B R O N C H I O L O A LV E O L A R C ARCINOMA AND M I N I M A L LY I N VA S I V E ADENOCARCINOMA Andre L. Moreira, MD, PhD KEYWORDS  Adenocarcinoma  Lung  Bronchioloalveolar carcinoma  Carcinoma in situ

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he most recent WHO classification of lung cancer defines bronchioloalveolar carcinoma (BAC) as a noninvasive carcinoma or adenocarcinoma in situ. However, the use of this terminology is not uniform and does not reflect standardized criteria. As a result, the diagnosis of BAC has been used in association with small, solitary, and well-differentiated adenocarcinoma as well as tumors with advanced clinical stage. At present, there is a growing consensus among specialists in thoracic oncology that BAC or adenocarcinoma in situ is a rare tumor, and the term should be restricted to adenocarcinomas that show a pure lepidic pattern of growth. The amount of invasive component present in a tumor with a predominant lepidic growth pattern has also been under intense scrutiny. The concept of minimally invasive adenocarcinoma is developing in order to differentiate a pure BAC from an invasive adenocarcinoma that still carries an excellent prognosis.

OVERVIEW Not long ago, all pulmonary adenocarcinomas were grouped together with squamous cell carcinoma and classified as non–small cell carcinomas. There was no attempt to differentiate among the histologic subtypes of adenocarcinoma, partially because all non–small cell carcinomas were regarded as having the same prognostic significance and treatment options. This concept has changed dramatically in the last decade. The observation that pure bronchioloalveolar carcinoma (BAC) had a 5-year survival rate of

100%1,2 has revolutionized the field by demonstrating that not all pulmonary adenocarcinomas are the same. This observation has been confirmed by several investigators3–6 and has resulted in the modification of the entire classification of pulmonary adenocarcinoma.2 The current definition of BAC by the World Health Organization (WHO) classification of lung cancer is that of an adenocarcinoma that grows along preexisting alveolar structures (lepidic growth pattern) without stromal, vascular, or pleural invasion. Therefore, it is defined as a noninvasive adenocarcinoma or adenocarcinoma in situ.2 There is intense investigation on the subtypes of adenocarcinomas and their histologic prognostic significance. In addition, targeted therapy toward specific mutations in adenocarcinomas subtypes has revolutionized the clinical management of patients with lung cancer. The WHO recognizes 2 main types of bronchioloalveolar carcinoma, mucinous and nonmucinous. These 2 entities, though sharing the lepidic growth pattern, are very different regarding histologic and molecular features, as well as natural history.7 This article discusses the diagnostic criteria, differential diagnosis, and diagnostic pitfalls for these entities. In addition, the emerging concept of minimally invasive adenocarcinoma is examined.

NONMUCINOUS BRONCHIOLOALVEOLAR CARCINOMA GROSS AND RADIOGRAPHIC FEATURES It is very difficult to identify a pure BAC grossly because of the intrinsic characteristic of growth

Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA E-mail address: [email protected] Surgical Pathology 3 (2010) 1–26 doi:10.1016/j.path.2010.03.006 1875-9181/10/$ – see front matter ª 2010 Elsevier Inc. All rights reserved.

surgpath.theclinics.com

ABSTRACT

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Key Features NONMUCINOUS BRONCHIOLOALVEOLAR CARCINOMA Adenocarcinoma that grows along preexisting alveolar structures without parenchymal, vascular, or pleural invasion, therefore BAC is an adenocarcinoma in situ. Tumor cells can be flat, columnar, or hobnail, and exhibit mild to significant cytologic atypia. The presence of any invasive component excludes the diagnosis of BAC. Rare tumor. Very often described radiographically ground-glass opacity (GGO).

as

Excellent prognosis when it presents as a solitary tumor. Can be multifocal. The diagnosis should be made only in complete excised tumors.

with preservation of the pulmonary alveolar structures. The tumor does not form a defined nodule but rather a slight discoloration or firmness of the pulmonary parenchyma (Fig. 1). The effect is more tactile than visual. The tumor is more

frequently discovered by radiographic examination. Radiologists very often describe the computed tomography (CT) scan appearance of a pure BAC as that of ground-glass opacity (GGO)8,9; however, there is no consensus among radiologists on a defined radiographic appearance for BAC, mostly because not all pure GGO lesions, when excised, correspond to pure BAC histologically. Studies of radiographic-histologic correlations have showed that pure GGO can have a component of invasive adenocarcinoma admixed with a BAC growth pattern,10 and invasive adenocarcinomas, such as pure papillary type, can present radiographically as a GGO. In addition, GGO is not a specific diagnosis for carcinoma. GGO represents pulmonary lesions that are characterized by the preservation of air spaces. Therefore, GGO can be seen in infectious, inflammatory, and neoplastic processes.11–13

MICROSCOPIC FEATURES BAC is defined by a pure lepidic growth pattern; lepidic means a pattern that resembles layers of scales. Histologically there is a continuous growth of neoplastic cells along the alveolar septa without disruption of the alveolar structures, although mild fibrosis or enlargement of the alveolar wall is permitted (Figs. 2 and 3). The neoplastic cells may have a different histologic appearance such Fig. 1. Wedge resection for a ground-glass opacity in the lung. Note the absence of a defined tumor mass. Arrow points to an area of slight discoloration of the pulmonary parenchyma where the histologic sections confirm the presence of a pure BAC.

