Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Late Soft Tissue Complications of Head and Neck Cancer Therapy: Lymphedema and Fibrosis

Late Soft Tissue Complications of Head and Neck Cancer Therapy: Lymphedema and Fibrosis Abstract Head and neck cancer and its treatment result in soft tissue damage secondary to lymphedema and fibrosis. Lymphedema is the result of pathological accumulation of interstitial fluid in tissues. It is caused by the inability of the lymphatic system to transport lymph fluid from the tissues to the central circulatory system and is manifested clinically by tissue swelling. Fibrosis is defined as an overaccumulation of fibrotic tissues within the skin and soft tissues after a single or repetitive injury and is characterized by hardening of the soft tissues with associated loss of elasticity. Lymphedema and fibrosis are common yet overlooked late effects of head and neck cancer and its therapy. They may result in profound long-term symptom burden, loss of critical functions, and altered quality of life. The following review will discuss the current pathobiology, clinical manifestations, and future directions for research related to lymphedema and fibrosis. Head and neck cancer (HNC) and its treatment results in acute and chronic soft tissue damage due to direct tumor infiltration, surgical extirpation of the tumor and surrounding tissues, and direct radiation injury (1,2). Recent investigation has underscored the important contribution of lymphedema and fibrosis (LEF) as critical manifestations of soft tissue damage in the HNC population (3–5). Soft tissues (which include fat, muscle, fibrous tissue, blood vessels, lymph vessels, and peripheral nerves) serve to connect, support, or surround other structures. Damage to soft tissues may result in profound long-term symptom burden, loss of critical functions, and altered quality of life. The exact impact varies and is determined by the site and severity of soft tissue involvement. For example, damage to the upper aerodigestive tract can result in alterations in key functions such as speech, swallowing, and breathing. Unfortunately, our understanding of the pathobiology and impact of tumor- and treatment-related soft tissue damage remains incomplete. The following manuscript describes the pathobiology of LEF, the clinical manifestations, and future directions for research. Pathobiology: Current Paradigm and New Frontiers Lymphedema The lymphatic system is a component of both the circulatory and immune systems and consists of lymph vessels and lymphatic organs (6,7). Lymph vessels return the capillary ultrafiltrate and escaped plasma proteins from most tissues back to the circulatory system (8). The lymphatic organs are part of the body’s defense system and thus play a role in the detection of pathogens, exogenous cells, and proteins, as well as malignant or degenerative cells (7). The prime functions of the lymphatic system include maintenance of interstitial fluid homeostasis, immune trafficking (transportation of antigen, antigen-presenting cells, and other immune cells to the lymphoid organs), and lipid absorption and transport from the gastrointestinal tract (6,9). Therefore, a fully functioning lymphatic system is essential to overall health (10). Lymphedema is the pathological accumulation of fluid in interstitial tissues. It results from the inability of the lymphatic system to transport lymph fluid from the tissues to the central circulatory system. This manifests clinically as tissue swelling, the hallmark of lymphedema. Lymphedema may be caused by developmental abnormalities (primary lymphedema) or external trauma to the lymphatic system (secondary lymphedema) (6,7). In the past few decades, the understanding of the lymphatic system has improved substantially; however, the understanding of pathobiological processes of lymphedema is still not well established. Gross Physiological Manifestations After a pathophysiologic insult, the host system must respond to the soft tissue damage. When soft tissue damage is mild, compensatory mechanisms and repair processes are activated, resulting in the regeneration of damaged tissue and return of adequate lymph flow (7,11). In this setting, injury to the lymphatic system may be subclinical and asymptomatic. If the soft tissue damage is more severe, the host’s capacity to compensate for or repair tissue damage may be overwhelmed, resulting in clinically evident soft tissue swelling, due to fluid accumulation in the interstitial spaces (early-stage lymphedema) (7,11). The trajectory of LEF in HNC has been well described in a large, prospective longitudinal study. A substantial percentage of patients had some degree of internal or external lymphedema, though generally mild, before starting radiation. The rates of both internal and external lymphedema increased up until 12 months posttreatment, at which time 95.5% of patients had external lymphedema, 89.4% had internal lymphedema, and 76.1% of patients had both. Two-thirds of patients developed moderate to severe lymphedema at some point across the trajectory of treatment and recovery. Clinically, this subset of patients would require referral for assessment by a lymphedema therapist. Untreated, the soft tissue swelling may subside spontaneously over time as tissues repair or, alternatively, fibrofatty scar tissue may deposit in the interstitial space (late stage lymphedema). Adequate lymphedema therapy may hasten the regression of soft tissue swelling through the return of lymph fluid into the circulatory system. This may hypothetically decrease deposition of fibrofatty scar tissue. The occurrence of fibrofatty scar tissue deposition is usually irreversible, resulting in permanent alterations in tissue texture and function (7,11,12) (Figure 1). Figure 1. View largeDownload slide Lymphedema and fibrosis in head and neck cancer Figure 1. View largeDownload slide Lymphedema and fibrosis in head and neck cancer Soft tissue fibrosis is manifested clinically as tissue that is firm to touch without evidence of soft tissue swelling. Tissues are often described as woody in texture. Although often thought of as a late effect of therapy, current data would indicate that fibrosis may manifest early in the course of cancer therapy. At 3 months posttreatment, 74.1% of patients had fibrosis on examination. The incidence of soft tissue fibrosis peaks at a later time point than either internal or external lymphedema (between 12 and 18 months). Recovery from fibrosis is limited. Indeed, fibrosis may continue to worsen for years after therapy is completed, resulting in late dysphagia, tracheal stenosis, and markedly abnormal posture. Patients treated with primary surgery have a higher rate of fibrosis than those treated with primary radiation-based techniques (odds ratio = 3.33, P = .02, 95% confidence interval = 1.26 to 8.76) (12). Histological Changes Histological assessment of lymphedema in animal and human models reveals dramatic inflammatory and architectural changes in the skin and soft tissues. In a murine model of surgically induced tail lymphedema, the following histological changes were noted: (1) an overall increase in cellularity; (2) an increase in the number of observed fibroblasts, histiocytes, and neutrophils; (3) hyperkeratosis and spongiosis of the epidermis; (4) elongated dermal papillae; (5) expansion of the tissue between the bone and epidermis; and (6) an increase in the number and size of cutaneous lymphatic vessels as identified by lymphatic vessel endothelium hyaluronan receptor staining (13). Similarly, early histological studies of human extremity lymphedema identified the following: (1) obliteration of lymphatic collectors; (2) hyperkeratosis of epidermis; (3) immune cell infiltrates of epidermis, dermis, and subcutaneous tissue; (4) fibrosis of the peri-lymphatic tissues and muscular fascia; and (5) proliferation of skin and fat tissue (6). More recent studies using normal skin specimens as control subjects demonstrated the following histologic changes on the lymphedematous skin of the human extremity: (1) a notable increase in the cellularity, particularly in the epidermis and dermal-epidermal junction; (2) prominent perivascular inflammatory infiltrates; (3) thickening and obliteration of the dermis; (4) dilated microvascular structures in the upper dermis; and (5) evidence of positive microvascular lymphatic remodeling (positive structures of lymphatic vessel endothelium hyaluronan receptor-1) (14). Available data are limited to lymphedema developing in tissues distal to the site of tissue damage. One example would be patients with breast cancer who undergo axillary lymph node dissection and subsequently develop lymphedema in the upper extremity distal to the tissue damage. By contrast, HNC patients develop lymphedema distal to the site of injury (eg, cheeks and periorbital region) as well as within tissue directly (eg, neck) affected by surgery and/or radiation. Whether lymphedema results in different histopathological changes due to direct tissue damage is unknown. Cellular and Molecular Discoveries Recent advances in knowledge of tissue repair at the cellular and molecular levels have enhanced our understanding of underlying mechanisms of lymphedema, particularly our understanding of the role of lymph stasis. Studies have been conducted in both murine models as well as humans with lymphatic dysfunction. These studies have elucidated several key pathobiological processes that may contribute to the development and progression of lymphedema, including inflammation, fibrosis, lymphangiogenesis, and adipose deposition. Lymphatic fluid stasis results in a dramatic increase in the number of mixed inflammatory cells within all layers of the affected tissues (15). In the murine lymphedema model, a statistically significant increase in T-helper, T-regulatory, and dendritic cells, as well as neutrophils and macrophages, can be observed (16). In humans with a lymphedematous upper extremity, there is a statistically significant increase in the number of CD4+ cells compared with normal upper extremity (11). Furthermore, the degree of CD4+ cell inflammation correlates with the severity of lymphedema (11). Additionally, a study in the human extremity with lymphedema reported that macrophages migrate to lymphedematous tissues and differentiate into M2 macrophages. Macrophages have an antifibrotic role in lymphedema and either directly or indirectly regulate and control CD4+ cell accumulation and T-helper 2 (Th2) differentiation (17). The presence of CD4+ cells appears to be necessary for development of fibrosis and lymphatic dysfunction. Depletion of CD4+ cells markedly decreases the pathological changes associated with lymphedema, including inflammation, fibrosis, and adipose deposition. In addition, depletion of CD4+ cells was associated with a statistically significant increase in lymphangiogenesis in the murine lymphedema model (16). The expression of Th2 cytokines was statistically significantly increased by lymphatic fluid stasis. Inhibition of Th2 differentiation decreases initiation and progression of fibrosis and improves lymphatic function (11). Advances in understanding of the development and growth of lymphatic vessels have revealed that the lymphangiogenesis in human embryonic tissue is mainly regulated by the vascular endothelial growth factor-C (VEGF-C), vascular endothelial growth factor-D (VEGF-D), and vascular endothelial growth factor receptor-3 signaling systems (18,19). The identification of these important molecular mediators provides a foundation for a better understanding of underlying pathobiological process of lymphangiogenesis in lymphedema. Studies show that regulation of lymphangiogenesis after lymphatic fluid stasis is a complicated process (11,17,20). Lymphatic fluid stasis in the murine model results in increased expression of pro-lymphangiogenic cytokines (VEGF-A, VEGF-C, and hepatocyte growth factor) as well as increased expression of anti-lymphangiogenic cytokines (transforming growth factor-β1 [TGF-β1], endostatin, and interferon-γ). These results support lymphatic fluid stasis as a driver of cytokine expression and an activator of both pro- and anti-lymphangiogenic cytokines that, in turn, regulate lymphangiogenesis (20). Therefore, lymphatic regeneration appears to depend on the delicate balance between pro- and anti-lymphangiogenic molecular signals after lymphatic fluid stasis or lymphatic injury. Adipose deposition is a defining characteristic of late-stage lymphedema (8). Emerging evidence suggests that disturbances in lymphatic