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1 Classification of Adenocarcinoma of the Lung in New WHO Classification

1.1 Introduction: Major Changes in the Classification

The 4th edition of WHO Classification of Tumours of the Lung, Pleura, Thymus, and Heart was published in 2015 [1]. In this new edition, the significant changes in the lung adenocarcinoma classification include (1) introduction of the new term “adenocarcinoma in situ (AIS)” as a preinvasive lesion in addition to atypical adenomatous hyperplasia (AAH), discarding the old and ambiguous term “bronchioloalveolar carcinoma (BAC)”; (2) introduction of the new term “minimally invasive adenocarcinoma (MIA)”; (3) classification of invasive adenocarcinomas according to the predominant subtype with additional description of minor subtypes; (4) introduction of the new term “invasive mucinous adenocarcinoma” (roughly corresponding to the former mucinous BAC) as a variant of adenocarcinoma; (5) refining the category of adenocarcinoma variants as including invasive mucinous adenocarcinoma, colloid adenocarcinoma, fetal adenocarcinoma (low- and high-grade), and enteric adenocarcinoma; (6) introduction of immunohistochememically defined “solid adenocarcinoma”, i.e., diagnosing the former large cell carcinoma as solid adenocarcinoma if tumor cells are immunopositive for pneumocyte markers (TTF1 and/or napsin A); and (7) avoiding the noncommittal diagnosis of non-small cell carcinoma in small biopsy/cytology samples as much as possible by introduction of the new immunohistochemically defined diagnostic category of “non-small cell carcinoma, favor adenocarcinoma” [1–4] (Table 1.1).

Table 1.1 Lung adenocarcinoma and its precursor. WHO classification [1]
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It should be emphasized that these major changes in adenocarcinoma classification are deeply related to the ever-growing recognition that a multidisciplinary approach is mandatory for the classification to be clinically relevant: (1) recent advance in molecular biology/oncology has led to the discovery of epidermal growth factor receptor (EGFR) mutations and ALK gene translocations almost exclusively in lung adenocarcinomas, and targeted therapy with tyrosine kinase inhibitors (TKIs) has become available for these tumors; (2) progress in treatment requires discrimination of squamous cell carcinoma from non-squamous, non-small cell carcinomas such as in application of certain drugs including pemetrexed and bevacizumab; and (3) advancement in knowledge of the intimate correlation between the developmental stages of adenocarcinoma and corresponding CT images has led to its utility in prediction of prognosis and choice of treatment in lung adenocarcinomas [3].

1.2 Preinvasive Lesions

1.2.1 Atypical Adenomatous Hyperplasia (AAH) (Fig. 1.1)

AAH, by definition, is a small, localized proliferation of mildly to moderately atypical type II pneumocytes and/or club cells (formerly named as Clara cells) lining alveolar walls and sometimes respiratory bronchioles [1]. This lesion is usually found incidentally in lung specimens resected for cancer or may incidentally be detected as a pure ground-glass nodule (GGN) on high-resolution CT scans during medical examination for some reasons.

Fig. 1.1
figure 1

Atypical adenomatous hyperplasia. (a) Low-power view. Note the slightly thickened alveolar septa with lining cells that show a sharp demarcation from the normal lung parenchyma occupying the lowermost quarter of the field. (b) High-power view. Cuboidal to somewhat flattened cells with mildly atypical nuclei and scant cytoplasm are growing along alveolar septa

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In gross examination, AAH typically is a few millimeter-sized, barely discernable gray-white nodule in the peripheral lung. Histopathologically, the distinction between AAH and AIS is sometimes difficult because both show the lepidic pattern or growth along the alveolar wall throughout the lesion, but AAH typically is up to 5 mm in size, and the constituent cells show less nuclear atypism and are less densely populated along alveolar walls than those of AIS [5, 6]. Somewhat paradoxically, the cell shape in AAH is more various with cuboidal, pyramidal, or flat appearances than that of AIS.

