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Ann Thorac Surg 2004;77:421-425
© 2004 The Society of Thoracic Surgeons

Original article: general thoracic

Nonanatomic prognostic factors in resected nonsmall cell lung carcinoma: the importance of perineural invasion as a new prognostic marker

Adnan Sayar, MDa, Akif Turna, MD, PhD, FETCSa*, Okan Solak, MDa, Ali Kiliçgün, MDa, Nur Ürer, MDb, Atilla Gürses, MDa

a Department of Thoracic Surgery, Zeytinburnu, Istanbul, Turkey
b Department of Pathology, Yedikule Teaching Hospital for Chest Diseases and Thoracic Surgery, Zeytinburnu, Istanbul, Turkey

Accepted for publication August 6, 2003.

* Address reprint requests to Dr Turna, Cami Sok, Muminderesi Yolu, Emintas Camlik Sit No: 32/22, Sahrayicedid, Kadikoy, Istanbul 81080, Turkey
e-mail: aturna{at}turk.net


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Comment
 References
 
BACKGROUND: A number of prognostic factors have been reported for resected nonsmall cell lung carcinoma. Although none of them reported to have greater prognostic impact than the TNM staging system, which is based on anatomical descriptions of tumors, the prognoses of a significant number of patients are not in agreement with real survival of the patients. Moreover, certain histopathologic properties of the tumor (such as lymphatic and vascular invasion) could help to predict the survival of the patients.

METHODS: A retrospective study was conducted on 82 surgically resected nonsmall cell lung carcinomas, and the following prognostic factors were evaluated in univariate analysis: age, gender, clinical and surgical-pathologic T and N status, histologic type of tumor, grade of differentiation, lymphatic invasion, vascular invasion, and perineural invasion.

RESULTS: Lymphatic invasion and perineural invasion of the tumor were found to be significant prognostic factors (p = 0.02 and p = 0004). Blood vessel invasion (venous or arterial involvement) had no prognostic impact (p > 0.05). According to multivariate analyses, three factors were selected as prognostic indicators: (1) clinical N status (p = 0.027), (2) lymphatic invasion (p = 0.027) and (3) perineural invasion (p = 0.0148). By combining these factors we identified a poor prognostic subgroup of patients with stage I disease.

CONCLUSIONS: Our study showed that lymphatic vessel and perineural invasion of the tumor could be prognostic factors, along with anatomical determinants such as cN and surgical-pathologic stage of the pulmonary carcinoma.


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Comment
 References
 
Survival curves and clinical observations confirm that generally similar patterns of biological behavior will prevail for groups of patients with lung cancer having the same disease stage and histologic type [1, 2]. The prognostic significance of this information has proved useful for physicians to select treatment, estimate prognosis, and compare the results of different therapies. As a source of the current staging system, revisions in the international system for staging lung cancer were proposed by Mountain [2]. In this series, the cumulative 5-year survival was 67% for stage IA, 57% for stage IB, 55% for stage IIA, 39% for stage IIB, 23% for stage IIIA [2]. However, great differences in outcome after resection have been currently observed in patients with the same stage. Although various histologic prognosticators have been investigated, such as tumor size or the presence of blood vessel invasion, they are not yet fully incorporated into the TNM classification [3]. Blood vessel invasion and lymphatic vessel invasion have been reported to be important prognostic factors in patients with resected nonsmall cell lung cancer (NSCLC) with intrapulmonary metastases [4]. Rigau and colleagues [5] found that blood vessel invasion could predict metastatic occurrence in resected early-stage NSCLC. Most of the research regarding the association between many different biological or histologic markers, or both, and the prognosis of NSCLC emphasizes the potential contribution of markers to understanding the heterogeneity of survival patterns for specific anatomic and histologic subsets of patients with this disease. Postoperative substaging of resected NSCLC patients may help to identify groups of patients, especially those who have early-stage disease and whose risk of recurrence or metastasis is sufficiently high to justify adjuvant therapy.

In the present study of 82 resected NSCLC patients, we utilized univariable and multivariable analyses to assess the prognostic value of blood vessel invasion, lymphatic vessel invasion, and perineural invasion, as well as that of clinical and histopathologic data.


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Comment
 References
 
Between January 1998 and November 2002, 82 consecutive patients with histologic evidence of NSCLC were enrolled in the study after complete pulmonary resection and lymph node dissection. Routine blood tests included hemoglobin, alkaline phosphatase, and serum calcium estimations. All patients underwent postero-anterior and lateral chest radiographs and bronchoscopy. Computed tomographic scans of the thorax, abdomen (or abdominal ultrasonography), cranium, and all body bone scintigraphies were done in all patients for pre-treatment staging.