vascular function have a profound impact on cutaneous adipose biology (15). Prospero homeobox 1 (Prox1) is essential in the development of lymphatic endothelial cells and may be a link between lymphatic function and adipose tissue deposition. Mice with Prox1 haploinsufficiency have abnormal lymph leakage due to a disruption in lymphatic vascular integrity that promotes adipose tissue accumulation. This lymphatic-specific Prox1 deletion model supports adipose deposition development via two phases: first, increased storage of leaking lipids in existing adipocytes causes adipocyte hypertrophy; and second, once the adipocytes reach maximum lipid storage capacity, the promotion of preadipocyte differentiation results in an increased number of mature adipocytes and adipocyte hyperplasia (21). Another study using the murine model found that lymphatic fluid stasis resulted in (1) an increased number of adipocytes and statistically significant subcutaneous fat disposition, (2) inflammation (eg, a marked mononuclear cell infiltration and increased number of monocytes/macrophages), and (3) fibrosis (eg, collagen fiber deposition) within the subcutaneous fat compartment (22). Macrophages trafficking to large adipose deposits have been described both in animal models and humans (23). These macrophages may be recruited to remove adipocyte cell debris resulting from cellular necrosis (24). Macrophages also produce multiple proinflammatory and procoagulant chemokines in adipose tissue (25). In the setting of lymph stasis and tissue injury, these chemokines may play an essential role in the differentiation of local mesenchymal stem cell populations into fibroblasts and adipocytes (24). Interestingly, a recent study in a murine model provides a better understanding of the relationship between obesity and lymphatic dysfunction. The study findings show that obese mice have impaired lymphatic function. Lymphatic dysfunction can be amplified by ongoing lymphatic injury associated with chronic inflammation, fibrosis, and ongoing adipose deposition (26). Biomarkers Investigators have explored possible biomarkers for lymphedema. A study cohort encompassing both primary and secondary lymphedema across a broad spectrum of etiologies found that a panel of six biomarkers was able to distinguish lymphedema subjects from healthy normal control subjects. The panel included the following: basic fibroblast growth factor (regulates lymphangiogenesis), interleukin 4 (IL-4, regulates inflammation), interleukin 10 (IL-10, regulates inflammation), tumor necrosis factor beta (regulates inflammation); TGF-β (regulates fibrosis), and leptin (regulates adipocytokine signaling) (14). Interleukin 6 (IL-6) did not demonstrate clinical predictive value. Conversely, a subsequent study evaluating serum and tissue IL-6 levels demonstrated increased levels in patients with postmastectomy lymphedema (27). Importantly, all seven of these proteins are known to be involved in lymphangiogenesis, inflammation, fibrosis, adipocytokine signaling, and adipose deposition. Clearly, more studies are needed to establish consistent and useful biomarkers for differentiating individuals with and without early stages of lymphedema, when clinical exam and imaging studies may lack sensitivity. Furthermore, investigations are warranted to determine whether these identified biomarkers will be able to detect early and latent lymphedema, a point along the trajectory where interventions may be more effective. Genetic Predisposition in Secondary Lymphedema Studies conducted in humans with secondary upper extremity lymphedema indicate that genetic predisposition and linked phenotypes may contribute to the risk of secondary lymphedema. Compared with control subjects, breast cancer patients with upper extremity secondary lymphedema had genetic mutations in hepatocyte growth factor or high-affinity hepatocyte growth factor receptors (hepatocyte growth factor or MET) and in connexin 47 (28,29). Another study reported that four genes (lymphocyte cytosolic protein 2 [rs315721], neuropilin-2 [rs849530], protein tyrosine kinase [rs158689], vascular cell adhesion molecule 1 [rs3176861]) and three haplotypes (Forkhead box protein C2 [haplotype A03], neuropilin-2 [haplotype F03], vascular endothelial growth factor-C [haplotype B03]) (30) play a role in lymphangiogenesis and angiogenesis. More recently, three pro- and anti-inflammatory cytokine genes were shown to be associated with the development of upper extremity secondary lymphedema: IL-4 (rs2227284), IL-10 (rs1518111), and nuclear kappa factor beta 2 (rs1056890) (31). Further studies are needed to evaluate whether these genes contribute to the development of secondary lymphedema in individuals with HNC. Fibrosis Fibrosis results from injury to soft tissues that initiates an inflammatory response following which mesenchymal cells, such as, fibroblasts and myofibroblasts are activated. These effector cells deposit extracellular matrix proteins that accumulate within the skin and soft tissues resulting in the characteristic hardening of tissues and loss of elasticity (32). In the extreme, fibrosis may take on a “woody” texture or lead to soft tissue contracture resulting in marked decrease in function or range of motion. Unlike lymphedema, tissue swelling is generally lacking. Furthermore, unlike the late fibrofatty scar tissue seen in patients with long-standing lymphedema, lymphatic vessel damage is not a prominent component of the pathobiology. Fibrosis is one of the most common long-term toxicities of HNC therapy. Surgical excision and reconstruction is considered a singular traumatic event; thus, surgery-induced fibrosis is usually a normal part of the wound-healing process (33). In addition, radiotherapy causes repeated damage to tissues resulting in an increased production of fibroblasts from bone marrow progenitors in the affected areas and excess deposition of extracellular matrix. Although the exact pathobiological processes of radiation-induced fibrosis (RIF) are not fully understood, research advances have provided some understanding of underlying mechanisms of RIF in the cellular and molecular levels, and genetic susceptibility. Although both surgery and radiation may result in fibrosis and associated soft tissue function loss, much of the recent work pertains to radiation therapy and will thus be the topic of further discussion. Cellular and Molecular Findings Acute effects of radiation are often defined as those that occur within 90 days of treatment. Radiation results in tissue injury via a number of pathways, including DNA damage and the generation of free radicals (eg, reactive oxygen species and reactive nitrogen species) (34–36). These may in turn damage cellular components, including proteins, nucleic acids, and lipids (37,38). Injured cells subsequently release molecules that upregulate the migration of inflammatory cells (eg, neutrophils, monocytes, and lymphocytes) (34,39) to the injured sites. Inflammatory cells release chemokines, cytokines, and growth factors that further contribute to the pathogenesis of acute tissue injury (40). For example, neutrophils release tumor necrosis actor alpha, IL-1, and IL-6 that exaggerate local inflammation (41,42). Monocytes, a key component of the inflammatory response, differentiate into M1 and M2 macrophages (43). M2 macrophages secrete platelet-derived growth factor, stimulating the migration of fibroblasts into the injured tissues (44). The chronic effects of radiation on soft tissues are related to several pathways. First, TGF-β appears to play a key role in this process (45). TGF-β is a regulatory protein and exerts a powerful fibrogenic action through the following: (1) inducing proliferation of collagen-producing postmitotic fibrocytes from their progenitor fibroblasts (3); (2) differentiation of fibroblasts into myofibroblasts that secrete excess collagen, fibronectin, and proteoglycans that are responsible for the increased stiffness and thickening of the tissue; and (3) dysregulation of matrix metalloproteinase activity and upregulation of tissue inhibitors of metalloproteinases contributing to the already excessive extracellular matrix deposition (33). TGF-β has been found to be upregulated in fibrotic tissue of irradiated patients but not in nonirradiated control subjects (46). Moreover, radiation causes endothelial cell apoptosis and increased endothelial permeability, thus activating the coagulation system and leading to local thrombin formation intravascularly and extravascularly (eg, the extracellular matrix). The abnormal accumulation of thrombin in both the intravascular and extravascular compartments is in part responsible for the progressive fibrotic tissue sclerosis that triggers the late toxicity of radiation therapy (40). In addition, bone marrow-derived cells (BMDCs) appear to play an integral role in recovery. The BMDCs are drawn to sites of radiation damage and stimulate vessel formation and repair via the release of angiogenic factors. Similar to those of BMDCs, adipose-derived stem cells appear to have wound-healing effects through promoting angiogenesis and stimulating dermal fibroblast proliferation during the re-epithelialization phase of wound healing (47,48). Genetic Predisposition Clinical observation indicates that normal tissue radiosensitivity varies from patient to patient (49). This observation has led to the hypothesis that an individual’s normal tissue response to radiation is partly determined by genetic variation. The role of specific genes and single nucleotide polymorphisms (SNPs) in RIF has been investigated in cancer populations with results supporting the associations between specific genes with radiation sensitivity and tissue repair. These include (1) TGF-β, which contributed to the initiation, development, and persistence of radiation fibrosis (50–53); (2) x-ray repair cross-complementing proteins 1, a base excision repair gene that has been associated with several radiation toxicities (eg, fibrosis, severe skin reaction) (54,55); and (3) ataxia-telangiectasia mutated gene, which has been linked with normal tissue radiosensitivity (eg, subcutaneous fibrosis) (56). In HNC patient populations, several other genes and SNPs have been found to contribute to RIF (54–65) (Table 1). Table 1 Summary of studies examining genetic variants associated with radiation-induced soft tissue toxicity Primary site and tumor Design Sample size (No.) Country and centers (participants recruited) Clinical endpoint and tissues affected Genes and SNPs References Head and neck cancer (47%); & breast cancer Retrospective, case-control Case: 16 Control: 18 Switzerland, single center Severe radiation-induced sequelae (eg, subcutaneous fibrosis) ATM, SOD2, XRCC1 and XRCC3, TGF-β1, RAD21 Azria et al., 2008 (49) Nasopharyngeal cancer Retrospective 120 China, Hong Kong, single center Neck fibrosis XRCC3 Cheuk et al., 2014 (50) Nasopharyngeal cancer Retrospective, case-control Case: 48 Control: 107 Saudi Arabia, single center Subcutaneous and deep tissue fibrosis HDM2, TGF-β1, XRCC1 Alsbeih et al., 2013 (51) Head and neck cancer Retrospective 6 US Single center Submental fibrosis CAV-1, COLLA1, TIMP1, MMP14, IL-13, IL-8, CXCL10, CCL7, MX1, IFIT2, CTGF, ET-1 Krisciunas et al., 2015 (52) Head and neck cancer Retrospective 78 Germany Single center Radiation-induced skin fibrosis and angiogenesis α-PC and TGF-β1 Koerdt et al., 2015 (54) Various cancers (47% head and neck cancer) Prospective Case: 179 Control: 26 U.S Single center Radiation-induced late normal tissue toxicity HMOX1, NFE2L2, TGF-β1 Alam et al., 2015 (55) Head and neck cancer Prospective 62 United Kingdom,Single center Trismus TGF-β1 Lyons et al., 2013 (56) Head and neck cancer Retrospective Case: 8 Control: 8 Germany Single center Radiation-induced late normal tissue toxicity (eg, fibrosis, xerostomia) Chromosomal damage in lymphocytes Borgmann et al., 2002 (53) Nasopharyngeal carcinoma Prospective 114 China, single center Acute dermatitis and mucositis XRCC1 Li et al., 2013 (47) Head and neck cancer Prospective 101 Italy, multi-site Acute reactions (mucositis, skin erythema, and dysphagia) XRCC1 and RAD51 Pratesi et al., 2011 (57) Nasopharyngeal Cancer Retrospective, case-control Case: 30 Control: 30 Saudi Arabia, single center Subcutaneous and deep tissue fibrosis TGF-β1, XRCC1 Alsbeih et al., 2010 (58) Nasopharyngeal Cancer Prospective, case-control Case: 16 Control: 16 Saudi Arabia, single center Subcutaneous and deep tissue fibrosis ND3 (mitochondrial DNAa)-Oxidative metabolism pathway Alsbeih et al., 2009 (59) Primary