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High-Grade Neuroendocrine Carcinoma with Bronchial Intraepithelial Tumor Spread

Possibly a New Histologic Feature of Large-Cell Neuroendocrine Carcinoma

      Introduction

      During surgical resection of a peripherally located high-grade neuroendocrine carcinoma (HGNEC), we unexpectedly discovered prominent bronchial intraepithelial tumor spread up to the surgical end of the bronchus. Because bronchial intraepithelial tumor spread of peripherally located HGNEC has been rarely reported, we conducted a retrospective analysis at our hospital.

      Methods

      We histologically reviewed surgically resected HGNEC cases to assess bronchial intraepithelial spread of tumor cells. HGNECs with bronchial intraepithelial tumor spread were further studied by immunohistochemistry for neuroendocrine markers, and their clinicopathological characteristics were evaluated.

      Results

      Of 1778 cases of surgically resected lung cancer in our hospital, 47 cases of HGNEC were evaluated. Bronchial intraepithelial tumor spread was observed in nine cases (19.1%); eight of these cases were large-cell neuroendocrine carcinoma (LCNEC) or small-cell lung carcinoma with an LCNEC component. Moreover, bronchial intraepithelial tumor spread was continuous from the primary tumor to the resected end of the bronchus in four cases, and all these cases had an LCNEC component. Furthermore, HGNEC with bronchial intraepithelial tumor spread was associated with a higher recurrence rate than no bronchial intraepithelial tumor spread.

      Conclusion

      The results of this study suggest that bronchial intraepithelial tumor spread is commonly observed in cases of peripherally located HGNEC and may be a unique form of tumor invasion, especially tumors with LCNEC morphology. Therefore, surgeons and pathologists should be cognizant of bronchial intraepithelial tumor spread in peripherally located HGNEC, as well as its potential role as an indicator of HGNEC aggressiveness.

      Key Words

      Both small-cell lung carcinoma (SCLC) and large-cell neuroendocrine carcinoma (LCNEC) are classified as high-grade neuroendocrine carcinoma (HGNEC).
      • Travis WD
      • Colby TV
      • Corrin B
      • Shimosato Y
      • Brambilla E
      • Travis WD
      • Brambilla E
      • Müller-Hermelink HK
      • Harris CC
      Centrally located SCLC usually involves tumor cells that invade along the bronchial mucosa.
      • Junker K
      • Wiethege T
      • Müller KM
      Pathology of small-cell lung cancer.
      However, bronchial intraepithelial tumor spread of peripherally located HGNEC has been rarely reported.
      In our hospital, during the surgical resection of a peripherally located HGNEC, we unexpectedly discovered tumor spread along the bronchial epithelium up to the surgical end of the bronchus. Prompted by our experience with this interesting case, we histologically reviewed other cases of HGNEC to evaluate bronchial intraepithelial spread of tumor cells to determine the frequency and characteristics of this rare presentation.

      PATIENTS AND METHODS

      Between September 2002 and December 2012, 1778 patients underwent surgical resection for primary lung cancer at the Shizuoka Cancer Center Hospital in Shizuoka, Japan. Of these, 67 (3.8%) patients had tumors that were pathologically diagnosed as HGNEC, either SCLC or LCNEC. We histologically reviewed 47 cases of HGNEC in patients who underwent segmentectomy, lobectomy, or pneumonectomy with lymph node dissection; our focus was on the potential bronchial intraepithelial spread of tumor cells. Bronchial intraepithelial tumor spread was defined as continuous tumor invasion into the bronchus or bronchiole located outside the main tumor mass, and we excluded any tumor cell invasion of the bronchial lamina propria and submucosa or along the peribronchial soft tissue.
      The histologic diagnoses of SCLC and LCNEC were based on the revised World Health Organization classification of lung carcinoma (2004).
      • Travis WD
      • Brambilla E
      • Müller-Hermelink HK
      • Harris CC
      Immunohistochemical analysis using CD56 antibodies (Nihonkayaku, Tokyo, Japan), chromogranin A (Dako, Glostrup, Denmark), and synaptophysin antibodies (Leica Microsystems, Newcastle, United Kingdom) was performed on paraffin-embedded tissue samples from all patients to confirm the neuroendocrine phenotype.
      To analyze the clinicopathological characteristics of HGNEC, clinical and pathological information was collected from the medical records. This study was approved by the Shizuoka Cancer Center Institutional Review Board.
      The clinicopathological features of patients were compared using the Fisher's exact test or the chi-square test. A p value of less than 0.05 was considered statistically significant. All statistical analyses were performed using JMP 9 software (SAS Institute, Cary, NC).

