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 Table of Contents  
Year : 2017  |  Volume : 5  |  Issue : 2  |  Page : 71-74

Does adverse histopathological features like perineural invasion, depth of invasion and lymphovascular invasion warrant adjuvant treatment in early oral squamous cell carcinoma?

1 Department of Head and Neck Surgical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
2 Department of Surgical Oncology, Malabar Cancer Centre, Kannur, Kerala, India
3 Sri Nagendra ENT Head and Neck Cancer Centre, Nellore, Andhra Pradesh, India
4 Mazumdar Shaw Cancer Centre, Bengaluru, Karnataka, India

Date of Web Publication22-Jan-2018

Correspondence Address:
Dr. P. Sajith Babu Thavarool
Department of Surgical Oncology, Malabar Cancer Centre, Thalassery, Kannur - 670 103, Kerala
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jhnps.jhnps_41_17

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Background: We know from the existing literature that perineural invasion (PNI), lymphovascular invasion , and depth of invasion (DOI) are important prognostic factor that influence locoregional control in oral squamous cell carcinoma (OSCC). However, there is a lack of robust data in literature to recommend adjuvant treatment when one or more of these soft adverse factors are present in early stage OSCC. Patients and Methods: All treatment naïve, early OSCC who received definitive treatment in the form of surgery in the institute between March 2010 and December 2013. The clinical and demographic details, histopathological features, and follow-up details were collected. Factors influencing the recurrence-free survival (RFS), including the soft adverse factors, were analyzed. Results: Of the 332 OSCC patients, 70 patients satisfied the eligibility criteria and were included in the study. Majority of them were men (54%), with a mean age of 59 years. All of them underwent surgery and a few received adjuvant treatment (n = 9). PNI was seen in 9% (n = 6) of the cases, median DOI was 6 mm, lymphovascular emboli was seen in only one patients. PNI was the only soft adverse factor, which influenced the RFS on univariate and multivariate analysis. Conclusion: In the present study, PNI seems to be an important soft adverse factor, which influences the RFS. Adding adjuvant radiotherapy may benefit these patients. Prospective studies are needed to further evaluate the need for adjuvant treatment in presence of soft adverse factors, especially PNI, in early OSCC to prevent recurrence.

Keywords: Adjuvant treatment, early oral squamous cell carcinoma, perineural invasion

How to cite this article:
Thiagarajan S, Thavarool SB, Kadapa N, Nandini H. Does adverse histopathological features like perineural invasion, depth of invasion and lymphovascular invasion warrant adjuvant treatment in early oral squamous cell carcinoma?. J Head Neck Physicians Surg 2017;5:71-4

How to cite this URL:
Thiagarajan S, Thavarool SB, Kadapa N, Nandini H. Does adverse histopathological features like perineural invasion, depth of invasion and lymphovascular invasion warrant adjuvant treatment in early oral squamous cell carcinoma?. J Head Neck Physicians Surg [serial online] 2017 [cited 2023 May 29];5:71-4. Available from: https://www.jhnps.org/text.asp?2017/5/2/71/223765

  Introduction Top

Conventionally, early stage (Stage I/II) cancer has been treated using single modality. Surgery has been the preferred modality of treatment for early oral squamous cell carcinoma (OSCC). Combined modality of treatment, in the form of adding adjuvant radiotherapy (RT) or chemoradiotherapy, is usually considered for late stage cancer (stage III/IV).[1],[2] However, in certain instances, adjuvant RT is added for patients with early OSCC following surgery, for indications such as the presence of perineural invasion (PNI), lymphovascular emboli (LVE), depth of invasion (DOI), and poor differentiation squamous cell carcinoma (PDSCC) in isolation or in combination. Conflicting data are available in the literature regarding the need for adjuvant treatment in these groups of patients.[3] Although certain guidelines recommend postoperative RT (PORT), especially in the presence of PNI alone, its benefit in early stage disease is still not clear.[4]

  Patients and Methods Top

This study was initiated with an aim to assess the impact of soft adverse factors, such as PNI, LVE, and DOI ≥10 mm,[5] on the recurrence, in pT1–T2, pN0 OSCC. The question of whether the addition of adjuvant treatment in such a situation offers any benefit was also analyzed. Institutional review board approval was obtained for this retrospective study. All treatment naïve, pT1/T2, pN0 OSCC as per the 7th edition of the American Joint Commission on Cancer (AJCC) (all subsites) patients, who underwent surgery upfront at our institute between March 2010 and December 2013, belonging to all age groups were included in the study. The case numbers of these patients were retrieved from the institute's cancer registry. The demographic and clinical data were obtained from the case records (Medical Records Department). Details regarding the disease status at the last follow-up were retrieved from the medical records and/or by telephonic conversation.

