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research-article2014
IJSXXX10.1177/1066896914525230International Journal of Surgical PathologyHwang et al
Original Article
Modified Histologic Classification as a Prognostic Factor in Pulmonary Adenocarcinoma
International Journal of Surgical Pathology 1–9 © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1066896914525230 ijs.sagepub.com
Ilseon Hwang, MD, PhD1, Keon Uk Park, MD, PhD2, Kun Young Kwon, MD, PhD1
Abstract Background. The histologic pattern of pulmonary adenocarcinoma is highly heterogeneous and considered to be an important prognostic factor. The predominant histologic pattern is emphasized in the 2011 International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society classification, but few studies present a detailed investigation of the histologic changes and prognosis pulmonary adenocarcinoma using resected specimens. Methods. We examined 125 cases of surgically resected pulmonary adenocarcinoma and carefully observed histologic patterns. Invasive adenocarcinoma was divided into 3 groups according to a modified histologic classification system: group 1 had a lepidic or papillary predominant pattern with ≤10% solid or micropapillary pattern; group 2 had an acinar predominant pattern with ≤10% of the solid or micropapillary pattern; and group 3 had a solid or micropapillary predominant pattern, or any predominant pattern with >10% solid or micropapillary pattern. Results. Proportions of predominant lepidic, papillary, acinar, solid, and micropapillary patterns were 11 (9.3%), 8 (6.8%), 54 (45.8%), 38 (32.2%), and 7 (5.9%), respectively. Vague areas between 2 different patterns were frequently observed, which were considered as transitional areas for one pattern to the other pattern (gradual dedifferentiation). Modified histologic classification was significantly associated with disease-free and overall survival rate (P = .026 and .010, respectively) using the Kaplan–Meier survival test, and an independent prognostic factor (P = .016) in overall survival using the Cox regression test. Conclusion. Pulmonary adenocarcinoma demonstrates heterogeneous histologic patterns with gradual dedifferentiation, and this modified histologic classification is an important prognostic factor for patients with pulmonary adenocarcinoma. Keywords lung, adenocarcinoma, histologic pattern, prognosis, gradual dedifferentiation
Introduction Lung cancer accounts for most cases of severe cancer incidence and mortality worldwide, and pulmonary adenocarcinoma is the most common histological lung cancer subtype.1 Pulmonary adenocarcinoma is heterogeneous in histologic pattern, molecular profile, clinical findings, radiological outcome, and surgical treatment.1,2 Pathological and radiological studies have revealed several prognostic subsets for the pulmonary adenocarcinoma.3-5 Histologic subtype in particular is a significant prognostic factor according to many studies.6-15 Therefore, the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society (IASLC/ATS/ERS) have sponsored a project to develop an international Multidisciplinary Lung Adenocarcinoma Classification (Table 1).16 Identification of the predominant pattern can be complicated because most pulmonary adenocarcinomas have more than 3 variable histologic patterns, and the decision
as to which histologic pattern is predominant holds a level of subjectivity for pathologists.17,18 In many cases, it is difficult to distinguish one histologic pattern from another. Warth et al18 reported that there is some disagreement among pathologists regarding the classification of histologic patterns, especially in relation to the lepidic-papillary, lepidic-acinar, papillary-acinar, and solid-acinar patterns. These patterns are similar, and it is speculated that one pattern may be derived from the other patterns. However, studies comparing the morphologic features of the histologic patterns in pulmonary adenocarcinoma are 1
Department of Pathology, Keimyung University School of Medicine, Daegu, Korea 2 Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea Corresponding Author: Kun Young Kwon, Department of Pathology, Keimyung University School of Medicine, Daegu, Korea. Email: [email protected]
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Table 1. 2011 International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society International Multidisciplinary Classification of Lung Adenocarcinoma.16 Preinvasive lesion Atypical adenomatous hyperplasia Adenocarcinoma in situ (≤3 cm, formerly bronchioloalveolar carcinoma) Nonmucinous and/or mucinous Minimally invasive adenocarcinoma (≤3 cm lepidic predominant tumor with ≤5 mm invasion) Nonmucinous and/or mucinous Invasive adenocarcinoma Lepidic predominant (formerly nonmucinous bronchioloalveolar carcinoma pattern) Acinar predominant Papillary predominant Micropapillary predominant Solid predominant Variants Invasive mucinous adenocarcinoma (formerly nonmucinous bronchioloalveolar carcinoma) Mixed mucinous/nonmucinous Colloid Fetal Enteric
rare. Therefore, detailed examination of these histologic patterns is required to understand changes in morphologic features, and this would also aid in the development of common criteria for determining the predominant pattern. Studies investigating the prognostic value of the 2011 IASLC/ATS/ERS classification showed a significant association between histologic pattern and disease-free or overall survival in pulmonary adenocarcinoma.1,19-21 These studies demonstrated that the lepidic predominant group is generally related to a good prognosis, acinar predominant group was generally related to an intermediate prognosis, and solid or micropapillary predominant group was generally related to a poor prognosis. However, other studies have suggested that the papillary predominant group has a relatively better prognosis,1,13,19,21 and additional studies have demonstrated a poor prognosis in the papillary predominant group.20,22,23 One explanation for the prognostic difference in the papillary predominant pattern is that papillary predominant adenocarcinomas are diverse,20 and the predominant histologic pattern is not a reliable indicator of patient prognosis. In other words, identification of one predominant histologic pattern is insufficient as a prognostic factor in pulmonary adenocarcinoma because studies investigating histologic classification using one predominant pattern did not reveal similar prognostic value.1,19-21 It is well known that solid or micropapillary predominant adenocarcinomas generally confer prognosis, and pulmonary adenocarcinomas with a minor solid or micropapillary pattern component generally confer a worse
prognosis than adenocarcinoma without solid and micropapillary components.6,7,11,12,24 However, the 2011 IASLC/ ATS/ERS classification does not consider minor component patterns as a crucial factor in histologic classification but includes a description of all histologic components and proportions, although minor histologic components with poor differentiation may be more important in cases with a poor prognosis.16 Therefore, modification of the classification of predominant histologic patterns is required to develop a precise and commonly accepted prognostic value in pulmonary adenocarcinoma. The aims of this study are to evaluate the variable histologic patterns of pulmonary adenocarcinoma and to suggest a novel modified histologic classification that is strongly correlated with patient prognosis.
