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High tumor budding activity may predict poor prognosis in laryngeal squamous cell carcinomas öztürk &, Paşaoğlu HE, Emre F, Ege T&, Tetikkurt &S



   Abstract  

Background: Laryngeal squamous cell carcinoma (SCC) which is the most common carcinoma of the respiratory system after lung carcinomas is graded by the World Health Organization (WHO) into three groups as grades 1, 2, and 3. This system does not correlate with the prognosis and has a low reproducibility among the pathologists. Searching for a new grading system, in this study, we investigated the relationship between tumor budding and histomorphological parameters and survival status. We examined the new grading system based on cell nest size and tumor budding. Methods: Partial and total laryngectomy materials of 130 patients diagnosed as laryngeal SCC between 2012 and 2018 in our clinic were evaluated retrospectively by two pathologists. Tumor budding activity and cell nests were scored and a new score was obtained by summing the scores. According to the scores obtained, a new grading system was created. Results: There was a statistically significant difference between the tumor budding activity and the overall and disease-free survival times of the groups. The overall and disease-free survival time of the patients with high tumor budding significantly reduced. Tumor budding was found to be low in the presence of an intense lymphocytic host response (P < 0.05). There was no relationship between the new grade system and cell nest size and life expectancy (P > 0.05). Conclusions: Tumor budding provides significant clues in predicting the life expectancy of the patients. Therefore, tumor budding might be a component of new grading systems and should take place in pathology reports.

Keywords: Cell nest size, larynx, squamous cell carcinoma, tumor budding

How to cite this article:
öztürk &, Paşaoğlu HE, Emre F, Ege T&, Tetikkurt &S. High tumor budding activity may predict poor prognosis in laryngeal squamous cell carcinomas. Indian J Pathol Microbiol 2022;65:280-7



How to cite this URL:
öztürk &, Paşaoğlu HE, Emre F, Ege T&, Tetikkurt &S. High tumor budding activity may predict poor prognosis in laryngeal squamous cell carcinomas. Indian J Pathol Microbiol [serial online] 2022 [cited 2022 May 3];65:280-7. Available from: https://www.ijpmonline.org/text.asp?2022/65/2/280/343182

   Introduction   Top

Laryngeal squamous cell carcinoma (SCC) is the most common carcinoma of the respiratory system after lung carcinomas.[1] The diagnosis of laryngeal SCC can be made easily on the basis of histopathological findings, but the relationship between morphological findings and prognosis is not clear.[2]

Although significant improvements have been made in the surgical and radiotherapy techniques of laryngeal cancers, no significant change has been detected in the prognosis of the patients and the 5-year survival rate is approximately 60%.[3] Laryngeal SCC is graded by the World Health Organization (WHO) into three groups as well-differentiated (G1), moderately differentiated (G2), and poorly differentiated (G3).[4] This grading system, which was proposed by Broders in 1920, is based on cellular pleomorphism and similar to normal squamous epithelium.[5] Although this system has been used for many years, it does not correlate with the prognosis and has low reproducibility among pathologists. Therefore, the search for a new grading system continues. The correlation with the prognosis based on morphological findings has been reported in the proposed new systems over the years.[6],[7],[8] Weichert et al.[9] suggest that the tumor cell nest size and tumor budding are important in the prognosis of patients in pulmonary SCCs. Based on this study, a new grading system is proposed by Boxberg et al.[10] in laryngeal SCCs.

In this study, we investigated the relationship between tumor budding and T stage, N stage, lymphovascular and perineural invasion, tumor-associated lymphocytic host response, the amount of tumor-stroma, disease-free, and overall survival status. We also researched the utility of the new grading system based on the cell nest size and tumor budding.

   Materials and Methods   Top

The surgical specimens of 130 patients who had undergone surgical treatment for laryngeal cancer at our institution between 2012 and 2018 were included in the study. Demographic characteristics, tumor localization, tumor diameter, cervical lymph node metastasis, total follow-up time, presence of recurrence, and distant metastasis were obtained from the original pathology reports and patient files. Also, some patients’ information was completed by a telephone interview with the patient and patient relatives.