site and tumor Design Sample size (No.) Country and centers (participants recruited) Clinical endpoint and tissues affected Genes and SNPs References Head and neck cancer (47%); & breast cancer Retrospective, case-control Case: 16 Control: 18 Switzerland, single center Severe radiation-induced sequelae (eg, subcutaneous fibrosis) ATM, SOD2, XRCC1 and XRCC3, TGF-β1, RAD21 Azria et al., 2008 (49) Nasopharyngeal cancer Retrospective 120 China, Hong Kong, single center Neck fibrosis XRCC3 Cheuk et al., 2014 (50) Nasopharyngeal cancer Retrospective, case-control Case: 48 Control: 107 Saudi Arabia, single center Subcutaneous and deep tissue fibrosis HDM2, TGF-β1, XRCC1 Alsbeih et al., 2013 (51) Head and neck cancer Retrospective 6 US Single center Submental fibrosis CAV-1, COLLA1, TIMP1, MMP14, IL-13, IL-8, CXCL10, CCL7, MX1, IFIT2, CTGF, ET-1 Krisciunas et al., 2015 (52) Head and neck cancer Retrospective 78 Germany Single center Radiation-induced skin fibrosis and angiogenesis α-PC and TGF-β1 Koerdt et al., 2015 (54) Various cancers (47% head and neck cancer) Prospective Case: 179 Control: 26 U.S Single center Radiation-induced late normal tissue toxicity HMOX1, NFE2L2, TGF-β1 Alam et al., 2015 (55) Head and neck cancer Prospective 62 United Kingdom,Single center Trismus TGF-β1 Lyons et al., 2013 (56) Head and neck cancer Retrospective Case: 8 Control: 8 Germany Single center Radiation-induced late normal tissue toxicity (eg, fibrosis, xerostomia) Chromosomal damage in lymphocytes Borgmann et al., 2002 (53) Nasopharyngeal carcinoma Prospective 114 China, single center Acute dermatitis and mucositis XRCC1 Li et al., 2013 (47) Head and neck cancer Prospective 101 Italy, multi-site Acute reactions (mucositis, skin erythema, and dysphagia) XRCC1 and RAD51 Pratesi et al., 2011 (57) Nasopharyngeal Cancer Retrospective, case-control Case: 30 Control: 30 Saudi Arabia, single center Subcutaneous and deep tissue fibrosis TGF-β1, XRCC1 Alsbeih et al., 2010 (58) Nasopharyngeal Cancer Prospective, case-control Case: 16 Control: 16 Saudi Arabia, single center Subcutaneous and deep tissue fibrosis ND3 (mitochondrial DNAa)-Oxidative metabolism pathway Alsbeih et al., 2009 (59) ATM = Ataxia-telangiectasia mutated; CAV-1 = Caveolin-1; CCL7 = Chemokine C-C motif ligand 7; COLLA1 = Collagen type I alpha I; CTGF = Connective tissue growth factor; CXCL10 = C-X-C motif chemokine 10; ET-1 = Endothelin-1; HMOX1 = Heme oxygenase 1; IFIT2 = Interferon-induced protein with tetratricopeptide repeats 2; MMP14 = Matrix metalloproteinase-14; MX1 = MX dynamin-like GTPase I; ND3 = Mitochondrially encoded NADH dehydrogenase subunit 3 gene; NFE2L2 = Encoding nuclear regulatory factor-2; α-PC = α-procollagen; RAD21 = Double-strand-break repair protein rad21 homolog; SNPs = Single-nucleotide polymorphisms; SOD2 = Superoxide dismutase 2; TGF-β1 = Transforming growth factor beta 1; TIMP1 = TMP metallopeptidase inhibitor 1; XRCC1 and XRCC3 = X-ray repair cross-complementing proteins 1 and 3. View Large Table 1 Summary of studies examining genetic variants associated with radiation-induced soft tissue toxicity Primary site and tumor Design Sample size (No.) Country and centers (participants recruited) Clinical endpoint and tissues affected Genes and SNPs References Head and neck cancer (47%); & breast cancer Retrospective, case-control Case: 16 Control: 18 Switzerland, single center Severe radiation-induced sequelae (eg, subcutaneous fibrosis) ATM, SOD2, XRCC1 and XRCC3, TGF-β1, RAD21 Azria et al., 2008 (49) Nasopharyngeal cancer Retrospective 120 China, Hong Kong, single center Neck fibrosis XRCC3 Cheuk et al., 2014 (50) Nasopharyngeal cancer Retrospective, case-control Case: 48 Control: 107 Saudi Arabia, single center Subcutaneous and deep tissue fibrosis HDM2, TGF-β1, XRCC1 Alsbeih et al., 2013 (51) Head and neck cancer Retrospective 6 US Single center Submental fibrosis CAV-1, COLLA1, TIMP1, MMP14, IL-13, IL-8, CXCL10, CCL7, MX1, IFIT2, CTGF, ET-1 Krisciunas et al., 2015 (52) Head and neck cancer Retrospective 78 Germany Single center Radiation-induced skin fibrosis and angiogenesis α-PC and TGF-β1 Koerdt et al., 2015 (54) Various cancers (47% head and neck cancer) Prospective Case: 179 Control: 26 U.S Single center Radiation-induced late normal tissue toxicity HMOX1, NFE2L2, TGF-β1 Alam et al., 2015 (55) Head and neck cancer Prospective 62 United Kingdom,Single center Trismus TGF-β1 Lyons et al., 2013 (56) Head and neck cancer Retrospective Case: 8 Control: 8 Germany Single center Radiation-induced late normal tissue toxicity (eg, fibrosis, xerostomia) Chromosomal damage in lymphocytes Borgmann et al., 2002 (53) Nasopharyngeal carcinoma Prospective 114 China, single center Acute dermatitis and mucositis XRCC1 Li et al., 2013 (47) Head and neck cancer Prospective 101 Italy, multi-site Acute reactions (mucositis, skin erythema, and dysphagia) XRCC1 and RAD51 Pratesi et al., 2011 (57) Nasopharyngeal Cancer Retrospective, case-control Case: 30 Control: 30 Saudi Arabia, single center Subcutaneous and deep tissue fibrosis TGF-β1, XRCC1 Alsbeih et al., 2010 (58) Nasopharyngeal Cancer Prospective, case-control Case: 16 Control: 16 Saudi Arabia, single center Subcutaneous and deep tissue fibrosis ND3 (mitochondrial DNAa)-Oxidative metabolism pathway Alsbeih et al., 2009 (59) Primary site and tumor Design Sample size (No.) Country and centers (participants recruited) Clinical endpoint and tissues affected Genes and SNPs References Head and neck cancer (47%); & breast cancer Retrospective, case-control Case: 16 Control: 18 Switzerland, single center Severe radiation-induced sequelae (eg, subcutaneous fibrosis) ATM, SOD2, XRCC1 and XRCC3, TGF-β1, RAD21 Azria et al., 2008 (49) Nasopharyngeal cancer Retrospective 120 China, Hong Kong, single center Neck fibrosis XRCC3 Cheuk et al., 2014 (50) Nasopharyngeal cancer Retrospective, case-control Case: 48 Control: 107 Saudi Arabia, single center Subcutaneous and deep tissue fibrosis HDM2, TGF-β1, XRCC1 Alsbeih et al., 2013 (51) Head and neck cancer Retrospective 6 US Single center Submental fibrosis CAV-1, COLLA1, TIMP1, MMP14, IL-13, IL-8, CXCL10, CCL7, MX1, IFIT2, CTGF, ET-1 Krisciunas et al., 2015 (52) Head and neck cancer Retrospective 78 Germany Single center Radiation-induced skin fibrosis and angiogenesis α-PC and TGF-β1 Koerdt et al., 2015 (54) Various cancers (47% head and neck cancer) Prospective Case: 179 Control: 26 U.S Single center Radiation-induced late normal tissue toxicity HMOX1, NFE2L2, TGF-β1 Alam et al., 2015 (55) Head and neck cancer Prospective 62 United Kingdom,Single center Trismus TGF-β1 Lyons et al., 2013 (56) Head and neck cancer Retrospective Case: 8 Control: 8 Germany Single center Radiation-induced late normal tissue toxicity (eg, fibrosis, xerostomia) Chromosomal damage in lymphocytes Borgmann et al., 2002 (53) Nasopharyngeal carcinoma Prospective 114 China, single center Acute dermatitis and mucositis XRCC1 Li et al., 2013 (47) Head and neck cancer Prospective 101 Italy, multi-site Acute reactions (mucositis, skin erythema, and dysphagia) XRCC1 and RAD51 Pratesi et al., 2011 (57) Nasopharyngeal Cancer Retrospective, case-control Case: 30 Control: 30 Saudi Arabia, single center Subcutaneous and deep tissue fibrosis TGF-β1, XRCC1 Alsbeih et al., 2010 (58) Nasopharyngeal Cancer Prospective, case-control Case: 16 Control: 16 Saudi Arabia, single center Subcutaneous and deep tissue fibrosis ND3 (mitochondrial DNAa)-Oxidative metabolism pathway Alsbeih et al., 2009 (59) ATM = Ataxia-telangiectasia mutated; CAV-1 = Caveolin-1; CCL7 = Chemokine C-C motif ligand 7; COLLA1 = Collagen type I alpha I; CTGF = Connective tissue growth factor; CXCL10 = C-X-C motif chemokine 10; ET-1 = Endothelin-1; HMOX1 = Heme oxygenase 1; IFIT2 = Interferon-induced protein with tetratricopeptide repeats 2; MMP14 = Matrix metalloproteinase-14; MX1 = MX dynamin-like GTPase I; ND3 = Mitochondrially encoded NADH dehydrogenase subunit 3 gene; NFE2L2 = Encoding nuclear regulatory factor-2; α-PC = α-procollagen; RAD21 = Double-strand-break repair protein rad21 homolog; SNPs = Single-nucleotide polymorphisms; SOD2 = Superoxide dismutase 2; TGF-β1 = Transforming growth factor beta 1; TIMP1 = TMP metallopeptidase inhibitor 1; XRCC1 and XRCC3 = X-ray repair cross-complementing proteins 1 and 3. View Large There are numerous limitations to available data, particularly with reference to the HNC population. First, most of the studies were conducted in a single center with small sample sizes. Thus, studies are needed to expand and replicate these findings. Clearly, the number of studies evaluating RIF in HNC patients is limited compared with the plethora of studies in other cancers (eg, breast and lung cancers). In addition, although it is valuable to identify genes and SNPs relying on the candidate gene approach, it is critical to employ a genome-wide approach in which the entire genome is screened for statistically significantly altered allele frequencies based on the linkage disequilibrium concept. The genome-wide approach is essential to enable reliable interpretation of study findings, especially if these findings are to be translated into biomarkers and used to determine personalized radiotherapy strategy (66). Despite the identification of an association of individual genes and SNPs with radiation sensitivity and related tissue damage, our understanding of the pathobiology of RIF remains incomplete at best. This is due in part to the involvement of numerous pathways, many of which have yet to be fully explored, the intricacy of the interactions between pathways and their positive and negative regulators, and the added complexity derived from human variability. Pathways yet to be thoroughly investigated that could be hypothetically involved in normal tissue radiosensitivity include oxidative stress responses, activation of cell cycle checkpoints, inflammation, and apoptosis, among others (67). Clinical Presentation: Head and Neck Lymphedema and Fibrosis Due to the multimodal tissue insult experienced by HNC patients, LEF may coexist. A primary fibrotic process is readily identified clinically because of the general lack of overt swelling in the tissues. Unfortunately, the lack of tissue swelling cannot exclude the possibility of subclinical lymphedema. Conversely, the presence of tissue swelling indicative of lymphedema does not exclude the possibility of concurrent prototypical fibrosis. Because it is clinically difficult to distinguish the relative contribution of LEF in most patients, these two physiological processes have been combined into the term LEF. LEF encompasses the clinical spectrum from prominent reducible swelling with minimal fibrosis all the way through those patients with fibrosis associated with tissue contracture and atrophy (Table 1). Incidence and Prevalence All data on the incidence and prevalence of LEF are based on clinical physical exams using available measurement tools. Previously available tools are conceptually flawed (68); thus, much of the available data underrepresent the incidence and severity of both LEF. To address this unmet need, new methods for measuring LEF in the head and neck population are under development (69). Whereas early studies suggested that the incidence of secondary lymphedema after HNC treatment varies from 12% to 54% (70), a more rigorous cross-sectional report found that 75% of HNC patients after more than 3 months of posttreatment had secondary lymphedema (71). The high incidence of LEF has been confirmed by a recent prospective report indicating that almost 100% of HNC patients develop LEF at some point during HNC treatment and recovery. Location and Anatomical Sites LEF affects both external structures (eg, face, neck, shoulders) (72,73) and internal structures (eg, larynx, pharynx) (74,75). LEF may be confined to internal or external structures, or it may involve both (combined LEF) (71). Because radiation therapy and some surgical procedures may cause a pan-tissue inflammatory process, it is not surprising that a statistically significant percentage of patients have combined LEF. HNC patients frequently manifest lymphedema at one site and fibrosis at another. For example, patients frequently develop facial and submental lymphedema concurrent with neck fibrosis. Whether this reflects the propensity of specific tissue to respond to damage in a specific way, or whether it is a reflection of the density, behavior, or sensitivity of lymphatics within a select anatomical site is unknown. To parse this out, it is critical to carefully document and evaluate soft tissue findings based on the sites