Materials and Methods Case Selection We searched the medical records at Keimyung University Dongsan Hospital for all cases of pulmonary adenocarcinoma diagnosed between 1994 and 2007, and we selected 125 patients who received surgical resection. Clinical data from these 125 included tumor size, date of diagnosis, date of recurrence, date of last follow-up, and cause of death. The mean age of the 125 patients was 60.74 years (range = 29-82 years). Of the patients, 65 (52.0%) were male and 60 (48.0%) were female. Most patients underwent lobectomy (115 cases, 92.0%), and the remainder underwent pneumonectomy (5 cases, 4.0%), bilobectomy (3 cases, 2.4%), segmentectomy (1 case, 0.8%), and wedge resection (1 case, 0.8%). There were 22 (17.6%), 28 (22.4%), 47 (37.6%), 5 (4.0%), and 22 (18.4%) patients in the pathologic stages of T1a, T1b, T2a, T2b, and T3, respectively. Sixty-five (52.0%), 28 (22.4%), 29 (23.2%), and 3 (2.4%) patients were in the pathologic stages of N0, N1, N2, and N3, respectively. The numbers of patients with stages IA, IB, IIA, IIB, IIIA, and IIIB were 35 (28.0%), 18 (14.4%), 25 (20.0%), 10 (8.0%), 33 (26.4%), and 4 (3.2%), respectively. Median tumor size was 3.48 cm (range = 1.3-10.0 cm). This study was approved by the institutional review board at Keimyung University Dongsan Medical Center (2013-05-014).
Histologic Examination and Modified Classification All slides were stained with hematoxylin and eosin and reviewed by 2 pulmonary pathologists (K. Kwon and L. Hwang). We examined histologic patterns in the invasive adenocarcinoma cases based on IASLC/ATS/ERS classification (Table 1), which included lepidic, acinar, papillary, solid, and micropapillary patterns. These patterns were previously described by Yoshizawa et al.1,25 The histologic pattern was described in greater detail when it was similar to the other patterns. We excluded preinvasive lesions and
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Hwang et al Table 2. Distribution of Histologic Patterns in the Invasive Adenocarcinomaa. No. of Patterns
Lepidic
Papillary
Acinar
Micropapillary
Solid
Frequency (%)
1
3 (2.5)
5 (4.2)
Subtotal (%) 8 (6.8)
1 (0.8) 3 (2.5) 1 (0.8)
2
1 (0.8)
33 (28.0)
5 (4.2) 21 (17.8) 1 (0.8) 3
10 (8.5)
4 (3.4)
9 (7.6)
6 (5.1)
8 (6.8)
4
22 (18.6)
5 (4.2)
5 (4.2)
5
8 (6.8)
37 (31.4)
32 (27.1) 8 (6.8)
a
The shaded boxes represent the presence of histological patterns in tumor.
variants of invasive adenocarcinoma such as invasive mucinous, colloid, fetal, and enteric types. Proportions of each histologic component were recorded using a method previously described by Yoshizawa et al.1,25 We modified the histologic classification, and all cases were divided into 3 groups according to the predominant pattern and the proportion of solid or micropapillary pattern: group 1 had a lepidic or papillary predominant pattern with ≤10% of the solid or micropapillary pattern; group 2 had an acinar predominant pattern with ≤10% solid or micropapillary pattern; and group 3 had a solid or micropapillary predominant pattern, or any predominant pattern with >10% solid or micropapillary pattern.
Statistical Analysis SPSS statistical package, version 20.0 for Windows, was used for all statistical analyses (IBM, Armonk, NY). The relationship between modified histologic classification and clinical variables was evaluated using the χ2 test and linear by linear test. Disease-free and overall survival were measured from the date of diagnosis to the date of recurrence or last follow-up, and the date of diagnosis to the date of death or the last follow-up, according to the Kaplan–Meier method and the Cox proportional hazard model. Null hypotheses of no difference were rejected if 2-sided P values were less than .05.
Results Composition of Histologic Patterns The lepidic pattern was predominant in 11 tumors (9.3%), and 8 tumors (6.8%) has a papillary predominant pattern. The acinar predominant pattern was most common, accounting for 54 (45.8%) cases. There were 38 (32.2%) solid pattern predominant tumors and 7 (5.9%) micropapillary pattern predominant tumors. The median number of histologic patterns in single tumor was 3.0 (range = 1-5). Only 6.8% of the tumors had a single pattern (papillary or solid), and 28.0% of the tumors showed 2 patterns. Thirtyseven (31.4%) and 32 (27.1%) tumors showed 3 and 4 histologic patterns, respectively, which always included the acinar pattern. All histologic patterns were observed in 8 (6.8%) of the tumors (Table 2). Of these 8 tumors, 7 (87.5%) were papillary predominant with a micropapillary pattern, and the mean proportion of micropapillary pattern was 13.3% (range = 5% to 25%). According to our modified histologic classification, there were 10 (8.5%), 23 (19.5%), and 85 (72.0%) cases of group 1, 2, and 3, respectively.