All slides stained with hematoxylin and eosin were evaluated by two pathologists (C. O., E. P.) using an Olympus B × 51 microscope with a field diameter of 0.55 mm (0.24 mm2) without knowing the clinicopathological data and follow-ups.

According to the WHO grading system based on the degree of differentiation, cellular pleomorphism, and mitotic activity, the cases were divided into three categories as well-differentiated (G1), moderately differentiated (G2), and poorly differentiated (G3). Perineural invasion (PNI) and lymphovascular invasion (LVI) status were also evaluated. The “N” stage was re-evaluated according to the 2017 American Joint Committee on Cancer (AJCC).

Isolated cancer cells or cancer cell clusters not exceeding five cells were identified as tumor budding.[10] In cases with tumor budding activity, the most intense budding areas were selected using the 10X objective. The tumor budding activity was counted at 10 high-power fields (HPFs) using the same light microscope for each case. The low-tumor budding activity was scored if 1–14 budding nests were detectable, and high-budding activity was scored if ≥15 budding nests were detectable in 10 HPFs.[10]

In addition, the tumor cell clusters on the invasive margin were evaluated. The tumor cell clusters consisted of more than 15 cells and were identified as large-sized cell nests; the tumor cell clusters consisted of 5–15 cells and were identified as intermediate-sized cell nests. The tumor cell clusters consisted of 2–4 cells and were identified as small cell nests. One tumor cell at the invasive margin was identified as a single-cell invasion.[10] Large cell nests were scored as 1 point, intermediate cell nests were scored as 2 points, small cell nests were scored as 3 points, and single-cell invasion was scored as 4 points. The high-budding activity was scored as 3 points, low-budding activity was scored as 2 points, and no budding was scored as 1 point. A new score was obtained by summing the scores from the tumor cell nests and tumor budding. Accordingly, the score was evaluated as 2–3: new grade 1 (nG1); 4–6: new grade 2 (nG2); and 7: new grade 3 (nG3) [Table 1].[11]

Table 1: Proposal of a new grading system based on tumor budding activity and cell nest size

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The amount of tumor-stroma was evaluated as recommended by Kappathiou et al.[12] The stroma was selected from the most intense site. If the stroma–tumor ratio was below 50%, the case was evaluated as stroma-poor; if the ratio was over 50%, it was evaluated as stroma-rich. Lymphocytic host response was assessed using the same study. A few or no lymphocytes that were seen at the invasive tumor front were evaluated as low lymphocytic host response (Score 1); a few lymphoid nodules that were seen at the invasive edge but not in all fields were evaluated as moderate lymphocytic host response (Score 2), and a dense complete reaction with lymphoid nodules was evaluated as intense lymphocytic host response (Score 3).[12]

In this study, statistical analysis was performed by NCSS (Number Cruncher Statistical System) 2007 Statistical Software (Utah, USA). Descriptive statistical methods (frequency and percentage distributions) were used to evaluate the data, and the Chi-square test was used to compare the qualitative data. The survival analysis was evaluated by the Kaplan–Meier and Log-Rank tests. The results were evaluated with a significance level of P < 0.05 and a 95% confidence interval.

   Results   Top

Of the 130 patients, 128 (98.46%) were males and 2 (6.2%) were females. The ages of the patients ranged from 42 to 89 years; 42 cases (32.31%) were supraglottic, 42 cases (32.31%) were glottic, 1 case (0.77%) was subglottic, and 45 cases (34.61%) were transglottic localization.

The patients had a follow-up period of 12–86 months and 90 (69.23%) patients were alive without recurrence or metastasis at the time of statistical analysis, 13 (10.00%) patients survived with relapse or metastasis, 20 (15.38%) patients died due to cancer; 7 (5,38%) patients died due to other reasons.

According to the WHO criteria, the majority of the cases were evaluated as G2 (91, 70.00%), 22 cases (16.92%) as G1, and 17 cases (13.08%) as G3. Lymphovascular invasion was detected in 50 (38.46%) cases and perineural invasion was found in 19 (14.62%) cases. Necrosis was present in 81 cases (62.31%), 82 cases (63.08%) were evaluated as stroma-poor, and 48 cases (36.92%) were evaluated as stroma-rich.

