cancers Article Outcomes Following Autologous Fat Grafting in Patients with Sequelae of Head and Neck Cancer Treatment Jorge Masià-Gridilla 1,2, *, Javier Gutiérrez-Santamaría 1 , Iago Álvarez-Sáez 1,2 , Jorge Pamias-Romero 1,2 , Manel Saez-Barba 1,2 and Coro Bescós-Atin 1,2,3 1 Noves Tecnologies i Microcirurgia Craniofacial, Vall d’Hebron Institut de Recerca (VHIR), Hospital Universitari Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, Passeig Vall d’Hebron 119-129, E-08035 Barcelona, Spain 2 Servei de Cirurgia Oral i Maxil·lofacial, Hospital Universitari Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, Passeig Vall d’Hebron 119-129, E-08035 Barcelona, Spain 3 Unitat Docent Vall d’Hebron, Facultat de Medicina, Universitat Autònoma de Barcelona, Passeig Vall d’Hebron 119-129, E-08035 Barcelona, Spain * Correspondence: jmasia@vhebron.net Simple Summary: In recent years, there have been relevant advances in the use of surgery, radiation therapy, and chemotherapy for the treatment of malignant tumors of the head and neck. Extensive tumor resection and radical radiotherapy frequently result in altered form and function of orofacial structures that can severely impact the patient’s quality of life. This study reports the benefits obtained with the injection of autologous fat to correct the deformities and improve functionality in a series of 40 patients who have been treated for head and neck cancer. Esthetic improvement was obtained in 77.5% of patients and functional improvement in 89.2%. In addition, there was a high degree of satisfaction regarding esthetic improvement and 92.5% of patients would recommend the procedure to other patients in the same situation. The injection of autologous fat is an effective procedure for the management of sequelae of head and neck cancer treatment. Abstract: A single-center retrospective study was designed to assess the outcomes of autologous fat Citation: Masià-Gridilla, J.; grafting for improving surgery- and radiotherapy-related sequelae in 40 patients with head and neck Gutiérrez-Santamaría, J.; cancer. All patients underwent surgical resection of primary tumors and radiotherapy (50–70 Gy) Álvarez-Sáez, I.; Pamias-Romero, J.; and were followed over 12 months after fat grafting. Eligibility for fat grafting procedures included Saez-Barba, M.; Bescós-Atin, C. Outcomes Following Autologous Fat complete remission after at least 3 years of oncological treatment. The cervical and paramandibular Grafting in Patients with Sequelae of regions were the most frequently treated areas. Injected fat volumes ranged between 7.5 and 120 mL Head and Neck Cancer Treatment. (mean: 23 mL). Esthetic improvement was obtained in 77.5% of patients, being significant in 17.5%, Cancers 2023, 15, 800. https:// and functional improvement in 89.2%, being significant in 29.7% of patients. Minor complications doi.org/10.3390/cancers15030800 occurred in three patients. There was a high degree of satisfaction regarding esthetic improvement, global satisfaction, and 92.5% of patients would recommend the procedure. This study confirms the Academic Editor: António Araújo benefits of fat grafting as a volumetric correction reconstructive strategy with successful cosmetic Received: 5 January 2023 and functional outcomes in patients suffering from sequelae after head and neck cancer treatment. Revised: 21 January 2023 Accepted: 26 January 2023 Keywords: autologous fat grafting; head and neck cancer; radiotherapy; reconstruction; sequelae; Published: 28 January 2023 quality of life Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. 1. Introduction This article is an open access article Head and neck cancer represents the seventh most common cancer worldwide, with distributed under the terms and 1.1 million new diagnoses reported annually [1,2]. However, there is a substantial geo- conditions of the Creative Commons graphical variation in the incidence and anatomical distribution of tumors, predominantly Attribution (CC BY) license (https:// attributed to differences in smoking and alcohol consumption, steady increase in human creativecommons.org/licenses/by/ papillomavirus-related cancer, genetic predisposition, or exposure to ionizing radiation, 4.0/). Cancers 2023, 15, 800. https://doi.org/10.3390/cancers15030800 https://www.mdpi.com/journal/cancers Cancers 2023, 15, 800 2 of 14 which are known to play an important role in the pathogenesis of the disease [3,4]. Radia- tion therapy, surgery or both combined and chemotherapy are currently available standard therapeutic strategies but are often prioritized differently depending on the site of tumor origin, histological diagnosis, tumor burden, quality of life considerations, patient prefer- ence, or hospital characteristics with the availability of specialized multidisciplinary care teams [5,6]. Advances in surgery, radiation therapy, and chemoradiotherapy have improved lo- coregional control and survival, but the outcomes of these treatment modalities have incorporated preservation and restoration of function in the focus of radical ablation and curative efforts [7]. However, despite improvements in the