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Ann Thorac Surg 2007;83:209-214
© 2007 The Society of Thoracic Surgeons

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Original Articles: General Thoracic

Prognostic Significance of a Histologic Subtype in Small Adenocarcinoma of the Lung: The Impact of Nonbronchioloalveolar Carcinoma Components

^a Department of General Thoracic Surgery, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan
^b First Department of Pathology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan

Accepted for publication July 21, 2006.

^_* Address correspondence to Dr Sakao, Department of General Thoracic Surgery, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan (Email: sakao{at}med.juntendo.ac.jp).

	Abstract

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
BACKGROUND: We tried to clarify whether the histologic subtypes and the size of the solid component of an adenocarcinoma are more important predictive factors for invasiveness or prognosis than is total tumor size, even in lung adenocarcinomas that were 2 cm or smaller.

METHODS: Between 1996 and December 2005, after standard surgical treatment, 82 patients were diagnosed as having adenocarcinoma with a maximum diameter of 2 cm or less. The group comprised 37 females and 45 males, with ages ranging from 41 to 80 years (median, 64). The clinicopathologic records of the patients were examined with regard to age, sex, nodal status, tumor size (largest diameter of the total tumor as well as the largest diameter without the bronchioloalveolar carcinoma [BAC] component [solid component]), serum carcinoembryonic antigen level, and histologic type. These variables were analyzed as risk factors for vascular or lymphatic invasion, lymph node metastasis, and prognosis. Histologic subtype was classified into two groups: mixed BAC (mixed adenocarcinoma with BAC) and minimal or non-BAC (tumors with little or no BAC component).

RESULTS: Histologic subtype was a significant predictive factor both for invasiveness (vascular or lymph vessels) and lymph node metastasis, in both univariate and multivariate analysis. Tumor diameter was not a significant factor in either univariate or multivariate analysis (p = 0.28, 0.15, respectively). However, diameter excluding the BAC component was a significant factor for invasiveness in mixed BAC type (p = 0.035), whereas total diameter was not significant (p = 0.28). Finally, histologic subtype and lymph node metastasis were significant prognostic factors for survival in both univariate (p = 0.03, 0.05, respectively) and multivariate (p = 0.04, 0.05, respectively) analyses. The 5-year survival rate was 94.4% (94.1% for pN0) for the mixed BAC type and 71.4% (78.7% for pN0) for the minimal or non-BAC type (p = 0.009; p = 0.04 for pN0 nodes).

CONCLUSIONS: Small adenocarcinomas can be classified into two categories. The first category is a minimal or non-BAC adenocarcinoma that shows aggressive biological behavior. The second category is a mixed BAC, which demonstrates less invasive or aggressive biological behavior than the minimal or non-BAC type, with the degree of invasiveness being associated with the size of the non-BAC component.

	Introduction

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Noguchi and colleagues [1, 2] suggested that small peripheral adenocarcinoma (2 cm or smaller) can be classified into two groups according to their growth pattern and biologic characteristics, namely, replacing or nonreplacing types. Specifically, the replacing type is a mixed adenocarcinoma that incorporates a bronchioloalveolar carcinoma (BAC) component and mainly exhibits a replacing growth pattern within the alveolar epithelium. The nonreplacing type consists of tumors with little or no BAC, comprising mainly forms classified by the World Health Organization [3] as acinar adenocarcinoma, papillary adenocarcinoma, or solid tumors with mucin production, and exhibiting compressive or destructive extension within the alveolar structure. We have already reported that the nonreplacing histologic subtype is an important prognostic factor for poor outcome, as is large tumor size (>20 mm), in clinical IA adenocarcinoma of the lung [4]. Furthermore, we reported that the size of the solid component on computed tomography (CT), which does not disappear in the mediastinal window, is related to tumor growth in the nonreplacing type or to the presence of a large fibrous scar component and is a significant prognostic factor for postoperative survival in T1 peripheral adenocarcinoma of the lung [5, 6].

Based on these principles, we hypothesized that the histologic subtypes and the size of the solid component (excluding the BAC component, on histologic examination) of the tumor are more important predictive factors for invasiveness or prognosis than total tumor size (including BAC lesions), even in lung adenocarcinomas that are 2 cm or smaller.

