Bronchioloalveolar carcinoma (BAC) is a variant of non-small cell lung cancer (NSCLC) that in recent years has received a new identity and nomenclature from the histology perspective. The orphan among lung cancers has found a family, albeit with some newfound stepbrothers and sisters. The overhaul in the classification system of solitary adenocarcinomas has been driven by the purpose of identifying tumors that have an indolent clinical course and can be treated with a more conservative approach and a higher success rate.
Until the previous decade, strict pathologic criteria defined a bronchioloalveolar carcinoma as a tumor arising from terminal bronchiolar and alveolar acinar epithelia with an absence of invasion through the alveolar basement membrane into the pulmonary parenchyma. A growing consensus has been to subclassify adenocarcinoma with radiologic features of ground-glass opacities, with no or minimal extrathoracic spread, and histology demonstrating a lepidic growth pattern, in presence or absence of associated minimally invasive or invasive disease. The subgroup has been renamed adenocarcinoma with lepidic growth and classified into subtypes based on the extent of invasive disease.
The earliest description of adenocarcinoma lung with peripheral pneumonic invasion can be traced to as early as 1876 by Malassez describing a multinodular pulmonary tumor as "cancer encephaloid du poumon." Subsequently, in 1903, Muser described a similar diffuse growth pattern in a pulmonary tumor. History waited another 57 years before Liebow coined the term " bronchioloalveolar carcinoma " in 1960. He used it to describe a well-differentiated form of adenocarcinoma which exhibits any of the three growth patterns: (1) Single nodular (2) multinodular, or (3) diffuse pneumonic pattern.
However, the pathologic criteria for bronchioloalveolar carcinoma remained somewhat nebulous. And as knowledge of radiology, histology, and immunophenotyping continued to evolve, the necessity to identify certain subtypes among the conglomerate of NSCLC with a more favorable prognosis and less invasive treatment became increasingly important.
The Liebow definition held its stature until 2004 when the World Health Organization (WHO) publication on the tumors of the lung, pleura, thymus, and heart redefined bronchioloalveolar carcinoma as adenocarcinoma with a lepidic growth pattern along alveolar walls without stromal, vascular, or pleural invasion. They classified bronchioloalveolar carcinoma into (1) mucinous and (2) non-mucinous subtypes. In addition, they delineated a continuum as adenocarcinoma with both bronchioloalveolar carcinoma and invasive component and invasive adenocarcinoma with stromal invasion and reactive fibroblastic response.
The extent of the invasive component has been under intense scrutiny to identify the limits of a subtype that still portends a favorable prognosis or a scope of limited resection. A joint collaborative of the International Association for the study of Lung Cancer (IASLC), American thoracic society (ATS), and European Respiratory Society (ERS) introduced a revised classification of pulmonary adenocarcinoma. Among salient modifications was a revised identification of adenocarcinoma precursors as well as a semi-quantitative assessment of adenocarcinoma growth patterns. The classification has been validated worldwide as a stage-independent predictor of survival.
The ATS/ERS/ IASLC classification in 2011, therefore, did away with the term bronchioloalveolar carcinoma altogether and focused on all tumors exhibiting lepidic growth pattern.
Salient Features of the Revised Classification of 2011
It is therefore important to remember that the terms "bronchioloalveolar carcinoma " and "adenocarcinoma with lepidic growth" are not synonyms but a reflection of our evolved histologic understanding of a less aggressive form of adenocarcinoma overall.
The classification was approved by the 2015 WHO classification of pulmonary adenocarcinoma. Finally, in 2017 the 8th Edition of the lung cancer TNM classification of acknowledged the new subclassifications and made appropriate changes to the T component based on nodule characteristics.
Adenocarcinoma with lepidic growth has been reported to have a 15% to 20% incidence among all NSCLC. Pure AIS and minimally invasive adenocarcinoma (MIA) are rare and have a 3% to 6% prevalence among all lung cancers.