BAC and Minimally Invasive Adenocarcinoma Fig. 2. Histologic section of a pure nonmucinous BAC. Note the growth of the neoplastic cells along the preexisting alveolar septa, the presence of pigmented alveolar macrophages within the alveolar spaces, the absence of reactive desmoplasia, and definite invasive component (H&E stain, original magnification 50).

as flat, cuboidal, columnar, or hobnail (Figs. 4–6). It has been demonstrated that nonmucinous BAC can be composed of 2 cell types, namely Clara cells (a secretory cell of the terminal bronchioles thought to be a reserve cell type) and type II pneumocytes—whether this represents tumor

Fig. 3. Low-power magnification of a nonmucinous BAC. Note the growth of the tumor cells along preexisting alveolar spaces without destruction of the alveolar structure, and bland neoplastic cells. The tumor in this case showed clear cell changes (H&E stain, original magnification 50).

cell differentiation or cell of origin remains uncertain. A recent study using specific antibodies for Clara cells showed that approximately 30% of nonmucinous BACs stain with specific Clara cell antibodies, whereas the majority of the BAC shows type II pneumocyte differentiation. Of

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Moreira Fig. 4. Higher magnification of a pure BAC, showing that the tumor in this case is composed of crowded columnar cells with mild cytologic atypia lining the alveolar septa (H&E stain, original magnification 200).

note, there are no differences in prognosis or natural history of the disease from BAC that have Clara cell or type II pneumocyte differentiation; therefore, the distinction of the 2 cell types has no clinical relevance.14 The paramount definition of BAC is that of a noninvasive tumor. Therefore, areas of fibrosis or scar associated with the tumor nodule and the presence of complex growth patterns such as acinar and papillary structures are exclusion criteria for the diagnosis of BAC.

DIFFERENTIAL DIAGNOSIS The differential diagnosis for nonmucinous bronchioloalveolar carcinoma includes, among others, minimally invasive adenocarcinoma and mucinous type bronchioloalveolar carcinoma. These 2 entities are discussed later in this article. One of the most important differential diagnoses of pure nonmucinous BAC is a well-differentiated mixed subtype adenocarcinoma, which can be defined as a pulmonary adenocarcinoma with Fig. 5. In this example of BAC, the tumor is composed of highly atypical hobnail cells lining the alveolar septa. Note the variation in cytologic atypia that can occur in BAC (H&E stain, original magnification 200).

BAC and Minimally Invasive Adenocarcinoma

Differential Diagnosis NONMUCINOUS BRONCHIOLOALVEOLAR CARCINOMA The presence of invasive component or desmoplastic reaction (scar) leads to the diagnosis of an invasive adenocarcinoma. The presence of a small amount of invasion (%5 mm) leads to the diagnosis of a minimally invasive adenocarcinoma. Atypical adenomatous hyperplasia is characterized by the presence of a small lesion with discontinued lepidic growth pattern of atypical cells along the alveolar septa, whereas BAC has a continuous and more complex growth along the alveolar septa.

a predominant component of BAC admixed with papillary or acinar growth patterns. Well-differentiated pulmonary adenocarcinoma, especially those with a papillary pattern of growth, can show histologic similarities to BAC by the appearance of open air spaces histologically. Alveolar macrophages can be seen in association with papillary growth pattern (Fig. 7), and pure papillary adenocarcinomas can even be described radiographically as GGO on CT scan. However, different from BAC, papillary adenocarcinoma has complex papillary projections into the alveolar space, and very often show blunt-ended finger-like projections (Fig. 8). Different from pure BAC, the entire alveolar structure is not observed and tertiary structures with the formation of fibrovascular cores lined by neoplastic cells are seen to replace the preexisting alveolar structure (Fig. 9). The

Fig. 6. In this example of BAC, the tumor is composed of cuboidal and flat cells with minimal cytologic atypia lining the alveolar septa (H&E stain, original magnification 100).

differential diagnosis between papillary adenocarcinoma and BAC is very challenging. Given the prognostic significance of a pure BAC to disease management, careful evaluation of the entire histologic sections with the intent to exclude an invasive component should be conducted before the diagnosis of BAC is made. The pattern of lepidic growth is not restricted to pulmonary adenocarcinoma, and can be seen in metastatic tumors to the lung (Fig. 10). However, this is easier to recognize because a metastatic tumor is in general associated with an invasive growth pattern that will induce a desmoplastic reaction in the surrounding parenchyma. A lepidic growth pattern in metastatic tumors, although rare, can be seen with adenocarcinomas from other organs, especially from the gastrointestinal tract,15 transitional cell carcinoma, squamous cell carcinoma, and even malignant melanoma. Atypical adenomatous hyperplasia (AAH) is an important differential diagnosis of BAC because of the overlap of histologic criteria for these entities.2 AAH is defined by the WHO classification as a precursor of pulmonary adenocarcinomas. AAH is frequently found incidentally in normalappearing areas of lungs that are excised for adenocarcinoma, although it has also been reported in association with other histologic tumor types.2 It is very unlikely that a pathologist will be confronted with this entity outside the examination of a lobectomy or segmentectomy specimen for a pulmonary nodule. The reason for this is that AAH is, in general, too small to be detected radiographically, and given the uncertainties in the management of small GGO, more likely a true AAH would be followed

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Moreira Fig. 7. Invasive papillary adenocarcinoma mimicking a pattern of BAC. Note the presence of thick alveolar septa containing chronic inflammation and true fibrovascular core that can be misinterpreted as thick alveolar septa. The presence of papillary tufts projecting within the alveolar spaces is evident. Pigmented alveolar macrophages can also be seen in papillary adenocarcinoma similar to BAC (H&E stain, original magnification 200).

