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Correlation of Histologic Subtypes and Molecular Alterations in Pulmonary Adenocarcinoma: Therapeutic and Prognostic Implications

Kim, Jiyoon MD; Jang, Se Jin MD, PhD; Choi, Chang Min MD, PhD; Ro, Jae Y. MD, PhD

doi: 10.1097/PAP.0000000000000121
Review Articles

Major driver mutations of pulmonary adenocarcinomas have been identified and highlighted as actionable targets for precision cancer medicine. As phenotype is largely determined by genotype, genetic changes associated with morphologic features have recently received more attention from both pathologists and clinicians. The morphologic features of adenocarcinomas with mutations in EGFR or KRAS, or translocated ALK, have rarely been described. Pulmonary adenocarcinomas with EGFR mutations, the most common driver mutation encountered in Asian patients with pulmonary adenocarcinoma, show lepidic or papillary organotypic growth patterns. KRAS-mutated adenocarcinomas demonstrate nonorganotypic growth patterns, especially mucin-containing cells. P53 mutations are associated with aggressiveness rather than growth patterns. HER2 mutations are observed in mucinous adenocarcinoma and adenocarcinoma with micropapillary features. The histologic features of BRAF-mutated adenocarcinomas have not yet been established, but papillary, lepidic, solid, and acinar patterns have been observed. Adenocarcinomas with rearrangement of ALK, ROS1, and RET genes share similar histologic features, such as solid signet-ring cells and cribriform formation. However, adenocarcinomas with NRG1 rearrangements frequently show mucinous morphology. The histologic features and related mutations of adenocarcinomas with expression of programmed cell death-1 and programmed cell death ligands-1 may be helpful in guiding immunotherapeutic treatment. This review describes histopathologic features of adenocarcinomas and their correlation with molecular alterations.

Departments of *Pathology

Oncology and Pulmonology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea

Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Weill Medical College of Cornell University, Houston, TX

Supported by the Leading Foreign Research Institute Recruitment Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science, and Technology (MEST) (2011-0030105).

The authors have no funding or conflicts of interest to disclose.

Reprints: Jae Y. Ro, MD, PhD, Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Weill Medical College of Cornell University, 6565 Fannin Street, Houston 77030, TX (e-mail: jaero@houstonmethodist.org) and Se Jin Jang, MD,PhD, 88 Olympic-ro 43 gil, Songpa-gu 05505, Seoul, Korea (jangsejin@amc.seoul.kr).

All figures can be viewed online in color at http://www.anatomicpathology.com.

Lung cancer is the most deadly form of cancer, and was responsible for approximately 28% of all cancer deaths in the United States in 2012.1 Adenocarcinoma is the most common histologic type of lung cancer and comprises the largest proportion of morphologically heterogenous cancers.1 The World Health Organization (WHO) classifies adenocarcinoma into 5 major histologic subtypes: lepidic, papillary, acinar, solid, and micropapillary.2 Recent large-scale genomic studies identified several different genetic changes in adenocarcinomas. Certain genetic changes, such as epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) translocations, are strongly associated with a positive targeted therapeutic response, and have readily identifiable adenocarcinoma histology.

Treatment of pulmonary adenocarcinoma varies based on the stage of the disease. In general, the treatment of choice for early stage adenocarcinoma is surgical excision, whereas patients with late-stage tumors undergo chemotherapy or chemoradiation therapy. However, the paradigm of treatment has changed as a number of potential targets for therapy have been identified. For example, the EGFR tyrosine kinase inhibitors (TKIs), gefitinib (Iressa), and erlotinib (Tarceva), are superior therapeutic alternatives for metastatic EGFR mutation-positive adenocarcinoma compared with standard platinum-based chemotherapy.3,4 As phenotypic morphology can occasionally be determined by gene expression patterns, genetic changes associated with morphologic features have recently received more attention from both pathologists and clinicians.

The number of therapeutic target genes is growing due to better understanding of driver mutations and their oncogenic potential (Fig. 1). Mutations in Kirsten rat sarcoma viral oncogene homolog (KRAS) and EGFR, and ALK gene rearrangement, are well-known driver mutations in pulmonary adenocarcinoma, are mutually exclusive, and represent the most important drugable targets.5–8 Tumor proliferation and survival depend exclusively on these mutations; therefore, inactivation of the mutation effects through molecular agents leads to cancer cell death. New drugable targets, including MET amplification and c-ros oncogene 1 (ROS1) gene rearrangement9–11 have been recently discovered.