Lymphocytic host response was intense in 39 cases (30.00%), intermediate in 65 cases (50.00%), and low in 26 cases (20.00%).

When the pathological T stages were examined, 10 cases (7.69%) were evaluated as T1; 70 cases (53.85%) as T2; 40 cases (30.77%) as T3; and 10 cases (7.69%) were evaluated as T4. Cervical lymph node metastasis was observed in 48 cases (36.92%); 9 cases (6.92%) were in the N1 stage; 16 cases (12.31%) were in the N2 stage; 23 cases (17.69%) were found in the N3 stage. Extracapsular dissemination was seen in 27 (54.00%) of the 48 patients with neck metastasis.

When the cases were evaluated according to the AJCC staging system, 9 cases (6.92%) were in stage I, 44 cases (33.85%) were in stage II, 33 cases (25.38%) were in stage III, 21 cases (16.15%) were in stage IVa, and 23 cases (17.69%) were in stage IVb.

Tumor budding was seen in 82 cases. In 61 (46.92%) of these cases, tumor budding was found to be less than 15/10 HPF (40× objective); 21 (16.15%) cases were found to be over 15/10 HPF [Figure 1] and [Figure 2]. There was no statistically significant difference between tumor budding and T, N stages, lymphovascular invasion, perineural invasion, the amount of tumor-stroma (P > 0.05).

Figure 2: Figure 1 details, single-cell invasions (arrows), tumor cell nests (ovals) (H and E X100), and details (H and E × 200)

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On the other hand, there was a significant difference between tumor budding and lymphocytic host response (P < 0.05). Tumor budding was found to be higher in the group with low lymphocyte host response [Table 2] [Figure 3], [Figure 4], [Figure 5].

Figure 3: Tumor budding activity in tumor with a low lymphocytic response (H and E X20)

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Figure 4: Figure 3 details, tumor budding activity (ovals) (H and E × 200)

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Figure 5: Intense lymphocytic host response in the tumor which has no tumor budding activity at invasive margin (H and E X100)

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The overall survival time was 71.44 ± 3.86 months in the without tumor budding group whereas 77.40 ± 3.44 months in the low-budding activity group and was 51.54 ± 6.39 months in the high-budding group. The 5-year overall survival was 63.87–79.01% in the group without tumor budding, whereas 70.66–84.13% in the group with low-tumor budding activity, and was 39.01% in the group with high-tumor budding activity. There was a statistically significant difference between the overall survival times of the groups (P < 0.05). The overall survival time of the patients with high-tumor budding activity (>15/10 HPF) was significantly reduced.

The disease-free survival of the group with no tumor budding was 71.29 ± 3.90 months. The disease-free survival was 76.77 ± 3.66 months in the low-tumor budding group and 36.73–62.89 months in the high-tumor budding group. The 5-year disease-free survival of the patient in the no tumor budding was found to be 63.64–78.95%, whereas it was observed as 69.59–83.95% in the low-budding group, and 39.01–64.07% in the high-budding group. There was a statistically significant difference between the disease-free survival of the groups (P < 0.05). The disease-free survival was significantly shorter in the patients with high-tumor budding activity (>15/10 HPF) [Table 3], [Table 4]. [Figure 6], [Figure 7].

Table 3: Overall survival Log-Rank analysis by years of tumor budding activity

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Table 4: Disease-free survival Log-Rank analysis by years of tumor budding activity

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Figure 6: Relationship between tumor budding and overall survival, P = 0,012 (Kaplan–Meier)

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Figure 7: Relationship between tumor budding and disease-free survival, P = 0,008. (Kaplan–Meier)

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Single-cell invasion was seen in 45 cases (34.62%) when the invasive tumor cell nest size was evaluated. In 38 cases (29.23%), the tumor cell nest consisting of 2–4 cells, and in 16 cases (12.31%), the tumor cell nest consisting of 5–15 cells was observed. In 31 cases (23.85%), the tumor cell nests were found to consist of more than 15 cells. There was no statistically significant difference between the tumor cell nest size and T and N stages, lymphovascular, perineural invasion, and the WHO grade groups (P > 0.05). A single-cell invasion was observed in 10 out of 28 patients with low lymphocytic infiltration [Table 5].

