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 Table of Contents  
EDITORIAL
Year : 2022  |  Volume : 10  |  Issue : 1  |  Page : 1-5

Depth of invasion in oral cavity squamous cell carcinomas: A radiologist's perspective


Clinical Director CT/MR, Division Chief - Body and Head and Neck Imaging, Department of Radiology, Sir. H. N. Reliance Hospital and Research Centre, Mumbai, Maharashtra, India

Date of Submission22-May-2022
Date of Acceptance22-May-2022
Date of Web Publication23-Jun-2022

Correspondence Address:
Karthik Ganesan
Clinical Director CT/MR, Division Chief - Body and Head and Neck Imaging, Department of Radiology, Sir. H. N. Reliance Hospital and Research Centre, Raja Ram Mohan Roy Road, Prarthana Samaj, Girgaum, Mumbai - 400 004, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jhnps.jhnps_31_22

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How to cite this article:
Ganesan K. Depth of invasion in oral cavity squamous cell carcinomas: A radiologist's perspective. J Head Neck Physicians Surg 2022;10:1-5

How to cite this URL:
Ganesan K. Depth of invasion in oral cavity squamous cell carcinomas: A radiologist's perspective. J Head Neck Physicians Surg [serial online] 2022 [cited 2022 Jun 27];10:1-5. Available from: https://www.jhnps.org/text.asp?2022/10/1/1/347988



Oral cavity cancers are the third-most common form of cancer in India, with an increasing trend. Resectable oral squamous cell carcinoma (SCCa) is primarily treated with surgery with the addition of postoperative radiotherapy (PORT) with or without chemotherapy in the presence of adverse pathological features. Cervical lymph nodal metastasis is an important negative prognostic factor of oral cavity cancer. In patients with oral cavity SCCa without clinically detectable lymph nodal metastases (N0 neck), the treatment of the neck is principally dependent on the potential risk of developing occult nodal metastases. If this potential risk is low, observation of the neck is the recommended line of management. However, if the potential risk is high, an elective neck dissection (END) should be performed. Ideally, the management of patients with cT1N0 SCCa must strike a balance between possible surgical morbidity and optimal oncological outcomes. To prevent unnecessary ENDs, reliable preoperative biomarkers and predictors need to be developed, to accurately identify N0 necks and reduce the number of unnecessary ENDs.

Depth of invasion (DOI) and tumor thickness are two such important predictors of lymph nodal metastases.[1] What is the difference between DOI and Tumor thickness? DOI is defined as the distance from the reconstructed mucosal surface or the basement membrane to the deepest level of invasion [Figure 1]a, [Figure 1]b, [Figure 1]c. Tumor thickness is defined as the distance between the top of the tumor to the deepest level of invasion. The two terminologies are not the same or interchangeable, and, it is believed by some authors that tumor thickness underestimates the aggressive potential of the tumor.[2],[3] Tumor thickness may be larger than DOI in a proliferative or exophytic tumor, and, lower than DOI in an ulcerative or endophytic tumor [Figure 1]d, [Figure 1]e, [Figure 1]f.
Figure 1: (a and d) DOI in a flat carcinoma is similar to the tumor thickness, (b and e) DOI in an exophytic carcinoma is lesser than the tumor thickness, (c and f) DOI in an ulcerative carcinoma is more than the tumor thickness. DOI: Depth of Invasion