      RESULTS

      A Representative Case

      Herein, we describe the details of the case that prompted us to perform this study, as a representative case. The patient was a 66-year-old man who was admitted to our hospital with an abnormal shadow on a chest radiograph. Chest computed tomography revealed a well-defined and lobulated solid nodule measuring 2.4 cm in diameter in the left peripheral S1+2b segment (Fig. 1). Transbronchial lung cytology yielded a pathological diagnosis of non-SCLC, and bronchoscopy showed normal epithelium of the B1+2 bronchus and the left upper bronchus. The clinical stage was T1bN0M0 (stage IA), and a left upper lobectomy was performed. The resected tumor was 1.6 × 1.5 × 1.5 cm. Microscopically, the tumor contained a vast necrotic area in the center and variably sized tumor nests around the necrotic area (Fig. 2A). Tumor nests were a mix of small cells with fine hyperchromatic oval- to spindle-shaped nuclei and large cells with large round nuclei, distinct nucleoli, and scant cytoplasm (Fig. 2B). The tumor cell border was clear, and many rosette-like structures were observed. Immunohistochemical analysis revealed that the cells were diffusely positive for CD56 (Fig. 2B, inset), partially positive for chromogranin A, and negative for synaptophysin. The final pathological diagnosis was SCLC combined with LCNEC, and the pathological stage was T1aN0M0 (stage IA).
      Figure thumbnail gr1
      FIGURE 1Radiographic findings of the tumor: Computed tomography of the chest reveals a well-defined and lobulated solid nodule measuring 2.4 cm in diameter in the left peripheral S1+2b segment.
      Figure thumbnail gr2
      FIGURE 2Microscopic findings of high-grade neuroendocrine carcinoma: The tumor has a vast necrotic area in the center (right side) and variably sized tumor nests around the necrotic area. Bronchiole is completely replaced by tumor cells (single arrow) and vascular invasion is seen in the center (A). The tumor nests are a mix of small cells (single arrow) with fine hyperchromatic oval- to spindle-shaped nuclei and large cells (double arrows) with large round nuclei, small nucleoli, and scant cytoplasm (B). The tumor cells are positive for CD56 (B, inset). Apart from the primary tumor, the bronchial epithelium and bronchial glands in the B1+2b region have tumor cell invasion (C). Two to three layers of tumor cells occupying the basal bronchial epithelium and normal respiratory epithelial cells are present on the surface at the resected end of the left upper bronchus (D).
      There was a peripheral B1+2b bronchiole within the primary tumor, and the mucosal epithelium of the bronchiole was completely damaged and replaced by tumor cells. Apart from the primary tumor, tumor cell invasion was seen in the bronchial epithelium and bronchial glands in the B1+2b region (Fig. 2C), but ciliated epithelium remained on the invading tumor cells. Moreover, tumor cells had invaded the epithelium of the B1+2 bronchus and the resected end of the left upper bronchus. Approximately 10% of the circumference of the left upper lobe bronchial resection margin showed two to three layers of tumor cells under the ciliated bronchial epithelium (Fig. 2D). Bronchial glands were not involved. The degree of bronchial intraepithelial tumor cell invasion decreased with increasing distance from the primary tumor. Immunohistochemistry revealed the same staining pattern in the bronchial intraepithelial tumor cells as in the primary tumor.