involved. Contributing Factors Several studies have reported factors contributing to the development of LEF in the HNC population. Two early studies suggested that radiation dose, positive lymph nodes, tumor stage, and surgery might be related to the development of secondary lymphedema in patients with HNC (76,77). Another cross-sectional study including 81 patients 3 months post HNC treatment identified the following factors associated with the presence of secondary external and internal lymphedema, including location of tumor (ie, tumors in the pharynx), total dosage of radiation therapy, number of days of radiation, radiation status of surgical bed (ie, surgery with postoperative radiation and salvage surgery in the irradiated field), number of treatment modalities, and time since end of HNC treatment (78). Available evidence indicates that select tumor and treatment parameters are associated with increased occurrence of lymphedema in the HNC population. Studies are ongoing to further explore causative risk factors for the development of lymphedema in this population. Clinician Assessment and Reporting: Characterizing Soft Tissue Abnormalities Characterizing the soft tissue abnormalities associated with HNC therapy is an ongoing challenge. Historically, soft tissue changes have been assessed by clinicians using physical examinations. There are multiple clinician-reported tools that assess external lymphedema or fibrosis; unfortunately, most of these tools are not specifically directed at the HNC patient population. Furthermore, many of the older tools are conceptually flawed and provide incomplete data. An effective tool would capture the dominant type of soft tissue abnormality, the severity of soft tissue abnormalities, and the anatomic sites. We have developed a clinical assessment tool in which four types of soft tissue change were defined based on the tissue characteristic noted on physical examination: (1) dermal thickening without soft tissue swelling or fibrosis (early-stage tissue damage); (2) visible tissue swelling that is reducible, soft, and fluctuating in nature; (3) visible tissue swelling that is firm, nonreducible, and without fluctuations; and (4) hard tissue without swelling. The reporting system allows for documentation of the type and severity of abnormalities within nine defined anatomical sites in the head and neck region (69). There is only one clinician-reported grading system for internal lymphedema: the Patterson scale (79). The Patterson scale uses an endoscopic examination to assess pharynx and larynx. This includes 11 sites and two spaces. Each anatomic site is graded with regards to severity based on a four-point system of none, mild, moderate, or severe. Ideally, it would be useful to have objective measures of LEF to compliment clinician-reported measures. Unfortunately, objective techniques for assessment of LEF are lacking. To address this unmet need, investigators are developing radiographic imaging methods to provide qualitative and quantitative measurement of LEF (4). Imaging modalities under instigation include CT, MRI, and ultrasound measurement techniques. Impact on Symptomology, Function, and Quality of Life It may be hypothesized that many late effects of therapy are due to soft tissue abnormalities caused by LEF. First, LEF causes unique sensory abnormalities that have been poorly described in the historical literature. This includes symptoms such as tightness, numbness, heaviness, and warmth (80). In addition, LEF is associated with loss of tissue compliance and plasticity resulting in statistically significant functional deficits. The manifestations of LEF vary based on the tissue involved. For example, when pharyngeal structures are involved, patients may experience dysphagia. Swelling of the laryngeal tissues secondary to LEF may result in shortness of breath and airway compromise. Fibrosis of the muscles and tissues involved in mastication may result in profound trismus and difficulty with chewing, speech, and oral care. Decreased range of motion and poor posture may occur when LEF involves the structures of the neck. Finally, alterations in function and cosmesis may lead to statistically significant body image issues, which result in depression, poor socialization (81), financial burden, and employment challenges (75). Management: Head and Neck Lymphedema and Fibrosis The core components of lymphedema management include patient education, completed decongestive therapy, exercises and stretching, and skin care (82–84). Education should include discussion of the chronic nature of LEF and the need for life-long self-care, the role of posture and body position in reducible lymphedema, the influence of diet and medication on tissue swelling, the need to monitor for infection, the need to monitor for function loss, and issues that should be brought to the attention of the health-care team. Complete decongestive therapy may involve manual lymph drainage and compression therapy. Exercise and stretching may improve both lymph flow and range of motion, thereby potentially limiting long-term functional deficits. Although these techniques are considered standard of care, data supporting their use are limited. The relative contribution of each of these interventions to long-term functionality and symptom burden is unclear. Clinical experience would indicate that early implementation of adequate lymphedema therapy may result in regression of lymphedema and minimization of late effects. That being said, prospective studies are lacking. Surgical revascularization is an emerging and effective treatment for selected patients with lymphedema. Reports in the HNC population are lacking. The combination of LEF may hinder investigation of this modality in the HNC population. It is often thought that fibrosis and loss of range of motion are intrinsically intertwined. However, clinical experience would indicate that early intervention with exercise and stretching may ameliorate some of the late effects of fibrosis, thereby retaining function. Once again, unfortunately, prospective studies defining the optimal therapeutic techniques are lacking. A number of studies have been conducted looking at pharmacologic and nonpharmacological techniques for improving or preventing fibrosis. To date, none of these techniques has been demonstrated to be unequivocally effective. Future Directions for Research Advances in our understanding of the cellular and molecular mechanisms regulating the pathobiology of lymphedema may lead to the development or testing of targeted anti-inflammatory or antifibrotic agents effective for prevention and treatment of lymphedema or fibrosis. Studies are needed to establish consistent and useful biomarkers that indicate the early development of LEF. This would potentially allow early detection of latent disease at a point along the trajectory where interventions may be more effective. Studies are needed to identify patients who are genetically predisposed to the development of soft tissue complications from treatment. This could potentially allow tailoring of therapy to the patient’s risk and benefit profile. In addition, this would allow preventive strategies to be tested in a high-risk population. Studies using promising pharmacologic therapies for prevention and treatment of lymphedema are warranted. For example, as noted above, T cells play an important role in lymphedema. Tacrolimus is a T cell inhibitor approved for fibrotic dermal processes such as atopic dermatitis and psoriasis. Animals studies with topical tacrolimus demonstrated improved lymphatic function (85). Studies investigating the prophylactic use of this agent in high-risk patients may result in attenuation or mitigation of LEF. Additional potential mechanisms that might be addressed based on the known pathophysiology include the use of anti-inflammatories, reduction of reactive oxygen species (86), inhibition of the 5-lipoxygenase metabolite leukotriene B4 (87), local inhibition of elastase (88), and photobiomodulation (89). Development of imaging modalities that can objectively measure both LEF are needed. This will facilitate interventional trials by providing sensitive and specific tools to assess LEF as an outcome. Studies are needed to clearly delineate optimal therapeutic methods, timing, and dosing to prevent and treat LEF. Notes Affiliations of authors: School of Nursing, University of Pennsylvania, Philadelphia, PA (JD); University of Kansas Medical Center, Kansas City, KS (EMW-B); Vanderbilt-Ingram Cancer Center, Nashville, TN (BAM). The authors declare that they have no conflicts of interest. For support see Funding Acknowledgement section of Monograph. References 1 Murphy BA , Deng J. Advances in supportive care for late effects of head and neck cancer . J Clin Oncol . 2015 ; 33 29 : 3314 – 3321 . Google Scholar Crossref Search ADS PubMed WorldCat 2 Ringash J. Survivorship and quality of life in head and neck cancer . J Clin Oncol . 2015 ; 33 29 : 3322 – 3327 . Google Scholar Crossref Search ADS PubMed WorldCat 3 O'Sullivan B , Levin W. Late radiation-related fibrosis: pathogenesis, manifestations, and current management . Semin Radiat Oncol . 2003 ; 13 3 : 274 – 289 . Google Scholar Crossref Search ADS PubMed WorldCat 4 Deng J , Ridner SH , Aulino JM. Measurement of head and neck lymphedema and fibrosis: a comprehensive review . Oral Oncol . 2015 ; 51 5 : 431 – 437 . Google Scholar Crossref Search ADS PubMed WorldCat 5 Smith BG , Lewin JS. Lymphedema management in head and neck cancer . Curr Opin Otolaryngol Head Neck Surg . 2010 ; 18 3 : 153 – 158 . Google Scholar Crossref Search ADS PubMed WorldCat 6 Lee B-B , Bergan JJ , Rockson SG , 2011 . Lymphedema: A Concise Compendium of the Theory and Practice . London : Springer; 2011 . Google Preview WorldCat COPAC 7 Földi M , Földi E , Strössenreuther RHK , Kubik S , editors. Földi's Textbook of Lymphology: For Physicians and Lymphedema Therapists . 2nd ed . Munchen, Germany : Mosby ; 2006 . Google Preview WorldCat COPAC 8 Mortimer PS , Rockson SG. New developments in clinical aspects of lymphatic disease . J Clin Invest . 2014 ; 124 3 : 915 – 921 . Google Scholar Crossref Search ADS PubMed WorldCat 9 Yarbro CH , Wujcik D , Gobel BH. Cancer Symptom Management . 4th ed . Burlington, MA : Jones & Bartlett Learning, LLC ; 2014 . Google Preview WorldCat COPAC 10 Carlson JA. Lymphedema and subclinical lymphostasis (microlymphedema) facilitate cutaneous infection, inflammatory dermatoses, and neoplasia: a locus minoris resistentiae . Clin Dermatol . 2014 ; 32 5 : 599 – 615 . Google Scholar Crossref Search ADS PubMed WorldCat 11 Avraham T , Zampell JC , Yan A. Th2 differentiation is necessary for soft tissue fibrosis and lymphatic dysfunction resulting from lymphedema . Faseb J . 2013 ; 27 3 : 1114 – 1126 . Google Scholar Crossref Search ADS PubMed WorldCat 12 Ridner SH , Dietrich MS , Niermann K , Cmelak A , Mannion K , Murphy B. A prospective study of the lymphedema and fibrosis continuum in patients with head and neck cancer . Lymphat Res Biol . 2016 ; 14 4 : 198 – 205 . Google Scholar Crossref Search ADS PubMed WorldCat 13 Rockson SG , editor. Lymphatic Continuum Revisited . 1st ed . New York : Wiley-Blackwell ; 2008 . Google Preview WorldCat COPAC 14 Lin S , Kim J , Lee MJ. Prospective transcriptomic pathway analysis of human lymphatic vascular insufficiency: identification and validation of a circulating biomarker panel . PLoS One . 2012 ; 7 12 : e52021. Google Scholar Crossref Search ADS PubMed WorldCat 15 Rockson SG. Update on the biology and treatment of lymphedema . Curr Treat Options Cardiovasc Med . 2012 ; 14 2 : 184 – 192 . Google Scholar Crossref Search ADS PubMed WorldCat 16 Zampell JC , Yan A , Elhadad S. CD4(+) cells regulate fibrosis and lymphangiogenesis in response to lymphatic fluid stasis . PLoS One . 2012 ; 7 11 : e49940. Google Scholar Crossref Search ADS PubMed WorldCat 17 Ghanta S , Cuzzone DA , Torrisi JS , et al. . Regulation of inflammation and fibrosis by macrophages in lymphedema . Am J Physiol Heart Circ Physiol . 2015 ; 308 9 : H1065 – H1077 . Google Scholar Crossref Search ADS PubMed WorldCat 18 Scavelli C , Weber E , Agliano M , et al. . Lymphatics at the crossroads of angiogenesis and lymphangiogenesis . J Anat . 2004 ; 204 6 : 433 – 449 . Google Scholar Crossref Search ADS PubMed WorldCat 19 Zheng W , Aspelund A , Alitalo K. Lymphangiogenic factors, mechanisms, and applications . J Clin Invest . 2014 ; 124 3 : 878 – 887 . Google Scholar Crossref Search ADS PubMed WorldCat 20 Zampell JC , Avraham T , Yoder N , et al. . Lymphatic function is regulated by a coordinated expression of lymphangiogenic and anti-lymphangiogenic cytokines . Am J Physiol Cell Physiol . 