FIGURE 1

FIGURE 1

To associate genetic alterations with tumor characteristics and patient demographics, previous studies attempted to ascribe clinicopathologic features to each mutation. For example, KRAS mutations are often found in hilar-based adenocarcinoma of smokers, whereas EGFR mutations and ALK gene rearrangements are exclusively seen in peripheral lung adenocarcinoma in never-smokers.5,12–14 Conversely, a number of studies reported an inferior correlation between genotype and phenotype in pulmonary adenocarcinoma except for KRAS mutations in mucinous adenocarcinoma.15,16 However, several recent studies revealed a strong relationship between histologic subtypes and genotypes.5–7,9,11

The purpose of pathologic lung cancer evaluation is to classify the tumor based on its histologic type, to determine all staging parameters and the specific molecular abnormalities that are critical in predicting sensitivity or resistance to the increasing number of available drugable targets.17 Therefore, general evaluation and association of the clinicopathologic points is helpful for both pathologists and oncologists in managing lung cancer patients. The aim of the present review is to correlate histologic subtypes with molecular alterations, and provide an overview of what is known in the literature.

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MUTATIONS

EGFR

Mutation of epidermal growth factor receptor (EGFR) is the most common driver mutation in pulmonary adenocarcinoma in Asian patients (35% to 45%) and the second most common driver mutation in white patients (10% to 20%).5,10,12 The predominant mutations are E746-A750del in exon 19 (45%) and L858R in exon 21 (40% to 45%).18 These are more frequent in women and never-smokers, and the resultant tumors tend to be peripherally located.5,14,18,19

Previous studies showed a morphologic similarity between bronchioloalveolar carcinoma (BAC),20 which is a subgroup of pulmonary adenocarcinomas (according to WHO 2004 classification), and papillary predominant adenocarcinoma.5,13,14,19,21–23 Hsieh et al21 described that pulmonary adenocarcinomas with any BAC features are strongly associated with EGFR mutations [odds ratio (OR), 9.708; 95% confidence interval, 1.464-64.393; P=0.019]. Matsumoto et al22 and Haneda et al24 also found that pulmonary adenocarcinomas with BAC pattern frequently showed EGFR mutations in Japanese patients [Matsumoto: 7/12 BACs (58%) and 3/5 adenocarcinoma with BAC components (60%); Haneda: 28/48 BACs (58%)]. Also, Finberg et al13 frequently observed EGFR mutations in nonmucinous BACs that were classified as lepidic (according to WHO Classification 2015) rather than mucinous adenocarcinoma (P=0.003). In a recent study conducted on Chinese patients, EGFR mutations were more commonly observed in papillary predominant adenocarcinoma (66.7%, 8/12).5 Kim et al25 also reported that papillary features were a predictive factor of sensitivity to gefitinib, a TKI. Micropapillary predominant adenocarcinoma has also been shown to harbor EGFR mutations.19,26,27 A negative correlation between mutation of EGFR and mucinous adenocarcinoma was observed in a few previous studies.5,13 Jie et al5 argued that EGFR mutation was significantly less frequent in solid predominant adenocarcinoma (P=0.038). Therefore, based on the literature, lepidic, papillary, and micropapillary are the most common subtypes of pulmonary adenocarcinoma resulting from EGFR mutations, whereas mucinous and solid predominant adenocarcinomas were less frequently observed. Most of the tumor cells analyzed above were positive for thyroid transcription factor-1 (TTF-1) and surfactant protein, suggesting that the tumor originated from terminal respiratory units.14 The growth patterns of pulmonary adenocarcinomas can be further classified into organotypic and nonorganotypic based on architectural and cellular similarities to pulmonary acini. Lepidic adenocarcinomas largely maintain alveolar architectures and are easily diagnosed as pulmonary even though the normal pulmonary parenchyma is not included in the microscopic field. With this viewpoint, lepidic, papillary, and a number of micropapillary and acinar adenocarcinomas can be classified into organotypic tumors (Fig. 2). As EGFR mutations are almost exclusively identified in pulmonary adenocarcinomas, it can be assumed that pulmonary organotypic adenocarcinomas are more likely to have these mutations.

FIGURE 2

FIGURE 2

As previously mentioned, TKIs, such as gefitinib, erlotinib and afatinib, are used as first-line treatment agents for pulmonary adenocarcinoma with EGFR mutations.3 However, tumors can become resistant to these drugs through acquisition of a T790M mutation in exon 20.18 Currently, T790M-specific inhibitors are used for the treatment of TKI-resistant pulmonary adenocarcinomas28,29; in these cases, a second biopsy is necessary after treatment to evaluate the presence of the T790M mutation in TKI-resistant patients. The histologic features of these tumors have not yet been precisely described, but our experience is that they display characteristic nuclear changes similar to small cell carcinoma (Fig. 3).

