoma is a cancer of an epithelium that originates in glandular tissue. Epithelial tissue includes, but is not limited to, the surface layer of skin, glands and a variety of other tissue that lines the cavities and organs of the body. Epithelium can be derived embryologically from...

. Therefore, it is considered a form of carcinoma in situ (CIS).

Epidemiology

BAC is the only lung cancer, besides Carcinoid, not associated with smoking,(more common in non-smokers, women and Asians). The criteria for diagnosing BAC have changed since 1999. Under the new definition, BAC is not considered to be an invasive tumor by pathologists
Surgical pathology
Surgical pathology is the most significant and time-consuming area of practice for most anatomical pathologists. Surgical pathology involves the gross and microscopic examination of surgical specimens, as well as biopsies submitted by non-surgeons such as general internists, medical subspecialists,...

, but as one form of carcinoma in situ
Carcinoma in situ
Carcinoma in situ is an early form of cancer that is defined by the absence of invasion of tumor cells into the surrounding tissue, usually before penetration through the basement membrane. In other words, the neoplastic cells proliferate in their normal habitat, hence the name "in situ"...

 (CIS). Like other forms of CIS, BAC may progress and become overtly invasive, exhibiting malignant
Malignant
Malignancy is the tendency of a medical condition, especially tumors, to become progressively worse and to potentially result in death. Malignancy in cancers is characterized by anaplasia, invasiveness, and metastasis...

, often lethal, behavior. Major surgery, either a lobectomy
Lobectomy
Lobectomy means surgical excision of a lobe. This may refer to a lobe of the lung, a lobe of the thyroid , or a lobe of the brain ....

 or a pneumonectomy
Pneumonectomy
A pneumonectomy is a surgical procedure to remove a lung. Removal of just one lobe of the lung is specifically referred to as a lobectomy, and that of a segment of the lung as a wedge resection .-Indications:...

, is usually needed to control it, and like other forms of non-small cell lung carcinoma, recurrences are frequent. Therefore, oncologists
Oncology
Oncology is a branch of medicine that deals with cancer...

 classify it among the other malignant tumors, which are invasive tumors
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...

.

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.

Histogenesis

Nonmucinous BAC is thought to derive from a transformed cell in the distal airways and terminal respiratory units, and often shows features of Clara cell
Clara cell
Clara cells are dome-shaped cells with short microvilli found in the small airways of the lungs.Clara cells are found in the ciliated simple epithelium...

 or Type II pneumocyte
Type II pneumocyte
Type II pneumocytes also called great alveolar cells or septal cells are granular and roughly cuboidal in shape. Type II pneumocytes are typically found at the alveolar-septal junction...

 differentiation
Differentiation
Differentiation may refer to:* Differentiation , the process of finding a derivative* Differentiated instruction in education* Cellular differentiation in biology* Planetary differentiation in planetary science...

. 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.

Treatment

The treatment of choice in any patient with BAC is complete surgical resection, typically via lobectomy
Lobectomy
Lobectomy means surgical excision of a lobe. This may refer to a lobe of the lung, a lobe of the thyroid , or a lobe of the brain ....

 or pneumonectomy
Pneumonectomy
A pneumonectomy is a surgical procedure to remove a lung. Removal of just one lobe of the lung is specifically referred to as a lobectomy, and that of a segment of the lung as a wedge resection .-Indications:...

, with concurrent ipsilateral lymphadenectomy.

Non-mucinous BAC's are highly associated with classical EGFR mutations, and thus are often responsive to targeted chemotherapy with erlotinib and gefinitib. 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 suggest that administration of EGFR-pathway inhibitors to patients with K-ras mutated BAC's 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.

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.
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