clinically and radiographically and not managed surgically. AAH is defined histologically as a small lesion, in general less than 5 mm in diameter, that shows a lepidic growth pattern with mild enlargement of the alveolar septum. Different from BAC, the cells are irregularly spaced within the alveolar septa and do not form a continuous layer of growth (Fig. 11). One criterion for exclusion of the diagnosis of AAH is inflammation within the alveolar

septum. If chronic inflammation is present then the best diagnosis is focal type II pneumocyte hyperplasia rather than AAH. It is very common in the practice to identify small lesions in the excised lung that have histologic criteria in between AAH and BAC. These lesions show focal areas of continuous growth of cells along the alveolar septa interspersed with areas that show a discontinued growth pattern (Fig. 12). In these instances, it is better to observe

Fig. 8. Invasive papillary adenocarcinoma. Note papillary branches with fibrovascular core mimicking alveolar spaces; the complexity of the neoplastic glands with finger-like projections; and the presence of neoplastic cells within the desmoplastic stroma (invasion). Similar to BAC, the neoplastic cells in papillary carcinoma can be bland with minimal cytologic atypia (H&E stain, original magnification 100).

BAC and Minimally Invasive Adenocarcinoma Fig. 9. Low-power magnification of a papillary adenocarcinoma, showing papillary projections within the pseudo alveolar spaces. Contrary to BAC there is no preservation of the alveolar spaces, but rather the tumor grows in a complex pattern with many blunt-ended fingerlike projections. In this example the tumor was described radiographically as pure ground-glass opacity (H&E stain, original magnification 50).

the clinical context in which these lesions are seen. If they are multiple, smaller than 5 mm, and present in the background of a clearly invasive adenocarcinoma, but separated from the main tumor, the diagnosis of AAH is best suited. However, if the lesion is single and larger than 5 mm, the diagnosis of an incidental BAC is the best interpretation. In reality this is an academic exercise because there is no definite clinical implication for the diagnosis of AAH and BAC in the

Fig. 10. High-grade urothelial carcinoma metastatic to the lung. In this case the metastatic carcinoma grows along alveolar septa, mimicking the lepidic pattern seen in BAC. Note the cytologic atypia and the mild enlargement of the alveolar septa. This patient presented with multiple pulmonary nodules, a feature that can be seen in metastatic disease as well as with BAC. However, in other areas of the excision, invasive urothelial carcinoma was seen within the pulmonary parenchyma (H&E stain, original magnification 100).

context of multiple small nodules seen in a resection for adenocarcinoma. There is growing consensus among thoracic oncologic specialists (including oncologists, surgeons, pathologists, and radiologists) that these small multifocal lesions are an indication of a propensity of these patients to develop multifocal adenocarcinomas. Peribronchiolar metaplasia is a small reactive process that is often encountered in the lung parenchyma of patients with interstitial lung

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Moreira Fig. 11. Small lesion with a lepidic growth pattern detected in an area of normal-appearing lung parenchyma in a lobectomy for invasive adenocarcinoma. This small lesion shows thickening of the alveolar septa with preservation of the alveolar structures, and a discontinued growth of mildly atypical cells along the alveolar space. These features are diagnostic of atypical adenomatous hyperplasia (AAH) (H&E stain, original magnification 50).

disease, collagenous vascular disease, or chronic obstructive pulmonary disease. It is characterized by the proliferation of bronchiolar epithelium into the peribronchiolar alveolar space. Peribronchiolar metaplasia can be multifocal and has been described as a cause of rare interstitial lung disease.16 Histologically, ciliated bronchial epithelium grows in a lepidic pattern along mildly fibrosed alveolar wall (Fig. 13), thus mimicking a BAC or AAH. The identification of ciliated epithelium is the best diagnostic criterion to make the correct diagnosis (Fig. 14). In addition, BAC and AAH can be seen anywhere in the pulmonary

parenchyma, whereas peribronchiolar metaplasia is invariably seen in the peribronchiolar space. Peribronchial metaplasia is not a neoplastic or preneoplastic process.

DIAGNOSIS The correct diagnosis of bronchioloalveolar carcinoma is extremely important because of the prognostic significance of this tumor. The diagnosis of BAC or adenocarcinoma in situ should be rendered only on complete histologic examination of an excised specimen. The diagnosis of BAC Fig. 12. Small lesion identified in an area of normalappearing lung from a lobectomy for adenocarcinoma. This lesion shows diagnostic features in between AAH and BAC. There are focal areas of continuous growth of atypical cells along the alveolar wall, in contrast to focal areas where the growth of neoplastic cells is discontinued. Therefore it does not fulfill the diagnostic criteria for either entity. The diagnosis very often is made in the context of how the lesion is seen clinically (H&E stain, original magnification 50).

BAC and Minimally Invasive Adenocarcinoma Fig. 13. Low-power magnification of a lesion seen in the peribronchiolar space. Continuous growth of atypical cells along preexisting alveolar spaces is seen. The location of the lesion in the peribronchiolar space is a good diagnostic clue. This represents bronchiolar metaplasia, a mimicker of BAC. The identification of columnar ciliated epithelium is diagnostic of this entity (H&E stain, original magnification 50).

should not be made in a core biopsy or cytology specimen. It is not uncommon to encounter a predominant lepidic growth pattern in a core biopsy specimen (Fig. 15). In these cases the diagnosis of adenocarcinoma with features of bronchioloalveolar carcinoma is favored, instead of fully classifying the tumor in a limited biopsy sample. BAC pattern can be seen as a component at the periphery of

Fig. 14. Peribronchiolar metaplasia. High-power magnification of Fig. 13. Note the presence of ciliated epithelium lining the preexisting alveolar space, therefore cementing the diagnosis of peribronchiolar metaplasia (H&E stain, original magnification 400).