2012 ; 302 2 : C392 – C404 . Google Scholar Crossref Search ADS PubMed WorldCat 21 Harvey NL , Srinivasan RS , Dillard ME , et al. . Lymphatic vascular defects promoted by Prox1 haploinsufficiency cause adult-onset obesity . Nat Genet . 2005 ; 37 10 : 1072 – 1081 . Google Scholar Crossref Search ADS PubMed WorldCat 22 Zampell JC , Aschen S , Weitman ES , et al. . Regulation of adipogenesis by lymphatic fluid stasis: part I. adipogenesis, fibrosis, and inflammation . Plast Reconstr Surg . 2012 ; 129 4 : 825 – 834 . Google Scholar Crossref Search ADS PubMed WorldCat 23 Sell H , Eckel J. Adipose tissue inflammation: novel insight into the role of macrophages and lymphocytes . Curr Opin Clin Nutr Metab Care . 2010 ; 13 4 : 366 – 370 . Google Scholar Crossref Search ADS PubMed WorldCat 24 Medina M , Orgill DP. Discussion: regulation of adipogenesis by lymphatic fluid stasis: part I. Adipogenesis, fibrosis, and inflammation . Plast Reconstr Surg . 2012 ; 129 4 : 835 – 837 . Google Scholar Crossref Search ADS PubMed WorldCat 25 Weisberg SP , McCann D , Desai M , et al. . Obesity is associated with macrophage accumulation in adipose tissue . J Clin Invest . 2003 ; 112 12 : 1796 – 1808 . Google Scholar Crossref Search ADS PubMed WorldCat 26 Savetsky IL , Torrisi JS , Cuzzone DA , et al. . Obesity increases inflammation and impairs lymphatic function in a mouse model of lymphedema . Am J Physiol Heart Circ Physiol . 2014 ; 307 2 : H165 – H172 . Google Scholar Crossref Search ADS PubMed WorldCat 27 Cuzzone DA , Weitman ES , Albano NJ , et al. . IL-6 regulates adipose deposition and homeostasis in lymphedema . Am J Physiol Heart Circ Physiol . 2014 ; 306 10 : H1426 – H1434 . Google Scholar Crossref Search ADS PubMed WorldCat 28 Finegold DN , Schacht V , Kimak MA , et al. . HGF and MET mutations in primary and secondary lymphedema . Lymphat Res Biol . 2008 ; 6 2 : 65 – 68 . Google Scholar Crossref Search ADS PubMed WorldCat 29 Finegold DN , Baty CJ , Knickelbein KZ , et al. . Connexin 47 mutations increase risk for secondary lymphedema following breast cancer treatment . Clin Cancer Res . 2012 ; 18 8 : 2382 – 2390 . Google Scholar Crossref Search ADS PubMed WorldCat 30 Miaskowski C , Dodd M , Paul SM , et al. . Lymphatic and angiogenic candidate genes predict the development of secondary lymphedema following breast cancer surgery . PLoS One . 2013 ; 8 4 : e60164. Google Scholar Crossref Search ADS PubMed WorldCat 31 Leung G , Baggott C , West C , et al. . Cytokine candidate genes predict the development of secondary lymphedema following breast cancer surgery . Lymphat Res Biol . 2014 ; 12 1 : 10 – 22 . Google Scholar Crossref Search ADS PubMed WorldCat 32 Rockey DC , Bell PD , Hill JA. Fibrosis: a common pathway to organ injury and failure . N Engl J Med . 2015 ; 372 12 : 1138 – 1149 . Google Scholar Crossref Search ADS PubMed WorldCat 33 Shaw SM , Skoretz SA , O'Sullivan B , et al. . Valid and reliable techniques for measuring fibrosis in patients with head and neck cancer postradiotherapy: a systematic review . Head & Neck . 2016 ; 38(suppl 1) : E2322 – E2334 . Google Scholar Crossref Search ADS PubMed WorldCat 34 Travis EL. Organizational response of normal tissues to irradiation . Semin Radiat Oncol . 2001 ; 11 3 : 184 – 196 . Google Scholar Crossref Search ADS PubMed WorldCat 35 Khan MA , Van Dyk J , Yeung IW , Hill RP. Partial volume rat lung irradiation; assessment of early DNA damage in different lung regions and effect of radical scavengers . Radiother Oncol . 2003 ; 66 1 : 95 – 102 . Google Scholar Crossref Search ADS PubMed WorldCat 36 Straub JM , New J , Hamilton CD , et al. . Radiation-induced fibrosis: Mechanisms and implications for therapy . J Cancer Res Clin Oncol . 2015 ; 141 11 : 1985 – 1994 . Google Scholar Crossref Search ADS PubMed WorldCat 37 Terasaki Y , Ohsawa I , Terasaki M , et al. . Hydrogen therapy attenuates irradiation-induced lung damage by reducing oxidative stress . Am J Physiol Lung Cell Mol Physiol . 2011 ; 301 4 : L415 – 426 . Google Scholar Crossref Search ADS PubMed WorldCat 38 Zhao W , Robbins M. Inflammation and chronic oxidative stress in radiation-induced late normal tissue injury: therapeutic implications . CMC . 2009 ; 16 2 : 130 – 143 . Google Scholar Crossref Search ADS WorldCat 39 Denham JW , Hauer-Jensen M. The radiotherapeutic injury--a complex ‘wound’ . Radiother Oncol . 2002 ; 63 2 : 129 – 145 . Google Scholar Crossref Search ADS PubMed WorldCat 40 Stubblefield M , O'Dell M. Cancer Rehabilitation: Principles and Practice . New York : Demos Medical Publishing ; 2009 . Google Preview WorldCat COPAC 41 Calveley VL , Khan MA , Yeung IWT , Vandyk J , Hill RP. Partial volume rat lung irradiation: temporal fluctuations of in-field and out-of-field DNA damage and inflammatory cytokines following irradiation . Int J Radiat Biol . 2005 ; 81 12 : 887 – 899 . Google Scholar Crossref Search ADS PubMed WorldCat 42 Porter DW , Ye J , Ma J , et al. . Time course of pulmonary response of rats to inhalation of crystalline silica: NF-kappa B activation, inflammation, cytokine production, and damage . Inhal Toxicol . 2002 ; 14 4 : 349 – 367 . Google Scholar Crossref Search ADS PubMed WorldCat 43 Sica A , Mantovani A. Macrophage plasticity and polarization: in vivo veritas . J Clin Invest . 2012 ; 122 3 : 787 – 795 . Google Scholar Crossref Search ADS PubMed WorldCat 44 Li M , Jendrossek V , Belka C. The role of PDGF in radiation oncology . Radiat Oncol . 2007 ; 2 2 : 5. Google Scholar Crossref Search ADS PubMed WorldCat 45 Bray FN , Simmons BJ , Wolfson AH , Nouri K. Acute and chronic cutaneous reactions to ionizing radiation therapy . Dermatol Ther (Heidelb) . 2016 ; 6 2 : 185 – 206 . doi: 10.1007/s13555-016-0120-y. Google Scholar Crossref Search ADS PubMed WorldCat 46 Canney PA , Dean S. Transforming growth factor beta: a promotor of late connective tissue injury following radiotherapy? BJR . 1990 ; 63 752 : 620 – 623 . Google Scholar Crossref Search ADS PubMed WorldCat 47 Singh M , Alavi A , Wong R , Akita S. Radiodermatitis: a review of our current understanding . Am J Clin Dermatol . 2016 ; 17 3 : 277 – 292 . Google Scholar Crossref Search ADS PubMed WorldCat 48 Akita S , Yoshimoto H , Akino K , et al. . Early experiences with stem cells in treating chronic wounds . Clin Plastic Surg . 2012 ; 39 3 : 281 – 292 . Google Scholar Crossref Search ADS WorldCat 49 Rattay T , Talbot CJ. Finding the genetic determinants of adverse reactions to radiotherapy . Clin Oncol (Royal College of Radiologists) . 2014 ; 26 5 : 301 – 308 . Google Scholar Crossref Search ADS WorldCat 50 Martin M , Lefaix J , Delanian S. TGF-Beta1 radiation fibrosis: a master switch and a specific therapeutic target? Int J Radiat Oncol Biol Phys . 2000 ; 47 2 : 277 – 290 . Google Scholar Crossref Search ADS PubMed WorldCat 51 Terrazzino S , La Mattina P , Gambaro G , et al. . Common variants of GSTP1, GSTA1, and TGFβ1 are associated with the risk of radiation-induced fibrosis in breast cancer patients . Int J Radiat Oncol Biol Phys . 2012 ; 83 2 : 504 – 511 . Google Scholar Crossref Search ADS PubMed WorldCat 52 Andreassen CN , Grau C , Alsner J , Overgaard J , editors. Are TGF-Beta 1 Polymorphisms Potential Predictors of Fibrosis Risk after Radiotherapy? - A Subset Analysis from the DAHANCA 6 and 7 Protocols . ECGO ; 2007 . Google Preview WorldCat COPAC 53 Spiegelberg L , Swagemakers SMA , van Ijcken WFJ , et al. . Gene expression analysis reveals inhibition of radiation-induced TGFβ-signaling by hyperbaric oxygen therapy in mouse salivary glands . Mol Med . 2014 ; 20 1 : 257 – 269 . Google Scholar Crossref Search ADS PubMed WorldCat 54 Li H , You Y , Lin C , et al. . XRCC1 codon 399Gln polymorphism is associated with radiotherapy-induced acute dermatitis and mucositis in nasopharyngeal carcinoma patients . Radiat Oncol . 2013 ; 8 1 : 31. Google Scholar Crossref Search ADS PubMed WorldCat 55 Azria D , Ozsahin M , Kramar A , et al. . Single nucleotide polymorphisms, apoptosis, and the development of severe late adverse effects after radiotherapy . Clin Cancer Res . 2008 ; 14 19 : 6284 – 6288 . Google Scholar Crossref Search ADS PubMed WorldCat 56 Borgmann K , Röper B , El-Awady R , et al. . Indicators of late normal tissue response after radiotherapy for head and neck cancer: fibroblasts, lymphocytes, genetics, DNA repair, and chromosome aberrations . Radiother Oncol . 2002 ; 64 2 : 141 – 152 . Google Scholar Crossref Search ADS PubMed WorldCat 57 Cheuk IW , Yip SP , Kwong DL , Wu VW. Association of XRCC1 and XRCC3 gene haplotypes with the development of radiation-induced fibrosis in patients with nasopharyngeal carcinoma . Mol Clin Oncol . 2014 ; 2 4 : 553 – 558 . Google Scholar Crossref Search ADS PubMed WorldCat 58 Alsbeih G , El-Sebaie M , Al-Harbi N , et al. . SNPs in genes implicated in radiation response are associated with radiotoxicity and evoke roles as predictive and prognostic biomarkers . Radiat Oncol . 2013 ; 8 : 125. Google Scholar Crossref Search ADS PubMed WorldCat 59 Krisciunas GP , Platt M , Trojanowska M , et al. . A novel in vivo protocol for molecular study of radiation-induced fibrosis in head and neck cancer patients . Ann Otol Rhinol Laryngol . 2016 ; 125 3 : 228 – 234 . Google Scholar Crossref Search ADS PubMed WorldCat 60 Koerdt S , Rohleder NH , Rommel N , et al. . An expression analysis of markers of radiation-induced skin fibrosis and angiogenesis in wound healing disorders of the head and neck . Radiat Oncol . 2015 ; 10 : 202. Google Scholar Crossref Search ADS PubMed WorldCat 61 Alam A , Mukhopadhyay ND , Ning Y , et al. . A preliminary study on racial differences in HMOX1, NFE2L2, and TGFβ1 gene polymorphisms and radiation-induced late normal tissue toxicity . Int J Radiat Oncol Biol Phys . 2015 ; 93 2 : 436 – 443 . Google Scholar Crossref Search ADS PubMed WorldCat 62 Lyons AJ , Crichton S , Pezier T. Trismus following radiotherapy to the head and neck is likely to have distinct genotype dependent cause . Oral Oncol . 2013 ; 49 9 : 932 – 936 . Google Scholar Crossref Search ADS PubMed WorldCat 63 Pratesi N , Mangoni M , Mancini I , et al. . Association between single nucleotide polymorphisms in the XRCC1 and RAD51 genes and clinical radiosensitivity in head and neck cancer . Radiot Oncol . 2011 ; 99 3 : 356 – 361 . Google Scholar Crossref Search ADS WorldCat 64 Alsbeih G , Al-Harbi N , Al-Hadyan K , El-Sebaie M , Al-Rajhi N. Association between normal tissue complications after radiotherapy and polymorphic variations in TGFB1 and XRCC1 genes . Radiat Res . 2010 ; 173 4 : 505 – 511 . Google Scholar Crossref Search ADS PubMed WorldCat 65 Alsbeih GA , Al-Harbi NM , El-Sebaie MM , et al. . Involvement of mitochondrial DNA sequence variations and respiratory activity in late complications following radiotherapy . Clin Cancer Res . 2009 ; 15 23 : 7352 – 7360 . Google Scholar Crossref Search ADS PubMed WorldCat 66 Ghazali N , Shaw RJ , Rogers SN , Risk JM. Genomic determinants of normal tissue toxicity after radiotherapy for head and neck malignancy: a systematic review . Oral Oncol . 2012 ; 48 11 : 1090 – 1100 . Google Scholar Crossref Search ADS PubMed WorldCat 67 Strauss J , Small W , Woloschak GE. Breast Cancer Biology for the Radiation Oncologist . Berlin, Heidelberg : Springer Verlag ; 2015 . Google Preview WorldCat COPAC 68 Deng J , Ridner SH , Dietrich MS , et al. . Assessment of external lymphedema in patients with head and neck cancer: a comparison of four scales . Oncol Nurs Forum . 2013 ; 40 5 : 501 – 506 . Google Scholar Crossref Search ADS PubMed WorldCat 69 Deng J , Ridner SH , Wells N , Dietrich MS , Murphy BA. Development and preliminary testing of a head and neck cancer related external lymphedema and fibrosis assessment criteria . Eur J Oncol Nurs . 2015 ; 19 1 : 75 – 80 . Google Scholar Crossref Search ADS PubMed WorldCat 70 Deng J , Ridner SH , Murphy BA. Lymphedema in patients with head and neck cancer . Oncol Nurs Forum . 2011 ; 38 1 : E1 – E10 . 2011; Google Scholar Crossref Search ADS PubMed WorldCat 71 Deng J , Ridner SH , Dietrich MS , et al. . Prevalence of secondary lymphedema in patients with head and neck cancer . J Pain Symptom Manage . 2012 ; 43 2 : 244 – 252 . Google Scholar Crossref Search ADS PubMed WorldCat 72 Hammond T. Symptoms of head and neck edema. http://www.lymphnotes.com/article.php/id/378/. Accessed January 2, 2016. 73 Zimmermann T , Leonhardt H , Kersting S , et al. . Reduction of postoperative lymphedema after oral tumor surgery with sodium selenite . Biol Trace Elem Res . 