INTRODUCTION
Head and neck cancer care has evolved in recent years in diagnosis, prognosis,
and treatment. Its therapeutic arsenal includes chemotherapy, radiotherapy, and
surgery, whose significant advances are concentrated in reconstructive
microsurgery1,2. Despite this, preserving and restoring
facial symmetry after treatment is still a challenge, significantly compromising
the quality of life of patients3-5.
In the last twenty years, there has been an increase in autologous fat grafts to
treat volume and contour defects in reconstructive cosmetic surgery6-8. Its popularization can be attributed to the material’s wide
availability, the low morbidity of the liposuction site in the donor area, and
the intrinsic benefits as a minimally invasive procedure9-11.
Adipose tissue contains multipotent stromal cells, which secrete various trophic
factors, such as transforming growth factor-beta (TGF-β). Among its
actions, inflammatory and apoptotic suppression and the promotion of
angiogenesis and parenchymal cell mitosis stand out12-15.
The survival and longevity of fat grafts are variable after the procedure.
Methods to increase their survival and that of their cellular constituents are
still under investigation16-18.
Despite the advances, the medical literature lacks studies regarding
complications, safety, and the results of aesthetic and functional improvement
in cancer patients undergoing reconstructive surgery through the use of a fat
graft for head and neck radiodermatitis.
OBJECTIVES
This study aims to review the medical literature regarding the side effects,
benefits, and harms of the therapeutic use of fat grafting in radiodermatitis
after treating head and neck cancer.
METHODS
It is an observational, analytical, and secondary study. The approval of the
Federal University of São Paulo’s research ethics committee was issued under
number 127310/2017. A literature review was carried out following the PRISMA
statement. The descriptors “adipose tissue”, “transplantation”, “neoplasms”,
“head and neck neoplasms” and “radiotherapy” were used; and the non-descriptive
terms “fat grafting”, “fat transplantation” and “fat graft”. The health science
descriptor system validated all descriptors. The PubMed and SciELO databases
were accessed in April 2020 to search for studies published between 01/01/2001
and 01/01/2020 in Portuguese, English, or Spanish.
Chart 1 summarizes the attributes used to
evaluate the studies found when searching the databases. Studies that met the
following criteria were included: (a) randomized or quasi-randomized clinical
trials, prospective/retrospective cohorts, and prospective/retrospective case
series; (b) population undergoing surgical and radiotherapy treatment for head
and neck cancer; (c) disease-free population for at least two years; (d)
intervention with fat grafting technique on the face and neck comparable to
another type of reconstruction or absence of reconstruction; (e) outcome with
analysis of side effects, benefits, and harms of fat grafting. Studies that did
not meet these criteria were excluded.
Chart 1 - PICO question for the inclusion of articles.
| Population |
Patients treated for head and neck cancer, with
radiodermatitis after and disease-free for at least two
years
|
| Intervention |
Fat grafting intervention for radiodermatitis after
head and neck cancer reconstruction
|
| Comparison |
Absence of radiodermatitis due to head and neck
cancer
|
| Outcome |
Analysis of side effects, benefits and harms |
Chart 1 - PICO question for the inclusion of articles.
RESULTS
Altogether, 212 articles were found, 133 in the PubMed database and 79 articles
in the SciELO database. Eighteen articles were selected for a thorough
evaluation, three of which were excluded because they addressed the non-cancer
population19-21, four reviews22-25,
and four experimental studies26-29. Only seven
studies met the inclusion criteria, being these case series4,30-35. No
randomized clinical trials or cohort studies in humans were found. Figure 1 illustrates the inclusion and
exclusion flows of the studies.
Figure 1 - Organization chart of the articles selected for review.
Figure 1 - Organization chart of the articles selected for review.
Phulpin et al.31, in 2009, submitted
eleven patients with remission of head and neck cancer after treatment with
external radiotherapy in the amount of 50 Gy or more to fat grafting. The group
consisted of seven men, and the age ranged from 44 to 73 years (median = 54
years). The postoperative follow-up periods ranged from 2 to 88 months (mean
=
39.9 months). Only two patients were followed for less than 24 months. All
patients tolerated surgery and the immediate postoperative period. Transient
ecchymosis, hyperemia, and edema occurred within the first 48 hours. Clinically,
fat grafts provided structural improvement. However, the resorption of grafted
fat, estimated at approximately 20 to 40%, was observed for all patients. Due
to
the defects’ importance, reinjections were performed in six patients at least
three months after the first injection. In the areas of fat filling, there was
an improvement in the quality of the irradiated skin. Clinically, the skin test
showed greater malleability, the skin being softer and allowing for some
functional improvement. Improvement in the quality of life of all patients has
also been reported.