invasive mixed subtype adenocarcinomas. In addition, the information that the biopsied tumor may have a well-differentiated component indicated by ‘‘BAC pattern’’ may give the treating physician important information about potential targeted therapy applications. Well-differentiated mixed subtype adenocarcinomas as well as BAC have been associated with epidermal growth factor receptor (EGFR) mutation, which is a target

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Moreira Fig. 15. Core biopsy of a lung nodule, showing the presence of atypical cells lining the alveolar space and mild fibrosis of the alveolar septa. These features are consistent with the diagnosis of BAC or adenocarcinoma in situ. However, this diagnosis is discouraged and instead the diagnosis of adenocarcinoma with features of BAC should be rendered. The diagnosis of BAC should be made only on evaluation of a complete excised specimen (H&E stain, original magnification 100).

for specific therapy in patients with lung cancer.17,18 However, there is no consensus that BAC is synonymous with EGFR mutation; rather, EGFR mutation is more frequently associated with tumors with BAC and papillary carcinoma components.19 Potential pitfalls for the diagnosis

of adenocarcinoma with BAC features in core biopsies are inflammatory conditions with florid type II pneumocyte hyperplasia, AAH, and sclerosing hemangioma. As discussed earlier, AAH is a small lesion that unlikely would be detected radiographically for biopsy. However, similar to

Fig. 16. Fragments of a core biopsy that show mild thickening of the alveolar septa and the presence of flat and mildly atypical cells lining the alveolar septa in a discontinued fashion. Although the criteria fit the diagnosis of AAH, this diagnosis should not be made in a core biopsy. More likely this may represent the target lesion being missed. In this case, the differential diagnosis includes the presence of an adenocarcinoma with BAC features, AAH, and type II pneumocyte hyperplasia. The latter can be seen around a tumor or in association with an inflammatory or infectious process. Therefore, the best diagnosis in these cases is to indicate the presence of atypical type II pneumocyte hyperplasia and describe the differential diagnosis in a note (H&E stain, original magnification 100).

BAC and Minimally Invasive Adenocarcinoma BAC it can be seen in the periphery of a mass lesion. In cases that a nodule is the targeted lesion but only atypical cells are seen in a biopsy dispersed along the alveolar wall (Fig. 16), the preferred diagnosis would be of an atypical pneumocyte proliferation instead of AAH or BAC, thus avoiding misclassification of the lesion. Similar nomenclature can be used in cases where in addition to a lepidic growth pattern, an inflammatory infiltrate is present in the biopsy. Type II pneumocyte hyperplasia can show significant cytologic atypia, thus mimicking a neoplastic process. Pneumocyte hyperplasia can also be seen in association with mild alveolar wall thickening, which is more often caused by the inflammatory infiltrate,

Fig. 17. Core biopsy showing sclerosed stroma lined by mildly atypical cells resembling type II pneumocyte. Note the presence of pale cuboidal cells within the sclerosed stroma. This core biopsy is diagnostic for slerosing hemangioma. Sclerosing hemangioma is a pitfall for the diagnosis of BAC because both entities share similar features, especially in a core biopsy. Immunostains that can highlight the 2 cell populations are helpful for the correct diagnosis (H&E stain, original magnification 100).

edema, and fibrin deposition. Inflammatory processes are often identified in lesions described radiographically as infiltrates or pneumonic processes; however, when associated with organizing pneumonia, it can present radiographically as a nodular process thus mimicking a neoplasm. Sclerosing hemangioma is a rare benign neoplasm of the lung that is characterized histologically as having papillary, solid, sclerosed, and hemorrhagic growth patterns. The tumor is composed of 2 bland cell types, superficial cells that resemble type II pneumocyte and stromal cells. The tumor is often described radiographically, as well as in the gross examination, as a circumscribed solid lesion in the pulmonary parenchyma.

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Moreira Fig. 18. Higher magnification of Fig. 17, showing the presence of bland cells lining sclerosed stroma, thus mimicking a BAC pattern of growth (H&E stain, original magnification 200).

The differential diagnosis of the excised tumor includes a well-differentiated adenocarcinoma with papillary pattern, not a pure BAC. However, a core biopsy of a sclerosing hemangioma can show bland pneumocytes arranged tightly around a fibrosed stroma (Figs. 17 and 18), which may lead to the incorrect classification of this lesion as an adenocarcinoma with BAC features. The identification of the 2 cell types and the presence of cuboidal cells within the sclerosed stroma may

prompt the use of immunostains that can help in the correct diagnosis. Surface cells in a sclerosing hemangioma stains for pancytokeratin, EMA, and TTF-1, whereas stromal cells are positive for EMA and TTF-1, but not for pancytokeratin.20 The cytologic diagnosis of BAC is not recommended. Studies that described the cytologic features for the diagnosis of BAC were performed before the strict definition of BAC by the WHO as an in situ carcinoma.21 In fact, these cytologic Fig. 19. Smear from an aspiration biopsy of a pulmonary nodule showing features of BAC. The cytologic features for the diagnosis of BAC are the presence of flat sheets of neoplastic cells with enlarged nuclei, and the presence of prominent nuclear grooves. Note that the cells are relatively homogeneous. The neoplastic cells resemble those seen in aspiration biopsy of papillary adenocarcinoma of the thyroid gland (H&E stain, original magnification 200).