2005 ; 106 3 : 193 – 203 . Google Scholar Crossref Search ADS PubMed WorldCat 74 Bruns F , Buntzel J , Mucke R , et al. . Selenium in the treatment of head and neck lymphedema . Med Princ Pract . 2004 ; 13 4 : 185 – 190 . Google Scholar Crossref Search ADS PubMed WorldCat 75 Micke O , Bruns F , Mucke R , et al. . Selenium in the treatment of radiation-associated secondary lymphedema . Int J Radiat Oncol . 2003 ; 56 1 : 40 – 49 . Google Scholar Crossref Search ADS WorldCat 76 Sanguineti G , Adapala P , Endres EJ , et al. . Dosimetric predictors of laryngeal edema . Int J Radiat Oncol Biol Phys . 2007 ; 68 3 : 741 – 749 . Google Scholar Crossref Search ADS PubMed WorldCat 77 Warren AG , Slavin SA. Scar lymphedema: fact or fiction? Ann Plastic Surg . 2007 ; 59 1 : 41 – 45 . Google Scholar Crossref Search ADS WorldCat 78 Deng J , Ridner SH , Dietrich MS , et al. . Factors associated with external and internal lymphedema in patients with head-and-neck cancer . Int J Radiat Oncol Biol Phys . 2012 ; 84 3 : e328. WorldCat 79 Patterson JM , Hildreth A , Wilson JA. Measuring edema in irradiated head and neck cancer patients . Ann Otol Rhinol Laryngol . 2007 ; 116 8 : 559 – 564 . Google Scholar Crossref Search ADS PubMed WorldCat 80 Deng J , Murphy BA , Dietrich MS , et al. . Differences of symptoms in head and neck cancer patients with and without lymphedema . Support Care Cancer . 2016 ; 24 3 : 1305 – 1316 . Google Scholar Crossref Search ADS PubMed WorldCat 81 McGarvey AC , Osmotherly PG , Hoffman GR , Chiarelli PE. Lymphoedema following treatment for head and neck cancer: impact on patients, and beliefs of health professionals . Eur J Cancer Care (Engl) . 2014 ; 23 3 : 317 – 327 . Google Scholar Crossref Search ADS PubMed WorldCat 82 Zuther J. Lymphedema Management: The Comprehensive Guide for Practitioners . 2nd ed . New York : Thieme ; 2009 . Google Preview WorldCat COPAC 83 Jeffs E , Huit M. Treatment and outcomes of head and neck oedema referrals to a hospital-based lymphoedema service . Br J Community Nurs . 2015 ;( suppl) : S6 – S13 . Google Scholar Crossref Search ADS PubMed WorldCat 84 Tacani PM , Franceschini JP , Tacani RE , et al. . Retrospective study of the physical therapy modalities applied in head and neck lymphedema treatment . Head Neck . 2016 ; 38 2 : 301 – 308 . Google Scholar Crossref Search ADS PubMed WorldCat 85 Gardenier JC , Kataru RP , Hespe GE , et al. . Topical tacrolimus for the treatment of secondary lymphedema . Nat Commun . 2017 ; 8 : 14345 . Google Scholar Crossref Search ADS PubMed WorldCat 86 Pfister C , Dawzcynski H , Schingale F. Sodium selenite and cancer related lymphedema: biological and pharmacological effects . J Trace Elem Med Biol . 2016 ; 37 : 111 – 116 . Google Scholar Crossref Search ADS PubMed WorldCat 87 Tian W , Rockson SG , Jiang X , et al. . Leukotriene B4 antagonism ameliorates experimental lymphedema . Sci Transl Med . 2017 ; 9 389 . doi:10.1126/scitranslmed.aal3920. WorldCat 88 Pivetta E , Wassermann B , Belluz LDB , et al. . Local inhibition of elastase reduces EMILIN1 cleavage reactivating lymphatic vessel function in a mouse lymphoedema model . Clin Sci . 2016 ; 130 14 : 1221 – 1236 . Google Scholar Crossref Search ADS PubMed WorldCat 89 Baxter GD , Liu L , Petrich S , et al. . Low level laser therapy (photobiomodulation therapy) for breast cancer-related lymphedema: a systematic review . BMC Cancer . 2017 ; 17 1 : 833. Google Scholar Crossref Search ADS PubMed WorldCat © The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JNCI Monographs Oxford University Press

Late Soft Tissue Complications of Head and Neck Cancer Therapy: Lymphedema and Fibrosis

Loading next page...
 
/lp/oxford-university-press/late-soft-tissue-complications-of-head-and-neck-cancer-therapy-g2brCbIoHY
Publisher
Oxford University Press
Copyright
© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com
ISSN
1052-6773
eISSN
1745-6614
DOI
10.1093/jncimonographs/lgz005
Publisher site
See Article on Publisher Site

Abstract

Abstract Head and neck cancer and its treatment result in soft tissue damage secondary to lymphedema and fibrosis. Lymphedema is the result of pathological accumulation of interstitial fluid in tissues. It is caused by the inability of the lymphatic system to transport lymph fluid from the tissues to the central circulatory system and is manifested clinically by tissue swelling. Fibrosis is defined as an overaccumulation of fibrotic tissues within the skin and soft tissues after a single or repetitive injury and is characterized by hardening of the soft tissues with associated loss of elasticity. Lymphedema and fibrosis are common yet overlooked late effects of head and neck cancer and its therapy. They may result in profound long-term symptom burden, loss of critical functions, and altered quality of life. The following review will discuss the current pathobiology, clinical manifestations, and future directions for research related to lymphedema and fibrosis. Head and neck cancer (HNC) and its treatment results in acute and chronic soft tissue damage due to direct tumor infiltration, surgical extirpation of the tumor and surrounding tissues, and direct radiation injury (1,2). Recent investigation has underscored the important contribution of lymphedema and fibrosis (LEF) as critical manifestations of soft tissue damage in the HNC population (3–5). Soft tissues (which include fat, muscle, fibrous tissue, blood vessels, lymph vessels, and peripheral nerves) serve to connect, support, or surround other structures. Damage to soft tissues may result in profound long-term symptom burden, loss of critical functions, and altered quality of life. The exact impact varies and is determined by the site and severity of soft tissue involvement. For example, damage to the upper aerodigestive tract can result in alterations in key functions such as speech, swallowing, and breathing. Unfortunately, our understanding of the pathobiology and impact of tumor- and treatment-related soft tissue damage remains incomplete. The following manuscript describes the pathobiology of LEF, the clinical manifestations, and future directions for research. Pathobiology: Current Paradigm and New Frontiers Lymphedema The lymphatic system is a component of both the circulatory and immune systems and consists of lymph vessels and lymphatic organs (6,7). Lymph vessels return the capillary ultrafiltrate and escaped plasma proteins from most tissues back to the circulatory system (8). The lymphatic organs are part of the body’s defense system and thus play a role in the detection of pathogens, exogenous cells, and proteins, as well as malignant or degenerative cells (7). The prime functions of the lymphatic system include maintenance of interstitial fluid homeostasis, immune trafficking (transportation of antigen, antigen-presenting cells, and other immune cells to the lymphoid organs), and lipid absorption and transport from the gastrointestinal tract (6,9). Therefore, a fully functioning lymphatic system is essential to overall health (10). Lymphedema is the pathological accumulation of fluid in interstitial tissues. It results from the inability of the lymphatic system to transport lymph fluid from the tissues to the central circulatory system. This manifests clinically as tissue swelling, the hallmark of lymphedema. Lymphedema may be caused by developmental abnormalities (primary lymphedema) or external trauma to the lymphatic system (secondary lymphedema) (6,7). In the past few decades, the understanding of the lymphatic system has improved substantially; however, the understanding of pathobiological processes of lymphedema is still not well established. Gross Physiological Manifestations After a pathophysiologic insult, the host system must respond to the soft tissue damage. When soft tissue damage is mild, compensatory mechanisms and repair processes are activated, resulting in the regeneration of damaged tissue and return of adequate lymph flow (7,11). In this setting, injury to the lymphatic system may be subclinical and asymptomatic. If the soft tissue damage is more severe, the host’s capacity to compensate for or repair tissue damage may be overwhelmed, resulting in clinically evident soft tissue swelling, due to fluid accumulation in the interstitial spaces (early-stage lymphedema) (7,11). The trajectory of LEF in HNC has been well described in a large, prospective longitudinal study. A substantial percentage of patients had some degree of internal or external lymphedema, though generally mild, before starting radiation. The rates of both internal and external lymphedema increased up until 12 months posttreatment, at which time 95.5% of patients had external lymphedema, 89.4% had internal lymphedema, and 76.1% of patients had both. Two-thirds of patients developed moderate to severe lymphedema at some point across the trajectory of treatment and recovery. Clinically, this subset of patients would require referral for assessment by a lymphedema therapist. Untreated, the soft tissue swelling may subside spontaneously over time as tissues repair or, alternatively, fibrofatty scar tissue may deposit in the interstitial space (late stage lymphedema). Adequate lymphedema therapy may hasten the regression of soft tissue swelling through the return of lymph fluid into the circulatory system. This may hypothetically decrease deposition of fibrofatty scar tissue. The occurrence of fibrofatty scar tissue deposition is usually irreversible, resulting in permanent alterations in tissue texture and function (7,11,12) (Figure 1). Figure 1. View largeDownload slide Lymphedema and fibrosis in head and neck cancer Figure 1. View largeDownload slide Lymphedema and fibrosis in head and neck cancer Soft tissue fibrosis is manifested clinically as tissue that is firm to touch without evidence of soft tissue swelling. Tissues are often described as woody in texture. Although often thought of as a late effect of therapy, current data would indicate that fibrosis may manifest early in the course of cancer therapy. At 3 months posttreatment, 74.1% of patients had fibrosis on examination. The incidence of soft tissue fibrosis peaks at a later time point than either internal or external lymphedema (between 12 and 18 months). Recovery from fibrosis is limited. Indeed, fibrosis may continue to worsen for years after therapy is completed, resulting in late dysphagia, tracheal stenosis, and markedly abnormal posture. Patients treated with primary surgery have a higher rate of fibrosis than those treated with primary radiation-based techniques (odds ratio = 3.33, P = .02, 95% confidence interval = 1.26 to 8.76) (12). Histological Changes Histological assessment of lymphedema in animal and human models reveals dramatic inflammatory and architectural changes in the skin and soft tissues. In a murine model of surgically induced tail lymphedema, the following histological changes were noted: (1) an overall increase in cellularity; (2) an increase in the number of observed fibroblasts, histiocytes, and neutrophils; (3) hyperkeratosis and spongiosis of the epidermis; (4) elongated dermal papillae; (5) expansion of the tissue between the bone and epidermis; and (6) an increase in the number and size of cutaneous lymphatic vessels as identified by lymphatic vessel endothelium hyaluronan receptor staining (13). Similarly, early histological studies of human extremity lymphedema identified the following: (1) obliteration of lymphatic collectors; (2) hyperkeratosis of epidermis; (3) immune cell infiltrates of epidermis, dermis, and subcutaneous tissue; (4) fibrosis of the peri-lymphatic tissues and muscular fascia; and (5) proliferation of skin and fat tissue (6). More recent studies using normal skin specimens as control subjects demonstrated the following histologic changes on the lymphedematous skin of the human extremity: (1) a notable increase in the cellularity, particularly in the epidermis and dermal-epidermal junction; (2) prominent perivascular inflammatory infiltrates; (3) thickening and obliteration of the dermis; (4) dilated microvascular structures in the upper dermis; and (5) evidence of positive microvascular lymphatic remodeling (positive structures of lymphatic vessel endothelium hyaluronan receptor-1) (14). Available data are limited to lymphedema developing in tissues distal to the site of tissue damage. One example would be patients with breast cancer who undergo axillary lymph node dissection and subsequently develop lymphedema in the upper extremity distal to the tissue damage. By contrast, HNC patients develop lymphedema