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Periodic reassessment of staging systems is an absolutely vital tool to better define the natural history of disease, incorporate emerging data and trends, identify newer disease variants and reflect on therapeutic impact. DOI is a well-established independent predictor of recurrence and survival in oral SCCa,[4],[5],[6] and, the 8th Edition of the American Joint Committee on Cancer's (AJCC) Cancer Staging Manual was modified by incorporating histopathological DOI cutoff values in the T categorization of oral cavity cancer,[7] with the respective DOI cutoff values of ≤5 mm, >5 mm but ≤10 mm, and >10 mm being the notable additions. DOI was selected over tumor thickness to avoid overstaging of more indolent cancers (verrucous lesions), which present as thick exophytic or superficial cancers with minimal invasion. DOI directly correlates with other adverse pathological features such as perineural invasion,[8] tumor differentiation, disease stage, presence of an involved or close surgical margin, extracapsular nodal spread,[6] invasion of the cortical bone and of blood and/or lymphatic structures. It has also been noted that DOI may represent an independent indicator for PORT in patients with small (≤4 cm) oral SCCas.[9],[10] Improved predictive capacity of DOI was demonstrated by Matos et al., with retrospective evaluation of nearly 300 patients using the new pT category of the 8th Edition, which showed that 22.9% of patients were upstaged using DOI, and, these patients did have higher recurrence rate and a lower disease-specific survival compared with rates seen with the use of the 7th Edition TNM criteria.[11] However, an important question which needs to be posed is whether in patients with small oral SCCas, would an isolated trend of increasing DOI in the absence of other adverse pathological features predict locoregional failure and prognostic deterioration. This is still questionable and has not been widely adopted into clinical practice.

The current standard of care for determining DOI is a specimen-driven intraoperative assessment of the resection margins as recommended by the AJCC 8th Edition.[7] Based on this technique, DOI would be determined only a few days after initial surgery based on a final pathological report, following which, an END may or may not have to be performed. Intraoperative assessment of DOI is an option, but has certain limitations, especially with respect to logistical issues including inefficient use of resources and higher costs, and, may not be possible where-in these facilities do not exist. Alternatively, DOI obtained from diagnostic biopsies is not accurate as the tissue yield is highly variable and is often not representative due to sampling error. Based on current data, DOI usually cannot be obtained either by frozen section or a biopsy, and therefore, perioperative DOI may have a limited role in benefiting decision-making regarding neck treatment.

Alternatively, preoperative noninvasive assessment of DOI may be ascertained by either clinical examination or imaging techniques. Clinical determination of DOI may be challenging at times, and, is significantly limited by one's ability to determine an accurate measure of DOI based on only palpation. The last two decades have borne witness to the rapid evolution of cross-sectional imaging techniques such as computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography-CT (PET-CT), and PET-MRI, resulting in a paradigm shift in the noninvasive assessment of oral cavity cancers. These noninvasive imaging techniques have enhanced the radiologists' ability to use a combination of structural and functional tools to identify key biomarkers which allow precise detection and prediction of biological aggressiveness and adverse prognostic factors such as perineural spread, vascular and bone involvement, nodal involvement, and extracapsular spread, and, DOI.

Of all these aforementioned noninvasive imaging techniques at the disposal of the radiologist, MRI is the most widely acceptable tool used to preoperatively assess DOI in oral SCCas due to its excellent soft-tissue resolution and its inherent multiparametric capabilities. I would like to stress on “multiparametric” which can be simply summarized as a methodology to obtain a combination of 2-D and 3-D structural (T2-weighted [T2-w] and T1-weighted [T1-w ]sequences), and, functional (diffusion weighted [DW]-Apparent Diffusion Coefficient [ADC] maps, T1-w dynamic contrast-enhanced [DCE] sequences) information of a particular anatomical structure. MRI-derived DOIs have proven to be more sensitive and specific vis-a-vis clinically derived DOIs, and, seem to correlate better with histopathologically derived DOIs. An important caveat is that MRI-derived DOI's obtained from different structural and functional sequences are variable. Although many centers across the world have developed their own MR interpretation techniques, there is no standardization of these sequences. Further, though accurate preoperative radiological measurements of DOI may aid the oncosurgeon to optimize and individualize surgical planning, no specific radiological criteria have been established for determining radiological DOI. Over the last few years, the measurement of DOI in oral SCCas has been one of the most challenging and intriguing issues I have encountered in my tenure as a subspecialty radiologist. The problem of accurately identifying radiological DOI has not got easier, currently represents an “abundance syndrome,” and, has provided contradictory views on numerous technical issues ranging from scanner strength, slice thickness, the utility of structural versus functional tools, and, also on how and where to measure the DOI. Simply put, there is a lack of standardization of the available radiological tools.

