| Abstract|| |
Background: A proportion of early-stage node-negative oral squamous carcinoma patients fail despite complete surgical resection. Adjuvant treatment in early oral cancer is controversial and is often individualized based on stage, depth, and margin status. Aims: We reviewed various histological markers in pT1/T2N0 cases, resected upfront with elective nodal dissection, with an emphasis on tumor-tissue interface characteristics of the worst pattern of invasion (WPOI), tumor cell nest size (sCNS), budding and lymphocytic host response (LHR), to assess their prognostic significance. Materials and Methods: Archived blocks of 95 cases were reviewed. Tumor stage, grade, size, depth of invasion, lymphovascular, and perineural invasion, WPOI, LHR, sCNS, and tumor bud (single cells or <5 cell clusters) score were recorded. Statistical Analysis: Prognostic significance was statistically analyzed using SPSS software version 20. Results: Depth of invasion (P = 0.008), WPOI- 4 and 5 (P = 0.033), sCNS (<5 cells) at tumor interface (P = 0.010), high bud count (≥3 buds/40 × hpf) (P = 0.021) and poor LHR (P = 0.019) correlated significantly with poor disease-free survival on univariate analysis. However, on multivariate analysis only LHR and WPOI-4 (that is presence of small cell nests or buds) were significant, with high hazard ratio of 4.351 (95% CI 1.290–14.676, P = 0.018) and 5.019 (95% CI 1.212–20.789, P = 0.026), respectively. Conclusion: We propose mandatory reporting of WPOI-4 at the tumor interface and absence of LHR, as significant markers of poor prognosis in early-stage oral cavity squamous carcinoma.
Keywords: Early-stage oral cancer (pT1/T2 N0), Lymphocytic host response, Tumor budding, Smallest cell nest size, Worst pattern of invasion
|How to cite this article:|
Parekh D, Kukreja P, Mallick I, Roy P. Worst pattern of invasion – type 4 (WPOI-4) and Lymphocyte host response should be mandatory reporting criteria for oral cavity squamous cell carcinoma: A re-look at the American Joint Committee of Cancer (AJCC) minimum dataset. Indian J Pathol Microbiol 2020;63:527-33
|How to cite this URL:|
Parekh D, Kukreja P, Mallick I, Roy P. Worst pattern of invasion – type 4 (WPOI-4) and Lymphocyte host response should be mandatory reporting criteria for oral cavity squamous cell carcinoma: A re-look at the American Joint Committee of Cancer (AJCC) minimum dataset. Indian J Pathol Microbiol [serial online] 2020 [cited 2021 Dec 7];63:527-33. Available from: https://www.ijpmonline.org/text.asp?2020/63/4/527/299319
| Introduction|| |
Primary resection with elective nodal dissection is the usual treatment protocol for early oral cavity squamous carcinoma (SCC). Margin status is the main prognostic factor guiding adjuvant treatment (postoperative radiotherapy and chemotherapy) decisions in early stage, node-negative patients., However, some patients fail despite adequate treatment. To identify these poor biology tumors, various prognostic parameters have been proposed. Tumor grade, perineural invasion (PNI), lymphovascular invasion (LVI) are well studied, whereas some novel ones are the worst pattern of invasion (WPOI), lymphocytic host response (LHR), smallest cell nest size (sCNS), and tumor budding (TB).,,,
In this study, we looked at a unique cohort of pathologically proven node-negative early-stage patients, to evaluate if these novel prognostic parameters can better guide adjuvant treatment decisions.
| Materials and Methods|| |
Available archived hematoxylin eosin (HE) stained slides of T1N0 and T2N0 oral cavitySCC (including gingiva–buccal complex, oral tongue, and lip), operated upfront at our center with elective nodal dissection (levels 1–4), between May 2011 and November 2015, were reviewed. Staging was based on the American Joint Commission on Cancer (AJCC) tumor node metastasis (TNM) staging, 7th edition. Recurrent cases or those with prior neoadjuvant treatment, less than 2 sections from T1 tumor, or less than 3 sections from T2 tumor, were rejected. Recuts of paraffin blocks were also done and all slides were reviewed by two pathologists.
The histological parameters recorded include tumor type, size, stage, depth of invasion (DOI), thickness, grade, lymphovascular emboli (LVI), PNI, WPOI, LHR, TBud, and sCNS [enlisted in [Table 1].