FIGURE 3

FIGURE 3

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KRAS

KRAS mutation is the most common and the second most common driver mutation in white (15% to 35%) and Asian (5% to 10%) populations, respectively. Codons 12 and 13 of KRAS are most frequently involved. KRAS and EGFR mutations are mutually exclusive.12,13 Characteristic features of adenocarcinomas with KRAS mutations are their hilar location, multifocality, and association with smoking.5,12–14

A genotypic and histologic association between KRAS mutations and the mucinous subtype was confirmed by several studies.8,12,13,30–33 Marchetti et al31 documented a correlation between mucinous BAC and KRAS mutation. Mucinous BAC, classified as invasive mucinous adenocarcinoma (according to WHO Classification 2015), typically shows goblet or columnar cell morphology and abundant intracytoplasmic mucin. Yatabe et al34 reported that a number of goblet cells stained positive for CDX-2 and CK20 with variable intensity. The authors also noted that the goblet cell morphology and staining results were similar to colorectal adenocarcinoma with KRAS mutation, and pancreatobiliary and ovarian mucinous tumors, suggesting that these tumors may be prototypical despite the difference in the organs of origin.34 Pathologists should interpret immunohistochemical results carefully to distinguish lung primary mucinous adenocarcinoma from metastatic carcinomas.34 Furthermore, the KRAS mutations G12D and G12V were frequently (73%) observed in mucinous adenocarcinomas, such as colorectal and pancreatobiliary, whereas nonmucinous adenocarcinoma had the G12C mutation more frequently.8,35 Extracellular mucin was also associated with KRAS mutations.30 In summary, nonorganotypic pulmonary adenocarcinomas such as mucinous, solid, and nonorganotypic acinar and micropapillary frequently have the KRAS mutation (Fig. 4).

FIGURE 4

FIGURE 4

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P53

Mutation of tumor protein 53 (P53) is observed in 30% to 40% of cases with lung adenocarcinoma. Mutation of P53 along with other mutations is associated with rapid and more aggressive tumor progression.prognostic significance of EGFR and p53 mutations in surgically resected lung adenocarcinomas 36 Mucinous adenocarcinomas show a negative correlation with P53 mutation.8,37,38 Shim et al8 observed that the frequency of P53 mutation was significantly lower in invasive mucinous carcinoma, and only 2 cases of P53 mutations were identified in 50 cases of invasive mucinous adenocarcinomas. Furthermore, Koga et al37 stated that BACs and BACs with invasive growth component showed significantly lower P53 mutation frequencies. In many human cancers, P53 is one of the most frequently mutated tumor suppressor genes. The mutation is more likely to be associated with tumor progression rather than histologic subtypes or organotypes.

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Oncogene HER2

A small percentage (1% to 5%) of pulmonary adenocarcinomas harbors an in-frame insertion at exon 20 of EGFR 2 (HER2).39–41 Adenocarcinomas with HER2 amplification are most commonly found in never-smokers and women.42

In a Japanese study, the mucinous micropapillary pattern showed a significantly higher proportion of HER2-mutated positive adenocarcinomas than other growth patterns.39 Zhang et al41 also cited that HER2 and KRAS mutations were frequently observed in invasive mucinous adenocarcinoma in Chinese female never-smokers. However, no data correlating histologic features of adenocarcinoma with the HER2 mutation are available from the west.

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BRAF

BRAF mutations, including V600E and other types, are less common in lung adenocarcinoma and are observed in only 2% to 4.5% of adenocarcinomas in general.43–46 Tumors with BRAF mutations frequently occur in women and never-smokers but this is controversial.43,45,46 They can coexist with other mutations, such as EGFR mutations.45,47 Several BRAF inhibitors, such as vemurafenib, dabrafenib, and sorafenib, can be used for treatment of BRAF mutation-positive pulmonary adenocarcinomas.43 Recently, Sereno et al48 reported dramatic responses to sorafenib in advanced adenocarcinoma with G469R mutation. Nonetheless, the histologic features of lung adenocarcinoma with BRAF mutation have not been established. In 2008, Yousem et al49 described histopathologic features of 10 pulmonary adenocarcinomas with V600E mutation, which largely consisted of mixed groups; papillary and lepidic features were observed in 80% and 50% of adenocarcinomas, respectively. However, seven cases of adenocarcinoma with BRAF mutation in Chinese patients consisted of 1 papillary, 2 solid, and 4 acinar subtypes.44 Although BRAFoma has been coined as a name of tumors sharing the therapeutic target,50 organ preponderance of BRAF mutations has neither been identified among epithelial malignancies, nor has histologic association of pulmonary adenocarcinoma.

