Pushing the Limits of Breast-Conserving Surgery with Extreme Oncoplasty

Abstract

Introduction

We aimed to report the long-term surgical outcomes of extreme oncoplasty techniques in selected patients with unifocal (UF)/cT3 or multifocal-multicentric tumors (MFMC).

Material and Methods

Patients who were initially recommended to have mastectomy underwent extreme oncoplastic breast-conserving surgery (eOBCS) including therapeutic reduction mammoplasty, racquet, and round-block mammoplasty, Grisotti flap, or combined technique were included. Preoperative tumor parameters, clinical outcomes, rate of local recurrence, survival, and patients' satisfaction were assessed.

Results

Eighty-six patients with a median age of 51 years were followed for a median follow-up of 75 (8–154) months; 31 (36%) had cT3 and 55 (64%) had MFMC tumors. The majority of patients (83.6%) had invasive cancer. The median UF tumor size was 58 mm (range 51–100) on imaging and 51 mm (range 50–60) on final pathology. The median tumor span for MFMC was 65 mm (range 53–95) on imaging, whereas the median of the largest tumor size was 30 mm (range 22–60) on final pathology. Seventy-one patients (82.5%) were ER-positive, 17 (19.7%) were HER2 positive, and 8 (9.3%) were triple-negative breast cancer. Four patients (4.7%) required further intervention for having positive margins (3 re-excisions, 1 completion mastectomy). Three local recurrences (3.4%) and 10 (11.6%) distant metastasis occurred. The cosmetic outcome was excellent in 37 (43%) patients. No major complications were observed.

Conclusions

eOBCS can be a good option for patients who initially require mastectomy. Appropriate patient selection, a multidisciplinary approach, and patient consent are essential steps of the procedure.

Introduction

The recent advances in imaging technologies have enabled physicians to diagnose breast cancer (BC) in the early stages. Better tissue visualization has also led to increase in the detection of multifocal and multicentric (MFMC) tumors with a wide range of 14–61% [1−3]. Definition of multicentric disease has been based on a minimal distance of uninvolved tissue between foci of disease, the distance ranging from 5 mm to 5 cm, with 2 cm being a common compromise. However, due to not having an exact definition of anatomical margins for breast quadrants and not being able to measure the distance between the foci properly, MF and MC terms are being used together [2, 4].

The local recurrence rate in MFMC tumors following breast-conserving surgery (BCS) was anywhere between 17 and 40% [5]. Luckily, the local recurrence rate has been dropped to 5.1% over 5 years after routine use of adjuvant radiotherapy and systemic therapy [6]. Breast-conserving surgery has also been shown to be a safe procedure in tumors larger than 4 cm [7] and intraductal cancers larger than 5 cm [8, 9].

Oncoplastic breast-conserving surgery (OBCS) is an oncologically safe technique with low local recurrence and high disease-free survival rates compared to conventional BCS [10]. OBCS has expanded the indications for BCS by providing a larger resection area compared to lumpectomy. The technique also yields better cosmetic outcomes by sparing breast [11, 12].

Silverstein et al. [13] were the first to describe extreme oncoplasty (EO) in large (>5 cm) and MFMC tumors as an alternative to mastectomy. The authors performed wise pattern therapeutic reduction mammoplasty (TRM) with or without contralateral symmetrization and found the local recurrence as 1.5%; 9.1% of the patients required re-excision during follow-up. Since their reports, there have been limited number of reports available showing the efficacy and safety of extreme OBCS (eOBCS) in selected patients [13−17]. In this study, we aim to report long-term clinical and safety outcomes of eOBCS techniques in our patients with large (>50 mm) and MFMC breast tumors who were first scheduled for mastectomy but underwent eOBCS after a comprehensive preoperative assessment at a tertiary referral center.

Materials and Methods

Patient Selection

The medical records of patients who underwent eOBCS for invasive or noninvasive BC at the Istanbul University, Oncology Institute by an experienced general surgeon (H.K) between February 2009 and July 2021 were reviewed and only consecutive patients undergoing eOBCS for >50 mm unifocal (UF) (cT3) and/or MFMC tumors confirmed by either radiologically or histopathologically were included. Exclusion criteria were as follows: de novo distant metastasis, presence of coexisting malignancy, missing data, or irregular follow-ups. Patients who received neoadjuvant chemotherapy (NACT) but could not show complete radiological response were not included, while patients with partial response were included. All patients were consented prior to the surgery. The study adhered to the tenets of the Declaration of Helsinki for research involving human subjects.