In this retrospective study, we tried to clarify the influence on prognosis and invasiveness of histologic subtypes and of the size of the solid component in mixed BAC. These findings may provide us with additional, important information when considering the surgical or therapeutic strategy for small adenocarcinoma of the lung.

	Patients and Methods

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This was a retrospective study and as individual patients were not identified, our Institutional Review Board waived the requirement to obtain patient consent in the study.

Between 1996 and December 2005, 637 patients underwent surgical resection of primary lung cancer within our department. Among these patients, 532 underwent lobectomy with hilar and mediastinal node dissection and, of these, 82 were diagnosed as having adenocarcinoma with largest diameter 2 cm or less, by evaluating resected materials. This subgroup was composed of 37 female and 45 male patients, with ages ranging from 41 to 80 years (median, 64). In all patients, preoperative staging was assessed according to the TNM classification of the International Union Against Cancer [7], using chest computed tomography (CT), abdominal CT or ultrasonography, brain CT or magnetic resonance imaging, and bone scanning. Clinical mediastinal and hilar lymph node status was assessed as positive if the results of the chest CT showed that the shorter axis was longer than 1.0 cm. The follow-up period ranged from 1 to 108 months (the median follow-up for living patients was 37 months). Patient characteristics are summarized in Table 1.

Histologic subtype was defined using a modification of Noguchi^’s classification of small adenocarcinomas [1, 2]. These subgroups are BAC, adenocarcinoma with little or no BAC component, and mixed BAC with other adenocarcinoma components. The BAC form was excluded from this study because it has been defined as a noninvasive lesion [3]. Therefore, two subtypes were examined in this study. The first subtype was called the "minimal or non-BAC" (nearly equivalent to nonreplacing type adenocarcinoma), a tumor with little or no presence of BAC (10% or less of the margin of the tumor). The minimal or non-BAC subtype included forms classified by WHO [3] as acinar adenocarcinoma, papillary adenocarcinoma, or solid tumor with mucin production, with little or no presence of BAC. The second subtype was called the "mixed BAC" (nearly equivalent to Noguchi’s type C or replacing type adenocarcinoma), a tumor with BAC composing at least 90% of its margin, and including other adenocarcinoma components such as acinar, papillary and mucin-producing solids.

These variables were analyzed as risk factors for blood or lymphatic vessel invasion or lymph node metastasis, and as predictive factors for postoperative survival.

Statistical Analysis
The length of survival was defined as the interval between surgery and either death as a result of the tumor or the most recent follow-up. The survival rates were calculated using the Kaplan-Meier method. Univariate analyses were performed using the log-rank test, ² test, and logistic regression procedure test. Multivariate analyses were performed for variables with a p value of less than 0.1 in univariate analysis, using the logistic regression procedure test in StatView J 5.0 (SAS Institute, Cary, North Carolina). A p value of less than 0.05 was treated as significant.

	Results

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Vascular or Lymph Vessel Invasion
Univariate analysis based on the variables listed in Table 2 revealed that both minimal or non-BAC subtype and high carcinoembryonic antigen concentration were significant risk factors for vascular or lymphatic invasion. In the multivariate analysis (performed only on variables with a p value of less than 0.1 in univariate analysis), the minimal or non-BAC subtype was a significant risk factor for vascular or lymphatic invasion (Table 3). The ratio of vascular or lymphatic invasion was 89.4% in the minimal or non-BAC group and 25.7% in the mixed BAC group (p < 0.001; Fig 1).

View larger version (32K): [in this window] [in a new window]   Fig 1. The ratio of vascular or lymphatic invasion according to histologic subtype. The black area of the bar indicates positive invasion; the white area of the bar is negative (p < 0.001). (BAC = bronchioloalveolar component.)

View larger version (32K): [in this window] [in a new window]   Fig 2. The ratio of lymph node involvement according to histologic subtype. The black bar area of the bar indicates positive metastasis; the white area indicates negative (p < 0.001). (BAC = bronchioloalveolar component.)

View larger version (19K): [in this window] [in a new window]   Fig 3. The ratio of vascular or lymphatic invasion according to tumor diameter. The subtype is mixed bronchioloalveolar component (BAC) type. (Diameter without BAC = tumor diameter excluding bronchioloalveolar component; total diameter = tumor diameter including bronchioloalveolar component.)