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GENE REARRANGEMENT

ALK

EML4-ALK fusion is the most common gene rearrangement in pulmonary adenocarcinoma (5%), and is associated with younger never-smokers and peripheral origin.7,51–53 The presence of ALK rearrangement and KRAS and EGFR mutations are mutually exclusive.51,54

Crizotinib is available for treatment of lung adenocarcinoma driven by ALK rearrangement.51,55 Although the presence of ALK gene rearrangement is not associated with survival probability, ALK-rearranged lung adenocarcinoma typically presents at an advanced stage (not resectable stage).7 Several methods are currently used to detect ALK rearrangement, including polymerase chain reaction, immunohistochemistry (IHC), and fluorescence in situ hybridization.51,56

The most prominent histologic feature of adenocarcinoma with EML4-ALK translocation is a solid type with signet-ring cell component6,52,53 (Fig. 5). Previously, a significant association between ALK rearrangement and acinar predominant adenocarcinoma was described in a Japanese report (P<0.0001).54 Although, Korean studies also reported that acinar predominant adenocarcinoma was the most common subtype in ALK-rearranged lung cancer, the frequency was significantly lower than that of ALK-negative tumors.6,7 The authors state that EML4-ALK lung adenocarcinoma is associated with a solid predominant pattern and mucin-containing cells.6 This result was similar to that of western studies.52,53 Furthermore, Kim et al6 noted that cribriform formation (OR, 3.253; P=0.028), tumor location next to bronchioles (OR, 5.361; P=0.001), and the presence of psamomma bodies (OR, 4.026; P=0.002) were more commonly observed in ALK-rearranged lung adenocarcinoma than in ALK-negative lung adenocarcinoma. In addition to EML4-ALK positivity, the tumors are typically positive for TTF-1 (70%) and P63 (67.1%) but negative for P40 (2.9%).6 Lack of P40 IHC staining is more useful than P63 IHC positivity as a criterion to distinguish ALK-rearranged adenocarcinoma with solid histology from squamous cell carcinoma.

FIGURE 5

FIGURE 5

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ROS1

ROS1 gene rearrangement, which is regarded as a distinct molecular subtype of non–small cell lung cancer, is observed in 1% of pulmonary adenocarcinomas. There are several fusion partners for ROS1 but CD74-ROS1 is the most common fusion variant in pulmonary adenocarcinoma.57,58 Clinically, ROS1-rearranged adenocarcinoma patients are predominantly younger, with female and never-smoker predominance, similar to the demographics of ALK-rearranged adenocarcinoma patients.59

Crizotinib, a known targeted molecular agent for ALK-rearranged adenocarcinoma, can be used to treat advanced ROS1-rearranged adenocarcinoma.60 Because ROS1 and ALK share the majority of their kinase domains, Crizotinib can bind both ROS1 and ALK.61 ROS1-rearrangement is associated with poor disease-free survival, but not with overall survival, and is not an independent prognostic factor.9

The histologic features of ROS1-rearranged adenocarcinoma are similar to ALK-rearranged adenocarcinoma.9,59,62 Acinar cell pattern, including cribriform pattern (7/12, 58.3%) and solid pattern (7/12, 58.3%) were the most common histologic types of ROS1-rearranged adenocarcinoma in East Asian patients.59 Four of 12 cases of ROS1-rearranged adenocarcinomas contained signet-ring cell and cribriform patterns.59 Lee et al62 stated that ROS1-rearranged adenocarcinoma exhibited solid signet-ring cell patterns and mucinous cribriform patterns and was similar to ALK-rearranged and RET-rearranged adenocarcinoma in Korean patients. In another Korean study, the predominant growth patterns were solid (3 cases, all containing signet-ring cells at least focally), acinar (3 cases), micropapillary (2 cases), and lepidic (1 case) patterns. A cribriform pattern was observed in all the cases and a micropapillary pattern was observed at least focally (range, 2% to 85%) in 8 cases.9 The authors noted that the micropapillary growth pattern was also significantly more common than tumors with wild-type ROS1 (P<0.001).9 Also, aerogenous spread was a significant feature of ROS1-rearranged adenocarcinoma (P=0.002).9 Loss of E-cadherin expression, determined by IHC, was observed in all cases (P=0.049).9