Rigotti et al.35, in 2007, also studied
fat grafting in the reconstruction of irradiated tissues. The fat was collected
using 2cc syringes and 2mm cannulas after tumescent infiltration. The aspirate
was purified by centrifugation at 2700rpm, and the oil and liquid layers were
discarded. Flow cytometry was used to isolate the stromal vascular fraction,
cultured to obtain mesenchymal stem cells for further study. All stem cells were
induced to differentiate into adipocytes, osteoblasts, or chondrocytes,
depending on the culture medium. Ultrastructural analyzes were performed on the
irradiated tissue before any grafting. It was found that it resembled tissues
affected by chronic ischemia, characterized by damaged adipocytes, decreased
capillary density, and abnormal capillary morphology. After transplantation of
adipose stem cells, the structure of the tissue improved. Based on tissue
analysis at different times in the post-treatment, it was hypothesized that
adipose stem cells release angiogenic factors that lead to neoangiogenesis and,
thus, improve tissue oxygenation. It has also been suggested that most mature
adipocytes are irreversibly damaged in the harvesting process. The real effects
of lipofilling, therefore, would come from the regenerative contributions of
adipose stem cells.
Karmali et al.30, in 2015, conducted a
retrospective analysis of 119 patients undergoing autologous fat grafting for
head and neck cancer reconstruction. The primary endpoint was cancer recurrence.
A total of 190 fat grafting procedures were performed on 116 eligible patients.
The average time between radiotherapy and the first fat grafting was 40.5
months. The average time from cancer surgery for the first fat graft treatment
was 35.1 ± 59 months. The average number of fat grafts per patient was
1.6 ± 1 (range 1 to 6), with an average injection volume of 24.8 ±
20.2mL. The follow-up time was 24 ± 22.3 months. Oncological recurrence
was observed in five patients, two of whom were local, one regional, and two
evolved with metastasis. All local and regional recurrences occurred in areas
without continuity with the injected area. The overall complication rate was
4%
and included two infections, two cysts at the injection site, and one
overcorrection.
Coleman34, in 2006, performed fat grafting
with the lower abdomen as a donor area. Fat grafting was performed in the cross
direction with overlapping planes in the deep and superficial subcutaneous
tissue. The mean volume of fat grafted was 24ml. The average procedure time was
1.8 hours with 21 hours of subsequent hospitalization. All patients underwent
general anesthesia and were followed for one year. It was observed that
injections of fat filled the soft tissue defects and improved the underlying
skin. One case has been reported with radical excision of facial
rhabdomyosarcoma and adjuvant radiotherapy. After lipofilling of the irradiated
area, a sustained increase in facial volume was observed clinically. During its
segment, no complications were observed. The result was assessed using the
Aesthetic and Functional Evaluation System questionnaire, which evaluates the
skin aesthetically by the dimension of the skin’s defect and flexibility and
functionally by quantifying dysphonia dysphagia, changes in the head, and neck
mobility, and changes in swallowing or chewing. There was an aesthetic
improvement in 83% and functional improvement in 92% of the patients. A 25 to
50% fat graft reabsorption was observed through photographic recording in all
patients.
Gutiérrez et al.4, in 2016, conducted a
study to evaluate the duration of the procedure, anesthetic technique, length
of
hospital stay, complications, and the aesthetic and functional result of the
treatment. Inclusion criteria were patients with a history of oral cancer and
surgical and radiotherapy treatment with at least three years of complete
remission; grade 3 or 4 in the Aesthetic and Functional Evaluation System, good
health condition confirmed by preoperative and anesthetic evaluation; and
consent to the consent form. Patients with previous fat grafting or those who
did not have enough adipose tissue for the procedure were excluded. Twelve
patients were included, ten of whom underwent surgical treatment and
radiotherapy and two only for surgery.
Mojallal and Foyatier33, in 2004,
published some cases involving grafting adipose tissue into irradiated tissue.
They reported positive results, including better tissue growth; the improvement
after the autologous fat graft was not limited to the subcutaneous.