BAC and Minimally Invasive Adenocarcinoma Fig. 20. High magnification of a cluster of neoplastic cells with characteristics of BAC. The cells are relatively homogeneous. There are prominent nuclear grooves and nuclear inclusions (Papanicolaou stain, original magnification 400).

criteria may correlate with the presence of a BAC component in a mixed subtype adenocarcinoma or the presence of a well-differentiated adenocarcinoma with BAC or papillary component.21–23 The use of the term BAC should be applied with caution

Fig. 21. Aspiration biopsy of a pulmonary nodule with solid and ground-glass opacity. Note the presence of cells arranged in flat sheets. The cells show prominent nucleoli and mild cytologic atypia, but have normal nucleus to cytoplasm ratio. The nuclei are relatively small as compared with a red blood cell seen in the background, which is a potential pitfall for the cytologic diagnosis of adenocarcinoma with BAC features. In this case, these cells are representative of type II pneumocyte hyperplasia. Excision of the lesion showed nodular organizing pneumonia (Romanowski stain, original magnification 200).

in such situations. Similarly to the core biopsy diagnosis, it is preferred to use the diagnostic term of adenocarcinoma with features of bronchioloalveolar carcinoma, which can give important management information to the treating physician.

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Moreira Fig. 22. Aspiration biopsy of a pulmonary nodule that is described radiographically as a coin-like lesion. The smear shows sheets of mildly atypical epithelial cells. Some of the cells are arranged in a tridimensional cluster. Two cell populations are identified: one smaller with abundant cytoplasm resembling type II pneumocytes, and another of cuboidal cells resembling macrophages. The bland nature of the cells is a pitfall for the diagnosis of an adenocarcinoma with BAC features. The radiographic description, however, does not indicate an adenocarcinoma. Excision of the lesion showed the presence of sclerosing hemangioma (Romanowski stain, original magnification 100).

The cytologic diagnostic criteria for the diagnosis of an adenocarcinoma with BAC features in a fine-needle aspiration biopsy specimen are the presence of flat sheets of neoplastic cells.

The tumor cells are relatively homogeneous with mild nuclear enlargement, and show prominent nuclear grooves and occasional nuclear inclusions (Figs. 19 and 20), similar to what is seen

Fig. 23. Aspiration biopsy of a sclerosing hemangioma. Note the presence of 2 cell types and the presence of metachromatic material that stains bright pink in Romanowski stains, which provides a good clue to the indication of a sclerosed stroma. This feature is not seen in the aspiration biopsy of adenocarcinoma with BAC features (Romanowski stain, original magnification 100).

BAC and Minimally Invasive Adenocarcinoma Fig. 24. Frozen-section slides of a wedge resection of a pulmonary nodule. The frozen section shows a dense pulmonary parenchyma with thickening of the alveolar septa and the growth of atypical cells along the alveolar septa, thusresemblinganeoplastic process. Another aspect of the frozen section was the presence of fibrin deposition within the alveolar space and a dense inflammatory infiltrate, which is a potentialpitfall forthediagnosis of BAC in a frozen section. Due to freezing artifact, the cells lining the alveolar septa appear highly atypical. Permanent section of this nodule shows organizing pneumonia (H&E stain, original magnification 100).

in the aspiration biopsy of papillary carcinoma of the thyroid. As in core biopsy, the differential diagnosis in cytology is reactive hyperplasia of type II pneumocytes and sclerosing hemangioma. Both entities can be very difficult to diagnose in cytologic preparation. Reactive hyperplasia is Fig. 25. Permanent section of the nodule in Fig. 24. Note the presence of plugs of fibroconnective tissue within the alveolar space, which is diagnostic of organizing pneumonia with type II pneumocyte hyperplasia (H&E stain, original magnification 100).

characterized by pleomorphic and hyperchromatic cells that, contrary to well-differentiated adenocarcinoma, maintains good nucleus to cytoplasm ratio (Fig. 21). There are abundant single atypical cells in the background as well as an inflammatory infiltrate. The cells may have prominent nucleoli.

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Moreira Fig. 26. Low-powermagnification showing the presence of a small focus of mucinous BAC. This tumor is seen as a separate focus of carcinoma around a main tumor mass of an invasive mucinous adenocarcinoma. Mucinous BAC is characterized by the presence of lepidic growth pattern of mucinous containing cells along preexisitng alveolar spaces. Note that, different from nonmucinous BAC, there is no fibrosis of the alveolar septa (H&E stain, original magnification 50).

Sclerosing hemangioma is almost impossible to differentiate from a well-differentiated adenocarcinoma with BAC features. Both show bland cells arranged in flat sheets or papillary structures (Figs. 22 and 23). Sclerosing hemangioma is, however, a very rare tumor. The information from the radiographic description of a circumscribed nodule or coin lesion in the lung should prompt the inclusion of this entity in the differential diagnosis.

The diagnosis of bronchioloalveolar carcinoma in a frozen section should also be made with care because the diagnosis of a pure BAC should be made only when the entire tumor is examined. When confronted with a frozen section of a tumor with a BAC pattern, the diagnosis of an adenocarcinoma with features of BAC is preferred, similar to other biopsy diagnoses. The reason for this is that although most surgeons will proceed to

Fig. 27. Higher magnification of a mucinous BAC showing lepidic growth pattern of bland columnar cells along alveolar septa. The neoplastic cells show basal nuclei and abundant cytoplasmcontainingmucin (H&E stain, original magnification 400).