multimodal treatment approach aimed at decreasing cosmetic and functional deficits with resultant psychological, physical, and nutritional detriments [8,9], management of sequelae following treatment of head and neck cancer, particularly in patients with locally advanced tumors, still remains a challenge difficult to solve in daily practice [10,11]. Fat grafting, also referred to as fat transfer or fat injections, dates back to 1893 when Neuber first described the technique and reported successful outcomes after transplanting fat beneath atrophic scars [12]. Structural autologous fat grafts for the enhancement of facial contours were proposed by Coleman in 1997 [13] and the Coleman’s lipostructure technique became subsequently recognized as a standard procedure for fat transfer [14,15]. In recent years, autologous fat grafting has been described by different authors as a very useful tool to improve residual esthetic and functional deformities after head and neck cancer treatment, and for its ability to correct volumetric defects and regenerative properties [16–19]. A systematic review and meta-analysis of 52 studies with 1568 patients confirmed that autologous fat transfer is an effective technique in facial reconstruction surgery with a low rate of minor complications [20]. The purpose of this study was to evaluate esthetic and functional outcomes as well as patients’ satisfaction and complications associated with autologous fat grafting in the context of integral management of head and neck cancer patients. 2. Materials and Methods 2.1. Design and Study Population A retrospective study was made of all consecutive patients who required autologous fat grafting procedures between January 2010 and January 2019 at the Service of Oral and Maxillofacial Surgery of Hospital Universitari Vall d’Hebron, in Barcelona, Spain. Fat grafting was indicated for the treatment of sequelae associated with any form of therapy of head and neck cancer. Inclusion criteria were history of head and neck cancer treated with surgery, radiation therapy, or chemotherapy followed by duration of complete clinical remission of at least 3 years; presence of severe or very severe esthetic defects and/or loss of skin flexibility, and severe or very severe dysphonia, dysphagia, alteration in head and neck mobility, and alteration in swallowing or chewing, corresponding to scores 3 or 4 of esthetic and/or functional evaluation of the scoring method described by Pulphin et al. [21]; good health, as confirmed by preoperative work-up studies; and signed informed consent. Patients previously treated with fat infiltration procedures or with insufficient fat tissue deposits for fat transfer were excluded from the study, as were those expected to have poor adherence to follow-up visits scheduled for at least 12 months after the intervention, and ineligibility as judged by the investigators. The study protocol was approved by the Clinical Research Ethics Committee of Hospi- tal Universitari Vall d’Hebron (code PR (ATR) 57/2016, approval date 26 February 2016) (Barcelona, Spain). Written informed consent was obtained from all participants. 2.2. Fat Grafting and Surgical Procedure The available fat deposits were evaluated, and the donor site was selected with consent from the patient. Fat harvesting was performed under general anesthesia or local anesthesia with intravenous sedation, and the patient was in the supine position. Ten minutes before Cancers 2023, 15, 800 3 of 14 liposuction, abdominal infiltration was performed through a 2–3 mm incision puncture at the level of both flanks or in the umbilical region, using a modified Klein solution (500 mL Ringer lactate) with 0.5 mg epinephrine, and adding 1% lidocaine for patients under sedation. Harvesting was performed through the same infiltration incisions using a liposuction cannula (COL-ASP15, 3 mm × 15 cm, Byron Medical Inc., Tucson, AZ, USA or COL-KHU12 Mitmed® , 3 mm × 20 cm, Surgest Medical, Sant Cugat del Vallès, Barcelona, Spain) connected to a 10 mL Luer-Loc syringe, by firm and regular back-and- forth movements under low negative digital pressure until the syringe was filled. Then, fat was purified either by the centrifugation method described by Coleman [22] (3000 rpm for 3 min) (Medigraft-BL® Centrifuge, Surgest Medical) or washing and filtration using the Puregraft system (Cytori Therapeutics, San Diego, CA, USA). The graft was injected in small amounts, separated between them in order to obtain a better vascularization and therefore longer graft survival, slowly and without overcorrec- tion, from the deep to the superficial cutaneous tissue using an atraumatic cannula (7–9 mm long, 16G, types I-III COL-19, Byron Medical, COL SPA9), creating multiple tunnels in a fan-like fashion following the recommendation of Coleman [22]. An abdominal bandage was applied for 48 h and substituted with an abdominal belt for the following 7 days. Amoxicillin–clavulanic acid (500/250 mg), 1 tablet every 8 h, was administered during the first 7 days after the procedure. 2.3. Evaluation and Follow-Up Patients were visited postoperatively by the same investigator (J.M.