Though case selection was done on the 7th edition AJCC TNM stage, after assessing DOI, as per College of American Pathologists (CAP) dataset guidelines from the adjacent basement membrane to the deepest point of the tumor, the cases were re-staged as per the AJCC TNM 8th edition.
Tumor grading was done as per World Health Organization (WHO) definition based on the degree of differentiation, cellular pleomorphism, and mitotic activity as recommended in CAP guidelines.
PNI was recorded as positive when nerves of any diameter/size were involved by tumor, and irrespective of whether the involved nerves were inside or outside the tumor. Nerve diameter size was not recorded in this study.
The sCNS both within the core of the tumor, and at the invasive front, was recorded, even if focal and graded into four categories: single cells, small 2–4 cell nests, intermediate 5–15 cell nests, and large >15 cell nests.
TBuds at the invasive front were counted by screening all sections of the tumor at 10× and the worst score (highest budding) in a single 40× high power field (hpf) with a field area of 0.95 mm2 was recorded (hot-spot method) [Figure 1]. TBuds were also counted in 10 highest hpfs, and score grouped into three categories: no buds, Low budding activity (1–14 buds/10 hpfs) and high budding activity (≥15 buds/10 hpfs). Intratumoral buds were not recorded in this study.
|Figure 1: Photomicrograph showing tumor budding and small cell nests at the tumor edge (400×; H and E stain)|
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Based on the Brandwein–Gensler model, the worst POI was recorded, even if focal. Nonaggressive patterns included broad pushing margin (WPOI-1), broad finger-like projections, or separate large islands (WPOI-2) and those showing invasive islands (>15 cells) (WPOI-3). Aggressive patterns are WPOI-4 with islands of <5 cells, strands of tumor or single-cell infiltration, and WPOI-5 which showed tumor satellites separate from the main tumor interface by >1 mm. Dispersed PNI or LVI were also considered WPOI-5. In ambiguous cases, the lower WPOI was recorded.
LHR was categorized into three types, based on the presence of dense continuous band of lymphoid infiltrate along the entire tumor interface (type 1), moderate infiltrate or discontinuous patches of lymphoid tissue (type 2) or absence or minimal lymphoid response, which did not form lymphoid patches (type 3).
The histopathological data were entered in REDCap online data capture tool and clinical follow-up recorded from the hospital electronic medical records. Recurrence at the same site after 5 years of treatment of the primary was considered as the second primary. Descriptive statistics was used to tabulate the various prognostic parameters. Interclass correlation coefficient (ICC) was evaluated to assess the inter-rater concordance. Kaplan–Meier analysis was done to evaluate disease-free survival (DFS). Univariate analysis and multivariate Cox regression analyses were done using Statistical Package for the Social Sciences (SPSS) software program, version 20.0.
| Results|| |
A total of 95 cases were studied, which included 34 females and 61 males. The details of the histopathological parameters studied and their prognostic significance are tabulated in [Table 1].
The most common site in our cohort was tongue (65/95 cases––68.4%). Other sites included 20 buccal mucosa, 3 lip, 5 lower alveolus, and 2 retromolar trigone cases. One case had multifocal (two foci) tumors. The tumor size ranged from 0.6 to 4 cm, including 40 pT1 tumors and 55 pT2 tumors (as per AJCC TNM 7th ed.ition staging). Margin status was close but free in four cases (≤5 mm from tumor) and >5 mm away from tumor in the remaining.
Median follow-up time was 37 months. Adjuvant radiotherapy was given in 32 patients, based mainly on the factors of involved margins, tumor DOI (of >5 mm) and presence of PNI. Local (regional), nodal, and distant failure (in the lungs) was noted in 13/95 (13.68%) patients. All cases with failure had clear margins and no lymphovascular emboli. The details of the type of failure and other histological features of the patients who failed are enlisted in [Table 2].
We recategorized patients according to DOI by the AJCC 8th edition recommendations and 14 (14.7%) patients were reclassified as pT3 by virtue of depth, whereas 12 T1 cases were reclassified as pT2. Comparing outcomes by AJCC 7th edition pT stage (log rank, P = 0.822) and the AJCC 8th edition pT stage, there was no significant difference between T1, T2, and T3 (log rank, P = 0.197), although DOI significantly correlated with poor prognosis [Table 1].
Traditional parameters such as tumor grade, LVI, and PNI did not show any prognostic significance (P > 0.05), in our early-stage cohort.