BAC and Minimally Invasive Adenocarcinoma Fig. 28. Mucinous BAC showing the presence of mucin within the alveolar space (H&E stain, original magnification 200).

a lobectomy even with the diagnosis of pure BAC, there have been some studies suggesting that these lesions can be managed with a wedge resection with clean margins and/or a segmentectomy.24–26 As the concept of BAC as an in situ carcinoma takes hold, it is very likely that the surgical management of the disease may change as well. However, as of the time of writing this article there was no consensus for the surgical

Fig. 29. Section of a mucinous adenocarcinoma with invasive component. Acinar and papillary patterns are seen, which can be confused with mucinous BAC. Most of the tumor previously diagnosed as mucinous BAC have in fact an invasive component, and should be diagnosed a mucinous adenocarcinoma. A pure mucinous BAC is a very rare tumor (H&E stain, original magnification 100).

management of BAC. Therefore the diagnosis of BAC should be rendered with caution in a frozen section and should be discussed with the surgeon during the procedure. The accuracy of frozen-section diagnosis for adenocarcinoma with BAC features is excellent, with reported predictive values of 93% to 100%.24–27 Potential pitfalls in a frozen-section diagnosis of BAC are architectural distortion

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Moreira Fig. 30. Colloid adenocarcinoma, a variant of mucinous adenocarcinoma characterized by large pools of mucin dissecting the pulmonary parenchyma. Because these tumors invariably have areas that resemble mucinous BAC, they represent a potential pitfall for the latter. Thick areas of fibrosis are seen, distended by large pools of mucin (H&E stain, original magnification 400).

caused by collapse of the alveolar structures and cellular atypia induced by freezing artifact and inflammatory conditions, such as organizing pneumonia with pneumocyte hyperplasia (Figs. 24 and 25) and even granulomatous inflammation. The latter can mimic a carcinoma clinically and radiographically, and in association with the

freezing artifacts may lead to an erroneous diagnosis of adenocarcinoma.

PROGNOSIS Pure BAC is rare. The incidence is that of approximately 2% to 6% of all lung cancers.5,28 There is

Fig. 31. Smear of an aspiration biopsy of a mucinous adenocarcinoma with features of mucinous BAC. The characteristics of these tumors are flat sheets of neoplastic cells with honeycomb arrangement. The cells have enlarged nuclei with abundant cytoplasm. Nuclear grooves and nuclear inclusion, although rare in this entity, can also be seen (Papanicolaou stain, original magnification 400).

BAC and Minimally Invasive Adenocarcinoma Fig. 32. Smear of an aspiration biopsy of mucinous adenocarcinoma with BAC features. Note the presence of abundant mucin in the background and the presence of bland neoplastic cells with abundant cytoplasm (H&E stain, original magnification 200).

a higher incidence of BAC in Asia. The prognosis of bronchioloalveolar carcinoma is excellent, reported by several investigators as having a 5-year survival of 100% when present as an isolated single nodule in the lung, therefore being a surgically manageable disease. However, if the tumor is present with a pneumonic pattern radiographically or as a multifocal adenocarcinoma, the prognosis is different, and these tumors do

Fig. 33. Smear of an aspiration biopsy of mucinous adenocarcinoma with BAC features. Neoplastic cells can be seen as single units of poorly cohesive clusters in a background of abundant mucin. The cells can mimic the appearance offoamy macrophages (H&E stain, original magnification 100).

not share the same 100% survival of the isolated nodular form.7,29,30 The pneumonic form, although rare, is more commonly seen in mucinous BAC. This concept, however, is troublesome because in most series, only a few studies report a central review mechanism for the histology of the tumor included in the study. In those studies that have included a mechanism for central review of the cases, most of the tumors classified initially as

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Moreira Fig. 34. High-power magnification of an adenocarcinoma with a predominant lepidic growth pattern. Careful observation of the sections shows the presence of acinar component, an invasive pattern, within fibrosed stroma. The invasive component represented less than 5 mm of the entire tumor mass, therefore this tumor fulfills the criteria for a minimally invasive adenocarcinoma (H&E stain, original magnification 100).

BAC had an associated invasive component.7 The clinical presentation of a pure pneumonic nonmucinous BAC may be very rare and therefore it is difficult to conduct specific clinical trials; however, the clinical reports of pneumonic adenocarcinomas show that these nonmucinous BAC have a better prognosis compared with that of mucinous BAC when treated with gefitinib, a tyrosine kinase inhibitor.7,31

Patients who present with synchronous multifocal GGO lung nodules pose a significant dilemma for diagnosis, staging, and treatment, because there are no established guidelines for the clinical management of these patients. Recent studies have showed that synchronous BAC can have a different EGFR mutational profile, thus suggesting that they more likely represent separate synchronous primaries than intrapulmonary Fig. 35. Adenocarcinoma with a predominant lepidic growth pattern, indicating the presence of a small focus of complex growth pattern characteristic of acinar carcinoma (H&E stain, original magnification 50).

BAC and Minimally Invasive Adenocarcinoma Fig. 36. Minimally invasive adenocarcinoma in which the invasive component is characterized by the presence of papillary adenocarcinoma (H&E stain, original magnification 50).

Pitfalls NONMUCINOUS BRONCHIOLOALVEOLAR CARCINOMA ! The diagnosis of BAC should be avoided in core biopsy and cytology specimens. ! Reactive and benign conditions can mimic BAC in core biopsy, cytology, and frozen section. ! Chronic inflammatory conditions can mimic BAC in frozen section due to freezing artifact and significant atypia of type II pneumocyte hyperplasia.

for mucinous BAC. Similar to nonmucinous BAC, most of the mucinous adenocarcinomas are detected by CT scan, and the images can be characterized as GGO or an infiltrative process with pneumonic growth pattern. Mucinous BAC very often presents as multifocal disease. There is no clear association of mucinous BAC with smoking habits; however, it is known that patients who have a history of congenital cystic adenomatoid malformation, a rare cystic hamartomatous lesion of the lung, have an increased incidence of mucinous BAC or mucinous adenocarcinomas.33,34

! Metastatic carcinoma can mimic a lepidic growth pattern.

metastatic disease.32 This area is the subject of intense study, which it is hoped will elucidate the natural history of the disease.