-G.) after 1 week of fat grafting and at 1, 3, 6, and 12 months thereafter. At each visit, patients were questioned and underwent a physical examination to assess the evolution of the graft and the eventual appearance of early or late complications. Twelve months after fat grafting, esthetic and functional results were evaluated using a 4-point scale described by Pulphin et al. [21], including no esthetic or functional problems (score 0), and esthetic defects and/or loss of skin flexibility and functional alterations of dysphonia, dysphagia, neck/head mobility or swallowing or chewing scored as 1 = slight, 2 = moderate, 3 = severe, and 4 = very severe. Improvement was defined in the presence of a postoperative score lower than the preoperative score, and significant improvement was defined if the postoperative score was 2 or more points lower than the preoperative score. The severity of complications was classified according to the Clavien–Dindo classification system [23]. Also, after 12 months of fat grafting, the patient’s satisfaction regarding esthetic improvement was evaluated on a scale of 0 to 10 (0 = nothing, 10 = maximum satisfaction) and the overall satisfaction with treatment according to responses to the following four questions: “What is the degree of satisfaction with the treatment received?”, “Do you consider that you have received sufficient and clear information?”, “Did the treatment meet your expectations?”, and “In case you request an advice, would you recommend this treatment to another patient in the same conditions?” using a 4-point Likert scale (1 = nothing, 2 = little, 3 = quite a lot, 4 = a lot/very much). 2.4. Statistical Analysis Descriptive statistics were calculated and presented as frequencies and percentages for categorical variables, and as mean and standard deviation (SD) for continuous variables. 3. Results The study population included 40 patients, 26 men and 14 women, with a mean age of 60.5 years (range 32–86 years). Complete data at the 12-month follow-up visit were obtained in all participants. Squamous cell carcinoma of the oral cavity was the most frequent primary tumor (n = 25, 62.5%) followed by a malignant tumor of the salivary glands (n = 7, 17.5%). All patients underwent radical surgery of the neoplasms and radiotherapy (50–70 Gy), and 23 of them (57.5%) received chemotherapy. Reconstruction procedures using different types of flaps were performed in 27 (67.5%) patients using microsurgical Cancers 2023, 15, 800 4 of 14 free fibula flaps in most of them. All patients presented with esthetic sequelae, including scarring, cervicofacial asymmetry, and cutaneous fibrosis. Limitations of neck movements, trismus, and dysphagia were the most frequent functional sequelae. The abdominal region was the donor site for fat grafting in all patients. The manual low pressure aspiration technique was used to obtain the fat graft in all cases using a 10 mL syringe with Luer-Loc connection and COL-KHU12 Mitmed® , 3 mm × 20 cm liposuction cannula. Regarding the processing method, the centrifugation method following Coleman’s recommendations [22] was used in the first series of 16 patients, and the filtration processing system was carried out using the Puregraft device in the remaining 24. In all patients, infiltration was performed following the Coleman technique [22]. Fat grafting was mostly performed under general anesthesia, with sedation and local anesthesia in only three patients. The cervical and paramandibular regions were the most frequently treated areas, with injected fat volumes ranging between 7.5 and 120 mL (mean: 23 mL). The length of surgery varied between 45 and 180 min, with a mean of 89 min. No intraoperative complications were recorded, and all patients were discharged within 24 h after the procedure. Minor complications occurred in three patients (7.5%) with abdominal pain, seroma, and lingual paresthesia in one patient each, and they resolved spontaneously. All these complications were classified as grade I of the Clavien–Dindo classification system [23]. Esthetic improvement was obtained in 31 patients (77.5%), being significant in 7 of them (17.5%). In relation to functional alterations, there were three patients who scored 0 preoperatively. In the remaining 37 patients, functional improvement was found in 33 (89.2%), being significant in 11 of them (29.7%). One of the most widespread findings in the treated patients was clinical improvement in the quality of irradiated skin on the neck or face, with apparent improvement in blood supply, skin smoothness, function, and elasticity. The analysis of graft stability was performed clinically by evaluating the patient and analyzing the photographic documentation, showing a progressive volumetric decrease close to 50% of the injected volume in all patients. Details of treatment characteristics and outcome of the study patients are shown in Table 1. Figures 1–5 show some representative cases. Postoperative photographs of these patients were obtained between 6 and 12 months of follow-up after the fat grafting procedure. Esthetic improvement evaluated by the patients