Histologic Examination of Variable Patterns We frequently observed vague areas between 2 different patterns, which we considered transitional areas between 2
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patterns. The lepidic pattern most closely resembled normal alveoli and showed relatively thickened alveolar septa with enlarged atypical cells, compared to normal alveolar cells (Figure 1A). The lepidic pattern was frequently identified in the peripheral areas of tumors, adjacent to normal alveoli. The papillary pattern was similar to the lepidic pattern, and structural deviation of the papillary pattern was mild. However, thickened alveolar septa with thin or thick fibrovascular cores were frequently observed in papillary pattern, compared to the lepidic pattern. The cellularity of the papillary pattern was increased compared to the lepidic pattern, and cytologic atypia was more aggressive (Figure 1B). The acinar pattern was frequently observed in areas adjacent to the lepidic or papillary patterns. It was difficult to distinguish areas between the lepidic and acinar patterns, which we assumed were the result of stromal invasion of the lepidic pattern. In areas dominated by the acinar pattern, stromal reaction was discovered, and tumor cells contained a gland-like structure. Cytologic atypia of tumor cells in the acinar pattern was more aggressive than that of the lepidic pattern (Figure 1C). Thus, we suggest that the acinar pattern in tumors with the lepidic pattern is derived from the lepidic pattern, with stromal invasion. The acinar pattern adjacent to the papillary pattern appeared to be a structural distortion or fusion structure of the papillary pattern. The gland-like structure of the acinar pattern is likely formed as a consequence of stromal invasion and papillae fusion of the papillary pattern (Figure 1D). The solid pattern was occasionally observed in the absence of other patterns; however, most solid pattern tumors occurred in conjunction with the acinar pattern. The solid pattern may occur as a consequence of fusion of the gland-like structures of the acinar pattern, and solid pattern tumor cells showed poor differentiation and nuclear pleomorphism (Figure 1E). Occasionally, the peripheral area of the solid pattern showed budding of the tumor cell nests, and this budding area was defined as the micropapillary pattern (Figure 1G). Cellular atypia of the solid pattern was similar to that of the micropapillary with the solid pattern. The micropapillary pattern may be formed by the small tumor budding nests of the other patterns. Furthermore, the micropapillary pattern was frequently observed with the papillary pattern, and the tumor cells of the micropapillary pattern demonstrated a more aggressive cellular atypia than that of the papillary pattern (Figure 1H). The micropapillary pattern was also observed in conjunction with the acinar pattern (Figure 1F). In the acinar with micropapillary pattern, the tumor cells in the micropapillary patterned area were observed to bud into the lumen of the gland-like structure of the acinar pattern, and the tumor cells of the micropapillary patterned area arising from the acinar pattern showed more aggressive cellular atypia than the micropapillary patterned area arising from the papillary pattern.
Correlation Between Clinical Manifestations and Histologic Patterns Tumor recurrence and patient survival were significantly associated with the modified histological classification (P = .024 and .002, respectively) using the χ2 test (Table 3). Other clinical manifestations, including tumor size, T stage, and N stage, were not associated with the modified classification. The disease-free and overall survival rates were analyzed using the Kaplan–Meier method, and modified classification was significantly associated with disease-free and overall survival rates (P = .026 and .010, respectively; Figure 2). Pathologic T and N stages were also significantly associated with disease-free survival (P < .00), and only pathologic T stage was significantly associated with overall survival (P = .019) using the Kaplan–Meier test. We further analyzed T stage, N stage, and modified classification with a multivariate Cox proportional hazard model (Table 4). Of T stage, N stage, and modified classification, T stage (T1 vs T2-3) and N stage (N0 vs N1-3) were significantly correlated with diseasefree survival (P = .035 and .001, respectively), whereas modified classification (P = .091) was not. However, modified classification (P = .016) was significantly correlated with overall survival, whereas T stage (P = .051) and N stage (P = .631) were not.
Discussion Predominant histologic pattern alone cannot entirely predict patient prognosis, such as disease-free or overall survival rate. However, modification of histologic classification more accurately represents patient survival. The modified classification scheme that we developed considered specific components of solid and micropapillary patterns, which are known to correlate with poor prognosis.2,4-6,8,12,24,26 This modification provides a more accurate prediction of patient survival compared to the unmodified 2011 IASLC/ATS/ ERS classification. Although this modified classification resulted in a relatively high proportion (72%) of group 3 (solid/micropapillary predominant pattern or any pattern with >10% solid/micropapillary pattern) cases, and demonstrated a strong correlation between high recurrence and poor survival, further study with a larger sample size is needed. Especially, a prospective study for pulmonary adenocarcinoma is needed to confirm the usefulness of the modified histologic classification as an important prognostic factor and the usefulness of chemotherapy for group 3. Histogenesis of pulmonary adenocarcinoma is very complicated and is related to multiple genetic alterations, and careful observation of the morphologic features may help investigate the histogenesis.27 Although the process of tumorigenesis of pulmonary adenocarcinoma cannot be completely explained by the morphologic features, the
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Figure 1. (A) The lepidic pattern (arrow) shows more thickened alveolar septa with enlarged tumor cells than normal alveolar walls (arrow head). (B0 The papillary pattern (arrow head) shows mild structural deviation with more thickened alveolar septae than lepidic pattern (arrow head). Ambiguous area (asterisk) is present between the lepidic and the papillary patterns. (C) The acinar pattern shows gland-like structure (arrow) and is similar to lepidic pattern (arrow head) with stromal invasion. Borderline area between the lepidic and the acinar patterns is present (asterisk). (D) The acinar pattern (arrow) looks like that structural distortion or fusion structure of the papillary pattern (arrow head). Borderline area between the papillary and the acinar patterns is also present (asterisk). (E) The micropapillary pattern shows small tumor budding nests of the papillary pattern (arrow heads and inlet). (F) The micropapillary pattern (arrow heads) also shows small tumor budding nests of the acinar pattern and budding tumor cells have more aggressive cellular atypia than tumor cells of the acinar pattern (inlet). (G) The solid pattern (arrow) seems to be fusion of gland-like structure of the acinar pattern (arrow head). Ambiguous area is present between the acinar and the solid pattern (asterisk). (H) Peripheral area of the solid pattern (arrow) shows budding of tumor cell nests and these nests are same as the micropapillary pattern (arrow head).
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Table 3. Correlation of Clinical Manifestation and Histologic Classifications. Modified Classification T stage T1 T2a-3 N stage N0 N1-3 Stage I II-III Tumor size ≤3 cm >3 cm Recurrence No Yes Survival No Yes
a
Group 1
Group 2b
Group 3c
5 5
9 14
33 52
7 3
10 13
42 59
5 5
10 13
33 52
7 3
9 14
43 40
6 4
12 11
27 58
9 1
16 7
39 46
P .580 .469 .460 .743 .024 .002
a
Group 1: Lepidic or papillary predominant pattern with ≤10% solid and/or micropapillary pattern. b Group 2: Acinar predominant pattern with ≤10% solid and/or micropapillary pattern. c Group 3: Solid or micropapillary predominant pattern, or any predominant pattern with >10% solid or micropapillary pattern.
