Volumetric and histologic responses to radiotherapy or radiochemotherapy of metastatic cervical lymph nodes of oral squamous cell carcinoma

J Oral Maxillofac Surg 61:904-908, 2003

Volumetric and Histologic Responses to Radiotherapy or Radiochemotherapy of Metastatic Cervical Lymph Nodes of Oral Squamous Cell Carcinoma Hiroshi Yusa, DDS, PhD,* Hiroshi Yoshida, DDS, PhD,† Masayuki Noguchi, MD, PhD,‡ and Kiyoshi Ohara, MD, PhD§ Purpose:

The relationship between the volumetric and histologic responses of metastatic cervical nodes to radiotherapy or chemotherapy in the oral and maxillofacial region is unclear. In this study, we evaluated the correlation between the initial volume and regression rate of metastatic nodes with their histologic response to preoperative radiotherapy or radiochemotherapy. Patients and Methods: The volume of 54 metastatic nodes in 32 patients with squamous cell carcinoma in the oral and maxillofacial region was measured by ultrasonography before and after preoperative therapy, and the rate of the volume change was calculated. All surgically removed nodes were histologically classified as poor, good, or complete response according to their histologic features. Results: There was no significant difference in initial volume among the 3 response groups. Good and complete response nodes showed a significant increase in regression rate compared with poor response nodes. All 11 nodes showing no regression were poor response nodes, and 7 with a regression rate of more than 90% were good or complete response nodes. The remaining 36 nodes (regression rate, 0% to 90%) represented all 3 types of histologic response. Of these, 7 of 9 complete response nodes were found in 5 patients who received combination chemotherapy consisting of 5-fluorouracil, leucovorin, and cisplatin. Conclusions: The initial nodal volume before therapy is not a good indicator for the response to radiotherapy and/or chemotherapy. A regression rate of more than 90% may be a useful predictor of the effectiveness of preoperative treatments, but it was difficult to define the cutoff values in regression rates for differentiating types of histologic response. © 2003 American Association of Oral and Maxillofacial Surgeons J Oral Maxillofac Surg 61:904-908, 2003 In patients with primary squamous cell carcinoma in the oral and maxillofacial region, metastasis to the

cervical lymph nodes is a very important factor in determining the prognosis of the patient and selecting the treatment strategy. Neck dissection is commonly performed to eradicate cervical lymph node metastases in head and neck cancer, and radiotherapy and/or chemotherapy is given before surgery as adjuvant therapy to control the progression of the metastases. However, preoperative radiotherapy, chemotherapy, or a combination of these has been recently found to be effective in preoperative treatment of cervical lymph node metastases.1,2 The response of metastatic nodes to the preoperative therapy is assessed by the change in nodal size, which can be reasonably estimated from clinical findings or diagnostic images.3-5 Some reports have indicated that the histologic response of metastatic nodes to radiotherapy and/or chemotherapy is strongly associated with the initial nodal diameter,6 nodal volume,4,5 or N classification7 before the treatment, whereas others have reported

*Research Associate, Department of Oral and Maxillofacial Surgery, Institute of Clinical Medicine, University of Tsukuba, Tsukuba. †Professor, Department of Oral and Maxillofacial Surgery, Institute of Clinical Medicine, University of Tsukuba, Tsukuba. ‡Professor, Department of Pathology, Institute of Basic Medical Science, University of Tsukuba; Tsukuba. §Assistant Professor, Department of Radiology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba. Address correspondence and reprint requests to Dr Yusa: Department of Oral and Maxillofacial Surgery, Institute of Clinical Medicine, University of Tsukuba. 1-1-1 Tennoudai, Tsukuba-shi, Ibaraki-ken305-8575; e-mail: [email protected] © 2003 American Association of Oral and Maxillofacial Surgeons