showed a mean (SD) score of 7.03 (1.83) and a mean satisfaction with treatment of 3.05 (0.68). In addition, 37 patients (92.5%) would recommend treatment with autologous fat grafting to other patients in a similar situation. After 12 months of follow-up of autologous fat grafting, two patients died; the causes of death were a new lung cancer and heart disease, respectively. Recurrence of the primary head and neck cancer occurred in three patients, but in all cases, the site of recurrence was far from the fat infiltrated area. Cancers 2023, 15, 800 5 of 14 Table 1. Clinical characteristics, details of treatment, and outcome in the 40 study patients. Length of Esthetic Score Functional Patient Histology Surgery RT Reconstruction Injection Site Volume Score /Location Chemotherapy Gy Type mL Surgery Anesthesia Preoperative/ Preoperative/ min Postoperative Postoperative 1 ACC/parotid PT + MD No 60 Not performed Laterocervical and 7.5 50 General 4/3 3/2 parotid area 2 DFSP/malar TEOM No 60 Mustarde cheek flap Hemifacial 23 45 General 3/2 3/2 3 SCC/tongue MD + ND Yes 70 Microsurgical fibula flap Laterocervical and 28 65 General 4/4 4/3 paramandibular 4 SCC/gums MD + ND Yes 60 Not performed Laterocervical and 20 120 General 4/2 2/1 paramandibular Submaxillary, lower 5 SCC/gums MD + ND No 66 Microsurgical fibula flap lip, nasolabial and 24 64 General 3/2 3/2 submental fold SCC/gums, Fibula flap + anterolateral Laterocervical and 6 MD + ND bilateral Yes 70 19 90 General 4/4 4/3 mouth floor thigh flap paramandibular 7 SCC/gums MD + ND Yes 50 Not performed Laterocervical and 24 115 General 4/3 3/2 paramandibular Jugal region, SCC/jugal nasolabial, 8 TEOM Yes 60 Local flap submental. 20 100 General 3/2 4/2 mucosa Laterocervical, tracheocervical 9 SCC/gums TEOM + MD + ND Yes 60 Microsurgical fibula flap Laterocervical and 37 135 General 4/4 3/2 paramandibular 10 SCC/gums MD + ND Yes 70 Fibula flap Laterocervical and 42 120 General 3/3 3/3 paramandibular SCC/tongue, Fibula flap + anterolateral Hemifacial and 11 TEOM + MD No 70 20 80 Sedation local 4/3 3/2 mouth floor thigh flap cervical 12 SCC/retromolar MD + ND No 70 Microsurgical fibula flap Hemifacial and 27 180 General 4/3 3/2 trigone cervical Laterocervical, 13 SCC/jugal TEOM + ND No 60 Radial flap paramandibular, 23 110 General 3/2 2/1 mucosa jugal Laterocervical, 14 SCC/mouth MD + ND Yes 70 Microsurgical fibula flap paramandibular, 70 100 General 4/3 4/2 floor tracheal Cancers 2023, 15, 800 6 of 14 Table 1. Cont. Length of Esthetic Score Functional Patient Histology Surgery RT Reconstruction Injection Site Volume Score /Location Chemotherapy Gy Type mL Surgery Anesthesia Preoperative/ Preoperative/ min Postoperative Postoperative Myoepithelial 15 carcinoma/ Maxillectomy No 60 Temporal muscle flap Temporal 13 150 General 3/1 0/0 minor salivary gland, maxillary Myoepithelial carci- Radical Laterocervical and 16 noma/parotid Yes 66 Not performed 8.5 58 General 3/2 2/1 Parotidectomy + ND parotid region gland 17 SCC/gums MD + ND Yes 70 Microsurgical fibula flap Hemifacial and 15 110 General 3/2 3/1 cervical 18 SCC/gums Maxillectomy + ND Yes 64 Microsurgical fibula flap Hemifacial and 23 70 General 3/2 3/2 cervical 19 Adenocarcinoma Total parotidectomy No 50 Not performed Hemifacial 13 87 General 2/0 2/0 parotid gland Nasolabial fold, SCC/retromolar upper and lower lip, 20 MD + ND Yes 70 Not performed 120 170 General 4/3 4/2 trigone jugal and laterocervical 21 SCC/cervical ND No 60 Not performed Laterocervical 15 52 Sedation 3/4 4/4 unknown origin local Upper and lower lips, paramandibular, superior SCC/tongue, Glossectomy + MD laterocervical, 22 No 66 Microsurgical fibula flap 20 117 General 4/2 3/1 mouth floor + ND bilateral submandibular, bilateral nasolabial folds Lower lip, 23 SCC/mouth MD + ND bilateral No 70 Microsurgical fibula flap paramandibular, 12 97 General 4/2 3/2 floor laterocervical Ductal carci- Superficial 24 noma/parotid No 60 Laterocervical and 15 71 Not performed parotid region General 2/1 2/1 gland parotidectomy Cancers 2023, 15, 800 7 of 14 Table 1. Cont. Length of Esthetic Score Functional Patient Histology Surgery RT Reconstruction Injection Site Volume Score /Location Chemotherapy Gy Type mL Surgery Anesthesia Preoperative/ Preoperative/ min Postoperative Postoperative Paramandibular, 25 SCC/retromolar MD + ND Yes 70 Microsurgical fibula flap submaxillary, upper 23 63 General 4/3 4/2 trigone and lower lip Laterocervical, 26 SCC/jugal TEOM + ND Yes 66 Local flap paramandibular, 23 79 General 3/2 4/2 mucosa jugal Paramandibular, 27 SCC/mandibular MD + ND bilateral Yes 63 Microsurgical fibula flap laterocervical, 23 103 General 4/2 4/2 intraosseous nasolabial fold, lower lip Undifferentiated Paramandibular and 28 parotid Total parotidectomy No 60 Not performed 25 83 General 4/2 3/1 carcinoma parotid region 29 SCC/cervical ND Yes 60 Not performed Laterocervical 14 47 General 3/2 4/3 unknown origin 30 SCC/tongue Glossectomy + ND Yes 54 Nor performed Laterocervical, 18 115 General 3/3 4/4 lingual ACC/minor Malar bilateral, left 31 salivary gland Maxillectomy No 66 Temporal muscle flap nasolabial fold, 20 47 