AAH is considered to be a precursor lesion of peripheral lung adenocarcinoma. Clinicopathological and clonality/mutational studies have demonstrated that AAH is a clonal lesion with the potential for progression to adenocarcinoma [5–7], harboring KRAS and EGFR mutations in up to 33 % and 35 %, respectively [1, 8–11]. There is some evidence that KRAS-mutated AAH may not progress to AIS or invasive adenocarcinoma as frequently as EGFR-mutated AAH and that major driver genes (EGFR/KRAS/ALK/HER2) mutation-negative AAH/AIS may not progress to invasive adenocarcinoma so frequently [8, 12]. A recent genetic analysis of AAH/AIS/MIA utilizing next-generation sequencing (NGS) [13] showed an average mutation rate of 2.2 non-synonymous mutations (range 0–6 mutations) per one lesion among 25 AAHs, the most frequently mutated genes being BRAF and ARID1B. Genes associated with DNA repair and chromatin remodeling network such as ATM and ATRX were also mutated in multiple lesions, suggesting AAH may be predisposed to the acquisition of secondary genetic aberrations. Mutations in TP53, EGFR, and IGFR1 were noted in all developmental stages of AAH/AIS/MIA, but BRAF mutation was rarely found in MIA or invasive adenocarcinoma, again suggesting the inequity in the progression potential among various mutations.

The natural history of AAH is not fully elucidated, but a recent radiographic study [14] showed that solitary pure GGNs 5 mm or smaller in CT images, the majority of which presumably represented AAH, grew in 10 % of the cases and developed into MIA or invasive adenocarcinoma in 1 % with the mean period of 3.6 years. This observation appears to corroborate the aforementioned genetic inequity in the progression potential of AAH.

1.2.2 Adenocarcinoma In Situ (AIS) (Fig. 1.2)

AIS is a newly introduced entity in the current WHO classification [1]. It is a small (<=3 cm), localized adenocarcinoma with neoplastic cell growth restricted along alveolar walls (pure lepidic growth), lacking stromal, vascular, or pleural invasion. The constituent cells are mostly non-mucinous, but mucinous in rare cases as well. AIS is usually found incidentally as a pure GGN or part-solid nodule on CT scan [14, 15]. Mucinous AIS tends to present as a solid or part-solid nodule with air-containing spaces [16].

Fig. 1.2
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Adenocarcinoma in situ (non-mucinous type). (a) The alveolar septa are lined by atypical type II pneumocyte/club cell-like cells. (b) The elastic framework of the alveolar septa in AIS is completely preserved. (Elastic van Gieson stain)

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Grossly, AIS is an ill-defined, gray-white to tan-colored nodule with somewhat spongy consistency. Histopathologically, type II pneumocyte/club cell-like cuboidal to columnar cells with mild to moderately atypical nuclei are seen along alveolar walls. The alveolar walls are almost normal to moderately thickened with collapse-type fibroelastosis [17]. In the rare mucinous AIS, the lining cells have mucinous cytoplasm, resembling gastric foveolar epithelium or goblet cells. Non-mucinous AIS expresses TTF1 and napsin A, whereas mucinous AIS is often negative for these immunohistochemical markers of alveolar pneumocytes and positive for gastric epithelium-associated mucin such as MUC5AC and MUC6 [18, 19].

Genetically, non-mucinous AIS harbors EGFR mutations frequently (40–86 %), but KRAS mutations rarely (0–4 %) [12, 19–23]. A recent NGS analysis of AIS in five patients showed an average mutational rate of 6.2 non-synonymous mutations per patient; the mutational landscape varied widely, most mutations including EGFR and TP53 mutations found only in one patient [13]. The lower mutational rate of EGFR compared with those of the aforementioned studies [12, 19–23] may be related to different ethnic backgrounds of the cohorts. EGFR mutations are rare in mucinous AIS [19, 24].

The clinical significance of diagnosing AIS lies in its connotation as a neoplasm with 100 % disease-free survival if it is resected completely [1, 17, 19–24] (Fig. 1.3) (Table 1.2). It is noteworthy that most of these data are from Japan, where EGFR mutation-related adenocarcinomas are common and CT-based examination is part of routine clinical practice. The frequency of AIS among resected lung adenocarcinomas has been 4.5–8.4 % in Japanese cohorts [19–21, 23], whereas it has been less than 1 % in Western countries [24]. The clinical behavior of mucinous AIS is less well elucidated but may also be good [15, 19, 20, 24, 25]. Thus, the most recent article on the eighth TNM classification of lung cancer has proposed the code Tis in place of T1 for AIS [15].