      Cases of High-Grade Neuroendocrine Carcinoma with Bronchial Intraepithelial Tumor Spread

      Of the 47 cases of surgically resected HGNEC, nine (19.1%) had bronchial intraepithelial spread of tumor cells. The clinicopathological characteristics of these nine patients are summarized in Table 1.
      TABLE 1Clinicopathological Summary of High-Grade Neuroendocrine Carcinoma Cases with Bronchial Intraepithelial Spread
      CaseSexAge (yr)p-StageHistologic TypeCD56SynaptophysinChromo-AResected End of the BronchusOutcome (mo)
      1M66IASCLC + LCNEC++PositiveANRD (24)
      2M73IBLCNEC+++PositiveDOD (14)
      3M63IBLCNEC + AD+PositiveARD (31)
      4M71IIIALCNEC++PositiveDOD (30)
      5M82IBLCNEC+++NegativeDOD (42)
      6M68IIALCNEC+NegativeDOD (65)
      7M75IIASCLC+++NegativeARD (14)
      8M71IIASCLC + LCNEC++NegativeDOD (7)
      9F68IIIASCLC + LCNEC+NegativeARD (26)
      AD, adenocarcinoma; ANRD, alive with no recurrent disease; ARD, alive with recurrent disease; Chromo-A, chromogranin A; DOD, died of the disease; LCNEC, large-cell neuroendocrine carcinoma; SCLC, small-cell lung carcinoma.
      Of these nine cases, four were pure LCNEC (Fig. 3), three were SCLC combined with LCNEC, one was pure SCLC, and one was LCNEC combined with adenocarcinoma. Moreover, in four of these cases, bronchial intraepithelial tumor spread was found not only around the primary tumor but also up to the resected end of the bronchus. All of these four cases involved an LCNEC component. In all cases except one, the tumor recurred after surgery. Five of the nine patients with bronchial intraepithelial spread died of their disease (Table 1).
      Figure thumbnail gr3
      FIGURE 3Microscopic findings of large-cell neuroendocrine carcinoma with bronchial intraepithelial spread (case 4 in ): The primary tumor, composed of large polygonal cells, shows prominent rosette-like structures with massive necrosis (A). Outside the primary tumor, tumor cells invade the bronchial epithelium (B); tumor cells are immunohistochemically positive for CD56 (B, inset).

      Comparison of High-Grade Neuroendocrine Carcinoma Cases with and without Bronchial Intraepithelial Tumor Spread

      The age range of the 47 patients (34 men and 13 women) with HGNEC was 51 to 82 years (median, 70 years). The results of the comparative study of clinicopathological features of HGNEC with or without bronchial intraepithelial tumor spread are shown in Table 2. Statistical analysis showed no significant differences in the clinicopathological features between HGNEC with or without bronchial intraepithelial tumor spread, except for the recurrence rate, which was higher in cases of HGNEC with bronchial intraepithelial tumor spread than in cases of HGNEC without bronchial intraepithelial tumor spread (88.9% versus 44.7%, p = 0.03). Although tumor cell invasion was observed at the surgical end of the bronchus in four HGNEC cases with bronchial intraepithelial tumor spread, no tumor cell invasion was seen at the resected end of the bronchus in HGNEC cases without bronchial intraepithelial tumor spread.
      TABLE 2Clinicopathological Features of High-Grade Neuroendocrine Carcinoma Cases with or without BIS
      VariablesWith BISWithout BISp Value
      No. of patients938
      Sex, n (%)
       Male8 (89)26 (68)0.41
       Female1 (11)12 (32)
      Age (yr)
       Median71700.41
       Range63–8251–79
      Smoking history, n (%)9 (100)37 (97)1.00
      Abnormal increase of serum tumor marker, n (%)
       CEA (ng/ml)3 (33)23 (61)0.26
       NSE (ng/ml)2 (22)11 (29)1.00
       ProGRP (pg/ml)1 (11)8 (21)0.67
      Tumor size (cm)
       Median3.52.80.11
       Range1.7–8.01.2–6.8
      Pathological nodal status, n (%)
       Pathological N04 (44)26 (68)0.25
       Pathological N1-N25 (56)12 (32)
      Surgical procedure, n (%)
       Segmentectomy0 (0)3 (8)1.00
       Lobectomy or more9 (100)35 (92)
      Histologic type, n (%)
       LCNEC5 (56)19 (50)1.00
       SCLC4 (44)19 (50)
      Recurrence, n (%)8 (89)17 (45)0.03
      BIS, bronchial intraepithelial spread; CEA, carcinoembryonic antigen; LCNEC, large-cell neuroendocrine carcinoma; NSE, neuron-specific enolase; ProGRP, progastrin-releasing peptide; SCLC, small-cell lung carcinoma.