View larger version (18K): [in this window] [in a new window]   Fig 4. The overall 5-year survival rate of all cases was dependent on histologic subtype. (BAC = bronchioloalveolar component.)

	Comment

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

Recently, attempts have been made to classify small peripheral adenocarcinomas into subgroups according to the pattern of tumor growth, which is thought to be associated with tumor biological characteristics derived from clinicopathological examination [1, 2, 8, 9]. Essentially, these subgroups are BAC (noninvasive cancer), adenocarcinoma with little or no BAC component (defined as minimal or non-BAC in this study), and mixed BAC with other adenocarcinoma components (mixed BAC, such as acinar, papillary, and mucin-producing solids). Noguchi and associates [1, 2] reported that lymph node involvement appeared in 22.4% of type mixed BAC versus 41.1% of type minimal or non-BAC, and that mitotic figures were more often observed in the minimal or non-BAC type than in the mixed BAC type [9, 11]. Terasaki and colleagues [9] divided adenocarcinoma into three groups according to tumor growth pattern: group 1 was BAC, group 2 was BAC with invasive lesion (scar or non-BAC component, or both; this type was almost equivalent to the replacing type of the present study), and group 3 was invasive adenocarcinoma (mainly acinar or papillary without BAC (this type being nearly equivalent to the nonreplacing adenocarcinoma type). They found that the rates of lymph node metastasis, as well as indicators of proliferation (Ki-67 labeling index) and invasiveness (frequency of laminin-5 overexpression), were highest in group 3 and lowest in group 1. These authors also demonstrated that group 1 accounted for 75.4%, group 2 for 16.4%, and group 3 for 8.2% of adenocarcinomas with diameter of 1 cm or less (n = 61). However, for adenocarcinomas with diameters 2 cm or less (n = 170) or 3 cm (n = 140), group 1 accounted for 23.5% and 7.9%, group 2 for 52.9% and 54.3%, and group 3 for 23.5% and 37.9%, respectively. Thus, the authors suggested that tumor size was associated with tumor subtype, but that tumor size itself was not associated with indicators of proliferation or invasiveness of the tumor. They concluded that histologic subgrouping based on growth pattern provides a much better indication of biological characteristics of peripheral small lung adenocarcinoma than does lesion size.

Based on these findings, we suggest that histologic subtype is a key predictive factor for invasion and prognosis in small adenocarcinoma. In addition, we have demonstrated that the size excluding the BAC component is an important indicator of invasiveness of the replacing-type tumor.

Previous studies showed that the density and the extent of desmoplasia (scar) found in the tumor were associated strongly with poor prognosis after surgery for small peripheral adenocarcinoma [1, 8, 10], and proposed that a small adenocarcinoma with a scar of 5 mm or less in diameter may be a microinvasive cancer, indicating a particularly favorable postoperative outcome. Those investigators demonstrated that size of, or presence of invasive findings with, the scar constituted an important prognostic factor. However, there were a multiplicity of criteria for defining "scar," and there is not yet a consensus for evaluating the degree of scar extension as an indicator of invasiveness. Furthermore, most mixed adenocarcinoma present with heterogeneous findings such as collapsed lung parenchyma and non-BAC component along with the scar. Accordingly, we chose to evaluate size with exclusion of the BAC component, but including the scar, adenocarcinoma components other than BAC, inflammatory changes, and other features, as a simple and reliable prognostic factor for small adenocarcinoma.

Recent studies have indicated that CT findings in peripheral lung adenocarcinoma are correlated with histologic classification, such as mixed BAC or minimal or non-BAC type adenocarcinoma. Certain CT findings, such as ground glass opacity (which is correlated with BAC), airbronchogram, or the presence of a bubblelike area, are features of mixed BAC, whereas solid attenuation is a feature of the minimal or non-BAC [5, 11–13]. Furthermore, we have reported that tumor dimension (adenocarcinoma) determined using the mediastinal window setting on CT, which is recognized as tumor size with the ground glass opacity component excluded, can indicate the degree of invasiveness of the tumor and can predict the prognosis. Nevertheless, total tumor size as detected by the lung window setting on CT is not a predictor for prognosis in T1 adenocarcinoma [6]. Thus, recent developments in diagnostic radiology have made it possible to detect histologic subtypes and the size of the non-BAC component preoperatively, providing the opportunity to design strategies for small adenocarcinoma before surgery, taking these findings into consideration.