Fig. 1.3
figure 3figure 3

Pulmonary adenocarcinoma subtypes and prognosis. Stage I (n = 514). (a) Disease-free survival (DFS) for all histological categories (P < 0.001). The favorable group includes adenocarcinoma in situ (AIS) and minimally invasive adenocarcinomas (MIA) with 100 % 5-year disease-free survival. Disease-free survival for the intermediate group was 90, 83, and 84 % for lepidic predominant, papillary (PAP) predominant and acinar predominant, and adenocarcinomas, respectively. Disease-free survival for the unfavorable group was 70, 67, 71, and 76 % for solid predominant, micropapillary (MPAP) predominant, colloid predominant, and mucinous and mixed adenocarcinomas, respectively. (b) Disease-free survival according to combined histological groupings according to low-, intermediate-, and high-grade clinical aggressiveness. (c) Overall survival (OS) according to combined histological groupings according to low-, intermediate-, and high-grade clinical aggressiveness (Adopted from Fig. 1.4 of reference [20]). (b) Stages I–III (n = 440). (A) Disease-free survival curves and (B) overall survival curves, for the groups, separated by the IASLC/ATS/ERS classification of lung adenocarcinomas (Adopted from Fig. 1.6 of reference [33]). AIS adenocarcinoma in situ, MIA minimally invasive adenocarcinoma, Lepidic lepidic predominant adenocarcinoma, Aci acinar predominant adenocarcinoma, Pap papillary predominant adenocarcinoma, Solid solid predominant adenocarcinoma, MP micropapillary predominant adenocarcinoma, IMA invasive mucinous adenocarcinoma, IASLC International Association for the Study of Lung Cancer, ATS American Thoracic Society, ERS European Respiratory Society

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Table 1.2 Pulmonary adenocarcinoma subtypes and prognosis
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1.3 Minimally Invasive Adenocarcinoma (MIA) (Fig. 1.4)

MIA is another new entity incorporated into the current WHO classification. It defines the solitary adenocarcinoma (<=3 cm) with a predominantly lepidic pattern and <=5 mm invasion in greatest dimension [1]. MIA should lack lymphatic/vascular/pleural/air space invasion or spread. MIA is non-mucinous in most cases but may rarely be mucinous as well. This lesion is usually discovered incidentally as a part-solid nodule, pure GGN, or rarely as a solid nodule on CT [15].

Fig. 1.4
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Minimally invasive adenocarcinoma. (a) The left upper field shows the lepidic pattern of tumor growth with preserved alveolar framework, whereas the right lower field shows a fibrotic focus with an invasive growth of neoplastic cells. (b) Note an invasive neoplastic acinar structure within the fibrous stroma

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Historically, the criteria for this entity were searched after the epoch-making publication of an article on AIS by Noguchi et al. in 1995 [17], and several pioneering studies contributed to its establishment [25–32]. Validation studies [19–23, 33–37] suggested the prognosis of MIA is virtually equal to that of AIS, supporting its recognition as a distinct entity (Fig. 1.3, Table 1.2). The code T1mi is proposed for MIA in the latest TNM system [15].

Histopathologically, the invasive focus may take one of the basic patterns of invasive adenocarcinoma, i.e., papillary, acinar, solid, or micropapillary pattern or tumor cells infiltrating myofibroblastic stroma [1].

Genetically, MIA shows high rates of EGFR mutation similar to AIS [20–23]. An NGA analysis of MIA in five patients revealed an average mutation rate of 10.8 non-synonymous mutation per patient with EGFR and TP53 being the most frequently mutated genes [13].

1.4 Invasive Adenocarcinoma (Fig. 1.3) (Table 1.2)

Invasive adenocarcinoma is a carcinoma with glandular differentiation, mucin production, or pneumocyte marker expression [1]. The growth pattern includes acinar, papillary, micropapillary, and solid. These patterns often appear admixed with and in transition to one another within the same tumor, and therefore the tumor is classified according to the predominant pattern in proportion with additional description of each component present in 5–10 % increment. Invasive adenocarcinoma is typically localized in the periphery of the lung. Pleural indentation is common due to the retraction caused by central collapse and fibrosis in the tumor. CT images of invasive non-mucinous adenocarcinoma appear solid or part solid depending on the proportion of lepidic growth vs. invasive growth as well as on the extent of alveolar collapse [1, 3].