Preoperative Evaluation

The eOBCS method began with a comprehensive preoperative assessment to choose eligible patients. Potential risks related to surgery were discussed with the patients, and patients were consulted with the various members of a multidisciplinary team including a medical oncologist, radiation oncologist, radiologist, and pathologist for a thorough assessment. Mastectomy was recommended for all patients as a standard treatment option. However, EO procedure was performed after subsequent counseling for the patients who refused to have mastectomy due to cosmetic reasons.

The surgical plan was made based on the tumor's characteristics and the patient's desire to achieve tumor-free margins as well as to preserve the breast's original shape. The best surgical option for each patient was decided after evaluating the tumor and breast size, location of the tumor, degree of breast ptosis, and density of breast glands. Individual EO technique was applied for each patient.

The standard preoperative screening included breast ultrasound and mammography (MMG). Magnetic resonance imaging (MRI) was routinely used. Location clips were placed by the breast radiologists for patients receiving NACT. Systemic treatment was given based on NCCNs guidelines.

Surgical Procedure

EO procedures included a combination of various oncoplastic surgery techniques including mastopexy, mobilization, and reshaping of the breast tissue to more advanced racquet, round-block, Grisotti mammoplasty, TRM which were performed by a wise pattern (inferior or superior pedicle mammoplasty) and vertical scar. These were classified as level II volume displacement procedures, combining wide tumor resection with immediate reconstruction of the defect.

Pedicle position varied from inferior, inferomedial, or lateral to superomedial depending on the pedicle length. In some patients with significant ptosis, nipple-areolar grafting was performed. In exceptional cases, a combined technique including a rotation flap, and mastopexy with or without reduction mammoplasty was performed. Patients were offered symmetry procedures for the contralateral side if needed. No perforator or musculocutaneous flaps were performed.

Before the surgery, a planned incision was drawn on the skin based on the location of the tumor in an upright position at the operation theatre. The tumor was excised until approaching microscopically clear margins. Intraoperative frozen section was routinely used for surgical margins and sentinel node analysis. When there was a residual tumor, re-excision/or mastectomy was performed, and axillary dissection was applied, if necessary. The axillary approach was made using the same skin incision or standard axillary incision. In patients who were marked with a preoperative stereotactic guided wire, MMG of the specimen was routinely taken after the specimen was removed.

There was no tumor on the final pathology margins of the surgical specimen. Before the 2014 ASCO consensus guideline, 2 mm was considered to be sufficient as a surgical margin, but after this date, “no ink on tumor” has been considered to be sufficient.

Adjuvant Therapy and Follow-Up

Patients were followed by the same experienced surgical oncologists postoperatively. Adjuvant radiotherapy was given to all patients as a standard treatment option. The patients were asked to come to visits every 3 months for the first postoperative year, and every 6 months for the second year, thereafter the patients had annual physical exams. Appropriate imaging surveillance was performed annually in conjunction with clinical exams to monitor for locoregional recurrence and/or distant metastasis.

Patients' demographics and tumor characteristics including focality, size, and location, histopathological features of the cancer were retrieved from the medical records. The surgical technique and weight of the specimen were obtained from the surgery notes. Peri- and postoperative complications were also noted. Perioperative and postoperative complications that were treated conservatively such as seroma, infection, and wound dehiscence were regarded as “minor” and other complications requiring surgical intervention were noted as “major.”

Patient's satisfaction was assessed by our institute's questionnaire after completion of adjuvant radiotherapy, which had a scoring scale ranging from 1 to 4. The parameters being evaluated were as follows: breast shape, the position of the nipple areola complex, a scar of the surgical incision, and the effects of the BCS. After answering 25 questions, the total score was obtained ranging from ≤40 to 100, and the total score was graded as excellent (81–100), good (61–80), fair (41–60), or poor (<40).

Statistical Analysis

Continuous parameters were reported as median and range, and continuous parameters were given as percentages (%). Kaplan-Meier graphs were generated for showing overall survival, locoregional recurrence-free interval, and distant metastasis-free survival. The estimated time for events was given as mean and 95 confidence interval (CI). Statistical analysis was performed by using Microsoft Excel and IBM Statistical Package version 21 (SPSS, Chicago, IL, USA).