Key Features MUCINOUS BRONCHIOLOALVEOLAR CARCINOMA Rare tumor. Very often is multifocal.

MUCINOUS BRONCHIOLOALVEOLAR CARCINOMA

Characterized by the presence of bland columnar cells with basal nuclei and abundant cytoplasm containing mucin.

OVERVIEW

Can be associated with congenital cystic adenomatoid malformation (CCAM), a rare condition more likely to be encountered in the pediatric population.

Mucinous BAC, although sharing the same name as its nonmucinous counterpart, seems to be a very different disease concerning its clinical presentation, histologic and molecular features.7 There are no defined gross features

The diagnosis should be made only in complete excised tumors.

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Moreira MICROSCOPIC FEATURES Mucinous BAC is characterized by the presence of tall columnar cells with abundant cytoplasm containing mucin. The nuclei are displaced to the base of the cells lining the alveolar septa. Very often the alveolar walls show no fibrosis (Figs. 26 and 27). Pools of mucin within the alveolar space can be seen (Fig. 28). The tumor cells show minimal cytologic atypia. Of note, the presence of multiple satellite nodules seen around the main mass is a common finding. In contrast to nonmucinous BAC, these tumors are more often present as multifocal disease or as a pneumonic pattern. A pure mucinous BAC is very rare. Histologic review of mucinous BAC using the strict criteria for the diagnosis of BAC as a tumor that shows no invasive component demonstrated that most of the tumors that have been previously diagnosed as mucinous BAC are in fact adenocarcinoma mixed subtype with a mucinous BAC component.35 The immunoprofile of mucinous BAC is different from that of its nonmucinous counterpart. The tumor cells can be focally and weakly positive for TTF-1 and cytokeratin 7, whereas a nonmucinous BAC is invariably strongly positive for these markers.36–38 Mucinous BAC may show positive reaction for cytokeratin 20. No positivity for CDX2 is reported in mucinous BAC.39 In general, the positivity for CDX2 is seen in tumors that have cells with goblet cells or intestinal metaplasia, a feature seen in colloid and intestinal type adenocarcinomas of the lung.39 The use of immunohistochemistry in mucinous BAC is an important factor in the differentiation of a more common metastatic mucinous adenocarcinoma to the lung, especially metastatic tumors from the gastrointestinal tract.

DIFFERENTIAL DIAGNOSIS The main differential diagnosis for a mucinous BAC includes a mucinous-producing mixed subtype adenocarcinoma. The presence of an invasive component or complex structures in the histologic section (Fig. 29) should exclude the diagnosis of a pure mucinous BAC. Colloid (mucinous) adenocarcinoma also enters the differential diagnosis. Colloid adenocarcinoma is a variant of adenocarcinoma, characterized by the presence of dissecting mucin within the pulmonary parenchyma, with scant and scattered malignant cells floating in the mucin pools or lining thin fibrous band (Fig. 30). Contrary to mucinous BAC, colloid adenocarcinoma presents as a lobulated gelatinous mass on gross examination.

Differential Diagnosis MUCINOUS BRONCHIOLOALVEOLAR CARCINOMA The presence of any invasive component leads to the diagnosis of a mucinous adenocarcinoma. Colloid carcinoma is a variant of mucinous adenocarcinoma characterized by the presence of large pools of mucin dissection the pulmonary parenchyma; however, the normal alveolar structures are not preserved, which is a requirement for the diagnosis of mucinous BAC. Contrary to nonmucinous BAC, mucinous tumors can be negative or focally positive for cytokeratin 7, cytokeratin 20, and TTF-1.

Microscopically there is distortion of the normal pulmonary alveolar structure, which excludes the diagnosis of a pure mucinous BAC. Similar to nonmucinous BAC, metastatic mucinous adenocarcinomas can present in the lung with a lepidic growth pattern, but invariably an invasive component is also present, which by definition excludes the diagnosis of BAC.

DIAGNOSIS To keep the strict criteria for the diagnosis of BAC, the diagnosis should be made only after complete examination of a surgically resected specimen. In the presence of invasive component, the diagnosis of adenocarcinoma mixed subtype should be rendered. A core biopsy of a mucinous adenocarcinoma shows similar features to those described earlier, but the definite diagnosis of mucinous BAC should be avoided. Similar to the nonmucinous BAC, the information in biopsy material of the presence of a mucinous component has clinical relevance. For instance, mucinous BAC shows a different mutational profile to nonmucinous BAC. Mucinous BAC has an increased frequency of KRAS mutations instead of EGFR mutations.7 Aspiration biopsy of adenocarcinomas with a mucinous BAC features shows flat sheets of tumor cells with honeycomb arrangement (Figs. 31–33). The cells are tall columnar, with basal nuclei and abundant foamy cytoplasm. Nuclei are bland. Nuclear inclusions and nuclear grooves, although rare, can be seen. Abundant mucin can be seen in the background (see Figs. 32 and 33). A cell block preparation may

BAC and Minimally Invasive Adenocarcinoma

Pitfalls MUCINOUS BRONCHIOLOALVEOLAR CARCINOMA ! The diagnosis of mucinous BAC should be avoided in core biopsy and cytologic material. ! Metastatic adenocarcinoma from the gastrointestinal tract can present with a lepidic pattern, thus mimicking mucinous BAC.

show the typical discontinued clusters of bland mucinous epithelial cells lining a thin alveolar structure. The diagnosis of mucinous BAC should be avoided in biopsy or cytologic preparation, and instead the diagnosis of adenocarcinoma with features of mucinous BAC should be given.