1.4.1 Lepidic Adenocarcinoma (Fig. 1.5)

In this tumor, the predominant pattern is lepidic with type II pneumocyte/club cell-like atypical cells growing along alveolar walls, but also present is an invasive component of various patterns such as papillary and acinar larger than 5 mm in greatest dimension. Grossly, part of the tumor, often centrally located, is grayish white in color with carbon dust deposition and solid in consistency, whereas the peripheral portion is somewhat ill defined, tan in color, and soft in consistency (Fig. 1.5). The former roughly corresponds to the invasive component with fibrosis and the latter the lepidic component with preserved airspace. This feature is usually reflected as a part solid image at CT scan. The frequency of this subtype among invasive adenocarcinomas varies from 5 % [34] to 18.3 % [23], probably reflecting different ethnic and clinical backgrounds of these cohorts.

Fig. 1.5
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Lepidic adenocarcinoma. Gross appearance: Note the peripheral tumor with a pleural indentation. The central portion of the tumor appears grayish white and solid, whereas the peripheral portion is tan in color with a somewhat spongy appearance and unclear margin

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Genetically, EGFR mutation is frequent [20, 21, 23]. Adenocarcinoma of lepidic pattern with type II pneumocyte/ club cell-like cells (bronchioloalveolar features) has been termed terminal respiratory unit (TRU)-type adenocarcinoma and known to be intimately associated with EGFR mutation [38].

Prognostically, this tumor lies intermediate between the good prognostic group of AIS/MIA and the poor prognostic group of micropapillary adenocarcinoma/solid adenocarcinoma [20, 21, 23, 33, 35] (Fig. 1.3, Table 1.2). The prognosis of lepidic adenocarcinoma is related to the proportion of the lepidic growth within the entire tumor, tumors with >50 % to >75 % lepidic pattern showing good prognosis similar to those of AIS/MIA [24, 27]. Adenocarcinomas even with a non-predominant lepidic component show a better outcome than adenocarcinomas without the component [39]. This tendency in prognosis will be more accurately reflected in the 8th edition of the TNM classification of lung cancer in which the invasive tumor size, excluding the lepidic growth, will be used as the T descriptor size [15]. Risk factors for recurrence in lepidic adenocarcinoma may include limited resection with a close margin, lymphovascular invasion, and a substantial component of high-grade pattern such as micropapillary [24].

1.4.2 Acinar Adenocarcinoma (Fig. 1.6)

Acinar adenocarcinoma is composed predominantly of acinar or glandular structures with cuboidal to columnar neoplastic cells forming central lumina of various size. Of all subtypes of pulmonary adenocarcinoma, acinar adenocarcinoma is less common (10.8–20.4 %) in Japan [20, 21, 23] than in Western countries (40–45.1 %) [33, 34, 40].

Fig. 1.6
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Acinar adenocarcinoma. (a) Neoplastic cells are arranged in acinar or tubular structures. (b) ALK-rearranged adenocarcinoma. The neoplastic cells are arranged in a so-called mucinous cribriform pattern. (c) ALK-rearranged adenocarcinoma. The luminal space and cytoplasmic vacuoles of tumor cells are abundant in mucin. (PAS reaction). (d) ALK-rearranged adenocarcinoma. The neoplastic cells are diffusely positive for ALK protein (immunostaining)

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Genetically, acinar adenocarcinoma shows EGFR mutation less frequently and ALK rearrangement more frequently than AIS/MIA and lepidic and papillary adenocarcinomas [20, 21, 41]. Mucinous cribriform pattern has been reported as a variant of acinar pattern intimately associated with ALK-rearranged pulmonary adenocarcinoma (Fig. 1.6) [41, 42].

