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Bronchioloalveolar carcinoma and the significance of invasion: predicting biologic behavior.


A screening computed tomography scan of the chest of an asymptomatic 64-year-old man revealed a nodule in his left upper lobe. He had smoked 1 to 1.5 packs of cigarettes daily for 25 years, but had quit 25 years before presentation. He was referred to the University of Michigan, Ann Arbor, for further care. A repeated computed tomography scan confirmed the presence of a 1.2-cm nodule in the left upper lobe, abutting the major fissure. The differential diagnosis based on imaging studies included infection and carcinoma. A positron emission tomography scan result was reported as "negative for metabolic activity." Wedge lung biopsy was submitted for frozen section, followed by completion lobectomy.

Permanent sections from the wedge biopsy show a subpleural scar (Figure 1, A; digital image of scanned slide available at [accessed April 8, 2010]) surrounded by a proliferation of bland but abnormal epithelial cells distributed in a lepidic fashion along alveolar septa (Figure 1, B). The overall alveolar architecture is preserved. Within the scar, irregularly shaped nests of cytologically identical epithelial cells are intimately associated with collage nous and elastotic stroma but without a desmoplastic reaction (Figure 1, C and D). Some of the irregularly shaped spaces created by the infiltrating neoplastic cells contain pigmented alveolar macrophages. A final diagnosis of bronchioloalveolar carcinoma (BAC) was made. There was no visceral pleural invasion. All submitted lymph nodes were negative for neoplasm. The patient was alive with no evidence of disease 23 months after lobectomy.


The most recent revision of the World Health Organization (WHO) classification of tumors divides lung adenocarcinoma into 2 groups: BAC and invasive adenocarcinoma. (1) Conventional invasive adenocarcinomas are further subdivided into acinar, papillary, solid, and mixed subtypes. Mixed subtypes account for the vast majority of tumors. Other less common variants include fetal, mucinous (colloid), signet ring cell, and clear cell adenocarcinomas, as well as rare mucinous cystadenocarcinomas.

Pure BAC, strictly defined as a form of adenocarcinoma in which there is no stromal, vascular, or pleural invasion, is an uncommon tumor. In a 2008 review of 100 surgically resected adenocarcinomas from patients with stage I, II, or III disease, none of the tumors fit the strict definition of BAC. (2) Most tumors in this series (94%) were classified as showing mixed histologic features, meaning that tumors demonstrated 1 or more histologic subtypes such as acinar, papillary, bronchioloalveolar, or solid adenocarcinoma. However, when tumors were classified according to the major histologic component, defined as the histologic pattern comprising at least 75% of the sampled tumor, BAC accounted for 7 cases (7%). Papillary carcinomas emerged as the most common adenocarcinoma subtype. Another recently published review of 178 consecutively resected lung adenocarcinomas (3) demonstrated similar findings, identifying only 8 BACs (4.5%).

The purpose of this review is to summarize the histologic spectrum of BAC and to provide an update on the prognostic and therapeutic implications of focal invasion in this uncommon but important subset of primary pulmonary adenocarcinomas.

Histology of BAC

The WHO defines BAC as a tumor characterized by "growth of the neoplastic cells along pre-existing alveolar structures without evidence of stromal, vascular or pleural invasion." (1) Because BAC is defined by the absence of invasion rather than specific cytologic features, it spans a spectrum of mucinous, nonmucinous, and mixed cell types.


The most common subtype of BAC is the nonmucinous type, described by the WHO as "a non-mucinous adenocarcinoma derived from Clara cells and/or type II pneumocytes." (1) Nonmucinous BACs are more likely to present as low-stage, isolated, peripheral nodules located just beneath the pleura (Figure 2, A). They are composed of low columnar ("hobnail") epithelial cells distributed along alveolar septa and characterized by crowded, overlapping, mildly enlarged nuclei, small nucleoli, and eosinophilic to amphophilic cytoplasm (Figure 2, B and C). Cytoplasmic intranuclear pseudoinclusions similar to those more commonly seen in papillary thyroid carcinomas occasionally occur. The neoplastic cells of BAC are usually low grade. High-grade cytology occurs in a subset of cases but carries a greater likelihood of being associated with an invasive component. Neoplastic cells of nonmucinous BAC are typically immunoreactive for cytokeratin (CK) 7, thyroid transcription factor 1, and surfactant proteins while being negative for CK20. (4-7) Sensitizing EGFR mutations occur more frequently in nonmucinous than mucinous BAC, which most likely accounts for greater response rates to tyrosine kinase inhibitors in the former. (8)