histologic findings are important to understand the histogenesis of pulmonary adenocarcinoma. We frequently observed areas with borderline features between 2 patterns, and defining a specific pattern in these areas was particularly difficult. These ambiguous areas may be caused by a gradual change from one pattern to another in the tumor area. For example, the lepidic pattern was observed to gradually change into the papillary or acinar pattern, and the acinar pattern was also observed to gradually change into the solid pattern. We suggest that the papillary and acinar patterns may dedifferentiate from the lepidic pattern, because the lepidic pattern is more similar in structure to normal alveoli than the other 2 patterns. Likewise, the solid and micropapillary patterns may be more dedifferentiated than the acinar or papillary pattern. Therefore, these gradual changes between 2 or 4 different histologic patterns may be interpreted as gradual dedifferentiation (Figure 3). Gradual dedifferentiation may be the cause of the heterogeneous morphologic features frequently observed in pulmonary adenocarcinoma, and specific genetic or epigenetic changes may occur during the processes of the dedifferentiation. Gradual dedifferentiation cannot completely explain histogenesis, but has an important role to prove the complicated nature of
the histogenesis of pulmonary adenocarcinoma. Further studies regarding the potential genetic or epigenetic changes relating to gradual dedifferentiation pulmonary adenocarcinoma are required. Although most pulmonary adenocarcinomas contain more than one histologic pattern, 6.8% of the samples analyzed in this study contained a single pattern (acinar or solid). In pulmonary adenocarcinoma with heterogeneous patterns, the more dedifferentiation of the patterns is mainly located in central area of tumor, and the less dedifferentiated pattern, such as lepidic or papillary pattern, is commonly located in peripheral area. Areas of higher dedifferentiation may have an increase growth potential and may replace the areas of less dedifferentiation through the efferent growth. Therefore, adenocarcinoma with variable histologic patterns may not have a lepidic pattern at all, owing to replacement by areas with high dedifferentiation, as in the case of tumor with acinar or solid patterns. However, we believe that gradual dedifferentiation may not occur in all tumors with a single pattern, and some tumors with a single histologic pattern may not have a mechanism for gradual dedifferentiation, but a different mechanism for abrupt transition or carcinogenesis (Figure 3, dotted line arrows). Specifically, an adenocarcinoma with a solid pattern, which confers a poor prognosis, may have a different genetic abnormality than an adenocarcinoma with gradual dedifferentiation.1,13 Additional studies regarding genetic differences in the various histologic patterns are necessary. In this study, papillary predominant adenocarcinoma was observed to have a similarly poor prognosis to micropapillary or solid predominant adenocarcinoma. Some studies have reported papillary predominant adenocarcinoma to have a survival rate similar to micropapillary or solid predominant adenocarcinoma,20,22,23 whereas other studies have reported a better survival rate for papillary predominant tumors.1,13,21 These differences may be due to the fact that papillary predominant tumors are relatively morphologically diverse, and it is possible that the different subtypes also differ with respect to prognosis.20 In this study, 87.5% of papillary predominant adenocarcinomas contained 10% to 25% micropapillary and/or solid patterns and revealed poor prognosis. Therefore, as the papillary pattern is similar in morphologic features to the lepidic pattern, these 2 patterns may confer a similar survival rate provided the tumor does not have micropapillary or solid components. In addition, many papillary predominant adenocarcinomas were classified as group 3 according to the modified histologic classification and were therefore associated with a poor prognosis. Other variants of pulmonary adenocarcinoma, such as mucinous, colloid, fetal, or enteric type, have specific histologic features, and the clinicopathologic characteristics of each variant are not well known.28-30 However, in
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Figure 2. Disease-free and overall survival rate according to predominant histologic pattern and modified classifications by Kaplan– Meier survival test. (A) Predominant patterns present no correlation of disease-free survival (P = .214). Papillary predominant group shows relatively poor survival rate. (B) Predominant patterns are correlated with overall survival (P = .003). Solid, micropapillary, or papillary predominant group shows poor survival and lepidic predominant group shows better survival. (C) Modified classification reveals significant relationship of disease-free survival (P = .026). (D) Modified classification also reveals significant relationship of overall survival (P = .010). Table 4. Multivariate Analysis of Disease-Free and Overall Survivals According to T Stage, N Stage, and Modified Classification (Cox Proportional Hazard Model). Variables Disease free survival T stage (T1 vs T2, 3) N stage (N0 vs N1, 2, 3) Modified classification Overall survival T stage (T1 vs T2, 3) N stage (N0 vs N1, 2, 3) Modified classification
P
Hazard Ratio
.035 .001 .091
1.753 2.392 1.484
.051 .631 .016
1.800 1.145 2.178
95% Confidence Interval 1.039-2.958 1.449-3.955 0.939-2.344 0.996-3.250 0.659-1.989 1.156-4.105
this study, the number of each variant was too small to evaluate the clinicopathologic characteristics, including
recurrence or survival rate; therefore, we excluded pulmonary adenocarcinoma variants. Nonetheless, further investigation of these variants is required. Furthermore, variants of pulmonary adenocarcinoma have characteristic features different from the histologic patterns of invasive adenocarcinoma. Thus, the variants could not be grouped into a histologic classification for invasive adenocarcinoma. Histologic tumor classification is often related to chemotherapeutic treatment, and postoperative chemotherapy is usually an effective predictor of disease-free or overall survival rates. However, the impact of postoperative chemotherapy could not be considered in this study because of the variability of the chemotherapeutic agents, duration of treatment, and the number cycles employed. Nevertheless, patients with target agents such as tyrosine kinase inhibitor for epidermal growth factor receptor were not included in
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Figure 3. Illustration of gradual histologic changes (dedifferentiation) in pulmonary adenocarcinoma. Lepidic pattern is basically a similar pattern to the normal alveolar pattern. The papillary pattern is partially transitioned from the lepidic pattern. The lepidic or papillary pattern is focally merged to the acinar pattern. The micropapillary pattern seems to be derived from the papillary or acinar pattern. The solid pattern also seems to be derived from the acinar pattern.