Key Features MINIMALLY INVASIVE ADENOCARCINOMA Adenocarcinoma with predominant lepidic growth pattern and small amount of invasive component (%5 mm). Pleura and/or vascular invasion exclude the diagnosis. New concept that offers some flexibility when dealing with small well-differentiated adenocarcinomas with small or questionable focus of invasion. Rare. All reported cases are associated with nonmucinous BAC. Excellent prognosis with 100% 5 year survival, similar to solitary BAC.

PROGNOSIS

GROSS FEATURES

The prognosis of mucinous bronchioloalveolar carcinoma depends on the clinical presentation. Although a focal pure mucinous bronchioloalveolar carcinoma is extremely rare, it is expected to have a good prognosis similar to other small noninvasive tumors of the lung. Because the concept of BAC as an in situ carcinoma is new, and the fact that pure BAC are rare tumors, there is no definite information on the prognosis or natural history of these tumors. Whether pure mucinous BAC shows the same prognostic significance as that of a nonmucinous BAC needs to be further evaluated.

Because MIA is a new concept, there is no clear definition of gross or radiographic features. Some unpublished anecdotal reports suggest that these tumors may have pure GGO, or a mixed GGO and solid component on CT scan. The solid component thus represents the scar tissue or invasive component. Further studies are needed to define the radiographic and gross features of these lesions.

MINIMALLY INVASIVE ADENOCARCINOMA OVERVIEW Minimally invasive adenocarcinoma (MIA) is a new concept that originated from observations that small tumors with a predominant lepidic growth pattern with a small component of fibrosis, scar, or invasive adenocarcinoma had a similar prognosis to that of a pure BAC.3–6 Several studies have suggested different parameters to identify MIA, such as the size of scar,4,5 extent of the invasive component,3,5 and lepidic component.6 The new recently developed consensus for the classification of pulmonary adenocarcinoma40 defines MIA as a small tumor with a predominantly lepidic pattern with 5 mm or less of an invasion component. MIA has an excellent prognosis with 100% 5-year survival, similar to that of a pure BAC.5,40,41

MICROSCOPIC FEATURES MIA is composed of a predominantly lepidic pattern and an invasive component that does not exceed 5 mm in greatest diameter. The invasive component can be seen centrally or in the periphery of the tumor mass. The invasive component is more frequently represented by acinar and papillary growth patterns.5 Travis40 also included the presence of a scar, associated with an invasive component as part of the measurement that defines MIA; however, this criterion is not mentioned in the consensus document. Most of the publications that helped define MIA indicate that this entity is associated with a nonmucinous

Differential Diagnosis MINIMALLY INVASIVE ADENOCARCINOMA Pure BAC. Invasive adenocarcinoma.

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Moreira BAC; however, mucinous MIA, although rare; may exist. The clinical relevance and natural history of a mucinous MIA remains to be elucidated.

DIAGNOSIS AND PROGNOSIS Similar to pure BAC, the diagnosis of MIA should be made only on complete histologic evaluation of the tumor. The biopsy or cytologic diagnosis of this entity is not encouraged. The diagnosis of MIA is excluded if the tumor shows lymphatic, blood vessel, or pleural invasion, or the presence of an invasive component (acinar, papillary, or solid) that is larger than 5 mm (Figs. 34–36). Similar to BAC, MIA is a rare tumor. Yim and colleagues5 identified only 21 adenocarcinomas that fulfilled the criteria for MIA reviewed in a tertiary medical center in a 12-year period. MIA can also be seen in the context of multifocal adenocarcinoma. However, the criteria for MIA can be accepted only if the multifocal tumors are synchronous and do not represent intrapulmonary metastasis. The readers may be asking, what is the importance of the diagnosis of MIA compared with a pure BAC or a mixed subtype adenocarcinoma? Part of the importance of recognizing this entity is that an area of complex growth or fibrosis is very often seen in tumors that could qualify as a pure BAC or adenocarcinoma in situ. Using the strict criteria for the diagnosis of BAC set forth by the WHO classification of lung carcinoma, tumors with an invasive component should be classified as invasive adenocarcinomas, and not as BAC or adenocarcinoma in situ. However, as several reports have indicated, this does not translate accurately the good prognostic significance of these MIAs. Therefore, the recognition of MIA gives the pathologist some flexibility in reporting tumors that are not pure BAC but can still convey to the treating physician the prognostic implications of this histologic subtype. Because this is a new concept in the classification of lung adenocarcinomas, there is no clear

Pitfalls MINIMALLY INVASIVE ADENOCARCINOMA ! New concept with no standard criteria for diagnosis and terminology. ! The diagnosis should be made only in complete excised material. ! Avoid diagnosis in core biopsy.

consensus on how to manage patients clinically with this diagnosis. In addition, the rate of recurrence for these tumors, or if they indeed recur, is not known.

SUMMARY As the concept of a pulmonary adenocarcinoma takes hold for the practitioner in thoracic oncology, the heterogeneity of tumors that used to be diagnosed as BAC will change. More than likely, the term BAC will be discontinued as a diagnostic entity and be replaced by pulmonary adenocarcinoma in situ. It is hoped that this change will lead to more standardized reporting of these tumors, which in turn will lead to a better understanding of the clinical and natural history of pulmonary adenocarcinomas.

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