distal to the site of injury (eg, cheeks and periorbital region) as well as within tissue directly (eg, neck) affected by surgery and/or radiation. Whether lymphedema results in different histopathological changes due to direct tissue damage is unknown. Cellular and Molecular Discoveries Recent advances in knowledge of tissue repair at the cellular and molecular levels have enhanced our understanding of underlying mechanisms of lymphedema, particularly our understanding of the role of lymph stasis. Studies have been conducted in both murine models as well as humans with lymphatic dysfunction. These studies have elucidated several key pathobiological processes that may contribute to the development and progression of lymphedema, including inflammation, fibrosis, lymphangiogenesis, and adipose deposition. Lymphatic fluid stasis results in a dramatic increase in the number of mixed inflammatory cells within all layers of the affected tissues (15). In the murine lymphedema model, a statistically significant increase in T-helper, T-regulatory, and dendritic cells, as well as neutrophils and macrophages, can be observed (16). In humans with a lymphedematous upper extremity, there is a statistically significant increase in the number of CD4+ cells compared with normal upper extremity (11). Furthermore, the degree of CD4+ cell inflammation correlates with the severity of lymphedema (11). Additionally, a study in the human extremity with lymphedema reported that macrophages migrate to lymphedematous tissues and differentiate into M2 macrophages. Macrophages have an antifibrotic role in lymphedema and either directly or indirectly regulate and control CD4+ cell accumulation and T-helper 2 (Th2) differentiation (17). The presence of CD4+ cells appears to be necessary for development of fibrosis and lymphatic dysfunction. Depletion of CD4+ cells markedly decreases the pathological changes associated with lymphedema, including inflammation, fibrosis, and adipose deposition. In addition, depletion of CD4+ cells was associated with a statistically significant increase in lymphangiogenesis in the murine lymphedema model (16). The expression of Th2 cytokines was statistically significantly increased by lymphatic fluid stasis. Inhibition of Th2 differentiation decreases initiation and progression of fibrosis and improves lymphatic function (11). Advances in understanding of the development and growth of lymphatic vessels have revealed that the lymphangiogenesis in human embryonic tissue is mainly regulated by the vascular endothelial growth factor-C (VEGF-C), vascular endothelial growth factor-D (VEGF-D), and vascular endothelial growth factor receptor-3 signaling systems (18,19). The identification of these important molecular mediators provides a foundation for a better understanding of underlying pathobiological process of lymphangiogenesis in lymphedema. Studies show that regulation of lymphangiogenesis after lymphatic fluid stasis is a complicated process (11,17,20). Lymphatic fluid stasis in the murine model results in increased expression of pro-lymphangiogenic cytokines (VEGF-A, VEGF-C, and hepatocyte growth factor) as well as increased expression of anti-lymphangiogenic cytokines (transforming growth factor-β1 [TGF-β1], endostatin, and interferon-γ). These results support lymphatic fluid stasis as a driver of cytokine expression and an activator of both pro- and anti-lymphangiogenic cytokines that, in turn, regulate lymphangiogenesis (20). Therefore, lymphatic regeneration appears to depend on the delicate balance between pro- and anti-lymphangiogenic molecular signals after lymphatic fluid stasis or lymphatic injury. Adipose deposition is a defining characteristic of late-stage lymphedema (8). Emerging evidence suggests that disturbances in lymphatic vascular function have a profound impact on cutaneous adipose biology (15). Prospero homeobox 1 (Prox1) is essential in the development of lymphatic endothelial cells and may be a link between lymphatic function and adipose tissue deposition. Mice with Prox1 haploinsufficiency have abnormal lymph leakage due to a disruption in lymphatic vascular integrity that promotes adipose tissue accumulation. This lymphatic-specific Prox1 deletion model supports adipose deposition development via two phases: first, increased storage of leaking lipids in existing adipocytes causes adipocyte hypertrophy; and second, once the adipocytes reach maximum lipid storage capacity, the promotion of preadipocyte differentiation results in an increased number of mature adipocytes and adipocyte hyperplasia (21). Another study using the murine model found that lymphatic fluid stasis resulted in (1) an increased number of adipocytes and statistically significant subcutaneous fat disposition, (2) inflammation (eg, a marked mononuclear cell infiltration and increased number of monocytes/macrophages), and (3) fibrosis (eg, collagen fiber deposition) within the subcutaneous fat compartment (22). Macrophages trafficking to large adipose deposits have been described both in animal models and humans (23). These macrophages may be recruited to remove adipocyte cell debris resulting from cellular necrosis (24). Macrophages also produce multiple proinflammatory and procoagulant chemokines in adipose tissue (25). In the setting of lymph stasis and tissue injury, these chemokines may play an essential role in the differentiation of local mesenchymal stem cell populations into fibroblasts and adipocytes (24). Interestingly, a recent study in a murine model provides a better understanding of the relationship between obesity and lymphatic dysfunction. The study findings show that obese mice have impaired lymphatic function. Lymphatic dysfunction can be amplified by ongoing lymphatic injury associated with chronic inflammation, fibrosis, and ongoing adipose deposition (26). Biomarkers Investigators have explored possible biomarkers for lymphedema. A study cohort encompassing both primary and secondary lymphedema across a broad spectrum of etiologies found that a panel of six biomarkers was able to distinguish lymphedema subjects from healthy normal control subjects. The panel included the following: basic fibroblast growth factor (regulates lymphangiogenesis), interleukin 4 (IL-4, regulates inflammation), interleukin 10 (IL-10, regulates inflammation), tumor necrosis factor beta (regulates inflammation); TGF-β (regulates fibrosis), and leptin (regulates adipocytokine signaling) (14). Interleukin 6 (IL-6) did not demonstrate clinical predictive value. Conversely, a subsequent study evaluating serum and tissue IL-6 levels demonstrated increased levels in patients with postmastectomy lymphedema (27). Importantly, all seven of these proteins are known to be involved in lymphangiogenesis, inflammation, fibrosis, adipocytokine signaling, and adipose deposition. Clearly, more studies are needed to establish consistent and useful biomarkers for differentiating individuals with and without early stages of lymphedema, when clinical exam and imaging studies may lack sensitivity. Furthermore, investigations are warranted to determine whether these identified biomarkers will be able to detect early and latent lymphedema, a point along the trajectory where interventions may be more effective. Genetic Predisposition in Secondary Lymphedema Studies conducted in humans with secondary upper extremity lymphedema indicate that genetic predisposition and linked phenotypes may contribute to the risk of secondary lymphedema. Compared with control subjects, breast cancer patients with upper extremity secondary lymphedema had genetic mutations in hepatocyte growth factor or high-affinity hepatocyte growth factor receptors (hepatocyte growth factor or MET) and in connexin 47 (28,29). Another study reported that four genes (lymphocyte cytosolic protein 2 [rs315721], neuropilin-2 [rs849530], protein tyrosine kinase [rs158689], vascular cell adhesion molecule 1 [rs3176861]) and three haplotypes (Forkhead box protein C2 [haplotype A03], neuropilin-2 [haplotype F03], vascular endothelial growth factor-C [haplotype B03]) (30) play a role in lymphangiogenesis and angiogenesis. More recently, three pro- and anti-inflammatory cytokine genes were shown to be associated with the development of upper extremity secondary lymphedema: IL-4 (rs2227284), IL-10 (rs1518111), and nuclear kappa factor beta 2 (rs1056890) (31). Further studies are needed to evaluate whether these genes contribute to the development of secondary lymphedema in individuals with HNC. Fibrosis Fibrosis results from injury to soft tissues that initiates an inflammatory response following which mesenchymal cells, such as, fibroblasts and myofibroblasts are activated. These effector cells deposit extracellular matrix proteins that accumulate within the skin and soft tissues resulting in the characteristic hardening of tissues and loss of elasticity (32). In the extreme, fibrosis may take on a “woody” texture or lead to soft tissue contracture resulting in marked decrease in function or range of motion. Unlike lymphedema, tissue swelling is generally lacking. Furthermore, unlike the late fibrofatty scar tissue seen in patients with long-standing lymphedema, lymphatic vessel damage is not a prominent component of the pathobiology. Fibrosis is one of the most common long-term toxicities of HNC therapy. Surgical excision and reconstruction is considered a singular traumatic event; thus, surgery-induced fibrosis is usually a normal part of the wound-healing process (33). In addition, radiotherapy causes repeated damage to tissues resulting in an increased production of fibroblasts from bone marrow progenitors in the affected areas and excess deposition of extracellular matrix. Although the exact pathobiological processes of radiation-induced fibrosis (RIF) are not fully understood, research advances have provided some understanding of underlying mechanisms of RIF in the cellular and molecular levels, and genetic susceptibility. Although both surgery and radiation may result in fibrosis and associated soft tissue function loss, much of the recent work pertains to radiation therapy and will thus be the topic of further discussion. Cellular and Molecular Findings Acute effects of radiation are often defined as those that occur within 90 days of treatment. Radiation results in tissue injury via a number of pathways, including DNA damage and the generation of free radicals (eg, reactive oxygen species and reactive nitrogen species) (34–36). These may in turn damage cellular components, including proteins, nucleic acids, and lipids (37,38). Injured cells subsequently release molecules that upregulate the migration of inflammatory cells (eg, neutrophils, monocytes, and lymphocytes) (34,39) to the injured sites. Inflammatory cells release chemokines, cytokines, and growth factors that further contribute to the pathogenesis of acute tissue injury (40). For example, neutrophils release tumor necrosis actor alpha, IL-1, and IL-6 that exaggerate local inflammation (41,42). Monocytes, a key component of the inflammatory response, differentiate into M1 and M2 macrophages (43). M2 macrophages secrete platelet-derived growth factor, stimulating the migration of fibroblasts into the injured tissues (44). The chronic effects of radiation on soft tissues are related to several pathways. First, TGF-β appears to play a key role in this process (45). TGF-β is a regulatory protein and exerts a powerful fibrogenic action through the following: (1) inducing proliferation of collagen-producing postmitotic fibrocytes from their progenitor fibroblasts (3); (2) differentiation of fibroblasts into myofibroblasts that secrete excess collagen, fibronectin, and proteoglycans that are responsible for the increased stiffness and thickening of the tissue; and (3) dysregulation of matrix metalloproteinase activity and upregulation of tissue inhibitors of metalloproteinases contributing to the already excessive extracellular matrix deposition (33). TGF-β has been found to be upregulated in fibrotic tissue of irradiated patients but not in nonirradiated control subjects (46). Moreover, radiation causes endothelial cell apoptosis and increased endothelial permeability, thus activating the coagulation system and leading to local thrombin formation intravascularly and extravascularly (eg, the extracellular matrix). The abnormal accumulation of thrombin in both the intravascular and extravascular compartments is in part responsible for the progressive fibrotic tissue sclerosis that triggers the late toxicity of radiation therapy (40). In addition, bone