this study. Analysis of the survival without consideration of postoperative chemotherapy is the one of limitations in this study. In conclusion, our modified 2011 IASLC/ATS/ERS classification, which considered components of solid and micropapillary patterns, accurately reflected the prognosis of pulmonary adenocarcinoma patients. Pulmonary adenocarcinoma often involves heterogeneous histologic patterns, characterized by gradual dedifferentiation. We suggest that the presence of >10% micropapillary or solid pattern may represent a poor prognosis. Declaration of Conflicting of Interest The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
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research-article2014
IJSXXX10.1177/1066896914525230International Journal of Surgical PathologyHwang et al
Original Article
Modified Histologic Classification as a Prognostic Factor in Pulmonary Adenocarcinoma
International Journal of Surgical Pathology 1–9 © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1066896914525230 ijs.sagepub.com
Ilseon Hwang, MD, PhD1, Keon Uk Park, MD, PhD2, Kun Young Kwon, MD, PhD1
Abstract Background. The histologic pattern of pulmonary adenocarcinoma is highly heterogeneous and considered to be an important prognostic factor. The predominant histologic pattern is emphasized in the 2011 International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society classification, but few studies present a detailed investigation of the histologic changes and prognosis pulmonary adenocarcinoma using resected specimens. Methods. We examined 125 cases of surgically resected pulmonary adenocarcinoma and carefully observed histologic patterns. Invasive adenocarcinoma was divided into 3 groups according to a modified histologic classification system: group 1 had a lepidic or papillary predominant pattern with ≤10% solid or micropapillary pattern; group 2 had an acinar predominant pattern with ≤10% of the solid or micropapillary pattern; and group 3 had a solid or micropapillary predominant pattern, or any predominant pattern with >10% solid or micropapillary pattern. Results. Proportions of predominant lepidic, papillary, acinar, solid, and micropapillary patterns were 11 (9.3%), 8 (6.8%), 54 (45.8%), 38 (32.2%), and 7 (5.9%), respectively. Vague areas between 2 different patterns were frequently observed, which were considered as transitional areas for one pattern to the other pattern (gradual dedifferentiation). Modified histologic classification was significantly associated with disease-free and overall survival rate (P = .026 and .010, respectively) using the Kaplan–Meier survival test, and an independent prognostic factor (P = .016) in overall survival using the Cox regression test. Conclusion. Pulmonary adenocarcinoma demonstrates heterogeneous histologic patterns with gradual dedifferentiation, and this modified histologic classification is an important prognostic factor for patients with pulmonary adenocarcinoma. Keywords lung, adenocarcinoma, histologic pattern, prognosis, gradual dedifferentiation
Introduction Lung cancer accounts for most cases of severe cancer incidence and mortality worldwide, and pulmonary adenocarcinoma is the most common histological lung cancer subtype.1 Pulmonary adenocarcinoma is heterogeneous in histologic pattern, molecular profile, clinical findings, radiological outcome, and surgical treatment.1,2 Pathological and radiological studies have revealed several prognostic subsets for the pulmonary adenocarcinoma.3-5 Histologic subtype in particular is a significant prognostic factor according to many studies.6-15 Therefore, the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society (IASLC/ATS/ERS) have sponsored a project to develop an international Multidisciplinary Lung Adenocarcinoma Classification (Table 1).16 Identification of the predominant pattern can be complicated because most pulmonary adenocarcinomas have more than 3 variable histologic patterns, and the decision
as to which histologic pattern is predominant holds a level of subjectivity for pathologists.17,18 In many cases, it is difficult to distinguish one histologic pattern from another. Warth et al18 reported that there is some disagreement among pathologists regarding the classification of histologic patterns, especially in relation to the lepidic-papillary, lepidic-acinar, papillary-acinar, and solid-acinar patterns. These patterns are similar, and it is speculated that one pattern may be derived from the other patterns. However, studies comparing the morphologic features of the histologic patterns in pulmonary adenocarcinoma are 1
Department of Pathology, Keimyung University School of Medicine, Daegu, Korea 2 Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea Corresponding Author: Kun Young Kwon, Department of Pathology, Keimyung University School of Medicine, Daegu, Korea. Email: [email protected]
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Table 1. 2011 International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society International Multidisciplinary Classification of Lung Adenocarcinoma.16 Preinvasive lesion Atypical adenomatous hyperplasia Adenocarcinoma in situ (≤3 cm, formerly bronchioloalveolar carcinoma) Nonmucinous and/or mucinous Minimally invasive adenocarcinoma (≤3 cm lepidic predominant tumor with ≤5 mm invasion) Nonmucinous and/or mucinous Invasive adenocarcinoma Lepidic predominant (formerly nonmucinous bronchioloalveolar carcinoma pattern) Acinar predominant Papillary predominant Micropapillary predominant Solid predominant Variants Invasive mucinous adenocarcinoma (formerly nonmucinous bronchioloalveolar carcinoma) Mixed mucinous/nonmucinous Colloid Fetal Enteric
rare. Therefore, detailed examination of these histologic patterns is required to understand changes in morphologic features, and this would also aid in the development of common criteria for determining the predominant pattern. Studies investigating the prognostic value of the 2011 IASLC/ATS/ERS classification showed a significant association between histologic pattern and disease-free or overall survival in pulmonary adenocarcinoma.1,19-21 These studies demonstrated that the lepidic predominant group is generally related to a good prognosis, acinar predominant group was generally related to an intermediate prognosis, and solid or micropapillary predominant group was generally related to a poor prognosis. However, other studies have suggested that the papillary predominant group has a relatively better prognosis,1,13,19,21 and additional studies have demonstrated a poor prognosis in the papillary predominant group.20,22,23 One explanation for the prognostic difference in the papillary predominant pattern is that papillary predominant adenocarcinomas are diverse,20 and the predominant histologic pattern is not a reliable indicator of patient prognosis. In other words, identification of one predominant histologic pattern is insufficient as a prognostic factor in pulmonary adenocarcinoma because studies investigating histologic classification using one predominant pattern did not reveal similar prognostic value.1,19-21 It is well known that solid or micropapillary predominant adenocarcinomas generally confer prognosis, and pulmonary adenocarcinomas with a minor solid or micropapillary pattern component generally confer a worse
prognosis than adenocarcinoma without solid and micropapillary components.6,7,11,12,24 However, the 2011 IASLC/ ATS/ERS classification does not consider minor component patterns as a crucial factor in histologic classification but includes a description of all histologic components and proportions, although minor histologic components with poor differentiation may be more important in cases with a poor prognosis.16 Therefore, modification of the classification of predominant histologic patterns is required to develop a precise and commonly accepted prognostic value in pulmonary adenocarcinoma. The aims of this study are to evaluate the variable histologic patterns of pulmonary adenocarcinoma and to suggest a novel modified histologic classification that is strongly correlated with patient prognosis.