General 3/2 0/0 maxillary upper lip, left jugal 32 SCC/gums MD + ND Yes 70 Pectoral flap Paramandibular and 10 48 General 4/2 2/1 jugal 33 SCC/retromolar MD + ND Yes 70 Pectoral flap + fibula flap Hemifacial, cervical, 15 114 General 4/2 3/2 trigone labial, tracheal 34 SCC/lip TEOM + ND No 55 Anterolateral thigh flap Jugal and labial 8 54 Sedation 2/2 0/0 local ACC/ 35 oropharynx- Glossectomy + ND No 66 Anterolateral thigh flap Laterocervical 20 104 General 3/3 3/3 tongue SCC/gums, Right laterocervical, 36 MD + ND Yes 69 Not performed 15 55 General 4/4 4/2 mouth floor paramandibular Angiofibroma/ 37 TEOM No 50 Not performed Temporal 20 95 General 3/2 1/0 nasal 38 SCC/mandibular MD + ND bilateral Yes 70 Microsurgical fibula flap Laterocervical and 10 48 General 4/3 3/2 symphysis submental Cancers 2023, 15, 800 8 of 14 Table 1. Cont. Length of Esthetic Score Functional Patient Histology Surgery RT Reconstruction Injection Site Volume Score /Location Chemotherapy Gy Type mL Surgery Anesthesia Preoperative/ Preoperative/ min Postoperative Postoperative 39 Osteosarcoma MD + maxillectomy Yes 60 Hemifacial and 10 70 mandibular + ND Anterolateral thigh flap cervical General 4/3 3/2 ACC/upper Temporal muscle flap + Hemifacial, cervical 40 Maxillectomy + ND Yes 72 27 76 General 3/2 3/1 maxilla microsurgical fibula flap and temporal ACC: adenoid cystic carcinoma, DFSP: dermatofibrosarcoma protuberans, MD: mandibulectomy, ND: neck dissection, PT: parotidectomy, RT: radiotherapy, SCC: squamous cell carcinoma, TEOM: tumoral exeresis with oncological margins. Cancers 2023, 15, x F 9 of 14 Cancers2023, Cancers 2023,15, 15,800 xF 9 of 9 of1414 Figure1. Figure 1. A A 59-year-old 59-year-old male male patient patient treated treated with with left left segmental segmental mandibulectomy mandibulectomy and and microsurgical microsurgical Figure 1. A 59-year-old reconstruction with a male patient treated microsurgical fibula withipsilateral flap, left segmental mandibulectomy cervical lymph node and microsurgical dissection, and post- reconstruction with a microsurgical fibula flap, ipsilateral cervical lymph node dissection, and reconstruction operative with a microsurgical radiotherapy at a dose offibula 66 Gyflap, for aipsilateral squamous cervical lymph node cell carcinoma dissection, of the and post- left alveolar crest. postoperative operative radiotherapy radiotherapy at a dose at a dosefat of 66 Gy of grafting for 66 Gy forinathe a squamous squamous cell carcinoma cell carcinoma of the of the left left alveolar alveolar crest. He was treated with autologous paramandibular and cervical regions withcrest. a total He He24was was treated with autologous fat fat grafting in the the paramandibular paramandibularand andcervical cervicalregions regionswith withaatotal total of mLtreated of fat with (left).autologous grafting The postoperative in photograph at follow-up shows the improvement of the of 24 mL of fat (left). of 24 mL of fat (left). paramandibular The postoperative The postoperative and cervical photograph at follow-up shows the improvement photograph at follow-up shows the improvement of the deformity (right). of the paramandibularand paramandibular and cervical cervical deformity deformity (right). Figure 2. Figure2. A 2. A 71-year-old A 71-year-old female patient 71-year-old female female patient treatedwith with rightbuccal buccal mucosaexcision, excision, andpostoperative postoperative Figure patient treated treated with right right buccalmucosamucosa excision,and and postoperative radiotherapy at a dose of 66 Gy for an oral squamous cell carcinoma. She was radiotherapy at a dose of 66 Gy for an oral squamous cell carcinoma. She was treated with treated withautolo- autolo- radiotherapy gous at a dose of 66and Gy for an oral squamous withacell carcinoma. She was treated with autologous gous fat fat grafting in cheek grafting in cheek cervical and cervical regions regions with atotal total ofof23 23mL mL ofoffat fat(left). (left). The The postoperative postoperative fat grafting in cheek photograph andshows cervical theregions with a of total of 23 mL of fat (left). The postoperative photograph at follow-up at follow-up shows the improvement improvement thefacial of the facial andcervical and cervical deformity deformity (right). (right). photograph at follow-up shows the improvement of the facial and cervical deformity (right). Cancers 2023,15, Cancers2023, 15,800 xF 10 10 of of1414 Cancers 2023, 15, x F 10 of 14 Figure 3. Figure 3. AA 54-year-old 54-year-old male male patient patient treated treated for for left left segmental segmentalmandibulectomy mandibulectomyand andmicrosurgical microsurgical Figure 3. A 54-year-old reconstruction male patientfibula with a microsurgical treated foripsilateral flap, left segmental mandibulectomy cervical and microsurgical lymph node dissection, and post- reconstruction with a microsurgical fibula flap, ipsilateral cervical lymph node dissection, and reconstruction with a microsurgical operative radiotherapy at a dose of fibula 64 Gyflap, for aipsilateral squamouscervical lymph node cell carcinoma dissection, of the and crest. left