0278-2391/03/6108-0077$30.00/0 doi:10.1016/S0278-2391(03)00292-1

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difficulty in assessing the effect of the therapy based on these variables.3,8 Consequently, the relationship between nodal size or volume and the histologic response is controversial. A few reports4,5 have indicated that a reduction in the volume of the nodes during or after treatment reflects the histologic response, but a correlation between volumetric change and histologic effect is still uncertain. Cervical lymph node metastasis is commonly diagnosed by palpation, computed tomography (CT), magnetic resonance imaging (MRI), or ultrasonography (US). Of these, US has been widely accepted to evaluate the cervical lymph node metastases of head and neck cancer patients, because it has the advantages over CT and MRI of low cost and easy reproducibility. Furthermore, US is useful to evaluate small nodes, and it measures lymph nodes multidirectionally.8-11 These properties make US a good method for obtaining accurate determinations of nodal volume, especially for lymph nodes that have been considerably reduced after preoperative therapy. In this retrospective study, the initial volume and the volume regression rate of metastatic cervical nodes were measured 3-dimensionally by US in patients with primary squamous cell carcinoma in the oral and maxillofacial region, and correlations with the corresponding histologic response to preoperative radiotherapy or radiochemotherapy were evaluated after future ablative surgery and neck dissection.

Materials and Methods Two hundred ninety-two patients with cancer in the oral and maxillofacial region underwent sonographic examination in the Department of Oral and Maxillofacial Surgery, Tsukuba University Hospital, from September 1990 to August 2000. Of these patients, 32 who received preoperative radiotherapy or radiochemotherapy for cervical lymph node metastasis and underwent neck dissection were participants in this study. The patients consisted of 22 men and 10 women ranging in age from 39 to 81 years, with a mean age of 61 years, and all of the tumors were diagnosed as squamous cell carcinoma by means of biopsy specimens. The primary tumor sites were the tongue (n ⫽ 17), the floor of the mouth (n ⫽ 5), the alveolus and gingiva (n ⫽ 4), the buccal mucosa (n ⫽ 3), oropharynx (n ⫽ 2), and the maxillary sinus (n ⫽ 1). No patients had distant metastases or had been previously treated. The total dosage of preoperative radiation to the neck ranged from 44.4 to 70.0 Gy, with a median dose of 50.4 Gy. Twenty-four of 32 patients received irradiation in combination with chemotherapy under the following regimens: cisplatin (CDDP) plus 5-fluorouracil (5-FU) plus leucovorin calcium (LV) for 13 patients; tegafur uracil (UFT) for 4

905 patients; CDDP plus peplomycin sulfate (PEP) plus pirarubicin (THP), and CDDP plus 5-FU for 2 patients each; and CDDP plus 5-FU plus THP, CDDP plus PEP, and 5-FU plus PEP for 1 patient each. Eight patients received no chemotherapy. The necks of the patients were examined by US before radiotherapy or radiochemotherapy, and metastatic lymph nodes were diagnosed using an equation criterion based on a logistic regression analysis, as previously described.10,11 The nodal volume of metastatic nodes was calculated from 3 dimensions as follows: v ⫽ 4/3 ⫻ ␲ ⫻ x/2 ⫻ y/2 ⫻ z/2 where v is the volume of each lymph node, x represents the largest diameter of each node, y represents the largest diameter perpendicular to x in the axial plane, and z represents the largest diameter in the plane perpendicular to the plane formed by x and y. A metastatic nodal map was made for each patient. Two weeks after the completion of preoperative radiotherapy or radiochemotherapy, the volume of the same metastatic nodes was measured again with US. The volume regression rate was derived from the following equation: VRR ⫽ (1 ⫺ v2/v1) ⫻ 100% where VRR is the volume regression rate, v1 represents the volume of the node before therapy, and v2 represents the volume of the node after the therapy. In this equation, 100% corresponded to complete resolution of the lymph node, 0% to no change, and negative percent values to progression. Neck dissection was performed within 4 weeks after preoperative therapy. All lymph nodes in the neck dissection specimens were carefully examined to determine whether they were the same ones that were detected sonographically with reference to size, anatomic location, and relationship to adjacent structures on the nodal maps, and only the nodes that correlated with the ultrasonograms served as material for this study. The histopathologic response of the nodes to the preoperative treatments was categorized according to the histologic grading system established by Shimosato et al12: grade 1, tumor structures were not obliterated; grade 2, obliteration of tumor structures was mild and viable tumor cells were frequently observed; grade 3a, obliteration of tumor structures was severe and viable tumor cells were few; grade 3b, viable tumor cells were rare; and grade 4, coagulation necrosis of tumor cells was present and granulation tissue with or without small foci of necrosis remained. To simplify the correlation of histologic response with nodal volume or volume regression rate, the histologic responses were classified as “poor” for grade 1 and grade 2, “good” for grade 3a and grade 3b, and “complete” for grade 4.