In 2018, Karmali et al.32 carried out a
new study with 116 patients (71 women). The average age was 55.9 years (ranging
from 30 to 79 years), and the average body mass index was 26.7 ± 5.7 kg /
m2. Eleven patients (9%) were active smokers. Eighty-one (69%) received
radiation therapy before fat grafting, and two patients (1.7%) received
radiation therapy after the graft. Seventy-six patients (66%) underwent some
form of reconstruction with a free flap for a defect caused by cancer surgery,
while 40 patients (34%) did not undergo a flap and only received autologous fat
grafting for reconstruction. Thirteen patients (11%) underwent neck surgery for
tumors with benign histology, while 103 (89%) had malignancy. Benign tumors were
locally aggressive, indicating radical resection. The average time between the
end of radiotherapy and the first treatment of fat grafting was 40.5 ±
24.3 months. The average time between head and neck cancer surgery and the first
fat grafting was 35.1 ± 59.0 months. The average time between the first
fat grafting treatment and the last follow-up was 35.8 ± 23.1 months.
In total, 190 fat grafting procedures were performed on 116 patients. The average
number of treatments per patient was 1.6 ± 1.0 (range 1 to 6), with an
average injection volume of 24.8 ± 20.2mL per session. All procedures
were performed under general anesthesia. The main donor areas were the abdomen,
hips, and flanks. Three local recurrences, one regional nodal recurrence, and
two distant metastases were observed. Complications related to the procedure
were observed in 5.1% of cases: two cases of infection, oil cysts, and fat
necrosis. There was no morbidity at the donor site. All complications were
resolved without further surgery or hospitalization
DISCUSSION
The effects of radiation on tissues can be classified as acute, consequential, or
delayed. Acute effects are more noticeable in tissues with rapid cell turnover,
such as epithelium or intestine. An increase in the pro-inflammatory cytokines
interleukins 1 and 8 is observed, overexpressing TGF-ß, VEGF (vascular
endothelial growth factor), TNF-α (tumor necrosis factor), and
interferon-γ, and functional cell death. The mechanisms of the
proliferation of stem cells damaged by radiation slowly replace lost cells.
Acute effects can persist and are then classified as consequential36.
Consequent effects continue after the completion of radiotherapy and are more
common in the urinary and intestinal tract, skin, and mucosa tissues. Late
effects, in turn, develop months to years after treatment. Although not fully
understood, the mechanisms integrate a defective cascade in healing: cytokines
infiltrate irradiated tissues, fibrin leaks into the interstitium, collagen is
deposited, and fibrosis occurs ischemia, atrophy, and associated circulatory
damage37. The irradiated
keratinocytes express low molecular keratins 5 and 14 instead of high molecular
keratin cells 1 and 10, expressed in normal wounds. Radiation also disrupts
matrix metalloproteins and tissue-inhibiting metalloproteins, causing deposition
of collagen disorganized by fibroblasts38.
Flacco et al.29, in 2018, found that
tissues chronically damaged by radiation presented epidermal thinning with
homogenized eosinophilic sclerosis of the dermal collagen, large and atypical
fibroblasts, and fibrous thickening with luminal obliteration of the deep
vessels. Such changes are products of the expression of cytokines induced by
radiation and reactive oxygen species, leading to cell apoptosis. Despite the
obvious efficacy of radiotherapy to reduce local recurrence rates in head and
neck cancers, collateral damage to the surrounding soft tissues can be deforming
and debilitating.
Garza et al., In 201426, reported that the
fat graft in the irradiated tissues decreased the dermal thickness and the
collagen content while increasing the vascularization. In his study, human fat
was obtained by liposuction and isolated by gravity. The liposuction was
injected into a rat’s scalp irradiated with 16-gauge needles within 2 hours
after collection. The skin was histologically inspected before and after the
fat
graft. The tissues irradiated before the fat graft showed dermal thickening and
increased collagen with low vascular density, as measured by immunohistochemical
staining of CD31. The retention of fat graft volume was significantly lower in
irradiated tissues. Fat graft survival, assessed with computed tomography (CT),
decreased significantly in irradiated tissues.
The experiences of Luan et al.27, in 2016,
also reported an improvement in the microstructure and vascularization of the
irradiated tissues after the fat graft. In their studies, irradiated mice were
injected with human liposuction with stem cells derived from supplementary
adipocytes. The volume retention of the fat graft was measured using 3D CT
images. Fat grafts and overlapping skin were harvested eight weeks after
injection and examined histologically for vascularity, dermal thickness, and
collagen density. Significantly increased volume retention of fat grafts was
found when they were enriched with adipose stem cells. Interestingly, the
expected histological changes in radiation, such as increased dermal thickness,
hypovascularity, and increased collagen density, were slightly attenuated with
fat grafting. These effects were accentuated with the addition of stem cells.