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RET

The rearranged during transfection (RET) proto-oncogene was discovered in 2012, and found in 1% to 2% of mutations driving pulmonary adenocarcinoma.63,64 The clinical characteristics of RET-rearranged adenocarcinoma are similar to those in ALK and ROS1 rearrangement.62,65–67 Kinesin family 5B gene (KIF5B) is the most common RET fusion partner.63,64 RET-rearranged adenocarcinoma responds to cabozantinib,65,68 and rearrangement does not seem to correlate with survival.66

The histologic features of RET-rearranged adenocarcinomas also resemble those of ALK-rearranged and ROS1-rearranged adenocarcinomas.62,66,67 Solid signet-ring cell and mucinous cribriform patterns were identified in one Korean study.62 Tsuta et al67 also showed signet-ring cell features (12/22, 54.5%), but histologic subtyping of 22 cases of RET-rearranged adenocarcinomas showed a micropapillary pattern in one case, and lepidic, papillary, and acinar patterns in 6, 9, and 2 cases, respectively. Pan et al66 also identified solid and cribriform patterns and signet-ring cell features. Furthermore, this group suggested that extracellular mucin (P<0.001) and hepatoid cytology (P<0.001) could be correlated to RET-rearrangement.66 In addition, psamomma bodies and lymphangitic spread within the lung was present in 4 of 5 cases in one western study.65

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NRG1

Neuregulin 1 (NRG1) gene fusion is a novel gene rearrangement first identified in Cologne in 2014.68–70 CD74 and vesicle-associated membrane protein 2 (VAMP2) have been reported as fusion partners.8,69–71 All NRG1 rearrangements were observed in invasive mucinous adenocarcinoma without KRAS mutation, and were mutually exclusive.8,69–71 Shim et al8 reported that NRG1 was the second most common mutation of invasive mucinous adenocarcinoma identified by deep next-generation sequencing. Nakaoku et al70 found that NRG1 rearrangement was observed in 6 of 34 invasive mucinous adenocarcinomas without the KRAS mutation (17.6%).

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PROGRAMMED CELL DEATH-1 AND PROGRAMMED CELL DEATH LIGANDS 1 AND 2

Recently, pulmonary adenocarcinomas showed response to blocking programmed cell death (PD)-1 in early clinical trials.72 However, the clinicopathological characteristics are still unclear. Koh et al73 studied the relationship between programmed cell death ligands (PD-L)1 and PD-L2 expression, histology, and driver oncogenes. The majority of patients (293/497 patients, 59%) who were treated with surgical resection stained positive for PD-L1 by IHC. The clinical characteristics of adenocarcinoma with PD-L1 expression showed a high incidence of nodal metastasis (P=0.006) and patients were typically smokers (P=0.056). Furthermore, the most frequent histologic subtypes were solid and micropapillary, and the tumors were associated with ALK rearrangement and expression of EGFR, MET, and HER2. They reported that PD-L1 expression was related to a high number of CD8-positive cells and high PD-1/CD8-positive cell ratio73 (Fig. 6). Yang and colleagues argued that about 40% of stage 1 and surgically resected adenocarcinomas (65/163 patients) showed PD-L1 expression, which was related to vascular invasion (P=0.038) and higher-grade differentiation (P=0.015). However, they stated that tumor-infiltrating lymphocytes were not associated with PD-L1 expression (P=0.312).74 The genetic alteration of EGFR and BRAF was also not associated with PD-L1 expression.74 The results of survival analysis were also conflicting. Koh et al73 reported that PD-L1 expression is poorly correlated to disease-free survival (P=0.030). However, Yang et al74 found that PD-L1 expression correlated with better relapse-free survival.

FIGURE 6

FIGURE 6

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CONCLUSIONS

Several driver mutations are therapeutic targets and may correlate to specific subtypes of adenocarcinoma. Each subtype shows a high prevalence of specific mutations. The majority of mucinous tumors have KRAS mutations, and papillary and acinar subtypes frequently have EGFR mutations.75 The histologic subtype can assist in predicting the efficacy of the targeted chemotherapeutic agent. Moreover, proper histologic evaluation is critical and molecular alterations are complementary to morphologic changes. Therefore, all lung tumors should be evaluated and diagnosed by pathologists and triaged based on histologic changes.

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Keywords:

pulmonary adenocarcinoma; molecular alteration; subtypes; therapeutic; prognostic

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