Statistical analysis was performed using the SPSS 20, IBM New york. The primary endpoint of the study was recurrence (locoregional or distant metastasis). Since the follow-up was available for a median period of only 18 months, a recurrence-free survival (RFS) alone was calculated. RFS was defined as the period from the date of surgery to the date of diagnosing the first recurrence (local, regional, distant, or a combination of them). Dates of recurrence were collected from the medical records when they were diagnosed histopathologically. RFS was calculated using Kaplan–Meier method. The variables for univariate analysis were selected based on their clinical relevance as well as those previously described in the literature and was done using log-rank test. Subsequently, relevant variables were tested (multivariate) with cox-regression analysis using forward stepwise selection. A P ≤ 0.05 was considered statistically significant.

  Results Top

A total of 332 patients of OSCC were operated between March 2010 and December 2013. Of these, 70 cases satisfied the inclusion criteria and were included in the study. The demographic, clinical, and histopathological data are summarized in [Table 1]. The AJCC 7th edition was used for staging the disease. All patients underwent surgery as the primary modality treatment. Surgery was in the form of wide excision and a supraomohyoid neck dissection addressing levels I–III. This was followed by appropriate reconstruction for the oral cavity surgical defect.
Table 1: Clinical, demographic, histopathological, and follow-up details of the patients

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The median age was 60 years (range: 29–80 years), predominantly men (n = 38, 54%), with pT1 pN0 OSCC (n = 41, 58%). Majority (n = 56, 80%) of the patients had habits in the form of smoking/tobacco chewing, alcohol consumption, or a combination of them. The most common subsite involved within the oral cavity was buccal mucosa – gingivobuccal sulcus complex (n = 34, 48.5%), followed by the tongue and floor of mouth lesions (n = 33, 47%). OSCC associated with premalignant lesions, in the form of leukoplakia, submucosal fibrosis or erythroplakia, were seen in 17 patients (24%). Majority of the patients had a well-differentiated squamous-cell carcinoma (n = 54, 77%). The DOI was measured in all the cases and the median depth was 0.6 cm (range: 0.1–2 cm). PNI was seen in six patients (9%). PNI was most commonly seen in lesions arising from the tongue (n = 4), but this association was not statistically significant. PNI was also commonly seen in pT2 (P = 0.04). Lymphovascular invasion (LVI) was seen in only one patient. Margins were tumor free in all the cases. Nine out of the seventy patients (13%) patients received adjuvant RT as per institutional protocol for certain soft factors (PNI, DOI), the exact details of which could not be retrieved from the medical records. The PORT was given using conventional beam, standard fractionation. A median follow-up of 18 months was available for the patients. Recurrences were seen in eight patients (10%), of which there were 6 local and 2 regional recurrences. None had distant metastasis. Patients with pT2 tumor had recurrences more often than those with pT1 tumors. The RFS was 26 months in the presence of PNI and 60 months in the absence of PNI. This association was statistically significant (P = 0.027) [Figure 1] and [Table 2]. Furthermore, the influence of adjuvant treatment in the presence of soft factors on RFS analyzed. This did not show any statistical significance.
Figure 1: Recurrence free survival in patients with and without perineural invasion

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Table 2: Factors influencing recurrence free survival

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  Discussion Top

The prognosis of early OSCC is generally considered to be good. The 5-year overall survival of Stage I–II disease is quoted at 80% or above.[6] The locoregional recurrence in these patients is nearly 30%–35%.[7] Soft adverse factors such as PNI, LVI, grade of tumor differentiation (PDSCC), and DOI have been considered to play an important role in the recurrence of early OSCC.