Results

Patients and Tumor Characteristics

Eighty-six patients with a median age of 51 years (range 27–91) were included in the study. Cup C was the most common breast cup size (47.6%), followed by cup size D (29.2%) and cup size B (23.2%) (Table 1). Thirty-one patients (36%) had UF and cT3 tumors, and 55 (64%) had MFMC tumors. The median tumor size for UF tumor was 58 mm (range 51–100 mm) on imaging and 51 mm (range 50–60 mm) on final pathology; whereas the median imaging span of MFMC tumors was 65 mm (range 53–95 mm), and the largest median tumor size was 30 mm (range 22–60 mm) for MFMC on final pathology. Although the largest tumor size on MRI was less than 50 mm in some patients, the total diameter of the lesions exceeded 50 mm in all patients.

Table 1.

Population and tumor characteristics

Patients, n	86
Median age (range), years	51 (27–91)
Body mass index, mean (range)	27.4 (18.4–47.4)
<25, n (%)	15 (16.6)
25–30, n (%)	62 (68.8)
>30, n (%)	13 (14.4)
Smoking status, n (%)
Yes/No	12 (13.9)/74 (76.1)
Density of breast tissue, n (%)
1	5 (5.8)
2	31 (36)
3	47 (54.6)
4	3 (3.4)
Cup size, n (%)
B	20 (23.2)
C	41 (47.6)
≥D	25 (29.2)
Tumor focality, n (%)
UF (>50 mm)	31 (36)
MFMC	55 (64)
Tumor size, median (range), mm
UF tumor
Imaging	58 (51–100)
Final pathology	51 (50–60)
MFMC tumor
Span of tumor	65 (53 95)
Largest tumor size	30 (22–60)
Location, n (%)
Outer quadrant	50 (58.1)
Upper	40 (46.5)
Lower	10 (11.6)
Inner quadrant	15 (17.4)
Upper	10 (11.6)
Lower	5 (5.8)
Central	10 (11.6)
Other	11 (12.7)
Histological type, n (%)
Invasive	72 (83.6)
Ductal	56 (65.1)
Lobular	10 (11.6)
Mixt	6 (6.9)
Ductal carcinoma in situ	2 (2.3)
Other	12 (13.9)
Stage, n (%)
0	2 (2.3)
IIA	28 (32.5)
IIB	42 (48.8)
IIIA	14 (16.2)
Grade, n (%)
1	11 (11.6)
2	33 (38.3)
3	42 (48.3)
Receptor status, n (%)
ER+	71 (82.5)
PR+	67 (77.9)
HER2+	17 (19.7)
TNBC	8 (9.3)
Pathological nodal status, n (%)
pN0	31 (36.1)
pN1	37 (43.1)
pN2	12 (13.9)
pN3	6 (6.9)
Systemic therapy, n (%)
Neoadjuvant chemotherapy	35 (40.7)
Adjuvant chemotherapy	47 (54.6)
Endocrine therapy	75 (87.2)
Radiation therapy, n (%)	86 (100)

UF, unifocal; MFMC, multifocal-multicentric; mm, millimeter; ER, estrogen receptor; PR, progesterone receptor; HER-2, human epidermal growth factor receptor-2; TNBC, triple-negative breast cancer.

Thirty-three patients with MFMC tumors (60%) had 2, 13 (23.6%) had 3, and 9 (16.4%) had 4 or more tumor foci. The median of foci was 3 (range 2–8) per breast. The tumor was mostly localized in the upper outer quadrants (46.5%). The majority of patients were at stage IIB (48.8%) or IIA (32.5%) cancer. Forty-eight percent of patients (42 patients) had Grade 3 tumor, and 38.3% (33 patients) had grade 2 tumor. Invasive ductal carcinoma (65.1%) was the most common cancer type, followed by invasive lobular carcinoma (ILC) (11.6%), and mixed type (6.9%). Most of the patients were ER-positive (82.5%). Sixty-four percent of patients (55 patients) were pathologically node (+), and 40.7% (35 patients) received NACT. None of them achieved a clinical and pathological complete response. In patients receiving NACT, excision was planned considering the initial tumor area. Even though the tumor area decreased after treatment, the planned excision area remained unchanged. All patients underwent adjuvant radiotherapy. External beam radiation therapy was given to the entire breast with or without peripheral lymphatic regions using 3D conformal or IMRT techniques. The dose was 50 Gy given in fractions of 1.8–2 Gy per day, 5 days a week. A boost to the primary tumor bed was given by photons, mostly after whole breast irradiation. The booster dose was 10–12 Gy in 5–6 daily fractions. Concurrent integrated support (SIB) was used in some patients. In the SIB technique, 50.4 Gy was given to the entire breast, while 59.9 Gy was given to the boost volume in 28 fractions.