Prognostically, acinar adenocarcinoma together with lepidic adenocarcinoma and papillary adenocarcinoma belongs to the intermediate group between the groups of AIS/MIA and micropapillary/solid adenocarcinoma [20, 21, 23, 33, 35] (Fig. 1.3, Table 1.2). In a study of stage I pulmonary adenocarcinomas [43], however, a cribriform pattern-predominant adenocarcinoma has been proposed as a distinct subtype of acinar adenocarcinoma with a poor prognosis compatible to those of the high-grade adenocarcinomas. This needs further validation.

1.4.3 Papillary Adenocarcinoma (Fig. 1.7)

Papillary adenocarcinoma shows a predominant papillary pattern with neoplastic cuboidal to columnar cells growing along fibrovascular cores in papillary configuration.

Fig. 1.7
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Papillary adenocarcinoma. Neoplastic columnar cells are arranged in a papillary configuration along with the central fibrovascular cores

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Genetically, papillary adenocarcinoma is among the subtypes with most frequent EGFR mutations, revealing the mutation in 50–68.5 % of cases [20, 21, 23]. This corroborates with the observation that this subtype is quite frequent (28–40.7 %) among various subtypes of adenocarcinoma in Japan [20, 21, 23], where EGFR mutation-related adenocarcinoma is prevalent, but is less common (12–27.8 %) in Western countries [33, 34, 44].

Prognostically, most studies placed papillary adenocarcinoma in the intermediate prognostic group [20, 21, 23, 33, 35] (Fig. 1.3, Table 1.2), but papillary adenocarcinoma belonged to the poor survival group together with micropapillary and solid adenocarcinomas in a study on a German cohort [40]. The reason for this discrepancy appears to be the presence of a range of papillary growth from the type architecturally close to lepidic pattern (type I) to the type showing the highest degree of architectural aberrations (type III) [44]: any presence of the type III papillary pattern was associated with poor overall and disease-free survivals, the aforementioned study having applied the most strict criteria (type III) to the recognition of the papillary pattern [41]. Tumors with any type I papillary growth were significantly more likely to harbor EGFR mutations than cases with any type II or type III papillary growth [44].

1.4.4 Micropapillary Adenocarcinoma (Fig. 1.8)

This is a newly introduced subtype in the current WHO classification [1]. This adenocarcinoma shows the predominant growth of neoplastic cells in micropapillary configuration, i.e., cells forming florets that lack fibrovascular cores, either connected to or detached from alveolar walls. This subtype frequently shows lymphatic permeation and spread through air spaces (STAS) [1, 45]. Micropapillary adenocarcinoma is relatively uncommon, constituting 2.3–19.5 % of all resected pulmonary adenocarcinomas [20, 21, 23, 24, 34–37, 40], most of the cohorts showing the frequency of less than 10 % [20, 21, 23, 24, 34, 37, 40]. However, the presence of micropapillary component itself is not uncommon, any presence (=>1 %) and =>5 % of this component representing 43.6 % and 21.7 % of 525 resected invasive adenocarcinomas, respectively, in one study [46].

Fig. 1.8
figure 8

Micropapillary adenocarcinoma. Neoplastic cells are arranged in a micropapillary pattern and show STAS in alveoli surrounding the tumor

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Genetically, micropapillary adenocarcinoma shows relatively high rates of EGFR mutation (39.7–43 %) next to the adenocarcinomas with predominant lepidic and papillary patterns [20, 21, 23].

Prognostically, there is an agreement that this subtype belongs to the poor prognostic group together with solid adenocarcinoma [20, 21, 23, 24, 33–37, 40] (Fig. 1.3, Table 1.2). The presence of a micropapillary component of 5 % or greater may be significantly associated with increased risk of local recurrence in patients treated with limited resection [47]. A recent study demonstrated overall survival was significantly better in patients without the micropapillary pattern (<1 %) than in those with the micropapillary pattern (<5 % of the entire tumor), emphasizing the recognition and description of this pattern even in a smallest proportion (=>1 %) [46].

1.4.5 Solid Adenocarcinoma (Fig. 1.9)

  1. 1.