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VOLUMETRIC AND HISTOLOGIC RESPONSES OF LYMPH NODES

Table 1. CORRELATION BETWEEN INITIAL NODAL VOLUME BEFORE THERAPY AND HISTOLOGIC RESPONSE

Histologic Response v1 (cm3)

Poor (n ⫽ 33)

Good (n ⫽ 8)

Complete (n ⫽ 13)

⬎0 to ⱕ1 ⬎1 to ⱕ10 ⬎10

14 15 4

2 4 2

3 7 3

Abbreviation: v1, volume of node before radiotherapy or radiochemotherapy.

Correlations of the initial volume and the volume regression rate with the histologic response were statistically analyzed by a Mann-Whitney U test. Differences with a P ⬍ .05 were considered statistically significant.

All 11 nodes with a negative volume regression rate were included in the poor response group. Seven nodes with a volume regression rate of greater than 90% were contained in the good or complete response group. Of 36 nodes with a regression rate within the range from 0% to 90%, 22 were diagnosed as poor, 5 as good, and 9 as compete response (Table 2). Different cutoff values in the regression rate were assigned in an attempt to differentiate the 3 types of histologic response for metastatic nodes, but clear cutoff values that were associated with specific responses could not be established. There was no significant correlation of the irradiation dose with the histologic response groups (Table 3). However, comparison of the chemotherapy regimen and the histologic response showed that the frequency of complete response increased significantly in the patients who received the chemotherapy

Results Of the cervical lymph nodes that were sonographically diagnosed as metastatic before radiotherapy or radiochemotherapy, 54 nodes could be reevaluated with US after the therapy. These 54 lymph nodes showed correlation between the nodal map and the neck dissection specimen and were histologically diagnosed as metastatic. All lymph nodes were incorporated in the drainage regions of the primary tumors, and the anatomic locations were as follows: 28 nodes at level 1, 21 at level 2, 3 at level 3, and 2 at level 4. The number of metastatic nodes in each patient was 1 in 19 patients, 2 in 6, 3 in 5, and 4 in 2. The histologic response to preoperative therapy was judged as grade 1 in 3 nodes, grade 2a in 30, grade 2b in 3, grade 3 in 5, and grade 4 in 13, so that 33 nodes were assigned as poor, 8 as good, and 13 as complete. The initial nodal volume before preoperative therapy ranged from 0.20 to 41.82 cm3 with a median of 1.10 cm3 for the poor response group, from 0.72 to 94.25 cm3 with a median of 1.41 cm3 for the good response group, and from 0.41 to 31.68 cm3 with a median of 2.24 cm3 for the complete response group. There was no significant correlation between the initial nodal volume and the type of histologic response (Table 1). The regression rate of the nodal volume after the completion of preoperative therapy ranged from ⫺181.9% to 87.7% with a median of 26.7% for the poor response group, from 9.2% to 96.3% with a median of 65.7% for the good response group, and from 7.8% to 99.9% with a median of 80.2% for the complete response group. The regression rate in the good and complete response groups was significantly higher than that of the poor response group (Fig 1).

FIGURE 1. The relationship between histologic response and volume regression rate for 54 metastatic lymph nodes. The abscissa and ordinate show the histologic response and the regression rate, respectively. Good and complete response nodes showed a significant reduction in volume compared with poor response nodes, using the Mann-Whitney U test.