alveolar post- postoperative operative radiotherapy radiotherapy at aatdose a dose of Gy 64 Gy ofgrafting 64 for forsquamous a squamous cellcell carcinoma of of thethe left alveolar crest. He was treated with autologous fat in athe paramandibular carcinoma and cervical left regionsalveolar with acrest. total He He was of 23was mLtreated of fatwith treated with autologous autologous (left). fat grafting fat grafting The postoperative in the in the paramandibular photograph paramandibular at follow-up and andcervical cervical shows regionswith regions the improvement withaofatotal total the of of 23 23 mL mL ofof fat paramandibular fat (left). (left). The The postoperative and cervical postoperative photograph at photograph deformity (right). at follow-up follow-upshowsshowsthe theimprovement improvementofofthe the paramandibular and paramandibular and cervical cervical deformity (right). Figure 4. A 71-year-old female patient treated for right buccal squamous cell carcinoma with local Figure resection Figure 4. A 4. A 71-year-old and71-year-old female radical patient ipsilateral female cervicaltreated patient lymph for treated for right node buccal buccalsquamous dissection right and cell cellcarcinoma postoperative squamous with withlocal radiotherapy carcinoma at a local resection dose of 66and Gy ipsilateral for a radicalcell squamous cervical lymph She carcinoma. nodewasdissection treated and postoperative with autologous radiotherapy fat grafting in at thea resection and ipsilateral radical cervical lymph node dissection and postoperative radiotherapy at a dose right of 66 Gyregion cervical for a squamous cell with a total of carcinoma. 23 mL of fatShe wasThe (left). treated with autologous postoperative fat grafting photograph in the at follow-up dose of 66 Gy for a squamous cell carcinoma. She was treated with autologous fat grafting in the right showscervical region withofathe the improvement total of 23 mL of fatand paramandibular (left). The postoperative cervical photograph at follow-up deformity (right). right shows cervical region withofathe the improvement total of 23 mL of fatand paramandibular (left). The postoperative cervical photograph at follow-up deformity (right). shows the improvement of the paramandibular and cervical deformity (right). Cancers 2023,15, Cancers2023, 15,800 xF 11 11 of of1414 Figure 5. Figure 5. A A 43-year-old 43-year-old male male patient patient treated treated for for an anintraosseous intraosseouscarcinoma carcinomaofofthe theleft leftmandible mandiblewith with segmental mandibulectomy and microsurgical reconstruction with a fibula flap, ipsilateral segmental mandibulectomy and microsurgical reconstruction with a fibula flap, ipsilateral cervical cervical lymph node dissection, and postoperative radiotherapy at a dose of 63 Gy. He was treated with lymph node dissection, and postoperative radiotherapy at a dose of 63 Gy. He was treated with autologous fat grafting in the paramandibular and cervical regions with a total of 24 mL of fat (left). autologous fat grafting The postoperative in the paramandibular photograph and cervical at follow-up shows regions with the improvement ofathe total of 24 mL of fat and paramandibular (left). The postoperative photograph cervical deformity (right). at follow-up shows the improvement of the paramandibular and cervical deformity (right). 4. Discussion 4. Discussion Autologous fat grafting is a feasible and valuable technique for patients with seque- Autologous fat grafting is a feasible and valuable technique for patients with sequelae lae following surgery and radiotherapy of primary head and neck cancer tumors [17,24]. following surgery and radiotherapy of primary head and neck cancer tumors [17,24]. How- However, the experience with the use of fat grafting for esthetic and functional improve- ever, the experience with the use of fat grafting for esthetic and functional improvement in ment in these patients is still limited [17–22,25]. The present clinical series is the largest these patients is still limited [17–22,25]. The present clinical series is the largest published published of head and neck cancer patients treated with combined surgery and radiation of head and neck cancer patients treated with combined surgery and radiation therapy of at therapy of at least 50 Gy, undergoing autologous fat grafting for the correction of esthetic least 50 Gy, undergoing autologous fat grafting for the correction of esthetic and functional and functional sequelae of treatment. In all cases, fat grafting was performed after a dis- sequelae of treatment. In all cases, fat grafting was performed after a disease-free interval ease-free interval of 3 years, a time period with the highest risk of tumor recurrence. In of 3 years, a time period with the highest risk of tumor recurrence. In other studies, fat other studies, fat grafting has been performed after a minimum follow-up of 1 year [19,26]. grafting has been performed after a minimum follow-up of 1 year [19,26]. All patients were operated on following the technique described by Coleman [13,22], All patients were operated on following the