Materials and Methods Case Selection We searched the medical records at Keimyung University Dongsan Hospital for all cases of pulmonary adenocarcinoma diagnosed between 1994 and 2007, and we selected 125 patients who received surgical resection. Clinical data from these 125 included tumor size, date of diagnosis, date of recurrence, date of last follow-up, and cause of death. The mean age of the 125 patients was 60.74 years (range = 29-82 years). Of the patients, 65 (52.0%) were male and 60 (48.0%) were female. Most patients underwent lobectomy (115 cases, 92.0%), and the remainder underwent pneumonectomy (5 cases, 4.0%), bilobectomy (3 cases, 2.4%), segmentectomy (1 case, 0.8%), and wedge resection (1 case, 0.8%). There were 22 (17.6%), 28 (22.4%), 47 (37.6%), 5 (4.0%), and 22 (18.4%) patients in the pathologic stages of T1a, T1b, T2a, T2b, and T3, respectively. Sixty-five (52.0%), 28 (22.4%), 29 (23.2%), and 3 (2.4%) patients were in the pathologic stages of N0, N1, N2, and N3, respectively. The numbers of patients with stages IA, IB, IIA, IIB, IIIA, and IIIB were 35 (28.0%), 18 (14.4%), 25 (20.0%), 10 (8.0%), 33 (26.4%), and 4 (3.2%), respectively. Median tumor size was 3.48 cm (range = 1.3-10.0 cm). This study was approved by the institutional review board at Keimyung University Dongsan Medical Center (2013-05-014).
Histologic Examination and Modified Classification All slides were stained with hematoxylin and eosin and reviewed by 2 pulmonary pathologists (K. Kwon and L. Hwang). We examined histologic patterns in the invasive adenocarcinoma cases based on IASLC/ATS/ERS classification (Table 1), which included lepidic, acinar, papillary, solid, and micropapillary patterns. These patterns were previously described by Yoshizawa et al.1,25 The histologic pattern was described in greater detail when it was similar to the other patterns. We excluded preinvasive lesions and
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Hwang et al Table 2. Distribution of Histologic Patterns in the Invasive Adenocarcinomaa. No. of Patterns
Lepidic
Papillary
Acinar
Micropapillary
Solid
Frequency (%)
1
3 (2.5)
5 (4.2)
Subtotal (%) 8 (6.8)
1 (0.8) 3 (2.5) 1 (0.8)
2
1 (0.8)
33 (28.0)
5 (4.2) 21 (17.8) 1 (0.8) 3
10 (8.5)
4 (3.4)
9 (7.6)
6 (5.1)
8 (6.8)
4
22 (18.6)
5 (4.2)
5 (4.2)
5
8 (6.8)
37 (31.4)
32 (27.1) 8 (6.8)
a
The shaded boxes represent the presence of histological patterns in tumor.
variants of invasive adenocarcinoma such as invasive mucinous, colloid, fetal, and enteric types. Proportions of each histologic component were recorded using a method previously described by Yoshizawa et al.1,25 We modified the histologic classification, and all cases were divided into 3 groups according to the predominant pattern and the proportion of solid or micropapillary pattern: group 1 had a lepidic or papillary predominant pattern with ≤10% of the solid or micropapillary pattern; group 2 had an acinar predominant pattern with ≤10% solid or micropapillary pattern; and group 3 had a solid or micropapillary predominant pattern, or any predominant pattern with >10% solid or micropapillary pattern.
Statistical Analysis SPSS statistical package, version 20.0 for Windows, was used for all statistical analyses (IBM, Armonk, NY). The relationship between modified histologic classification and clinical variables was evaluated using the χ2 test and linear by linear test. Disease-free and overall survival were measured from the date of diagnosis to the date of recurrence or last follow-up, and the date of diagnosis to the date of death or the last follow-up, according to the Kaplan–Meier method and the Cox proportional hazard model. Null hypotheses of no difference were rejected if 2-sided P values were less than .05.
Results Composition of Histologic Patterns The lepidic pattern was predominant in 11 tumors (9.3%), and 8 tumors (6.8%) has a papillary predominant pattern. The acinar predominant pattern was most common, accounting for 54 (45.8%) cases. There were 38 (32.2%) solid pattern predominant tumors and 7 (5.9%) micropapillary pattern predominant tumors. The median number of histologic patterns in single tumor was 3.0 (range = 1-5). Only 6.8% of the tumors had a single pattern (papillary or solid), and 28.0% of the tumors showed 2 patterns. Thirtyseven (31.4%) and 32 (27.1%) tumors showed 3 and 4 histologic patterns, respectively, which always included the acinar pattern. All histologic patterns were observed in 8 (6.8%) of the tumors (Table 2). Of these 8 tumors, 7 (87.5%) were papillary predominant with a micropapillary pattern, and the mean proportion of micropapillary pattern was 13.3% (range = 5% to 25%). According to our modified histologic classification, there were 10 (8.5%), 23 (19.5%), and 85 (72.0%) cases of group 1, 2, and 3, respectively.