Surgical Procedure

In all patients, after tumor removal, the breast defect was closed with level II volume displacement techniques. The details of the surgery performed are given in Table 2.

Table 2.

Surgical procedure and complications

Margins on final pathology
Clear, n (%)		82 (95.3)
Positive, n (%)		4 (4.7)
Re-excision		3 (3.5)
Completion mastectomy		1 (1.2)
Contralateral symmetrization, n (%)		26 (30.2)
Specimen weight, median (range), g		243 (86–945)
Surgical complications
Major complications (requiring surgery)		None
Minor complications, n (%)		12 (13.92)
Early
Delayed wound healing		3 (3.48)
Wound detachment		2 (2.32)
Infection, requiring antibiotic		2 (2.32)
Seroma		1 (1.16)
Hematoma		1 (1.16)
Fat necrosis		1 (1.16)
Late
Radiation-induced calcifications		2 (2.32)

	Excellent, n = 37 (43%)	Good, n= 44 (51%)	Fair, n= 5 (6%)	Poor, n= 0
Satisfaction rates* by techniques, n = 86 (100%)
TRM (wise pattern incision), n = 40 (46.5%)	20 (23.2%)	18 (20.8%)	2 (2.5%)	0
Vertical mammoplasty, n = 20 (23.2%)	8 (9.3%)	11 (12.8%)	1 (1.2%)	0
Racquet mammoplasty, n = 8 (9.3%)	3 (3.5%)	5 (5.8%)	0	0
Grisotti flap, n = 7 (8.1%)	2 (2.3%)	4 (4.6%)	1 (1.2%)	0
Combined procedure, n = 7 (8.1%)	3 (3.5%)	3 (3.5%)	1 (1.1%)	0
Donut (round block) mastopexy, n = 4 (4.6)	1 (1.2%)	3 (3.4%)	0	0

TRM, therapeutic reduction mammoplasty.

^*According to the Institutional Questionnaire.

No ink on tumor or within >2 mm margins was achieved in 82 (95.3%) patients, 4 (4.7%) patients had inadequate margins at detailed paraffin analysis and required further surgical intervention; 3 of those (3.5%) underwent re-excision and 1 (1.2%) with more extensive margin involvement required a completion of mastectomy. Clear margins were achieved in all patients on final histopathological analysis. We performed sentinel lymphnode biopsy and intraoperative frozen section for metastasis in patients who had an invasive tumor. Immediate contralateral symmetrization was carried out in 26 (30.2%) patients.

Postoperative Assessment and Oncological Outcomes

The median follow-up time of all patients was 75 (range 8–154) months. During follow-up, 3 (3.4%) locoregional recurrences were diagnosed by oncosurgeons, consisting of 2 with triple negative and had NACT, another one was hormone positive. Recurrence time was at 25th, 47th, and 82nd months after surgery, respectively. Distant metastasis occurred in 10 (11.6%) patients, of whom 2 developed local recurrence at the time of metastasis. Eight (9.3%) patients died during follow-up, 6 (6.9%) of them were due to disease recurrence, and 2 (2.4%) died of ovarian and brain metastasis. Half of the patients (4 patients) who died from distant metastasis had MFMC tumors, and half (4 patients) had tumors larger than 5 cm.

None of the patients had major complications. Minor complications included delayed wound healing (3.4%), wound dehiscence and infection requiring antibiotics (2.32%), seroma (1.16%), and fat necrosis (1.16%). On long-term follow-up, radiation-induced calcifications were found in 2 (2.32%) patients. All of these complications were managed with a conservative approach without a delay in their adjuvant therapy. The overall score of patient's satisfaction was “excellent” in 37 (43%) patients, “good” in 44 (51%), and “fair” in 5 (6%) patients (Table 2).