Mediastinal lymph node samplings from the lymph nodes using cervical mediastinoscopy were carried out in all patients. The mediastinal exploration was supplemented by a left anterior mediastinotomy or extended mediastinoscopy in patients whose tumor lay in the left upper lobe or left main bronchus and in patients with enlarged (> 1 cm) anterior mediastinal or aorticopulmonary lymph nodes, or both. The following patients were excluded: (1) patients who underwent partial resection or segmentectomy, (2) patients with multiple lung tumors, (3) patients with low grade malignancy such as bronchial carcinoid, and (4) patients who were found to have mediastinal nodal tumor involvement and who underwent neoadjuvant therapy. All patients underwent a uniform staging protocol (Union Internationale Contre le Cancer, TNM classification, revised in 1997) [2] in construction of a final surgical-pathologic stage (pTNM) using information obtained at thoracotomy and supplemented by pathologic examination. Informed consent was not required because it was an observational study.

Pathologic evaluation
All of the histologic slides from 82 patients were evaluated according to the World Health Organization [6] 1999 classification and grade for NSCLC by one of the authors (NU). The specimens were evenly planed with a cryostat. Sections (3 to 4 mm) were taken followed by hemotoxylin and eosin staining. All resected lymph nodes were formalin fixed. The sections were taken similarly and examined microscopically by standard hematoxylin-eosin stain. Special attention was paid to tumor invasions to lymphatic, vascular vessels, and perineural structures. Tumor invasion to lymphatic and vascular vessels was defined as tumor infiltrating vessels directly or tumor thromboses seen inside the vessels. All slides were reviewed under microscope to observe qualitatively whether vessels had been invaded. The presence of perineural invasion was defined to be the tumoral involvement of epineurium in the peri-tumoral tissue (Fig 1).



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  		Fig 1. Perineural invasion (tumoral involvement of epineurium in the peritumoral tissue; arrows). (Hemotoxylin & eosin; x400 original magnification.)

 
Lymphatic vessels were found invaded by tumor cells in 37 patients. It was also found that vascular vessels were invaded in 44 patients, and perineural invasion was detected in 24 patients.

Statistical analyses
Patient survival was expressed by actuarial analysis according to the method of Kaplan and Meier, using time zero as the date of thoracotomy and death as the end point. The prognostic predictors were studied by univariate analyses (age, gender, clinical and surgical pathologic T and N status, histologic type of tumor, grade of differentiation, lymphatic invasion, vascular invasion, and perineural invasion) and multivariate analyses using the Cox proportional hazard regression model. The SPSS software (SPSS Inc, Chicago, IL) for Power Macintosh computers was used on a personal Apple computer for statistics (Apple Computers Inc; Cuppertino, CA). If the p value was below 0.05, the result was considered significant.


   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Comment
 References
 
The main clinical and pathologic characteristics of the enrolled 82 patients are summarized in Table 1.


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  		Table 1. Clinical and Surgical Characteristics of Patients

 
For the entire group, the mean follow-up period was 15.9 months (range, 1 to 43 months), and the median survival time was 45 months. The 1- and 3-year actuarial survival rates were 84.7% and 50.9%, respectively (Fig 2).



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  		Fig 2. Survival curve of all patients.

 
Univariable analyses revealed the following conventional prognostic factors as significant: surgical and pathologic N status (p = 0.027) and surgical and pathologic stage (p = 0.009). Lymphatic invasion and perineural invasion of the tumor were also found to be significant prognostic factors (p = 0.027 and p = 00148) (Table 2). Blood vessel invasion (venous or arterial involvement) had no prognostic impact (p > 0.05). According to multivariate analyses, three factors were selected as prognostic indicators: (1) clinical N status (p = 0.01), (2) lymphatic invasion (p = 0.008), and (3) perineural invasion (p = 0.0148). By combining these factors we identified several poor prognostic subgroups of patients with Stage I disease. The 1- and 3-year survival rates for patients with pathologic stage I NSCLC with perineural invasion were 69.8% and 23.3%, respectively, whereas the 1- and 3-year survival rates for patients with pathologic stage I without perineural invasion were 91.6% and 63.2%, respectively (p = 0.02) (Fig 3).


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  		Table 2. Significant Prognostic Factors Revealed by Univariate Analyses in Surgically Resected Nonsmall Cell Lung Carcinoma Patients

 


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  		Fig 3. Survival curves for patients with resected stage I nonsmall cell lung cancer were compared based on perineural invasion. A statistically significant difference was observed (log-rank test; p = 0.02).