      DISCUSSION

      Among lung cancers, it is well known that centrally located squamous cell carcinoma frequently shows bronchial intraepithelial (in situ) spread as one of the major patterns of tumor spread. In SCLC, tumor cell spread is known to occur along peribronchial lymphatic tissues or around bronchovascular bundles. However, bronchial intraepithelial spread of tumor cells is very rarely reported in HGNEC. Until now, only two articles have described bronchial intraepithelial tumor spread associated with invasive SCLC.
      • Nicholson SA
      • Beasley MB
      • Brambilla E
      • et al.
      Small cell lung carcinoma (SCLC): a clinicopathologic study of 100 cases with surgical specimens.
      • Rosen Y
      • Nicole M
      Small cell lung carcinoma with marked bronchial involvement.
      Nicholson et al.
      • Nicholson SA
      • Beasley MB
      • Brambilla E
      • et al.
      Small cell lung carcinoma (SCLC): a clinicopathologic study of 100 cases with surgical specimens.
      studied 100 cases of surgically resected SCLC and found four cases of pagetoid tumor cell spread undermining the normal respiratory epithelium. They described these lesions as preinvasive lesions, but did not focus on this phenomenon in detail. Recently, Rosen and Nicole
      • Rosen Y
      • Nicole M
      Small cell lung carcinoma with marked bronchial involvement.
      reported a case of SCLC with marked bronchial epithelial involvement. Interestingly, their case was not of a pure SCLC, but rather there was an LCNEC component. This finding is in accordance with the results of our study of HGNEC with bronchial intraepithelial tumor spread. Rosen and Nicole concluded that the bronchial intraepithelial lesion was a precursor lesion of SCLC, and they stressed the need for further comprehensive study of the structure and immunophenotype of bronchial mucosal abnormalities associated with SCLC.
      Although these previous studies have concluded that bronchial intraepithelial lesions are preinvasive or precursor lesions of SCLC, we consider that intraepithelial lesions represent a unique form of tumor invasion in HGNEC for the following reasons. First, the intraepithelial tumor spread extended along the bronchial mucosa, including the bronchial gland, and reached the resected end of the bronchus in four cases. Second, the degree of bronchial intraepithelial spread decreased according to the distance from the primary tumor. Third, HGNEC with bronchial intraepithelial tumor spread had a high recurrence rate, suggesting that it has a high malignant potential. Finally, HGNEC with bronchial intraepithelial tumor spread was closely related to the structure of LCNEC.
      To the best of our knowledge, this is the first comprehensive study about bronchial intraepithelial tumor spread as a way of tumor progression in peripherally located HGNEC, especially in tumors with LCNEC structure. Therefore, we hypothesized that LCNEC cells might have biological characteristics of bronchial epithelial cells.
      It would have been difficult to predict the bronchial intraepithelial tumor spread preoperatively, because there were no significant differences in clinical factors (e.g., age, tumor size, and tumor markers) between patients with or without bronchial intraepithelial tumor spread. Bronchoscopy would not have helped detect this lesion, because the ciliated respiratory epithelium covered the tumor cells. Therefore, during surgery of peripherally located HGNEC, we decided to submit the resected end of the bronchus to the intraoperative diagnosis. If we find the bronchial intraepithelial spread in the resected end of the bronchus, we consider a larger anatomical resection such as sleeve lobectomy. As surgeons and pathologists may generally be unaware of this phenomenon as an indicator of the aggressiveness of peripherally located HGNEC, further studies and case analysis are necessary to verify this unique pathological observation and establish widespread awareness of it.

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        • Colby TV
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        • Shimosato Y
        • Brambilla E
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