The mean estimated overall survival time was 130 months (95% CI: 119–142 months) (shown in Fig. 1a). The cumulative proportion of surviving was 90% at 5 years and 68% at 10 years. The mean estimated time for being local recurrence-free survival was 148 months (95% CI: 142–154 months). The mean estimated time for distant metastasis-free survival was 136 months (95% CI: 126–146 months) (shown in Fig. 1b). The cumulative proportion of being distant metastasis-free was 87% at 5 years. The cumulative proportion of being local recurrence-free was 96% at 5 years and 94.4% at 7 years (82 months) (shown in Fig. 1c).

Fig. 1.

a Kaplan-Meier plots showing overall survival. b Survival for being distant metastasis-free. c Survival of being local recurrence-free.

Figure 2 shows a representative case from our study population. A 52-year-old patient with E-cup breasts presented with a large diffuse lesion in the lateral part of the right breast, and she had two non-palpable lesions in the medial part (shown in Fig. 2a). The biggest one of her tumors was very close to the skin. MMG and MRI revealed a MFMC tumor that extended from 2 o'clock position to 11 o'clock position measuring 33 × 24 mm, 25 × 16 mm, and two non-palpable lesions were 10 × 9 mm and 9 × 5 mm, respectively (shown in Fig. 2b, c). Ultrasound-guided core biopsy revealed intermediate-grade invasive cancer and immunohistochemistry showed Luminal A tumor; ER/PR positive status and Ki-67: 10%. Mastectomy was initially recommended due to the large span of the disease. She insisted on conserving her breast and sought an alternative breast-conserving approach. Hence, the combined technique involving TRM was planned.

Fig. 2.

a Preoperative image of our representative case. b, c MMG and MRI show the MFMC lesions. d Two non-palpable lesions were marked with wire preoperatively (Red arrows). e Repair of lateral skin defect with a dermoglandular rotation flap. Breast reshaping with inferior pedicle therapeutic reduction mammoplasty. f A 322-gram specimen was removed. The postop histopathology revealed grade II-IDC and a lesion spanning 95 mm. g, h Postoperative images of the patient.

Two non-palpable lesions localized in the upper inner quadrant were marked with wire, preoperatively (shown in Fig. 2d). Since the lateral large tumor was close to the skin, the partial skin was excised. The lateral defect was repaired with a dermoglandular rotation flap. The breast tissue was reshaped and the rest of the breast was reconstructed with inferior pedicle mammoplasty. The nipple-areolar complex was used as a nipple areola graft. The sentinel lymph node was positive, further axillary dissections were performed through the same incision. 2/11 nodes were positive (shown in Fig. 2e). After surgery, the patient received adjuvant endocrine therapy and RT, followed by electron boost to the tumor bed. She's been disease-free for 7 years.

Discussion

In this study with a median follow-up of 75 months (range: 8–154), we have performed eOBCS in 86 patients and showed that eOBCS provided clear margins in 95.3% of patients with large (>5 cm) and MFMC tumors who might have required total mastectomy. We found the overall survival rate as 90% at 5 years and 68% at 10 years. Moreover, the rate of being local recurrence-free survival was found to be as high as 96% at 5 years, with a rate of 87% of being distant metastasis-free. These results suggest that eOBCS may be a safe option in patients with large (>5 cm) or MFMC breast tumors.

Margins

There have been limited the number of studies showing the results of eOBCS with a wide range of clinical outcomes. In the first study [13], a clear margin was achieved in 83% of 66 patients, 6 (9.1%) patients underwent re-excision to achieve wider margins, and 4 (6.1%) patients were converted to mastectomy after EO. All patients underwent excision and oncoplastic reconstruction using a standard wise pattern reduction mammoplasty procedure and immediate contralateral surgery for symmetry. In the largest series of 111 cases, Crown et al. [18] performed re-excision in 42 patients (37%) due to positive margins, with a mastectomy rate of 15 (13%). The high re-excision rate was attributed to having more cases with DCIS (73%) on final pathology. Savioli et al. [19] performed re-excision in 3 (6%) patients and mastectomy in 6 (12%) patients. Pearce et al. [14] applied TRM to 28 patients and mini Latissimus Dorsi flaps in 62 patients in a median time of 80 (10–380) months. Re-excision was performed only in 3 (5%) patients in the mini Latissimus Dorsi group due to an incomplete margin. Eight (9%) underwent total mastectomy. Koppiker et al. [15] obtained clear margin index surgery in all patients with a median tumor diameter of 75 mm in their series of 39 patients, and re-excision or mastectomy was required in none of the patients. In all mentioned studies above, patients had large (>5 cm) and/or MFMC tumors. In our study, 4 patients (4.7%) required further intervention for having positive margins, 3 (3.5%) had re-excisions, and 1 (1.2%) patient required completion of mastectomy. These favorable results suggested that eOBCS was an effective treatment option in selected patients.