Review of the literature shows that MRI-derived DOIs were significantly larger than histopathological derived DOIs, which led to the overstaging of small Oral SCCas. As of now, no consensus has been reached to mathematically depict the difference between the two derived DOIs. However, two contributory factors have been proposed for the larger MRI-derived DOI. The first is the presence of peritumoral edema and reactive inflammation which contributes to the overestimation of MRI-derived DOI. The second is the shrinkage of tumor during formalin fixation, the quantum of which is reported to range between 14.9% and 23.9% in oral cavity tissues.[12] It is, therefore, pertinent to review the individual MR sequences and the potential challenges we encounter when estimating MRI-derived DOIs.


  T2-weighted and T1-weighted sequence Top


These two sequences form the basis of ultrastructural imaging on MR, and, provide the radiologist key anatomical landmarks to co-localize, delineate and map the tumor. Peritumoral edema and reactive inflammation are often seen along the edges of the tumor, at its interface with normal tissue, often blurring the transition zone [Figure 2]a, [Figure 2]b, [Figure 2]c, [Figure 2]d. This can be differentiated most of the times on T2-w images; however, this distinction may be blurry at times resulting in a wide zone of transition, which leads to larger radiologically derived DOIs. At this time, it is also important to note that some forms of chronic inflammation may be indistinguishable from certain tumors, both radiologically and clinically,[13] which further aggravates the potential for overestimation of DOI on structural sequences. T1-w sequences allow the radiologist to precisely identify fat planes, a key determinant in the assessment of tumoral invasion and regional spread. However, both entities may look identical on the unenhanced T1-w sequence. At present, the jury is out on this point, with some authors preferring the T2-w sequence over the T1-w sequence,[14],[15] while others share a contrarian view. In routine clinical practice, the problem has not get any easier, wherein structural sequences slightly underperform as compared with the functional sequences in predicting DOI.
Figure 2: Axial T2-w (a) image shows an intermediate signal intensity (asterix) lesion with infiltrative edges along the mid and posterior third of the right lateral border of the oral tongue (red arrows). Along its medial leading edge, note the presence of a thin hyperintense rim (yellow arrows) which extends into the adjacent normal tongue substance representing peritumoral inflammation and edema. On the axial T1-w (b) and DW (c) images, the distinction between the lesion and peritumoral inflammation is not conspicuous. ADC (d) image enhances the conspicuity as the lesion reveals restricted diffusivity (white arrows), whereas, the peritumoral inflammation reveals facilitated diffusivity (black arrows). ADC: Apparent diffusion coefficient. DW: Diffusion-weighted, T2-w: T2-weighted, T1-w: T1-weighted

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  Diffusion Weighted and Apparent Diffusion Coefficient MAPS Top


DW imaging is a functional technique which is based on the random movement of water molecules in a region of interest. Theoretically, tumors restrict random motion, whereas inflammation would be expected to facilitate this form of motion. The assessment is performed using different b-values by sequentially changing the gradient amplitude. Higher b-values more precisely represent true impediment to the motion of water molecules, though multiple other factors also contribute to restricted motion including the tumor ultrastructure, cellularity, extracelullar space, mitosis, nuclear-cytoplasm ratio, and perfusion. ADC maps are functional parametric maps that are automatically or manually generated, and, represent the magnitude of diffusivity within the tumor and its surrounding tissues. Most of the clinically significant oral SCCas appear hypointense on the ADC maps, as compared to inflamed tissue which would appear as hyperintense on these maps [Figure 3]c and [Figure 3]d. DW-ADC maps represent a low-cost functional alternative; however, this sequence intrinsically has a lower signal-to-noise (SNR) ratio and is severely affected by susceptibility artifacts which emanate from dental implants or air within the paranasal sinuses. Tang et al. showed a 4.1% failure rate exists with DW sequence even with the use of improved echo-planar imaging technology, dedicated coils, and dedicated sequence optimization.[16]
Figure 3: Axial T2-w (a), T1-w (b), DW (c), ADC (d), and T1-w DCE (e) images at the same level reveal a hyperperfused lesion with infiltrative edges along the mid and posterior third of the right lateral border of the oral tongue. Note the differences in the DOI measure in each sequence. Though DW (c) and T1-w DCE (e) provide the maximum contrast-to-noise ratio enabling the radiologist to differentiate the pathology from the native normal tissue, T1-w DCE provides the best depiction of the transition zone allowing for a more precise measurement of DOI. ADC: Apparent Diffusion Coefficient, DOI: Depth of Invasion, DCE: Dynamic contrast-enhanced, DW: Diffusion-weighted, T2-w: T2-weighted, T1-w: T1-weighted