    Solid adenocarcinoma shows the predominant growth of neoplastic polygonal cells in a sheetlike arrangement without any recognized pattern of adenocarcinoma described above. In tumors entirely with the solid pattern, intracellular mucin should be present in =>5 tumor cells in each of two high-power fields histochemically, or tumor cells should be positive for pneumocyte markers, i.e., TTF1 and/or napsin A immunohistochemically [1]. The latter immunohistochemically defined solid adenocarcinoma is a newly introduced entity in the current WHO classification. This represents the incorporation of a subset of former large cell carcinomas, the rationale for which is that these immunomarker-defined large cell carcinomas had a distinct adenocarcinoma-related spectrum of therapeutically relevant-driver mutations, including EGFR, KRAS, and ALK [48–50]. The frequency of solid adenocarcinoma among resected lung adenocarcinomas (based on the 2011 IASLC/ATS/ERS international lung adenocarcinoma classification) varies widely from 13 to 37.6 % [21, 22, 34–37, 40].

Fig. 1.9
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Solid adenocarcinoma. (a) The neoplastic cells are arranged in a sheet with no keratinization or acinar formation. (b) The neoplastic cells of this tumor express TTF1, qualifying as solid adenocarcinoma in the new WHO classification

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Genetically, the frequency of KRAS mutation is especially high in solid adenocarcinoma, which parallels the observation that KRAS mutations are enriched in poorly differentiated adenocarcinomas with a solid component [20, 48–53].

Prognostically, solid adenocarcinoma belongs to the poor prognostic group [20, 21, 23, 33–37, 40] (Fig. 1.3, Table 1.2). Patients who had adenocarcinomas with a solid component had significantly lower overall survival and recurrence-free survival rates than patients who had adenocarcinomas with nonsolid components [53]. In patients with stage I pulmonary adenocarcinomas, solid adenocarcinoma recurred significantly earlier than nonsolid adenocarcinomas and was associated with worse post recurrence survival [54].

1.5 Variants of Adenocarcinoma

The new WHO classification lists invasive mucinous adenocarcinoma, fetal adenocarcinoma, colloid carcinoma, and enteric adenocarcinoma as variants of pulmonary adenocarcinoma [1]. These variants are all rare but should always be kept in mind as differential diagnoses for appropriate treatment of the patients.

1.5.1 Invasive Mucinous Adenocarcinoma (IMA) (Fig. 1.10)

IMA shows growth of neoplastic columnar cells with goblet cell-like or gastric foveolar epithelium-like morphology. The growth pattern can be various but predominantly lepidic in most cases. Tumors solely with the lepidic growth pattern, however, are rare and diagnosed as mucinous AIS. Most of the tumors formerly diagnosed as mucinous bronchioloalveolar carcinoma fall into the category of IMA in the current classification. The CT findings of IMA are variable, including consolidations, air bronchograms, and multifocal and sometimes multilobar solid or subsolid nodules or masses [56]. The frequency of IMA in resected lung adenocarcinomas ranges from 2.2 to 5 % [21, 22, 24, 33–37, 40].

Fig. 1.10
figure 10

Invasive mucinous adenocarcinoma. (a) Gross appearance: A mucinous grayish-white nodule with an ill-defined border. (b) Columnar cells with mucinous cytoplasm are growing in lepidic and papillary patterns. (c) The neoplastic cells express HNF4α in their nuclei (immunostaining)

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In gross examination, IMA typically displays a somewhat ill-defined, mucinous grayish-white nodule. It may sometimes show a multinodular pattern or a broad lobar consolidation [1]. Histopathologically, the neoplastic columnar cells have basally situated, relatively small and round to oval nuclei with mild atypism. Alveolar spaces within and surrounding the tumor area are often filled with mucin.

Various growth patterns such as papillary and acinar can be seen in addition to the lepidic growth. Frankly invasive areas may show desmoplastic fibrosis.

Immunohistochemically, IMA cells express CK7 and MUC5AC in most cases, and sometimes CK20 as well, but TTF1 only in 11–27.5 % of the cases [18, 56]. Recently, HNF4α was reported as a new immunohistochemical marker for IMA, which was expressed in 92 % of IMA but was negative in normal lung tissues [57]. This transcription factor, however, is expressed in all gastrointestinal adenocarcinomas, pancreatic adenocarcinomas, and mucinous adenocarcinomas of the ovary and uterine cervix, precluding its utility for differentiating lung metastases of these tumors from IMA, which is a major challenge in the histopathological diagnosis of this variant [57].