Younger age, women, and nonsmokers were reported as more predominant in the bronchioloalveolar carcinoma subgroup than adenocarcinoma in general. Women represented more than 50% while nonsmokers comprised one-third of the overall prevalence of bronchioloalveolar carcinoma.
The term "lepidic" originates from Latin and alludes to a sense of "scale-like" appearance of flat cells without papillary outgrowths. The lepidic growth pattern lacks alveolar thickening; evidence of inflammation; vascular, stromal or pleural invasion; or desmoplastic reaction.
Histomorphological Overview of Current Tumors in Adenocarcinoma with Lepidic Growth
Atypical Adenomatous Hyperplasia (AAH)
Less than 0.5 cm, localized areas of hyperplasia of type 2 pneumocytes and/or Clara cells replacing normal alveolar epithelium.
Adenocarcinoma in Situ (AIS)
The closest to the previous non-mucinous BAC. Less than 3 cm, solitary nodules with pure lepidic growth with somewhat higher cellular atypia than AAH. They have small monomorphous nuclei with pinpoint nucleoli and occasional nuclear inclusions.
Minimally Invasive Adenocarcinoma (MIA)
Less than 3 cm solitary lesions with lepidic growth pattern with less than 5 mm areas of invasive foci in addition. The invasive component can be uni- or multifocal and can be of any histologic pattern other than lepidic (papillary, micropapillary, acinar, or solid). By definition, they do not have any evidence of vascular, stromal, or pleural invasion. It can be challenging at times to distinguish alveolar collapse from stromal invasion, and elastin stains can be of use.
Lepidic Predominant Adenocarcinoma (LPA)
Adenocarcinoma with areas of lepidic growth and greater than 5 mm invasive foci or evidence of invasion of stroma with blood vessel, pleura, or lymphatic invasion or necrosis. A higher percentage of lepidic growth patterns were associated with a lower risk of recurrence. Multiple studies have demonstrated that the invasive component size and the histomorphologic subtype are better predictors of survival than total tumor size.
Cytological features include a flat sheet of homogenous neoplastic cells with mild nuclear enlargement and prominent nuclear grooves. In the case of minimally invasive adenocarcinoma, apart from the lepidic growth pattern, the invasive component is represented by papillary or acinar growth patterns in the center or periphery of the tumor mass.
Kuwata et al. looked at the microenvironmental changes in the transition of AIS to lepidic predominant invasive adenocarcinoma (LPA) of the lung. During the progression from AIS to LPA, expression of laminin 5 and ezrin in the invasive component was significantly increased. Tumor-promoting stromal cells were also expressed in higher proportions. High expression of ezrin is associated with lymphovascular invasion and poorer prognosis of LPA. It can thus be explored as a marker for the metastatic potential for these groups of neoplasms.
Features of high differentiation or lepidic pattern, irrespective of the invasive component, do provide the treating physician a direction in terms of the search for therapeutic targets. EGFR mutations are more frequently associated with lepidic growth pattern and prior BACs. Even when adjusted for sex, smoking status, and EGFR amplification, exon 21 missense mutation has been found to be significantly more common in LPA. Ground glass volume percentage within a tumor was found to correlate significantly with exon 21 missense mutation. Whereas a nonmucinous bronchioloalveolar carcinoma is highly positive for TTF-1 and CK-7, mucinous bronchioloalveolar carcinoma is focally and weakly positive for those markers. Mucinous bronchioloalveolar carcinoma may show strong positivity for CK 20.
Daly et al. evaluated presenting symptoms of 134 patients diagnosed with BAC. Of those, 68% were asymptomatic at presentation with 17% presenting with a cough. Unlike other NSCLCs, bronchorrhea or excessive airway secretions were more common in this subgroup (17%) as was nonspecific chest pain (10%). Copious frothy secretions up to a few liters per day have been reported to the extent of causing a fluid-electrolyte imbalance. Its presence usually portends a poor prognosis.