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Table 2. CORRELATION BETWEEN REGRESSION RATE AFTER THERAPY AND HISTOLOGIC RESPONSE

Table 4. RELATIONSHIP BETWEEN CHEMOTHERAPY AND HISTOLOGIC RESPONSE

Histologic Response

Histologic Response VRR (%)

Poor (n ⫽ 33)

Good (n ⫽ 8)

Complete (n ⫽ 13)

Regimen of Chemotherapy

ⱕ0 ⬎0 to ⱕ50 ⬎50 to ⱕ80 ⬎80 to ⱕ90 ⬎90

11 13 6 3 0

0 4 0 1 3

0 3 3 3 4

FLP chemotherapy Others Radiotherapy alone

Poor (n ⫽ 33)

Good (n ⫽ 8)

Complete (n ⫽ 13)

4 16 13

4 3 1

9 3 1

*

†

‡

*P ⬍ .01. †P ⬍ .001. ‡Not significant.

Abbreviation: VRR, volume regression rate.

combination of 5-FU, leucovorin, and CDDP (FLP chemotherapy) (Table 4).

Discussion The present study sought to compare the initial volume and regression rate of metastatic nodes with their histologic response following preoperative radiotherapy or radiochemotherapy. In previous studies of this type, the nodal diameter was measured using relatively crude methods, and the nodal volume was calculated as the cube of the average of the maximal and minimal diameters, with the assumption that the node is spherical in shape.9 However, this measurement does not correctly represent the nodal volume because nodes are not perfectly spherical but are ellipsoid. The present study used US to obtain a more accurate calculation of the nodal volume. Several reports have indicated that small metastatic lymph nodes are more easily controlled with certain radiation doses than large ones,6,7,13 whereas Bartelink has reported that large metastatic nodes do not have a higher chance of recurrence in the neck after radiotherapy, compared with small nodes.14 Thus, the correlation between nodal volume and the effectiveness of radiotherapy has been controversial. In the current study, some small nodes that were suspected of being metastatic before the therapy disappeared after the therapy. These nodes were clinically evaluated as completely resolved, but excluded from the current study because the diagnosis of metastasis and

Table 3. CORRELATION BETWEEN RADIOTHERAPY AND HISTOLOGIC RESPONSE

the grading of such a response could not be confirmed histologically. Although radiotherapy might be effective for small metastatic nodes, the results of this study, except for these small nodes, showed no significant differences in the initial nodal volume before the therapy among the 3 types of histologic responses, suggesting that the initial nodal volume is not a good indicator for the response to radiotherapy and/or chemotherapy. Histologic response has been reported to be strongly associated with the nodal volumetric change during or after radiotherapy and/or chemotherapy.4, 5 Labadie et al4 reported that a volume reduction of greater than 90% after treatment was correlated with the eradication of diseased cervical lymph nodes. The current study showed that good and complete response nodes were significantly reduced in volume compared with poor response nodes and that lymph nodes with a regression rate of greater than 90% were histologically evaluated as good or complete response nodes. Consequently, a regression rate of greater than 90% might be considered as a predictor to avoid unnecessary neck dissection. However, the great majority, 47 (87%) of 54 nodes, showed a regression rate of less than 90%. 3 of 7 nodes with regression rates from 80 to 90% were poor response nodes, and 3 nodes with regression rates less than 50% were complete response. Moreover, the histologic response was also dependent on the regimen of chemotherapy. These results demonstrate why it remains difficult to establish a cutoff value in the regression rate for differentiating the 3 types of histologic responses in metastatic nodes. A further study using a larger sample size will be needed to better define the relationship between the volumetric and histologic responses to preoperative treatment.

Histologic Response Dose of Radiotherapy ⱖ60 Gy ⬍60 Gy *Not significant.

Poor (n ⫽ 33)

Good (n ⫽ 8)

Complete (n ⫽ 13)

7 26

3 5

1 12

*

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