The presence of malignant cells within the lymphatic vessels is considered to be LVI. The incidence of LVI has been reported between 8% and 28%.[8],[9] Presence of LVI is associated with nodal metastasis and locoregional recurrence.[10],[11] In our series, there was only one patient with LVI. There was no statistical association of its presence on recurrence.

Liao et al. in their series of 1279 patients of T1–T2, N0 OSCC treated by surgery, noticed that DOI >4 mm and PDSCC was associated with poor survival and hence, they suggested that addition of adjuvant RT may be of benefit in these subset of patients.[12] Ebrahimi et al., in their retrospective multicentric study emphasized the need to include the DOI into the AJCC staging system based on its influence on the disease-specific survival.[13] In our series, DOI did not show any significant statistical association with RFS. Furthermore, none of the patients, in our series, had PDSCC. Hence, no correlation between PDSCC and RFS could be made.

In our series, PNI was the only soft adverse factor, which influenced RFS [Figure 1]. PNI was first described in 1963 by Ballantyne et al.[14] Presence of PNI is associated with local recurrence and higher incidence of nodal metastasis.[15] Lydiatt et al., described the poor impact of PNI on early stage OSCC.[16] The incidence of PNI in head and neck squamous cell carcinoma (HNSCC) is between 3% and 52%.[15] This variation in the incidences is due to the lack of a standardized definition and diagnostic criteria's for PNI in literature. A widely accepted definition of PNI was described by Liebig et al.[17] Accordingly PNI was considered in the presence of clusters of tumor cells located within the peripheral nerve sheath infiltrating into any of the three layers, namely, the epineurium, perineurium, or the endoneurium or when the tumor cells encircle at least 33% of the circumference of the nerve. Presence of PNI is considered as a poor prognostic factor in HNSCC as it is associated with loco-regional recurrence and poor survival.[18],[19] Aivazian et al. demonstrated that the presences of more than one foci of PNI (multifocal) and PNI of nerves >1 mm was associated with increased local failures and a reduced disease-specific survival.[20] Adjuvant RT has been suggested for patients with PNI to reduce recurrence and improve survival. The premise with which adjuvant RT is recommended in the presence of PNI would be that it may reduce the recurrence by disrupting the possible paracrine interactions between the nerve and the tumor cells.[21] A systematic review of 13 retrospective studies concluded that adjuvant RT following surgery for early OSCC with PNI as the only indication adds no additional benefit.[22] The question of the need to add adjuvant RT in the presence of PNI, LVI, DOI, and PDSCC, still remains unanswered. A randomized controlled trial may give the most definite answer and if it shows any survival benefit then the toxicity of adjuvant RT in these patients may be justifiable.