On grouping cases into two groups based on the sCNS at the edge––those showing nests of <5 cells (single cells or nests of 2–4 cells) and those with nests of ≥5 cells (5–15 and >15 cells), the 3-year DFS was 77.9% for patients with small CNS (<5 cells), versus 97.9% for patients with large CNS (P = 0.010) [Figure 2]. sCNS at the tumor core however did not show prognostic significance on similar grouping (P = 0.145).
|Figure 2: Kaplan Meier curves comparing recurrence free survival in patient groups based on cell nest size groups at the tumor interface (sCNSgroup 1 : single or small nests of <5 cells (tumor buds/WPOI-4); and group 2 : intermediate nests of 5-15 cells or large nests of >15 cells); P = 0.010|
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TBuds counted on the worst 40× hpf ranged from 0 to 13 with a mean of 2 and a median of 1. ICC for TBud counting by three observers on 15 cases was 0.897 (average measure), which indicates excellent inter-rater agreement/correlation. The cases were grouped into two groups using a cutoff of ≥3 buds per 40× hpf. The 3-year DFS of patients with 3 or more buds was 79.9% vs. 90.8% in those with 0–2 buds, with a significant P value of 0.021. TBuds groups based on the average of ten 40× hpf counts, showed a nonsignificant correlation (P = 0.061) [Table 1].
WPOI-4 was the most common pattern of invasion in our cases (36 cases; 37.9%), followed by nonaggressive pattern 3 (28/95 cases; 29.5%). WPOI-5 when compared with the other patterns (WPOI1-4) grouped together did not show the significant prognostic difference (P = 0.910). However, when the aggressive WPOIs (patterns 4 and 5) were compared with the nonaggressive ones (patterns 1, 2, and 3), the 3-year DFS of patients with WPOI-4 or 5 was 72.2% vs. 90.1% in those with WPOI 1–3, with a significant P value of 0.035. Patterns 4 and 5 compared individually with WPOI1-3 as a group, also showed prognostic significance (P = 0.033).
Presence of LHR types 1, 2, and 3 showed prognostic significance (P = 0.047). On two-tiered grouping, LHR (types 1–2) showed a significant survival advantage with 3-year DFS of 96% over cases with LHR type 3, where minimal response was seen (79.6% 3-year DFS; P = 0.019) [Figure 3].
|Figure 3: Kaplan Meier curves comparing recurrence free survival in patient groups based on the lymphocyte host response at the tumor interface (LHR 1&2: strong/moderate response; LHR 3 : limited response); P = 0.019|
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A multivariate analysis was performed using the following parameters: pT stage according to AJCC 8th edition (considering DOI), PNI, LHR (groups 1 and 2 versus 3), and presence of cell nests at the interface [small nests vs. intermediate and large, i.e., presence of WPOI-4]). Bud count score and WPOI 4 and 5 group (aggressive WPOI) were not included in the multivariate analysis as these had a direct correlation with the cell nest size and would confound the results. We found that both presence of sCNS (buds/WPOI-4) and LHR were the only independent prognostic factors with HR of 5.019 (95% CI 1.212 to 20.789, P = 0.026) and 4.351 (95% CI 1.290 to 14.676, P = 0.018), respectively.
| Discussion|| |
Most of the risk assessment studies in oral SCCs have been done in clinically detected early-stage cancers with unknown pathological nodal status, or in preoperative biopsies, to predict for nodal metastasis.
In this study, we looked at a unique cohort of pathologically proven node-negative early-stage patients who still failed treatment and may benefit from adjuvant treatment. Tumor size and stage, grade, LVI, and PNI are the usual prognostic data captured in oral SCCs, but in lymph node-negative (hence rare or no LVI), early-stage (T1/T2; small T size) cases, these traditional parameters do not provide clinically significant prognostic information.
One of the earliest studies on tumor prognostication in oral SCC is by Bryne et al., who modified Broder's grading based on keratinization, nuclear atypia, and mitotic count. The histologic risk assessment model proposed by Brandwein et al. is based on a five tiered WPOI, presence of PNI in small or large nerves (>1 mm), and a three-tiered LHR grading., This model has been validated for low stage patients by Li et al. LHR grading quantifies the degree of adaptive host immunity, against the tumor, which comprises mainly of cytotoxic T cells. A novel grading system using tumor budding activity and sCNS at the invasive front has recently been validated for oral SCC by Boxberg et al., for risk stratifying head and neck SCCs. Tumor buds (TBuds) are small cell nests (<5 cells clusters) or single cells, which dissociate/bud into the surrounding stroma. Though the clinical significance of TBud is well established in sites like colon and incorporated into routine reporting datasets,, it has not been adequately evaluated for oral SCCs. More recently, Arora et al. advocated the Aditi-Nuzhat lymph node prediction score in clinically early-stage oral cancers, based on the DOI, PNI, LVI, LHR, and TBuds.