 

   Comment
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Comment
References
 
The staging system for NSCLC provides a framework for the assessment of prognosis and the assignment of therapy for all the patients. Similar to previous staging systems, the recent system has been established on a large database [2]. The power of this large database in prognosis is self-evident. Nevertheless, the inherent inaccuracy of the staging process should be brought to attention. According to the recent TNM system, the predicted 5-year survival after complete resection for T1N0 MO NSCLC is only 67% [2]. Although the systematic anatomic staging of lung cancer will continue to play a critical role in treatment of patients, characterization of biological, molecular, or histologic factors may eventually yield more-accurate staging of lung cancer than the current anatomic staging system allows [3–5, 7–9]. Many specific histologic measures have been assessed as possible prognostic indicators in resected lung carcinomas [1, 3–5]. The purpose of the assessment of additional prognostic markers in the primary tumor is to discriminate groups of patients with early-stage disease whose risk of recurrence is sufficiently high to justify adjuvant therapy. Ichinose and colleagues [10] reported that conventional pathologic prognostic factors had a different impact pattern on the prognosis of patients with disease in each pathologic stage. Thomas and associates [11] indicated that blood vessel invasion, arteriosclerosis, and performance of pneumonectomy independently determined the prognoses of patients with resected stage I NSCLC. These studies showed that a number of nonanatomical prognostic factors could be as important as anatomical ones in patients with resected NSCLCs.

Vascular invasion has been proposed as a prognostic factor in patients with resected NSCLC [5, 10–13]. However, vascular invasion was not defined to be a significant prognosticator in our study. Ichinose and colleagues [10] reported that venous invasion was one of the significant prognostic factors, but that arterial invasion was not. Arterial and venous invasions have been separately studied in our pathology department, and none of these studies have showed any evidence of significant importance as prognostic indicators. These findings probably could be due to the higher number of pN2 patients in our series, which may shadow the possible marginal, predictive power of vascular invasion. On the other hand, our study may be underpowered to show the statistically significant impact of vascular invasion and the T factor on the survival. To clarify this issue, prospective clinical trials including a large patient population are required.

In our study, lymphatic vessel invasion showed a significant determinant for survival. This phenomenon was consistent with a number of reports [4, 5, 14–16]. Along with lymphatic invasion, blood vessel invasion could play a role in distant metastatic spread of tumor cells and formation of satellite tumor mass in patients with NSCLC [15, 17]. Cote and associates [18] reported that these additional factors could contribute to the development of bone marrow metastasis.

Perineural invasion was found to be a statistically significant prognostic factor. Multivariable analysis confirmed that perineural invasion in tumor tissue was an independent factor for survival prediction. All follow-up patients with NSCLC involving perineural structures died 3 years after resectional surgery. Conversely, patients with NSCLC without perineural invasion had a 3-year survival rate of 100%.

Peripheral nerves are formed by axons, Schwann's cells, perineural cells, and fibroblasts. Most of the fibroblasts are located in the epineurium, which is the outer sheath of fully developed nerves. In pathologic examinations, perineural invasion denotes the tumoral involvement of epineurium. Perineural invasion has been defined as a determinant for poor prognosis in squamous cell skin carcinoma of the head and neck [19], bile duct carcinoma [20], rectal cancer [21], gastric cancer [22], transitional cell carcinoma of the bladder [23], pancreatic cancer [24] and prostate cancer [25]. However, we believe there are no studies that have showed the significance of perineural invasion as a prognostic factor in NSCLC patients.

On the other hand, molecular biological staging is the assessment of tumor markers associated with various oncogenic mechanisms to improve the risk stratification provided by conventional TNM staging [26]. The use of a panel of markers may improve the effectiveness of this approach because expression of individual oncogenic markers is low in NSCLC (n = 53), p53, and epidermal growth factor receptors are expressed in approximately 43% and 52% of tumors, respectively [27]. In addition, biological techniques such as antibody-directed assessment of markers (immunohistochemical analysis) and reverse transcriptase polymerase chain reaction technique require adequate and relatively expensive laboratory equipment and technically skillful personnel who can achieve tests for molecular biological markers. The results have been promising, however, we await confirmation by larger studies [26]. The assessment of lymphatic, blood vessel or perineural invasion require no additional equipment or instrumentation, and they only represent a more detailed conventional histopathologic analyses.

However, the limitations of our study included the relatively small number of patients and relatively shorter follow-up. However, the statistical power of the perineural invasion in survival analysis was quite high and it was shown to be an independent predictor of poor prognosis in patients with NSCLC.

Our study showed that lymphatic vessel and perineural invasion of the tumor, along with anatomical determinants such as pN and surgical and pathologic stage of the pulmonary carcinoma, were prognostic factors. However, the validity of the importance of perineural invasion needs to be clarified in a larger series with longer follow-up period.


   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Comment
 References
 

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