Histologic Examination of Variable Patterns We frequently observed vague areas between 2 different patterns, which we considered transitional areas between 2
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patterns. The lepidic pattern most closely resembled normal alveoli and showed relatively thickened alveolar septa with enlarged atypical cells, compared to normal alveolar cells (Figure 1A). The lepidic pattern was frequently identified in the peripheral areas of tumors, adjacent to normal alveoli. The papillary pattern was similar to the lepidic pattern, and structural deviation of the papillary pattern was mild. However, thickened alveolar septa with thin or thick fibrovascular cores were frequently observed in papillary pattern, compared to the lepidic pattern. The cellularity of the papillary pattern was increased compared to the lepidic pattern, and cytologic atypia was more aggressive (Figure 1B). The acinar pattern was frequently observed in areas adjacent to the lepidic or papillary patterns. It was difficult to distinguish areas between the lepidic and acinar patterns, which we assumed were the result of stromal invasion of the lepidic pattern. In areas dominated by the acinar pattern, stromal reaction was discovered, and tumor cells contained a gland-like structure. Cytologic atypia of tumor cells in the acinar pattern was more aggressive than that of the lepidic pattern (Figure 1C). Thus, we suggest that the acinar pattern in tumors with the lepidic pattern is derived from the lepidic pattern, with stromal invasion. The acinar pattern adjacent to the papillary pattern appeared to be a structural distortion or fusion structure of the papillary pattern. The gland-like structure of the acinar pattern is likely formed as a consequence of stromal invasion and papillae fusion of the papillary pattern (Figure 1D). The solid pattern was occasionally observed in the absence of other patterns; however, most solid pattern tumors occurred in conjunction with the acinar pattern. The solid pattern may occur as a consequence of fusion of the gland-like structures of the acinar pattern, and solid pattern tumor cells showed poor differentiation and nuclear pleomorphism (Figure 1E). Occasionally, the peripheral area of the solid pattern showed budding of the tumor cell nests, and this budding area was defined as the micropapillary pattern (Figure 1G). Cellular atypia of the solid pattern was similar to that of the micropapillary with the solid pattern. The micropapillary pattern may be formed by the small tumor budding nests of the other patterns. Furthermore, the micropapillary pattern was frequently observed with the papillary pattern, and the tumor cells of the micropapillary pattern demonstrated a more aggressive cellular atypia than that of the papillary pattern (Figure 1H). The micropapillary pattern was also observed in conjunction with the acinar pattern (Figure 1F). In the acinar with micropapillary pattern, the tumor cells in the micropapillary patterned area were observed to bud into the lumen of the gland-like structure of the acinar pattern, and the tumor cells of the micropapillary patterned area arising from the acinar pattern showed more aggressive cellular atypia than the micropapillary patterned area arising from the papillary pattern.
Correlation Between Clinical Manifestations and Histologic Patterns Tumor recurrence and patient survival were significantly associated with the modified histological classification (P = .024 and .002, respectively) using the χ2 test (Table 3). Other clinical manifestations, including tumor size, T stage, and N stage, were not associated with the modified classification. The disease-free and overall survival rates were analyzed using the Kaplan–Meier method, and modified classification was significantly associated with disease-free and overall survival rates (P = .026 and .010, respectively; Figure 2). Pathologic T and N stages were also significantly associated with disease-free survival (P < .00), and only pathologic T stage was significantly associated with overall survival (P = .019) using the Kaplan–Meier test. We further analyzed T stage, N stage, and modified classification with a multivariate Cox proportional hazard model (Table 4). Of T stage, N stage, and modified classification, T stage (T1 vs T2-3) and N stage (N0 vs N1-3) were significantly correlated with diseasefree survival (P = .035 and .001, respectively), whereas modified classification (P = .091) was not. However, modified classification (P = .016) was significantly correlated with overall survival, whereas T stage (P = .051) and N stage (P = .631) were not.
Discussion Predominant histologic pattern alone cannot entirely predict patient prognosis, such as disease-free or overall survival rate. However, modification of histologic classification more accurately represents patient survival. The modified classification scheme that we developed considered specific components of solid and micropapillary patterns, which are known to correlate with poor prognosis.2,4-6,8,12,24,26 This modification provides a more accurate prediction of patient survival compared to the unmodified 2011 IASLC/ATS/ ERS classification. Although this modified classification resulted in a relatively high proportion (72%) of group 3 (solid/micropapillary predominant pattern or any pattern with >10% solid/micropapillary pattern) cases, and demonstrated a strong correlation between high recurrence and poor survival, further study with a larger sample size is needed. Especially, a prospective study for pulmonary adenocarcinoma is needed to confirm the usefulness of the modified histologic classification as an important prognostic factor and the usefulness of chemotherapy for group 3. Histogenesis of pulmonary adenocarcinoma is very complicated and is related to multiple genetic alterations, and careful observation of the morphologic features may help investigate the histogenesis.27 Although the process of tumorigenesis of pulmonary adenocarcinoma cannot be completely explained by the morphologic features, the
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Figure 1. (A) The lepidic pattern (arrow) shows more thickened alveolar septa with enlarged tumor cells than normal alveolar walls (arrow head). (B0 The papillary pattern (arrow head) shows mild structural deviation with more thickened alveolar septae than lepidic pattern (arrow head). Ambiguous area (asterisk) is present between the lepidic and the papillary patterns. (C) The acinar pattern shows gland-like structure (arrow) and is similar to lepidic pattern (arrow head) with stromal invasion. Borderline area between the lepidic and the acinar patterns is present (asterisk). (D) The acinar pattern (arrow) looks like that structural distortion or fusion structure of the papillary pattern (arrow head). Borderline area between the papillary and the acinar patterns is also present (asterisk). (E) The micropapillary pattern shows small tumor budding nests of the papillary pattern (arrow heads and inlet). (F) The micropapillary pattern (arrow heads) also shows small tumor budding nests of the acinar pattern and budding tumor cells have more aggressive cellular atypia than tumor cells of the acinar pattern (inlet). (G) The solid pattern (arrow) seems to be fusion of gland-like structure of the acinar pattern (arrow head). Ambiguous area is present between the acinar and the solid pattern (asterisk). (H) Peripheral area of the solid pattern (arrow) shows budding of tumor cell nests and these nests are same as the micropapillary pattern (arrow head).
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Table 3. Correlation of Clinical Manifestation and Histologic Classifications. Modified Classification T stage T1 T2a-3 N stage N0 N1-3 Stage I II-III Tumor size ≤3 cm >3 cm Recurrence No Yes Survival No Yes
a
Group 1
Group 2b
Group 3c
5 5
9 14
33 52
7 3
10 13
42 59
5 5
10 13
33 52
7 3
9 14
43 40
6 4
12 11
27 58
9 1
16 7
39 46
P .580 .469 .460 .743 .024 .002
a
Group 1: Lepidic or papillary predominant pattern with ≤10% solid and/or micropapillary pattern. b Group 2: Acinar predominant pattern with ≤10% solid and/or micropapillary pattern. c Group 3: Solid or micropapillary predominant pattern, or any predominant pattern with >10% solid or micropapillary pattern.