When the cases were evaluated according to the new grading system (nG), there was no statistically significant difference between the new grade groups and pT, pN stage, the presence of LVI, and PNI, and the amount of tumor-stroma (P > 0.05).

In 39 cases, an intense lymphocytic host response was observed. Of the 39 cases, 21 were nG1, 15 were nG2, and 3 were nG3. As the grade decreased according to the new grading system, more lymphocytic host response was observed. This was found to be statistically significant (P < 0.05) [Table 6].

The mean survival time of the nG1 group was 69.35 months and the overall 5-year survival rate was 61.28–77.41%. The mean survival time of the nG2 group was 76.11 months and the overall 5-year survival rate was 68.09–84.13%. The survival time of the nG3 group was 67.76 months and the overall 5-year survival rate was 57.84–77.68%. There was no statistically significant difference between the overall survival of the groups (P > 0.05).

The mean disease-free survival of the nG1 group was 69.22 months and the 5-year disease-free survival was 61.13–77.39%. The mean disease-free survival of the nG2 group was 75.61 months and the 5-year disease-free survival was 67.18–84.04%. The mean disease-free survival of the nG3 group was 66.62 months and the 5-year disease-free survival was 56.06–77.18%. No statistically significant difference was observed between the disease-free survival of the groups (P > 0.05) [Figure 8] and [Figure 9].

Figure 8: Relationship between new grade groups and overall survival, P > 0.05 (Kaplan–Meier)

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Figure 9: Relationship between new grade groups and disease-free survival, P > 0.05 (Kaplan–Meier)

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   Discussion   Top

Laryngeal SCC is the most common carcinoma of the respiratory system after lung carcinomas.[1] Laryngeal SCC is graded by the WHO into three groups as well-differentiated (G1), moderately differentiated (G2), and poorly differentiated.[4] This grading system which was proposed by Broders in 1920, is based on cellular pleomorphism and the similarity to normal squamous epithelium.[5] Although the system has been used for many years, it does not correlate with the prognosis and has low repeatability among pathologists. For this reason, new classifications have been searched for many years. The correlation with the prognosis has been reported at varying rates in the proposed new systems based on morphological findings.[6],[7],[8]

In the literature, there are only a few studies about tumor budding in laryngeal SCCs. Tumor budding in the larynx was first studied by Sarıoglu et al.[13] In Sarıoglu’s study, intense tumor budding was associated with disease-free survival. Similar to the study of Sarıoglu et al.,[17] Ekmekçi et al.[14] found a significant relationship between tumor budding and neck metastasis, LVI, and PNI in larynx carcinomas. Sarıoglu and Ekmekçi defined tumor budding as five or less dedifferentiated tumor cells in their studies; they determined tumor budding activity as semiquantitative as mild/moderate/intense in the invasive margin of tumors. In our study, the budding activity was evaluated as suggested by Boxberg since it is a more quantitative and reproducible method. Tumor buds less than 15/10 HPF were evaluated as low-budding activity, 15/10 HPF and over were evaluated as high-budding activity. It was seen that in patients with high-budding activity, disease-free and overall survival was significantly decreased. The findings support that tumor budding has an important role in the prognosis of laryngeal carcinomas. Therefore, tumor budding promises to be a parameter of new grading system studies.

In our study, it was also found that the lymphocytic host response was mild in the presence of high-tumor budding activity. In the study of Schneider et al.[15] in which the immune response was evaluated in SCCs of the head and neck, low lymphocytic host response was found to be associated with poor prognosis. In addition, in a study involving 377 patients, the tumor-related lymphocytic response has been shown to be an independent prognostic parameter in esophageal SCC.[16] Similarly, Brown et al.[17] reported that low lymphocytic response and tumor budding were associated with poor prognosis in esophageal and gastroesophageal junction tumors. Accordingly, the low lymphocytic response may facilitate tumor budding.