The adoptions of various risk assessment models defined by authors like Brandwein et al. and Boxberg et al. in routine reporting has been limited by the complexity of some of these systems, lack of concordance of methodology, or lack of adequate validation of some of these parameters.
The CAP has only recently recommended reporting the presence or absence of WPOI – pattern 5. However, reporting of WPOI-4, size of PNI (> or < 1 mm), TB, sCNS or LHR is still not accepted universally or recommended by CAP.
Of the CAP dataset mandatory list of prognostic parameters to be captured, only DOI showed prognostic significance in our cohort (P = 0.008). This parameter is now incorporated into the AJCC 8th edition tumor staging, although the calculated AJCC 8 stage also did not show prognostic significance.
Lymphocytic host response
Similar to other researchers, we found LHR to be significantly correlating with prognosis both on univariate analysis based on the three-tiered grading proposed by Brandwein et al., and on multivariate analysis based on two groups: limited response (type 3) and moderate patchy to dense continuous response (Types 2 and 1 combined) with a hazard ratio of 4.351 (95% CI 1.290 to 14.676, P = 0.018).,, Arora et al. and Kolokythas have also found LHR to be a significant marker of prognosis. Though this parameter is not novel and its role in tumor behavior has been recognized in other site groups, it is still not incorporated in minimum dataset reporting guidelines. Maleki et al. showed that it was the amount of CD8 cytotoxic T-cell component which directly correlated with prognosis. In a recent meta-analysis, Ruiter et al. reported a favorable prognostic role for CD3+, CD8+, and FoxP3 positive tumor-infiltrating lymphocytes. Various researchers are working on developing an immunoscore based on the T-cell type, to better prognosticate patients, though the mechanism by which tumor cells interact with their micro-environment to evoke this T-cell response, is still not well understood.
Cell nest size and tumor budding
Tumor budding is a measure of the cellular discohesion of the tumor and represents epithelial-mesenchymal transition., The prognostic role of TBuds in SCCs of the oral cavity has not yet been adequately explored, in spite of its undeniable significance in other sites (adenocarcinomas of lung, breast, and colon). Almangush et al. recently compiled a meta-analysis of 16 studies which showed that though most studies demonstrated prognostic significance of budding, researchers have varied in the methodology used, use of immunohistochemistry to detect TBud, field size used (20× versus 40× objective), and in cutoff scores for high bud count.
Most researchers,,,, have evaluated bud count in oral SCC using a single hot-spot field with 20 × objective and scored TBuds as low or high using a cutoff of ≥5 buds/20 × hpf. Angadi et al. reported the presence of TBuds in 89% of the 75 cases of oral squamous carcinoma reviewed by them, with 45.3% showing high-intensity budding (>10 buds/20 × hpf). In contrast, we found TBuds in 52/95 cases (54.7%), with 15 of those being 1 bud/40× hpf (with a field area of 0.95 mm2) only. We had only 3 cases with >10 buds/hpf in our series. We found TBuds more commonly (38/49) in cases with aggressive WPOI (WPOI 4 or 5) than in cases of nonaggressive WPOI (1-3) (13/46 cases). Seki et al. have also evaluated the prognostic role of TBud scoring in 209 early-stage node-negative squamous carcinomas, and have proposed a more sensitive lower cutoff of ≥3 buds/x20 hpf as significant, similar to our findings.
Our 40× hotspot method is simple and quick for use in routine reporting with good interobserver concordance (ICC 0.897). TBud count on ten 40× hpfs not only showed no clinical significance (P = 0.061) in our cohort, we also found this method very tedious for adoption in routine reporting. We did not use immunohistochemistry (cytokeratin) for counting TBuds as it increases costs and turnaround time, and is not practical for wide-spread adoption, though Leao et al. have shown it to be a more accurate method. Moreover, our series has shown good clinical significance and excellent inter-observer agreement using HE based method.