In several studies [16, 19], DCIS and ILC were predictive risk factors for positive surgical margins and reoperation. Fischer et al. [20] reported that MRI reduced the rate of re-excision for positive margins. In our study, the number of cases with DCIS (2.4%) was too small to associate this finding with a positive margin. Although MRI carries a risk of false negativity in DCIS patients, we performed detailed radiological examinations in all high-risk patients and used MRI as routine imaging in all patients along with intraoperative routine margin analysis and specimen radiology, when necessary. We believe that detailed thorough preoperative assessment of the patients resulted in satisfying surgical outcomes.

Follow-Up and Local Recurrence Rate

In a study with 2-year follow-up, the rate of local recurrence was found as 1.5% following eOBCS [13]. Crown et al. [18] found the local recurrence rate as 2.7% over a mean of 36 months (range 12–60) follow-up. Savioli et al. [19] reported the local recurrence rate as 10% in a median of 62-month follow-up. In our study with a median of 75-month follow-up, the local recurrence rate was found as 3.4% which was comparable to other studies.

Complications

In EO procedures, numerous safety concerns may arise, including the risk of positive margins and postoperative complications that may delay adjuvant therapy. The overall complication rate was 13.92% in our study, which was lower than that of reported before as 16.2–23% [16, 18]. None of our patients had a delay in timing of postoperative adjuvant therapy, and no major complication requiring further surgical intervention was occurred.

Cosmetic Results

BC poses a threat to the organ that symbolizes femininity and mastectomy has significant negative effects in terms of psychological and sexual life [21]. The psychological depression that occurs after mastectomy can continue even after many years of cancer diagnosis and treatment, which highlights the importance of BCS [22]. In our study, only one (1.2%) patient who was normally scheduled to undergo a mastectomy underwent a completion mastectomy. Also, a high percentage of patients (94%) reported “excellent” or “good” satisfaction scores that may encourage us to perform this technique.

Limitations

Although we achieved promising results with eOBCS during long follow-up, our study had some limitations including retrospective nature from a single institution, not having a control group, long operation duration, and causing more visible incision scars compared to the standard BCS. However, the acceptable complication rates and potential benefits regarding margin control and esthetic outcomes seen in this study support the availability of this technique in appropriate patients.

In 2017 St. Gallen consensus [23], it has been reported that surgery could be performed based on residual tumor margins following NACT. Thus, the excision area could have been reduced and EO might have been neglected in some patients. However, due to lacking of long-term follow-up studies, we planned the surgeries based on the initial tumor area in our study group so the consensus of the meeting was not applied to all patients.

Conclusion

New advances in oncoplastic techniques provide relief from physical defects while maximizing esthetic results with oncological safety. Our study showed that extreme oncoplastic surgery followed by radiotherapy was oncologically safe and effective procedure in selected patients during the long-term follow-up with good local control, low complication rate, and high patient satisfaction. However, selecting the appropriate patient, collaboration with a multidisciplinary team, and informing the patients appropriately should remain the critical steps of the decision stage.

Statement of Ethics

This study protocol was reviewed and approved by the Ethics Committee of Istanbul University (the approval reference number: 2022/147). A written informed consent was obtained from participants to participate in the study.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This research did not receive any specific grant from funding agencies.

Author Contributions

Berkay Kilic: mentoring the contouring, reviewing the results, data collection, and writing the manuscript. Suleyman Bademler: helping in writing, contouring, and follow-up of the patients. Burak Ilhan: literature review and drafting the paper. Ilknur Yildirim: preparation of figures and statistical analysis of the data. Seden Kucucuk: follow-up of all patients receiving radiotherapy. Aysel Bayram: comprehensive pathological examinations and intraoperative pathological evaluations. Hasan Karanlik: the corresponding author, initiation of the project, reviewing the whole project, and helping in writing and editing the manuscript.

Funding Statement

This research did not receive any specific grant from funding agencies.