Limitations of this study included the retrospective nature of the analysis, the small sample size, and the small number of cases with a tumor diameter less than 10 mm. In summary, small adenocarcinoma can be classified into two groups: a minimal or non-BAC type, which shows aggressive biological behavior when 2 cm or smaller and with a minimal BAC component, and a mixed BAC type, which exhibits less invasive and aggressive biological behavior, the degree of which is associated with the size of the non-BAC component. Our results suggest that when evaluating the impact of a new treatment strategy (namely, limited surgery for small lung adenocarcinoma and adjuvant chemotherapy), we must consider not only the tumor size but also the tumor subtype and the size of the non-BAC component.

	Acknowledgments

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We thank Professor Masayuki Noguchi and Dr Yohichi Anami, Department of Pathology (Diagnostic Pathology), Tsukuba University, Tsukuba, Japan, for their critical reviews of the manuscript.

	References

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 

1. Noguchi M, Morikawa A, Kawasaki M, et al. Small adenocarcinoma of the lung: histologic characteristics and prognosis Cancer 1995;75:2844-2852.[Medline]
2. Morishita Y, Fukasawa M, Takeuchi M, Inadome Y, Matsuno Y, Noguchi M. Small-sized adenocarcinoma of the lung Cancer 2001;93:124-131.[Medline]
3. World Health Organization Histological typing of lung and pleural tumours. 3rd ed.. Berlin: Springer-Verlag; 1999.
4. Sakao Y, Sakuragi T, Natsuaki M, Itoh T. Clinicopathological analysis of prognostic factors in clinical IA peripheral adenocarcinoma of the lung Ann Thorac Surg 2003;75:1113-1117.[Abstract/Free Full Text]
5. Sakao Y, Nakazono T, Sakuragi T, Natsuaki M, Itoh T. Predictive factors for survival in surgically resected clinical IA peripheral adenocarcinoma of the lung Ann Thorac Surg 2004;77:1157-1162.[Abstract/Free Full Text]
6. Sakao Y, Nakazono T, Tomimitsu S, et al. Lung adenocarcinoma can be subtyped according to tumor dimension by computed tomography mediastinal-window settingAdditional size criteria of clinical T1 adenocarcinoma. Eur J Cardiothorac Surg 2004;26:1211-1215.[Abstract/Free Full Text]
7. Hermanek P, Sobin LH. UICC TNM classification of malignant tumors. 4th ed.. Berlin: Springer-Verlag; 1992.
8. Maeshima A, Niki T, Maeshima A, Yamada T, Kondo H, Matsuno Y. Modified scar gradeA prognostic indicator in small peripheral lung adenocarcinoma. Cancer 2002;95:2546-2554.[Medline]
9. Terasaki H, Niki T, Matsuno Y, et al. Lung adenocarcinoma with mixed bronchioloalveolar and invasive components Am J Surg Pathol 2003;27:937-951.[Medline]
10. Shimosato Y, Suzuki A, Hashimoto T, et al. Prognostic implications of fibrotic focus (scar) in small peripheral lung cancers Am J Surg Pathol 1980;4:365-373.[Medline]
11. Aoki T, Nakata H, Watanabe H, et al. Evolution of peripheral lung adenocarcinomas: CT findings correlated with histology and tumor doubling time AJR Am J Roentgenol 2000;174:763-768.[Abstract/Free Full Text]
12. Takashima S, Maruyama Y, Hasegawa M, et al. Prognostic significance of high-resolution CT findings in small peripheral adenocarcinoma of the lung: a retrospective study on 64 patients Lung Cancer 2002;36:289-295.[Medline]
13. Nakazono T, Sakao Y, Yamaguchi K, Imai S, Kumazoe H, Kudo S. Subtypes of peripheral adenocarcinoma of the lung: differentiation by thin-section CT Eur Radiol 2005;15:1563-1568.[Medline]

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