Boxberg and Weichert et al., added a new parameter, that is documenting the presence of the smallest size of the tumor cell nests at the tumor interface, even if it was focal and showed significant correlation with overall survival (OS), DFS and Local Recurrence (LR) (P < 0.001). They hypothesized that sCNS was the qualitative measure of degree of dissociation of the tumor, whereas TBuds was the quantitative measure of the extent of this nesting, and hence evaluation of both was a better assessment of grade and prognosis.
In our cohort, presence of sCNS of <5 cells at the tumor edge, significantly correlated with prognosis (0.010), and on regrading 69 of our cases, based on the Boxberg grading criteria scored on TBud and sCNS, there was a significant grade shift (P = 0.001), with better stratification of the large majority of moderately differentiated tumors to well differentiated (in 32/69 cases) and poorly differentiated (in 11/69 cases) groups. The conventionally graded well and poorly differentiated tumors did not change significantly. Reporting the size of the smallest cell nest is essentially the same as documenting the presence or absence of WPOI-4 or TBud. In view of the clinical significance of the cell nest size, and as the bud count was predominantly low in our cohort, we advocate reporting the presence of absence of buds (i.e., Presence of WPOI-4), rather than doing the actual bud count in these patients.
Worst pattern of invasion
Brandwein-Gensler et al. validated that their histologic risk assessment model was strongly predictive for OS and DFS (HR 9.16, 95% CI 2.65, 31.66, P = 0.0050). They showed that aggressive patterns of invasion (WPOI-4 and 5) were significantly associated with poorer OS and positive lymph nodes, in comparison to nonaggressive ones (groups 1-3) in their cohort. They also showed that though WPOI was associated with LR the predominant pattern of invasion was not, and advocated reporting WPOI, even if focal., Presence or absence of WPOI-5 is now incorporated in the CAP minimum dataset for reporting in oral SCCs., Similar to the study by Rodriges et al., in our cohort, type 4 WPOI was the most common pattern (36/95 = 37.9%) and WPOI-4 and -5 taken together showed clinical significance (P = 0.035) when compared with patterns 1–3 (P = 0.035), whereas only pattern 5 did not (P = 0.910). Therefore, in contrast to the CAP recommendation of only reporting the presence or absence of WPOI-5, documenting both WPOI-4 and WPOI-5 is important. Presence of WPOI-4 also represents the presence of small cell nests (<5 cell clusters) and TBud at the tumor edge, and these 3 parameters capture the same aggressive feature of the tumor. We could not apply the Brandwein histologic risk score to our series as we did not record nerve diameter for PNI, and reported involvement of any sized nerve both within and outside the tumor, as PNI (as per CAP guidelines).
Tumor interface markers of poor biology
A 3-year-DFS of 88.7%, despite adequate primary resection and elective nodal dissection, as seen in our cohort, mandates the need to identify markers of poor biology which can guide multi-modality adjuvant treatment. It has been hypothesized and demonstrated by many researchers that the nature of the cells at the invasive front or tumor interface, connotes tumor behavior. Presence of aggressive WPOI (especially WPOI 4, comprising of small islands of invasive tumor), small size of cell nests at the invasive front and tumor budding are different measures of recording and categorizing the same tumor characteristic, which is tumor dissociation into small nests at the invasive front, which is a marker of poor behavior.
In addition to this tumor characteristic, we also found the lack of host immune lymphocytic response to be a significant marker of poor tumor behavior. It is the interaction of these two parameters, which possibly best define tumor behavior and predict outcome in these patients. Moreover, in multivariate analysis, we found both LHR and presence of small cell nests at the invasive front (WPOI- 4) show the independent prognostic significance of both the tumor interface features of invasive small tumor nests and host immune lymphocytic response.
| Conclusion|| |
Our study is an exploratory retrospective analysis of a group of patients with long follow-up where new histopathological criteria predicting failure have been found. Tumor interface characteristics of WPOI-4 and the degree of LHR help to identify poor biology early-stage tumors, who can fail traditional therapy, even when adequately excised, and should be considered for more aggressive adjuvant treatment. Our results will require validation in an independent prospective dataset.
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Conflicts of interest
There are no conflicts of interest.
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Senior Consultant, Department of Oncopathology, Tata Medical Centre, 14 MAR (E.W), Newtown, Kolkata-700 156, West Bengal
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]