S
Similarly, Hadad et al.28, in 2010, found
that when a combination of adipose stem cells and platelet-rich plasma was
injected into irradiated tissues, microvascular density increased, and the wound
healing time accelerated significantly.
The review by Haubner et al.24, in 2012,
investigated the possible mechanisms by which adipose stem cells improve wound
healing in irradiated tissue. It has been reported that stem cells derived from
adipose tissue synthesize growth factors and cytokines, such as VEGF,
platelet-derived growth factor (PDGF), and TGF-β, which have accelerated
the healing of irradiated tissues in some cases.
Specifically, the skin, mucosa, and salivary glands are prone to acute radiation
effects on the head and neck. Skin cells are depleted, causing erythema,
desquamation, itching, hypersensitivity, and pain39. Damage to the salivary glands causes dry mouth, edema, and pain.
Mucositis can develop with dysphagia and severe pain that disables food. Damage
caused by radiation to the neck muscles aggravates dysphagia and causes trismus
in severe cases. Other known complications include fibrosis and
osteoradionecrosis40.
The use of fat grafting has been gaining ground in plastic surgery, with
increasingly refined techniques and a better understanding of mesenchymal cells’
action, abundant in fat tissue6-8,21. Autologous
fat transplantation is effective and inexpensive for the correction of facial
deformities, preferable to synthetic implantation since it has more natural
texture, contour, and facial expressions19,24,25,30-34.
Some alternative methods to treat fat grafting used are dermal filling agents,
such as bovine collagen implants, injections and silicone prostheses, or
hyaluronic acid. These, however, lead to a greater local inflammatory reaction
and loss of skin texture. For bone correction, alternatives include bone
autografts, acrylic prostheses, hydroxyapatite, and alloplastic implants.
However, these materials can cause infection or extrusion19,30.
Autologous fat grafting may need new interventions since the entire structure
designed in cosmetic surgery is lost over time due to gravity or tissue
reabsorption19,35. Although lipofilling has been explored
and used for more than a century to improve aesthetic concerns or deformities,
fat injection in head and neck cancer reconstruction is relatively new. There
are published reports of fibrosis regression after lipotransfer. Many studies
are limited by small patient populations, fragmented evidence, and varying
patterns of analysis.
However, motivated by these sporadic reports, Kumar et al.22, in 2016, carried out a systematic review to define the
role and mechanism of lipotransfer in radiation-induced tissue fibrosis. They
emphasized the complex interaction between fibroblasts, fibrogenic cytokines,
and myofibroblasts, leading to various patterns of adhesion formation to
cytoskeletal proteins with consequent scarring fibrosis. Some possible
mechanisms were pointed out: activation of myofibroblasts by the cascade
transformation of growth factor ß1 and connective tissue, fibrogenesis
induced by chronic hypoxia, and radiation-stimulated release reactive oxygen
species and free radicals with direct DNA damage.
The meta-analysis by Krastev et al.25, in
2018, regarding autologous fat injections in facial reconstruction revealed a
general complication rate of 3.7%. The most-reported complications were
asymmetries or irregularities after the injection. Other complications included
infection (0.1%), fatty necrosis (1%) and hematoma (0.6%). Many plastic surgeons
have avoided injecting fat into areas of previous cancer because of cancer
concerns. However, based on current evidence, we believe that the cautious use
of fat grafting is recommended to reconstruct head and neck cancer. More strong
recommendations cannot be made until the publication of studies with a higher
volume of cases and follow-up time. Prospective human studies are lacking for
a
better understanding of the procedure after head and neck cancer surgery. As
the
fifth most common cancer type and causing significant aesthetic and functional
sequelae after surgical treatment, studies are necessary12,26.
No comparative analysis of results were found between fat grafting and other
reconstructive cancer head and neck surgery techniques. Due to the small number
of eligible articles, results are limited.
CONCLUSION
The sequelae of radiation from the head and neck can be challenging. Adipose
tissue can be a valuable complement to improve these complications. Given the
known benefits and the lack of obvious contraindications, we suggest that the
fat graft can be considered carefully for reconstruction when faced with
complications from the head and neck’s radiation.
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1. Federal University of São Paulo, Discipline
of Plastic Surgery, São Paulo, SP, Brazil.
Corresponding author: Roney Gonçalves
Fechine-Feitosa, Rua Napoleão de Barros, 715, 4º andar, Vila
Clementino, São Paulo, SP, Brazil. Zip Code: 04024-002. E-mail:
roneyfechine@gmail.com
Article received: June 21, 2020.
Article accepted: January 10, 2021.
Conflicts of interest: none