Mucinous BAC has the same low-power architecture of nonmucinous tumors in which tumor cells spread along alveolar septa with overall preservation of lung architecture (Figure 3, A). However, the tumor cells in mucinous BAC are tall columnar cells with varying amounts of cytoplasmic mucin displacing the nucleus to the base of the cell (Figure 3, B). The bland cytology can make it difficult to separate mucinous BAC from benign processes. Helpful features include the absence of an underlying disease process that might explain nonneoplastic epithelial hyperplasia, a monomorphic population of mucinous columnar cells without ciliated or nonmucinous Clara cells, sharp transitions from normal to columnar mucinous cells, and tumor cells that are markedly enlarged compared to normal ciliated and nonciliated bronchiolar epithelium despite having abundant cytoplasm and therefore a low nucleus to cytoplasm ratio. Mucinous BAC cells are frequently immunoreactive for CK7 but unlike nonmucinous BAC also frequently coexpress CK20 and are usually negative for thyroid transcription factor-1. (4-7) Sensitizing EGFR mutations are less common and K-ras mutations more common in mucinous BAC compared to nonmucinous tumors, suggesting important differences in carcinogenesis. (8-10)

Mucinous BAC more often presents as a multifocal process or as pneumonic consolidation, and therefore tends to be associated with a more aggressive course (Figure 3, C). It is tumor stage however, rather than cell type or grade, that determines prognosis in BAC. (11-13)

Invasion in BAC: Impact on Prognosis

The presence or absence of stromal invasion in otherwise typical BAC has a proven impact on prognosis and therefore on potential therapeutic strategies. (3,14-16) A seminal study published in 1995 by Noguchi and associates (14) first demonstrated the profound impact of an invasive component in small peripheral adenocarcinomas, prompting the authors of the 1999 and 2004 WHO lung tumor classification to restrict the term bronchioloalveolar carcinoma to adenocarcinomas that lack stromal invasion.

Small amounts of stromal invasion may have only minimal if any impact on patient outcomes. Sakurai et al (15) assessed the impact of minimal invasion in small ([less than or equal to]2 cm) peripheral adenocarcinomas by separating tumors into 4 groups: grade 0, pure BAC without invasion; grade 1, predominantly BAC with a small focus of invasion; grade 2, predominantly BAC with invasion localized to the periphery of a central scar; and grade 3, BAC with obvious and unequivocal invasion involving a central scar. The 5-year disease-free survival rates associated with grades 0, 1, and 2 adenocarcinomas were 100% but it was only 59.5% for patients with grade 3 tumors. Similar studies using a quantitatively less strict definition for invasion show a similarly good prognosis for patients undergoing resection for small ([less than or equal to]2cm or [less than or equal to]3 cm) adenocarcinomas of mixed type with a predominant BAC component as compared to patients with tumors lacking a BAC component. (17,18)