It is known that tumor stroma is an important parameter that indicates the invasiveness of the tumor.[18] When the cases were evaluated according to the amount of tumor-stroma, a small proportion (n: 48) was found to be stroma-rich. In the literature, Karpathiou et al.[12] evaluated the amount of tumor-stroma using a cut-off value of 50%, and found that stroma-rich tumors were more advanced pT stage tumors. In our study, stroma-rich tumors were mostly advanced pT stage tumors; however, no statistically significant results were obtained. In addition, tumor budding was seen in 34 of 48 patients who were evaluated as stroma-rich, however, there was no statistically significant relationship between tumor budding and the amount of tumor-stroma.

In the literature, additional systems have been proposed to increase the prognostic value of the grading and to reduce interobserver variability. Some studies detected that the system, in which tumor budding and depth of invasion measurement are used together, is an independent prognostic parameter.[8.19] However, the depth of invasion provides information about the stage rather than the grade of the tumor and can only be evaluated in resection material. Therefore, the search for a new system continues. The tumor cell nest size, which was first proposed in lung SCCs and found a significant relationship with T, N, and clinical stages, is being investigated in the head and neck cancers.[9] Boxberg et al. formed a new grading system based on scoring cell nest size and tumor budding in oral SCCs.[10] This proposed a new grading system which was found to be related to disease-free survival. Jesinghaus et al.[20] proposed the same grading system in esophageal SCCs and found a significant relationship between the new grade groups and disease-free survival of patients. The same grading system was evaluated in the patients with laryngeal and hypopharyngeal SCCs and new grade groups were found to have a significant relationship with disease-free and overall survival of patients.[10] Based on this proposed new grading system, our patients were divided into three new grade groups. The relationship between the new grade groups and the lymphocytic host response, the amount of tumor-stroma, LVI, PNI, the WHO grade group, and the survival time were evaluated. According to the new classification, 47 cases (36.15%) were classified as new G1, 64 cases (49.23%) as new G2, and 46 cases (14.61%) as new G3. According to these results, the cases were more homogeneously distributed among the grades in the new classification. But, there was no statistically significant relationship between the new grade groups and pT, pN stage, LVI, PNI, the amount of tumor-stroma.

When the distribution of the new grading system according to the lymphocytic host response was examined, 21 of the 39 cases with intense lymphocytic host response were found to be new G1; 26 cases with low lymphocytic host response were observed as new G1, 11 as new G2, and 6 as new G3. Accordingly, as the grade of the cases increased, the lymphocytic host response decreased significantly (P < 0.05).

In our study, the relationship between the new grading system and disease-free and overall survival of patients was also investigated. Although it was observed that the survival rates decreased with the increasing grade, no statistically significant difference was observed. Geographical differences, socioeconomic conditions, and treatment management may cause different results from the other studies.

Boxberg et al.[11] re-evaluated 108 cases of oral squamous cells to investigate the compatibility of the proposed new grading system between the pathologists and recurrent views of the same pathologists. Their study shows that the new proposed system has more repeatability in contrast to the WHO grading system. More comprehensive studies are needed in more centers to make the proposed new system widely used all over the world.

In our study, we investigated the relationship between the new grading system and its constituents with the clinicopathological parameters and prognosis. Tumor budding, which was one of these constituents, has been found to be related to the survival of patients. However, no relationship was found between the survival of patients and both tumor nest size and the new grading system. This may be due to the insufficient number of our cases and the small number of cases representing the groups when subdivided.

The WHO grading system currently used in laryngeal carcinomas is based on subjective criteria and has a low reproducibility among pathologists. Although immunohistochemical and molecular studies are ongoing in order to find new markers that may be effective in predicting prognosis and treatment management, morphological findings still have a priority and importance for pathologists.

Among the morphological findings, tumor budding provides significant clues in predicting the life expectancy of the patients. Therefore, tumor budding might be a component of the new grading systems and should take place in the pathology reports.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 

   References   Top


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Correspondence Address:
Çiğdem öztürk
Islampaşa, Şehitler Cd. No: 74, 53020 Rize Merkez/Rize
Turkey
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/IJPM.IJPM_1299_20

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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9]
 
 
 
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]

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