Genetically, IMA is intimately associated with KRAS mutation, disclosing the gene mutation 40–86 % of the examined cases [21, 58–65]. The distribution of KRAS amino acid changes more resembled that of colorectal and pancreatobiliary adenocarcinomas than that of pulmonary non-mucinous adenocarcinomas [58, 60, 63, 65]. Smoking status may not be related to KRAS mutations in IMA [63]. In addition, NRG1 fusion genes were recently discovered as novel driver mutations in 6.7–27 % of IMA [62–64]. Interestingly, NRG1is known as a regulator of goblet cell formation with MUC5AC/ MUC5B expression in primary cultures of bronchial epithelial cells, suggesting a possible relationship between NRG1 gene mutation and goblet cell-like morphology/phenotype of IMA [64, 66]. EGFR mutations are rare in IMA, ranging 0–22 % in reported studies [21, 22, 24, 60–65]. KRAS and EGFR mutations are mutually exclusive in IMA but for a few exceptional cases [61, 65]. Rarity of TP53 mutations in IMA was noted in one study [63].

Prognosis of IMA is somewhat controversial. Some studies found IMA in the poor prognostic group [33, 34], others in the intermediate group [20, 21, 23], while another in the good prognostic group [40] (Fig. 1.3, Table 1.2). Some recent studies show there is no statistically significant difference in prognosis between IMA and non-mucinous invasive adenocarcinomas [58, 63]. Recurrence of IMA after surgical resection was limited to the lungs in one study, suggesting a nonaggressive nature of IMA [63].

1.5.2 Colloid Adenocarcinoma (Fig. 1.11)

Colloid adenocarcinoma is an adenocarcinoma in which abundant mucin pools replace air spaces, destroying alveolar framework [1]. This variant may be seen in a pure form or in association with conventional adenocarcinomas.

Fig. 1.11
figure 11

Colloid adenocarcinoma. Note abundant mucinous pool destroying the alveolar framework and incomplete fibrous tissue walls partially lined by neoplastic columnar cells

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In gross examination, this variant typically shows a well-demarcated solid or cystic tumor filled with abundant gelatinous material. Histopathologically, the neoplastic cells constitute a relatively small portion of the tumor, columnar cells growing along incompletely developed fibrous tissue septa or small neoplastic cell clusters floating within mucinous pool. Immunohistochemically, the neoplastic cells, especially of goblet cell morphology, often express intestinal markers such as CDX2, MUC2, and CK20, whereas pneumocyte markers such as TTF1and napsin A are variably expressed [56, 67, 68]. Expression of CK7 is usually retained [67, 68].

The genetic profile of colloid adenocarcinoma is not well known. KRAS mutations were identified in a few cases, while EGFR mutation and ALK fusion genes were so far not found [68]. Prognostically, a few recent studies suggest this variant may belong to the poor prognostic group [33, 34] in contrast to the previous notion of a relatively favorable prognosis for this tumor [67] (Fig. 1.3a, Table 1.2).

1.5.3 Fetal Adenocarcinoma (Fig. 1.12)

Fetal adenocarcinoma is an adenocarcinoma resembling fetal lung [1]. Low-grade and high-grade tumors exist, and they are considered histogenetically different despite their morphologic similarities [69, 70]. Low-grade fetal adenocarcinoma is considered as the epithelial prototype of pulmonary blastoma and occurs in a pure form, whereas high-grade fetal adenocarcinoma frequently coexists with other conventional adenocarcinomas and requires at least 50 % fetal morphology for its diagnosis.