Mixed adenocarcinomas comprising BAC and an invasive component measuring no more than 0.5 cm in greatest dimension are associated with outcomes equivalent to otherwise pure BAC. (3,16,19) Yim and colleagues (16) reported 141 consecutive surgical resections for low-stage (stages I and II) adenocarcinomas and divided them into 3 groups by using a size threshold based on the greatest measurable dimension of invasive disease. Group 1 tumors were those fitting the current WHO definition of BAC. Group 2 cases had no more than 5 mm of invasion and a concomitant bronchioloalveolar component. Group 3 tumors had a bronchioloalveolar component but with a larger invasive component that exceeded 5 mm. Group 4 tumors were invasive tumors without a bronchioloalveolar component. Group 1 was the smallest group, representing only 8 of 141 cases (5.7%), further demonstrating that BAC is a rare entity in its pure form. Group 2 tumors were more frequent (21 of 141; 14.9%) and also tended to be larger than group 1 tumors. The largest group of patients were those with conventional invasive tumors (66 of 141, 46.8%), followed by those with invasive tumors that showed an associated bronchioloalveolar pattern (46 of 141; 32.6%). Follow-up data showed that patients in groups 1 and 2, meaning those with 5 mm or less of invasion, had no deaths from disease within the study period. This compared to an 18% to 20% mortality rate for patients in groups 3 and 4.

Borczuk and associates (3) demonstrated nearly identical findings with a similar retrospective case-based study design that assessed 178 patients who underwent resection for adenocarcinoma. The term microinvasive carcinoma was used to describe tumors with 5 mm or less of invasion based on a linear measurement of invasive size. Neither pure BAC (8 of 178; 5%) nor microinvasive carcinomas (24 of 178; 13%) had nodal metastases. In contrast, tumors with mixed BAC and invasive components measuring greater than 5 mm and frankly invasive adenocarcinomas without a BAC component demonstrated nodal disease in 23% and 41% of patients, respectively. In addition, patients with tumors demonstrating less than 5 mm of invasion, including pure BAC, showed an overall survival advantage that was statistically significant. In multivariate analysis, only invasive size, nodal disease, and visceral pleural invasion had a statistically significant impact on survival. Gross tumor size, tumor grade, and tumor differentiation were not prognostically significant.

These studies affirm that the presence of invasion does provide valuable prognostic information but is not significant unless and until this component measures more than 0.5 cm in greatest dimension. Patients with mixed adenocarcinomas characterized by a predominant BAC component and a minor ([less than or equal to]5 mm) invasive component have the same survival experience as patients with pure BAC. While some have advocated for a new category consisting of microinvasive or minimally invasive adenocarcinoma to draw attention to this important subset of patients, an alternative argument can be made to revise the current definition of BAC to include not only pure ("in situ") tumors but also those with a predominant BAC component and no more than 0.5 cm of invasive tumor.

Invasion in BAC: Diagnosis

Recognizing invasion in what might otherwise be BAC is sometimes difficult. Distinguishing a truly invasive adenocarcinoma from BAC is especially challenging for those tumors in which neoplastic cells are intimately associated with a central scar, a phenomenon termed alveolar collapse by Noguchi and colleagues. (14) Our case nicely illustrates the challenge of identifying invasion in scar-associated tumors. Although the neoplastic cells inhabit an area of scar, they appear to exist within mature collagen scar without a true desmoplastic stroma (Figure 1, C and D). Focally the glands are irregularly shaped, but there are no single cells to establish with certainty a diagnosis of invasion. The 2004 WHO acknowledges this dilemma stating that the "distinction between sclerosing BAC and early invasive adenocarcinoma may be difficult." (1) The 2 features most helpful in identifying invasion include a true desmoplastic stromal response, characterized by proliferating myofibroblasts, and the presence of isolated neoplastic cells. Higher-grade cytologic atypia and necrosis are other occasionally helpful clues to the presence of invasive disease. Special stains for basement membrane components, such as type IV collagen or laminin, may also have value but in our experience are frequently difficult to intepret. (20)