Computed tomography (CT) of the chest may show an isolated, or more often, a multifocal or diffuse opacity with a predominant ground-glass pattern.
Size and mass of the nodule are important predictors of an invasive component.
Differential diagnosis of a ground glass area of opacity in CT may include organizing pneumonia, focal inflammation, or focal fibrosis. Precise measurement of a subsolid nodule size can often be challenging in axial CT. An alternative method of measurement could be volumetry though it has not been standardized and validated.
While erstwhile non-mucinous bronchioloalveolar carcinoma presents most commonly as ground-glass nodules with a variable solid component, mucinous bronchioloalveolar carcinoma more often present as pneumonic infiltrates with consolidation, pseudo cavitation, and often visualization of blood vessels within the area of mucinous consolidation – known as " angiogram sign."
Consolidation tumor ratio, defined as a ratio of the maximum diameter of the area of consolidation to the tumor, has also been used as a prognostic marker in the non-solid adenocarcinoma with lepidic growth.
Cellular density and turnover being somewhat lower, fluorodeoxyglucose (FDG) uptake in a positron emission tomography (PET) scan is often underwhelming, and these lesions are often, therefore, PET negative.
Forty-five percent to 60% of the erstwhile bronchioloalveolar carcinomas have been reported to present in radiologic stage 1 or stage 2 disease.
Tissue diagnosis by biopsy is the confirmatory step. However complete histologic evaluation of an excised specimen or biopsy is increasingly stressed upon to determine the extent of invasiveness. The diagnosis of adenocarcinoma with lepidic growth made by cytology or core biopsy can contain a more invasive component in an excised specimen.
The specificity of frozen section biopsy of diagnosing adenocarcinoma with lepidic growth is excellent, however, with positive predictive values of 93% to 100%.
Complete surgical excision is the most definitive therapy to align with the reported recurrence-free survival rates. Lobectomy has been the most followed approach although, in clinical practice, patients with limited lung functions or multifocal synchronous disease pose a challenge at times. Limited resection by segmentectomy or sublobar resection has, therefore, been considered under less than ideal circumstances for lobectomy.
Radiologic pure solid adenocarcinoma is found to have intraoperative nodal involvement in 15% to 20% of cases, and is, therefore, not considered to be ideal candidates for sublobar resection. Hattori et al. retrospectively reviewed 200 radiologic stage 1a lung adenocarcinoma cases to identify clinical factors associated with histologic lepidic predominant adenocarcinomas. They found that SUV max level of less than 3.3 in PET scan correlated well with lepidic predominant growth even in pure solid stage 1a adenocarcinomas, and therefore opens up scope for sublobar resection in the subgroup that would not tolerate lobectomy otherwise.
Differential diagnosis of bronchioloalveolar carcinoma with similar histological findings but much more favorable prognosis includes:
Immunophenotyping is helpful in differentiation.
Early chemotherapy trials with paclitaxel in advanced bronchioloalveolar carcinoma showed a somewhat better outcome than another similar stage adenocarcinoma otherwise but poor nevertheless. Hirsch et al. demonstrated that these tumors do have a high expression of EGFR mutation, opening up a potential early therapeutic target. Two large trials (SWOG and MSKCC- VANDERBILT) demonstrated a robust response to erlotinib and gefitinib, as frontlines of therapy more often in bronchioloalveolar carcinoma patients.
Erstwhile mucinous bronchioloalveolar carcinomas, however, are more frequently K ras mutation-positive (reported at 75%) with low expression of EGFR mutation. They are, therefore, somewhat more responsive to taxane-based chemotherapy and are not ideal candidates for EGFR targeted therapy.
Finally, like other variants of adenocarcinoma, the treatment of locally advanced or metastatic adenocarcinoma with lepidic growth has also been positively impacted by the advent of immunotherapy in general, and PD1-L1 inhibitors to be specific.