technique described by Coleman [13,22], although in 60% of cases (n = 14), purification was performed using the Puregraft system although in 60% of cases (n = 14), purification was performed using the Puregraft system as it was considered that this method better preserved the sterility of the circuit and elim- as it was considered that this method better preserved the sterility of the circuit and inated the exposure of fat to air, thus avoiding rapid desiccation and preserving the sur- eliminated the exposure of fat to air, thus avoiding rapid desiccation and preserving the vival of adipocytes. Zhu et al. [27] have compared three preparation methods for fat grafts survival of adipocytes. Zhu et al. [27] have compared three preparation methods for fat in twenty-two donors: gravity separation, Coleman centrifugation, and simultaneous grafts in twenty-two donors: gravity separation, Coleman centrifugation, and simultaneous washing with filtration using the Puregraft system. Grafts prepared by washing with fil- washing with filtration using the Puregraft system. Grafts prepared by washing with tration exhibited significantly reduced blood cell and free lipid content, with significantly filtration exhibited significantly reduced blood cell and free lipid content, with significantly greater adipose tissue viability than other methods. greater adipose tissue viability than other methods. In our study, esthetic and functional outcomes were evaluated at 12 months after fat In our study, esthetic and functional outcomes were evaluated at 12 months after fat grafting using the 4-point scale described by Pulphin et al. [21]. Esthetic improvement was grafting using the 4-point scale described by Pulphin et al. [21]. Esthetic improvement was obtained in 77.5% of patients, being significant in 17.5%, and functional improvement in obtained in 77.5% of patients, being significant in 17.5%, and functional improvement in 89.2%, being significant in 29.7% of patients (significant improvement defined as postop- 89.2%, being significant in 29.7% of patients (significant improvement defined as postoper- erative score of 2 or more points lower than preoperative score). The rate of improvement ative score of 2 or more points lower than preoperative score). The rate of improvement is difficult to compare to other previously published studies because of differences in the is difficult to compare to other previously published studies because of differences in the scoring system for the assessment of results, except for similar findings in a preliminary scoring system for the assessment of results, except for similar findings in a preliminary feasibility study of 12 patients reported by our group [17], and the clinical series of 11 feasibility study of 12 patients reported by our group [17], and the clinical series of 11 pa- patients reported by Pulphin et al. [21] who were the authors that described the evaluation tients reported by Pulphin et al. [21] who were the authors that described the evaluation Cancers 2023, 15, 800 12 of 14 score system. In this study, significant esthetic improvement was obtained in nine patients (81.8%) and functional improvement in seven (63.6%). The total injected volume ranged between 10 and 119 mL, with an average of 48.5 mL, which is a somewhat greater volume than the 23 mL used in our study. No complications were recorded. Patients were followed for a mean of 39.9 months (range 2–88 months), but the resorption of engrafted fat was observed for all patients and was estimated to be approximately 20% to 40%. Because of the importance of the defects, reinjection was performed in six patients. In addition, histological examination of biopsies taken from the treated areas of six patients showed reduction in irradiated morphology patterns, with normal histological structure, high vascular network density, and reduction in fibrosis. In our study, biopsies from fat grafting areas were not obtained. In 2003, Ducic et al. [19] reported data of a retrospective series of 23 patients under- going lipotransfer as part of their craniofacial reconstructive procedure. In this study, six patients underwent a total of eight fat transfer procedures (two procedures in two patients), with good results in five and inadequate results in one. No intraoperative or postoperative complications were observed. Vitagliano et al. [26] described 10 patients with squamous and basal cell carcinomas of the lower or upper lips treated with resection and nasolabial flaps. After 6 months of the primary surgery, 5 of these 10 patients underwent fat grafting to improve persistent depressions and deformities. All treated patients showed favorable cosmetic and favorable results in terms of improvement of their clinical appearance, oral competence, sensitivity, and lip movements. In the study of Karmali et al. [18], 116 pa- tients with head and neck cancer (or benign locally aggressive tumors), with history of radiotherapy in 69% of cases, underwent 190 fat grafting procedures. However, the esthetic outcomes were evaluated in only 17 patients after a mean follow-up of over 2 years, with significant