Current and Future Therapeutic Strategies in BAC

A subset of patients with BAC can be managed with limited, lung-sparing resections. (21) In a review of 100 consecutive patients undergoing wedge resection or segmentectomy for lung carcinoma, Nakamura and colleagues (22) identified 27 patients with "pure groundglass" opacities on high-resolution computed tomography scan and all had histologically pure BAC. (22) No cancer-related deaths occurred in this group of patients. A more recent study of highly selected patients with BAC, (23) who were treated by either wedge resection or segmentectomy, showed a 5-year cancer-specific survival rate of 100%. This suggests that subtotal lung resections may be equivalent to lobectomy in patients with small BACs. Selecting patients for lung-sparing surgeries will probably hinge on a combination of preoperative imaging and intraoperative frozen-section techniques. Koike and associates (23) reported a 94% diagnostic accuracy rate when comparing frozen section to permanent section diagnoses of BAC versus invasive adenocarcinomas. Separating BAC from benign mimics can be challenging in a minority of cases. Gupta and associates (24) concluded that multiple growth patterns, anisocytosis, atypia in most (>75%) epithelial proliferations, macronucleoli, and atypical mitoses are helpful in separating BAC from nonneoplastic epithelial proliferations at the time of frozen section.

Histology, including BAC, has limited value in identifying patients likely to benefit from targeted therapies, most importantly tyrosine kinase inhibitors (TKIs). Numerous predictors of response to TKIs have emerged in the literature, including smoking status, sex, ethnic background, and adenocarcinoma histology including especially tumors with at least some BAC component. A recent review summarizing combined data from 5 Western trials totaling 317 patients who received TKIs as first-line therapy demonstrated that sensitizing epidermal growth factor receptor (EGFR) mutations had the highest impact on predicting response rates, time to disease progression, and overall survival rates. (25) Other putative predictors of TKI response, such as race, sex, smoking status, and histologic features, served mainly to enrich for tumors more likely to harbor sensitizing mutations. Since then, a large retrospective review of 100 patients with adenocarcinoma has indicated that papillary histology, rather than BAC, predicts sensitizing mutations. (2)


Bronchioloalveolar carcinoma is a form of noninvasive pulmonary adenocarcinoma that exists in both nonmucinous and mucinous forms. In addition to the absence of invasion, the histologic hallmark of this tumor is its bland cytology, sometimes making it difficult to distinguish from a reactive process. Bronchioloalveolar carcinoma is defined by its lack of invasion, but this distinction can be diagnostically challenging if tumor is involving a scar. Small area of invasion in what is otherwise typical BAC does not significantly impact prognosis, suggesting that current diagnostic criteria may be too strict. Recognition of BACs and their minimally invasive counterparts is important, given significant prognostic as well as therapeutic implications.


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(22.) Nakamura H, Saji H, Ogata A, Saijo T, Okada S, Kato H. Lung cancer patients showing pure ground-glass opacity on computed tomography are good candidates for wedge resection. Lung Cancer. 2004;44(1):61-68.

(23.) Koike T, Togashi K, Shirato T, et al. Limited resection for noninvasive bronchioloalveolar carcinoma diagnosed by intraoperative pathologic examination. Ann Thorac Surg. 2009;88(4):1106-1111.

(24.) Gupta R, McKenna R Jr, Marchevsky AM. Lessons learned from mistakes and deferrals in the frozen section diagnosis of bronchioloalveolar carcinoma and well-differentiated pulmonary adenocarcinoma: an evidence-based pathology approach. Am J Clin Pathol. 2008;130(1):11-20.

(25.) Jackman DM, Miller VA, Cioffredi LA, et al. Impact of epidermal growth factor receptor and KRAS mutations on clinical outcomes in previously untreated non-small cell lung cancer patients: results of an online tumor registry of clinical trials. Clin Cancer Res. 2009;15(16):5267-5273.

Lindsay Schmidt, MD; Jeffrey Myers, MD

Accepted for publication June 9, 2010.

From the Department of Pathology, University of Michigan, Ann Arbor.

The authors have no relevant financial interest in the products or companies described in this article.

Presented at New Frontiers in Pathology: An Update for Practicing Pathologists, University of Michigan, Ann Arbor, Michigan, October 8, 2009.

Reprints: Lindsay Schmidt, MD, Department of Pathology, University of Michigan, 1500 E Medical Center Dr, Room 2G332, Ann Arbor, MI 48109 (e-mail:
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Author:Schmidt, Lindsay; Myers, Jeffrey
Publication:Archives of Pathology & Laboratory Medicine
Date:Oct 1, 2010
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