Fig. 1.12
figure 12

Fetal adenocarcinoma. (a) Low-grade fetal adenocarcinoma. Note complex glandular structures lined by columnar cells with relatively small and regular nuclei and supra- and subnuclear vacuoles resembling fetal airway epithelium. A characteristic morular formation is also seen. (b) High-grade fetal adenocarcinoma. The histology resembles the low-grade form, but nuclear atypism is more obvious and morular formation is absent. (c) Low-grade fetal adenocarcinoma. The neoplastic cells show aberrant nuclear/cytoplasmic localization of β-catenin, especially in the morular area (immunostaining). (d) High-grade fetal adenocarcinoma. The localization of β-catenin is predominantly membranous (immunostaining)

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Fig. 1.13
figure 13

Enteric adenocarcinoma. The neoplastic cells form glandular structures resembling colorectal adenocarcinoma. Central necrosis is prominent

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Clinically, low-grade fetal adenocarcinoma occurs in relatively young population with a peak incidence in the fourth decade of life and with a slight female preponderance, whereas high-grade fetal adenocarcinoma occurs predominantly in male heavy smokers [69–71]. High-grade fetal pattern as a minor component of a tumor, however, can be seen more widely in age and gender [72].

Histopathologically, both low-grade and high-grade tumors are characterized by neoplastic columnar cells with glycogen-rich clear cytoplasm in complex papillotubular structures. Low-grade tumors have characteristically small and round nuclei of mild atypia and show morules or cell balls in most cases, whereas high-grade tumors show more obvious nuclear atypia and lack morular formation. Neuroendocrine cells are often admixed with the glandular component. Other types of carcinoma such as large cell neuroendocrine carcinoma, hepatoid adenocarcinoma, and choriocarcinoma may be seen in association with high-grade fetal adenocarcinoma [71, 72]. TTF1 is expressed in low-grade tumors, whereas its expression is often diminished or absent in high-grade tumors [71, 72].

Genetically, low-grade fetal adenocarcinoma is characterized by frequent β-catenin gene mutations with aberrant nuclear/cytoplasmic localization of the protein [68, 73], whereas high-grade fetal adenocarcinoma lacks the mutation, rarely showing major driver mutations of conventional pulmonary adenocarcinomas such as EGFR, KRAS, and PIK3CA mutations [71–73]. Somewhat surprisingly, DICER 1 mutation, which is a characteristic genetic feature of pleuropulmonary blastoma, has recently been reported in a case of low-grade fetal adenocarcinoma occurring in a patient with DICER1 syndrome [74, 75].

The prognosis of fetal adenocarcinoma is not fully elucidated because of the rarity of the tumors. Low-grade fetal adenocarcinomas are usually found at stage I and show an indolent behavior with approximately 10 % tumor death rate [67], whereas high-grade fetal adenocarcinomas are often found at more advanced stages and show much higher mortality rates [69, 71, 72] .

1.5.4 Enteric Adenocarcinoma (Fig. 1.13)

This variant is simply defined as an adenocarcinoma that resembles colorectal adenocarcinomas [1]. Adenocarcinomas may partially take this form, and tumors that show this component at least 50 % of the whole are diagnosed as this variant. This is a very rare tumor; all previous studies on this tumor have been based on a single case or a series of less than ten cases [76–86]. Clinically, this tumor occurs in both sexes almost equally with a median age of 66 [81]. Smoking may be related to the development of this variant [81, 82].

Histopathologically, enteric adenocarcinoma shows acinar, cribriform, or papillotubular structures lined by columnar cells with eosinophilic cytoplasm and brush borders just like conventional colorectal adenocarcinomas [1]. Central necrosis is common. Thus, it is mandatory to rule out the possibility of a metastasis of colorectal origin, especially if the tumor is entirely enteric in morphology. Immunohistochemically, the expression of CK7 is retained in the majority of the reported cases, and TTF1 over half of the cases, but the expression of intestinal markers such as CK20 and CDX2 is also noted approximately in one third and a half of the cases, respectively [79, 80]. Rare cases have also been reported in which tumor cells revealed a completely intestinal immunophenotype, i.e., CK7–, TTF1–, CK20+, and CDX2+ [80, 82, 83].

The genetic profile of this variant is not well known. A few cases revealed KRAS mutations [83, 85, 86] and EGFR mutation [83]. A rare KRAS Q22K mutation with concomitant KRAS polysomy was noted in one case, which could be related to the aggressive clinical course [85]. A recent MicroRNA profiling of this tumor disclosed similarities to non-small cell lung carcinoma and some overlap with pancreatic ductal adenocarcinoma [86].

Prognostically, it is not certain if this variant behaves differently from conventional invasive adenocarcinomas of the lung [82, 84].