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  T1-W Dynamic Contrast-Enhanced Sequence Top


This is a functional sequence which attempts to assess and quantify tumor angiogenesis and microvascular density, and, is based on the principle that the signal intensity of a tumor rises faster than that of inflammation or normal tissue, with a nearly linear relationship between contrast concentration and signal intensity on DCE sequence [Figure 3]a, [Figure 3]b, [Figure 3]c, [Figure 3]d, [Figure 3]e. Tumors are expected to reveal an early wash-in and rapid wash-out; however, this relationship is not linear, and, is fraught with very contradictory opinions as tumors are often heterogeneous and may give false-positive results in the presence of concomitant inflammation. Technically, it may be possible to avoid the error in DOI measurement related to the peritumoral edema and reactive inflammation by performing measurements during the early postcontrast phases <60 s.[17],[18] Baba et al.[19] reported that the measurement of contrast-enhanced T1w-derived DOI was slightly more accurate than that of T2-w derived DOI for a better correlation with histopathological DOI. Tang et al.[16] showed that e-THRIVE (T1-w DCE)-derived DOI had the highest correlation with pathological DOI. The AUC values of MR-derived DOI distinguishing T1 stage from T2 stage and distinguishing T2 stage from T3 stage were 0.969 and 0.974, respectively, and, the T staging criteria of MRI-derived DOI were 6.2 mm and 11.4 mm, with a staging accuracy of 86.9% compared to pathological DOI criteria of 5 mm and 10 mm.[16] Improved accuracy of T1-w DCE vis-a-vis DW or structural imaging techniques is partly attributable to the 1-mm slice thickness; however, there is a need to strike a fine balance between SNR, contrast-to-noise, spatial resolution, and image quality, to enhance the quantum of information generated.

In summary, MRI-derived DOI strongly correlates with pathological DOI vis-a-vis clinical DOI, and, represents the current gold standard of imaging. In radiologically inert or undetectable early T1 stage lesions, it is safe to predict that pathological DOI is often smaller than 4 mm; alternatively, if MR demonstrates invasion of the hyoglossus or styloglossus muscles, pathological DOI was always larger than 4 mm. This correlation has a significant impact as National Comprehensive Cancer Network recommends END in cases with DOI >4 mm. It is important to note that patient management has become more evidence based and individualized, with a risk-averse and conservative approach, what some may call precision medicine. Subspecialized radiologists have to adapt to and adopt these changing trends by incorporating MRI derived structural and functional data in their reports. However, for a developing nation with a high prevalence of oral SCCa such as ours, the choice of a particular investigation is keenly wedged between the availability of a resource and the test costs, and, not just its positive predictive value. To improve MR utilization, radiologists may need to strategically develop and create abbreviated MR protocols with ultrafast sequences to reduce costs and scanning times, and, minimize the usage of contrast, without significantly compromising on diagnostic accuracy. To strike a balance is the key, but for now, there does exist a conundrum!.

Acknowledgments

  1. Dr. Toshi Mishra, Consultant Pathologist at Sir. H. N. Reliance Foundation Hospital and Research Center [for the HP images in [Figure 1]]
  2. Isha Karthik Ganesan [for the schematic in [Figure 1]].


Disclosure

This material has never been published and is not currently under evaluation in any other peer-reviewed publication.

Ethical approval

Not applicable as this is an editorial article with no patients involved.

Informed consent

Not applicable as this is an editorial article with no patients involved.



 
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