Tumors identified as bronchioloalveolar carcinoma or adenocarcinoma with lepidic growth rarely follow the traditional progression through nodal or vascular involvement. Multifocal disease within lung parenchyma has been seen and attributed to synchronous disease or aerogenous spread. Given their intrathoracic spread, even lung transplantation has been performed in cases of multifocal BACs but has often exhibited recurrence in the donor's lung as late as 48 months post-transplantation.
Considering all forms of adenocarcinoma, the solid component (contrary to ground glass) and mucinous pattern are widely considered to be predictors of metastatic potential.
The reason the name " bronchioloalveolar carcinoma" was destined to die was that it clubbed two very unrelated forms of adenocarcinoma in histology, immunophenotype and invasive nature. It also became important to recognize minimally invasive adenocarcinoma, which portends a similar prognostic significance as AIS or reclassify adenocarcinoma purely from the prognostic viewpoint.
Since the introduction of the newer classification, there have been several articles with caution and counterarguments. The purpose of those is not to be ignored as they convey a valued message that identification of adenocarcinoma as one with lepidic growth does not label them as one with potential curability or 100% disease-free survival until a surgical staging has been achieved with adequate evaluation of the specimen in its entirety along with evaluation of pleura and lymph nodes. Finally, it has opened up scope for early planning of definitive therapy with sometimes less limited resection and preservation of lung function with equally optimistic outcomes.
Smoking cessation counselling and education are imperative with the diagnosis of this disease. Screening should be conducted in patients over the age of 50 who have the following risk factors:
The survival of most patients with lung cancer is poor. Thus, a streamlined approach to diagnosis and treatment is recommended. the earlier the cancer is diagnosed, the higher the cure rate with surgery. Since the majority of patients with lung cancer initially present to the primary caregiver, a high index of suspicion should be held. Any patient with risk factors for lung cancer should at least have a chest x-ray and possibly a CT scan of the chest. The radiologist is essential for biopsy of any lung lesion, and the pathologist is necessary to determine the type of cancer. A thoracic surgeon should be involved in the care of the patient since early surgery is curative. Even after surgery, an interprofessional team of healthcare workers needs to follow the patient to ensure that there is no recurrence or metastatic disease. [Level V] For those patients deemed non-surgical candidates, the treatment is chemotherapy. When metastases occur, a pain management specialist and a radiation oncologist must be consulted to determine the options for pain management. With the availability of the newer targeted agents, the oncology specialist pharmacist plays a key role in selecting agents and monitoring the patient for adverse reactions and reporting concerns to the team. There are many guidelines established to assess patients for lung cancer but the key is an index of suspicion.
BAC is managed by an interprofessional team. Besides the pulmonologist and thoracic surgeon, other team members may include a pathologist, oncologist, radiation oncologist, pharmacist, and specialty trained nurses in surgery and oncology. The surgical nurse should assist in the coordination of care, patient and family education regarding surgery, and monitoring the patient for surgical complications with reporting of untoward events to the team. Pharmacists should evaluate medications prescribed, drug-drug interactions, and patient compliance and communicate with the team. Specialty trained oncology nurses should assist with aftercare by helping with the education of the patient and their family, coordination of followups, and evaluating for recurrence and report issues to the team.[Level 5]
Tumors classified as MIA and AIS have been shown to have a near 100% disease-free survival once completely resected. (100% 10-year disease-free survival for AIS and 97.3% to 100% for MIA)[Level II]
Tumors identified as bronchioloalveolar carcinoma or adenocarcinoma with lepidic growth rarely follow the traditional progression through nodal or vascular involvement. Multifocal disease within lung parenchyma has been seen and attributed to synchronous disease or aerogenous spread. Given their intrathoracic spread, even lung transplantation has been performed in cases of multifocal BACs but has often exhibited recurrence in the donor's lung as late as 48 months post-transplantation. [Level II]
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