  Conclusion Top

Despite the limitations of our study, in terms of its retrospective nature and small numbers, it again raises a very important question regarding the need for adding adjuvant RT in the presence of soft adverse factors, especially PNI, in early OSCC. The answer to this question can be sought in a randomized controlled trial. Till then, the treating physicians will have to take a cautious decision of adding adjuvant RT weighing the risk versus benefit. The patients will have to be informed regarding the same and their wishes and concerns will have to be factored into the decision-making.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Bernier J, Cooper JS, Pajak TF, van Glabbeke M, Bourhis J, Forastiere A, et al. Defining risk levels in locally advanced head and neck cancers: A comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501). Head Neck 2005;27:843-50.  Back to cited text no. 1
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Subramaniam N, Balasubramanian D, Murthy S, Limbachiya S, Thankappan K, Iyer S, et al. Adverse pathologic features in early oral squamous cell carcinoma and the role of postoperative radiotherapy-a review. Oral Surg Oral Med Oral Pathol Oral Radiol 2017;124:24-31.  Back to cited text no. 3
National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology. Available from: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. [Last accessed on 2017 May 08].  Back to cited text no. 4
Thiagarajan S, Nair S, Nair D, Chaturvedi P, Kane SV, Agarwal JP, et al. Predictors of prognosis for squamous cell carcinoma of oral tongue. J Surg Oncol 2014;109:639-44.  Back to cited text no. 5
Shim SJ, Cha J, Koom WS, Kim GE, Lee CG, Choi EC, et al. Clinical outcomes for T1-2N0-1 oral tongue cancer patients underwent surgery with and without postoperative radiotherapy. Radiat Oncol 2010;5:43.  Back to cited text no. 6
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Chen TC, Wang CP, Ko JY, Yang TL, Hsu CW, Yeh KA, et al. The impact of perineural invasion and/or lymphovascular invasion on the survival of early-stage oral squamous cell carcinoma patients. Ann Surg Oncol 2013;20:2388-95.  Back to cited text no. 8
Jerjes W, Upile T, Petrie A, Riskalla A, Hamdoon Z, Vourvachis M, et al. Clinicopathological parameters, recurrence, locoregional and distant metastasis in 115 T1-T2 oral squamous cell carcinoma patients. Head Neck Oncol 2010;2:9.  Back to cited text no. 9
Close LG, Brown PM, Vuitch MF, Reisch J, Schaefer SD. Microvascular invasion and survival in cancer of the oral cavity and oropharynx. Arch Otolaryngol Head Neck Surg 1989;115:1304-9.  Back to cited text no. 10
Olsen KD, Caruso M, Foote RL, Stanley RJ, Lewis JE, Buskirk SJ, et al. Primary head and neck cancer. Histopathologic predictors of recurrence after neck dissection in patients with lymph node involvement. Arch Otolaryngol Head Neck Surg 1994;120:1370-4.  Back to cited text no. 11
Liao CT, Lin CY, Fan KH, Wang HM, Ng SH, Lee LY, et al. Identification of a high-risk group among patients with oral cavity squamous cell carcinoma and pT1-2N0 disease. Int J Radiat Oncol Biol Phys 2012;82:284-90.  Back to cited text no. 12
International Consortium for Outcome Research (ICOR) in Head and Neck Cancer, Ebrahimi A, Gil Z, Amit M, Yen TC, Liao CT, et al. Primary tumor staging for oral cancer and a proposed modification incorporating depth of invasion: An international multicenter retrospective study. JAMA Otolaryngol Head Neck Surg 2014;140:1138-48.  Back to cited text no. 13
Ballantyne AJ, Mccarten AB, Ibanez ML. The extension of cancer of the head and neck through peripheral nerves. Am J Surg 1963;106:651-67.  Back to cited text no. 14
Fagan JJ, Collins B, Barnes L, D'Amico F, Myers EN, Johnson JT, et al. Perineural invasion in squamous cell carcinoma of the head and neck. Arch Otolaryngol Head Neck Surg 1998;124:637-40.  Back to cited text no. 15
Lydiatt DD, Robbins KT, Byers RM, Wolf PF. Treatment of stage I and II oral tongue cancer. Head Neck 1993;15:308-12.  Back to cited text no. 16
Liebig C, Ayala G, Wilks J, Verstovsek G, Liu H, Agarwal N, et al. Perineural invasion is an independent predictor of outcome in colorectal cancer. J Clin Oncol 2009;27:5131-7.  Back to cited text no. 17
Brown B, Barnes L, Mazariegos J, Taylor F, Johnson J, Wagner RL, et al. Prognostic factors in mobile tongue and floor of mouth carcinoma. Cancer 1989;64:1195-202.  Back to cited text no. 18
Conte CC, Ergin MT, Ricci A Jr., Deckers PJ. Clinical and pathologic prognostic variables in oropharyngeal squamous cell carcinoma. Am J Surg 1989;157:582-4.  Back to cited text no. 19
Aivazian K, Ebrahimi A, Low TH, Gao K, Clifford A, Shannon K, et al. Perineural invasion in oral squamous cell carcinoma: Quantitative subcategorisation of perineural invasion and prognostication. J Surg Oncol 2015;111:352-8.  Back to cited text no. 20
Bakst RL, Lee N, He S, Chernichenko N, Chen CH, Linkov G, et al. Radiation impairs perineural invasion by modulating the nerve microenvironment. PLoS One 2012;7:e39925.  Back to cited text no. 21
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  [Figure 1]

  [Table 1], [Table 2]

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