histologic findings are important to understand the histogenesis of pulmonary adenocarcinoma. We frequently observed areas with borderline features between 2 patterns, and defining a specific pattern in these areas was particularly difficult. These ambiguous areas may be caused by a gradual change from one pattern to another in the tumor area. For example, the lepidic pattern was observed to gradually change into the papillary or acinar pattern, and the acinar pattern was also observed to gradually change into the solid pattern. We suggest that the papillary and acinar patterns may dedifferentiate from the lepidic pattern, because the lepidic pattern is more similar in structure to normal alveoli than the other 2 patterns. Likewise, the solid and micropapillary patterns may be more dedifferentiated than the acinar or papillary pattern. Therefore, these gradual changes between 2 or 4 different histologic patterns may be interpreted as gradual dedifferentiation (Figure 3). Gradual dedifferentiation may be the cause of the heterogeneous morphologic features frequently observed in pulmonary adenocarcinoma, and specific genetic or epigenetic changes may occur during the processes of the dedifferentiation. Gradual dedifferentiation cannot completely explain histogenesis, but has an important role to prove the complicated nature of
the histogenesis of pulmonary adenocarcinoma. Further studies regarding the potential genetic or epigenetic changes relating to gradual dedifferentiation pulmonary adenocarcinoma are required. Although most pulmonary adenocarcinomas contain more than one histologic pattern, 6.8% of the samples analyzed in this study contained a single pattern (acinar or solid). In pulmonary adenocarcinoma with heterogeneous patterns, the more dedifferentiation of the patterns is mainly located in central area of tumor, and the less dedifferentiated pattern, such as lepidic or papillary pattern, is commonly located in peripheral area. Areas of higher dedifferentiation may have an increase growth potential and may replace the areas of less dedifferentiation through the efferent growth. Therefore, adenocarcinoma with variable histologic patterns may not have a lepidic pattern at all, owing to replacement by areas with high dedifferentiation, as in the case of tumor with acinar or solid patterns. However, we believe that gradual dedifferentiation may not occur in all tumors with a single pattern, and some tumors with a single histologic pattern may not have a mechanism for gradual dedifferentiation, but a different mechanism for abrupt transition or carcinogenesis (Figure 3, dotted line arrows). Specifically, an adenocarcinoma with a solid pattern, which confers a poor prognosis, may have a different genetic abnormality than an adenocarcinoma with gradual dedifferentiation.1,13 Additional studies regarding genetic differences in the various histologic patterns are necessary. In this study, papillary predominant adenocarcinoma was observed to have a similarly poor prognosis to micropapillary or solid predominant adenocarcinoma. Some studies have reported papillary predominant adenocarcinoma to have a survival rate similar to micropapillary or solid predominant adenocarcinoma,20,22,23 whereas other studies have reported a better survival rate for papillary predominant tumors.1,13,21 These differences may be due to the fact that papillary predominant tumors are relatively morphologically diverse, and it is possible that the different subtypes also differ with respect to prognosis.20 In this study, 87.5% of papillary predominant adenocarcinomas contained 10% to 25% micropapillary and/or solid patterns and revealed poor prognosis. Therefore, as the papillary pattern is similar in morphologic features to the lepidic pattern, these 2 patterns may confer a similar survival rate provided the tumor does not have micropapillary or solid components. In addition, many papillary predominant adenocarcinomas were classified as group 3 according to the modified histologic classification and were therefore associated with a poor prognosis. Other variants of pulmonary adenocarcinoma, such as mucinous, colloid, fetal, or enteric type, have specific histologic features, and the clinicopathologic characteristics of each variant are not well known.28-30 However, in
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Figure 2. Disease-free and overall survival rate according to predominant histologic pattern and modified classifications by Kaplan– Meier survival test. (A) Predominant patterns present no correlation of disease-free survival (P = .214). Papillary predominant group shows relatively poor survival rate. (B) Predominant patterns are correlated with overall survival (P = .003). Solid, micropapillary, or papillary predominant group shows poor survival and lepidic predominant group shows better survival. (C) Modified classification reveals significant relationship of disease-free survival (P = .026). (D) Modified classification also reveals significant relationship of overall survival (P = .010). Table 4. Multivariate Analysis of Disease-Free and Overall Survivals According to T Stage, N Stage, and Modified Classification (Cox Proportional Hazard Model). Variables Disease free survival T stage (T1 vs T2, 3) N stage (N0 vs N1, 2, 3) Modified classification Overall survival T stage (T1 vs T2, 3) N stage (N0 vs N1, 2, 3) Modified classification
P
Hazard Ratio
.035 .001 .091
1.753 2.392 1.484
.051 .631 .016
1.800 1.145 2.178
95% Confidence Interval 1.039-2.958 1.449-3.955 0.939-2.344 0.996-3.250 0.659-1.989 1.156-4.105
this study, the number of each variant was too small to evaluate the clinicopathologic characteristics, including
recurrence or survival rate; therefore, we excluded pulmonary adenocarcinoma variants. Nonetheless, further investigation of these variants is required. Furthermore, variants of pulmonary adenocarcinoma have characteristic features different from the histologic patterns of invasive adenocarcinoma. Thus, the variants could not be grouped into a histologic classification for invasive adenocarcinoma. Histologic tumor classification is often related to chemotherapeutic treatment, and postoperative chemotherapy is usually an effective predictor of disease-free or overall survival rates. However, the impact of postoperative chemotherapy could not be considered in this study because of the variability of the chemotherapeutic agents, duration of treatment, and the number cycles employed. Nevertheless, patients with target agents such as tyrosine kinase inhibitor for epidermal growth factor receptor were not included in
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Figure 3. Illustration of gradual histologic changes (dedifferentiation) in pulmonary adenocarcinoma. Lepidic pattern is basically a similar pattern to the normal alveolar pattern. The papillary pattern is partially transitioned from the lepidic pattern. The lepidic or papillary pattern is focally merged to the acinar pattern. The micropapillary pattern seems to be derived from the papillary or acinar pattern. The solid pattern also seems to be derived from the acinar pattern.
this study. Analysis of the survival without consideration of postoperative chemotherapy is the one of limitations in this study. In conclusion, our modified 2011 IASLC/ATS/ERS classification, which considered components of solid and micropapillary patterns, accurately reflected the prognosis of pulmonary adenocarcinoma patients. Pulmonary adenocarcinoma often involves heterogeneous histologic patterns, characterized by gradual dedifferentiation. We suggest that the presence of >10% micropapillary or solid pattern may represent a poor prognosis. Declaration of Conflicting of Interest The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
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