improvements in all of them according to a 5-point Likert scale as evaluated by 10 plastic surgeons and 10 laypersons. Procedural-related complications were observed in 5.1% of cases (infection, oil cysts, fat necrosis) and all four locoregional recurrences were in areas outside of where the fat was grafted. Griffin et al. [28] reported a retrospective analysis of 38 patients who underwent fat grafting, with a history of head and neck malig- nancy, multimodal treatment including at least surgery or radiotherapy, and at least 2-year disease-free survival. Esthetic and functional improvements in their radiation-induced skin fibrosis, and volumetric defects at a follow-up of 32 months were shown in 37 (97%) patients. Lipotransfer was also associated with psychological and quality of life improve- ment. In this study, recurrence was detected in two patients (5.3%) after a mean follow-up of 10 years. Patients’ satisfaction was also evaluated in our study, showing a high degree of satis- faction in terms of esthetic improvement, global satisfaction with treatment, and percentage of patients who would recommend fat grafting to other patients in similar conditions. However, despite the refinement of technical aspects of lipotransfer and encouraging results for improving esthetic and functional sequelae of surgery and radiotherapy in head and neck cancer patients, the variability of fat absorption rates has been recognized as a limitation of the procedure. Although the restoration of altered contour can be achieved reproducibly intraoperatively and in the early postoperative period, the long-term durabil- ity of results remains to be established. Moreover, methods for quantifying the stability of grafted fat have not been standardized. Hörl et al. [29] reported an average volume decline of 55% at 6 months, evaluated by resonance magnetic imaging (RMI) studies in a group of 53 patients with facial defects repaired using autogenous fat tissue. Meier et al. [30] provided three-dimensional volumetric measurements demonstrating an average graft survival of 32% at 16 months after autologous fat grafting for midfacial rejuvenation. How- ever, Coleman [25] indicates that the volume of the graft stabilizes at 3–4 months, and a subtle volumetric decrease may occur up to 1 year after infiltration; beyond that, he states that the volume remains constant for 8–12 years. Quantifiable data of graft survival are rarely reported. In our series, clinical examination and comparison of photographs Cancers 2023, 15, 800 13 of 14 over the follow-up period showed a progressive volumetric decrease, close to 50% of the injected volume. Although recurrences in our study, like others [18,28], occurred in areas far from the treatment site, the use of autologous fat grafting in a bed with a history of cancer involvement is a matter of concern. Further clinical studies with longer follow-up periods are needed to confirm these findings. Finally, patients should be informed regarding the possibility of having to repeat fat grafting in order to achieve more stable and visible results. 5. Conclusions Autologous fat grafting is a valuable technique for improving esthetic and functional sequelae of extensive surgical resections and radiation therapy in patients with malignant head and neck tumors. The technique is a minimally invasive procedure for which a sufficient volume of abdominal fat can be easily obtained. The results of the present study confirm the benefits of fat grafting as a volumetric correction reconstructive strategy, with successful cosmetic and functional outcomes, a high degree of patient satisfaction, low complication rate, and no evidence of being associated with cancer recurrence. Author Contributions: Conceptualization, J.M.-G., J.P.-R. and C.B.-A.; methodology, J.M.-G., J.G.-S., I.Á.-S., J.P.-R. and C.B.-A.; validation, J.M.-G.; formal analysis, J.M.-G. and J.P.-R.; resources, J.P.-R. and C.B.-A.; data curation, J.M.-G.; writing—original draft preparation, J.M.-G.; writing—review and editing, J.M.-G., J.G.-S., I.Á.-S., M.S.-B., J.P.-R. and C.B.-A.; supervision, J.P.-R. and C.B.-A. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Institutional Review Board Statement: The study was conducted in accordance with the Declaration of Helsinki, and approved by the Institutional Review Board of Hospital Universitari Vall d’Hebron (code PR (ATR) 57/2016, date of approval 26 February 2016) (Barcelona, Spain). Informed Consent Statement: Informed consent was obtained from all subjects involved in the study. Data Availability Statement: Clinical data are not shared. Acknowledgments: The authors would like to thank Rosa Pujol Pina, Research Project Manager, for logistic support and Marta Pulido, for editing the manuscript and editorial assistance. Conflicts of Interest: The authors declare no conflict of interest. References 1. Chow, L.Q.M. Head and neck cancer. N. Engl. J. Med. 2020, 382, 60–72. [CrossRef] [PubMed] 2. Mody, M.D.; Rocco, J.W.; Yom, S.S.; Haddad, R.I.; Saba, N.F. Head and neck cancer. Lancet 2021, 398, 2289–2299. [CrossRef] 3. 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