marrow-derived cells (BMDCs) appear to play an integral role in recovery. The BMDCs are drawn to sites of radiation damage and stimulate vessel formation and repair via the release of angiogenic factors. Similar to those of BMDCs, adipose-derived stem cells appear to have wound-healing effects through promoting angiogenesis and stimulating dermal fibroblast proliferation during the re-epithelialization phase of wound healing (47,48). Genetic Predisposition Clinical observation indicates that normal tissue radiosensitivity varies from patient to patient (49). This observation has led to the hypothesis that an individual’s normal tissue response to radiation is partly determined by genetic variation. The role of specific genes and single nucleotide polymorphisms (SNPs) in RIF has been investigated in cancer populations with results supporting the associations between specific genes with radiation sensitivity and tissue repair. These include (1) TGF-β, which contributed to the initiation, development, and persistence of radiation fibrosis (50–53); (2) x-ray repair cross-complementing proteins 1, a base excision repair gene that has been associated with several radiation toxicities (eg, fibrosis, severe skin reaction) (54,55); and (3) ataxia-telangiectasia mutated gene, which has been linked with normal tissue radiosensitivity (eg, subcutaneous fibrosis) (56). In HNC patient populations, several other genes and SNPs have been found to contribute to RIF (54–65) (Table 1). Table 1 Summary of studies examining genetic variants associated with radiation-induced soft tissue toxicity Primary site and tumor Design Sample size (No.) Country and centers (participants recruited) Clinical endpoint and tissues affected Genes and SNPs References Head and neck cancer (47%); & breast cancer Retrospective, case-control Case: 16 Control: 18 Switzerland, single center Severe radiation-induced sequelae (eg, subcutaneous fibrosis) ATM, SOD2, XRCC1 and XRCC3, TGF-β1, RAD21 Azria et al., 2008 (49) Nasopharyngeal cancer Retrospective 120 China, Hong Kong, single center Neck fibrosis XRCC3 Cheuk et al., 2014 (50) Nasopharyngeal cancer Retrospective, case-control Case: 48 Control: 107 Saudi Arabia, single center Subcutaneous and deep tissue fibrosis HDM2, TGF-β1, XRCC1 Alsbeih et al., 2013 (51) Head and neck cancer Retrospective 6 US Single center Submental fibrosis CAV-1, COLLA1, TIMP1, MMP14, IL-13, IL-8, CXCL10, CCL7, MX1, IFIT2, CTGF, ET-1 Krisciunas et al., 2015 (52) Head and neck cancer Retrospective 78 Germany Single center Radiation-induced skin fibrosis and angiogenesis α-PC and TGF-β1 Koerdt et al., 2015 (54) Various cancers (47% head and neck cancer) Prospective Case: 179 Control: 26 U.S Single center Radiation-induced late normal tissue toxicity HMOX1, NFE2L2, TGF-β1 Alam et al., 2015 (55) Head and neck cancer Prospective 62 United Kingdom,Single center Trismus TGF-β1 Lyons et al., 2013 (56) Head and neck cancer Retrospective Case: 8 Control: 8 Germany Single center Radiation-induced late normal tissue toxicity (eg, fibrosis, xerostomia) Chromosomal damage in lymphocytes Borgmann et al., 2002 (53) Nasopharyngeal carcinoma Prospective 114 China, single center Acute dermatitis and mucositis XRCC1 Li et al., 2013 (47) Head and neck cancer Prospective 101 Italy, multi-site Acute reactions (mucositis, skin erythema, and dysphagia) XRCC1 and RAD51 Pratesi et al., 2011 (57) Nasopharyngeal Cancer Retrospective, case-control Case: 30 Control: 30 Saudi Arabia, single center Subcutaneous and deep tissue fibrosis TGF-β1, XRCC1 Alsbeih et al., 2010 (58) Nasopharyngeal Cancer Prospective, case-control Case: 16 Control: 16 Saudi Arabia, single center Subcutaneous and deep tissue fibrosis ND3 (mitochondrial DNAa)-Oxidative metabolism pathway Alsbeih et al., 2009 (59) Primary site and tumor Design Sample size (No.) Country and centers (participants recruited) Clinical endpoint and tissues affected Genes and SNPs References Head and neck cancer (47%); & breast cancer Retrospective, case-control Case: 16 Control: 18 Switzerland, single center Severe radiation-induced sequelae (eg, subcutaneous fibrosis) ATM, SOD2, XRCC1 and XRCC3, TGF-β1, RAD21 Azria et al., 2008 (49) Nasopharyngeal cancer Retrospective 120 China, Hong Kong, single center Neck fibrosis XRCC3 Cheuk et al., 2014 (50) Nasopharyngeal cancer Retrospective, case-control Case: 48 Control: 107 Saudi Arabia, single center Subcutaneous and deep tissue fibrosis HDM2, TGF-β1, XRCC1 Alsbeih et al., 2013 (51) Head and neck cancer Retrospective 6 US Single center Submental fibrosis CAV-1, COLLA1, TIMP1, MMP14, IL-13, IL-8, CXCL10, CCL7, MX1, IFIT2, CTGF, ET-1 Krisciunas et al., 2015 (52) Head and neck cancer Retrospective 78 Germany Single center Radiation-induced skin fibrosis and angiogenesis α-PC and TGF-β1 Koerdt et al., 2015 (54) Various cancers (47% head and neck cancer) Prospective Case: 179 Control: 26 U.S Single center Radiation-induced late normal tissue toxicity HMOX1, NFE2L2, TGF-β1 Alam et al., 2015 (55) Head and neck cancer Prospective 62 United Kingdom,Single center Trismus TGF-β1 Lyons et al., 2013 (56) Head and neck cancer Retrospective Case: 8 Control: 8 Germany Single center Radiation-induced late normal tissue toxicity (eg, fibrosis, xerostomia) Chromosomal damage in lymphocytes Borgmann et al., 2002 (53) Nasopharyngeal carcinoma Prospective 114 China, single center Acute dermatitis and mucositis XRCC1 Li et al., 2013 (47) Head and neck cancer Prospective 101 Italy, multi-site Acute reactions (mucositis, skin erythema, and dysphagia) XRCC1 and RAD51 Pratesi et al., 2011 (57) Nasopharyngeal Cancer Retrospective, case-control Case: 30 Control: 30 Saudi Arabia, single center Subcutaneous and deep tissue fibrosis TGF-β1, XRCC1 Alsbeih et al., 2010 (58) Nasopharyngeal Cancer Prospective, case-control Case: 16 Control: 16 Saudi Arabia, single center Subcutaneous and deep tissue fibrosis ND3 (mitochondrial DNAa)-Oxidative metabolism pathway Alsbeih et al., 2009 (59) ATM = Ataxia-telangiectasia mutated; CAV-1 = Caveolin-1; CCL7 = Chemokine C-C motif ligand 7; COLLA1 = Collagen type I alpha I; CTGF = Connective tissue growth factor; CXCL10 = C-X-C motif chemokine 10; ET-1 = Endothelin-1; HMOX1 = Heme oxygenase 1; IFIT2 = Interferon-induced protein with tetratricopeptide repeats 2; MMP14 = Matrix metalloproteinase-14; MX1 = MX dynamin-like GTPase I; ND3 = Mitochondrially encoded NADH dehydrogenase subunit 3 gene; NFE2L2 = Encoding nuclear regulatory factor-2; α-PC = α-procollagen; RAD21 = Double-strand-break repair protein rad21 homolog; SNPs = Single-nucleotide polymorphisms; SOD2 = Superoxide dismutase 2; TGF-β1 = Transforming growth factor beta 1; TIMP1 = TMP metallopeptidase inhibitor 1; XRCC1 and XRCC3 = X-ray repair cross-complementing proteins 1 and 3. View Large Table 1 Summary of studies examining genetic variants associated with radiation-induced soft tissue toxicity Primary site and tumor Design Sample size (No.) Country and centers (participants recruited) Clinical endpoint and tissues affected Genes and SNPs References Head and neck cancer (47%); & breast cancer Retrospective, case-control Case: 16 Control: 18 Switzerland, single center Severe radiation-induced sequelae (eg, subcutaneous fibrosis) ATM, SOD2, XRCC1 and XRCC3, TGF-β1, RAD21 Azria et al., 2008 (49) Nasopharyngeal cancer Retrospective 120 China, Hong Kong, single center Neck fibrosis XRCC3 Cheuk et al., 2014 (50) Nasopharyngeal cancer Retrospective, case-control Case: 48 Control: 107 Saudi Arabia, single center Subcutaneous and deep tissue fibrosis HDM2, TGF-β1, XRCC1 Alsbeih et al., 2013 (51) Head and neck cancer Retrospective 6 US Single center Submental fibrosis CAV-1, COLLA1, TIMP1, MMP14, IL-13, IL-8, CXCL10, CCL7, MX1, IFIT2, CTGF, ET-1 Krisciunas et al., 2015 (52) Head and neck cancer Retrospective 78 Germany Single center Radiation-induced skin fibrosis and angiogenesis α-PC and TGF-β1 Koerdt et al., 2015 (54) Various cancers (47% head and neck cancer) Prospective Case: 179 Control: 26 U.S Single center Radiation-induced late normal tissue toxicity HMOX1, NFE2L2, TGF-β1 Alam et al., 2015 (55) Head and neck cancer Prospective 62 United Kingdom,Single center Trismus TGF-β1 Lyons et al., 2013 (56) Head and neck cancer Retrospective Case: 8 Control: 8 Germany Single center Radiation-induced late normal tissue toxicity (eg, fibrosis, xerostomia) Chromosomal damage in lymphocytes Borgmann et al., 2002 (53) Nasopharyngeal carcinoma Prospective 114 China, single center Acute dermatitis and mucositis XRCC1 Li et al., 2013 (47) Head and neck cancer Prospective 101 Italy, multi-site Acute reactions (mucositis, skin erythema, and dysphagia) XRCC1 and RAD51 Pratesi et al., 2011 (57) Nasopharyngeal Cancer Retrospective, case-control Case: 30 Control: 30 Saudi Arabia, single center Subcutaneous and deep tissue fibrosis TGF-β1, XRCC1 Alsbeih et al., 2010 (58) Nasopharyngeal Cancer Prospective, case-control Case: 16 Control: 16 Saudi Arabia, single center Subcutaneous and deep tissue fibrosis ND3 (mitochondrial DNAa)-Oxidative metabolism pathway Alsbeih et al., 2009 (59) Primary site and tumor Design Sample size (No.) Country and centers (participants recruited) Clinical endpoint and tissues affected Genes and SNPs References Head and neck cancer (47%); & breast cancer Retrospective, case-control Case: 16 Control: 18 Switzerland, single center Severe radiation-induced sequelae (eg, subcutaneous fibrosis) ATM, SOD2, XRCC1 and XRCC3, TGF-β1, RAD21 Azria et al., 2008 (49) Nasopharyngeal cancer Retrospective 120 China, Hong Kong, single center Neck fibrosis XRCC3 Cheuk et al., 2014 (50) Nasopharyngeal cancer Retrospective, case-control Case: 48 Control: 107 Saudi Arabia, single center Subcutaneous and deep tissue fibrosis HDM2, TGF-β1, XRCC1 Alsbeih et al., 2013 (51) Head and neck cancer Retrospective 6 US Single center Submental fibrosis CAV-1, COLLA1, TIMP1, MMP14, IL-13, IL-8, CXCL10, CCL7, MX1, IFIT2, CTGF, ET-1 Krisciunas et al., 2015 (52) Head and neck cancer Retrospective 78 Germany Single center Radiation-induced skin fibrosis and angiogenesis α-PC and TGF-β1 Koerdt et al., 2015 (54) Various cancers (47% head and neck cancer) Prospective Case: 179 Control: 26 U.S Single center Radiation-induced late normal tissue toxicity HMOX1, NFE2L2, TGF-β1 Alam et al., 2015 (55) Head and neck cancer Prospective 62 United Kingdom,Single center Trismus TGF-β1 Lyons et al., 2013 (56) Head and neck cancer Retrospective Case: 8 Control: 8 Germany Single center Radiation-induced late normal tissue toxicity (eg, fibrosis, xerostomia) Chromosomal damage in lymphocytes Borgmann et al., 2002 (53) Nasopharyngeal carcinoma Prospective 114 China, single center Acute dermatitis and mucositis XRCC1 Li et al., 2013 (47) Head and neck cancer Prospective 101 Italy, multi-site Acute reactions (mucositis, skin erythema, and dysphagia) XRCC1 and RAD51 Pratesi et al., 2011 (57) Nasopharyngeal Cancer Retrospective, case-control Case: 30 Control: 30 Saudi Arabia, single center Subcutaneous and deep tissue fibrosis TGF-β1, XRCC1 Alsbeih et al., 2010 (58) Nasopharyngeal Cancer Prospective, case-control Case: 16 Control: 16 Saudi Arabia, single center Subcutaneous and deep tissue fibrosis ND3 (mitochondrial DNAa)-Oxidative metabolism pathway Alsbeih et al., 2009 (59) ATM = Ataxia-telangiectasia mutated; CAV-1 = Caveolin-1; CCL7 = Chemokine C-C motif ligand 7; COLLA1 = Collagen type I alpha I; CTGF = Connective tissue growth factor; CXCL10 = C-X-C motif chemokine 10; ET-1 = Endothelin-1; HMOX1 = Heme oxygenase 1; IFIT2 = Interferon-induced protein with tetratricopeptide repeats 2; MMP14 = Matrix metalloproteinase-14; MX1 = MX dynamin-like GTPase I; ND3 = Mitochondrially encoded NADH dehydrogenase subunit 3 gene; NFE2L2 = Encoding nuclear regulatory factor-2; α-PC = α-procollagen; RAD21 = Double-strand-break repair protein rad21 homolog; SNPs = Single-nucleotide polymorphisms; SOD2 = Superoxide dismutase 2; TGF-β1 = Transforming growth factor beta 1; TIMP1 = TMP metallopeptidase inhibitor 1; XRCC1 and XRCC3 = X-ray repair cross-complementing proteins 1 and 3. View Large There are numerous limitations to available data, particularly with reference to the HNC population. First, most of the studies were conducted in a single center with small sample sizes. Thus, studies are needed to expand and replicate these findings. Clearly, the number of studies evaluating RIF in HNC patients is limited compared with the plethora of studies in other cancers (eg, breast and lung cancers). In addition, although it is valuable to identify genes and SNPs relying on the candidate gene approach, it is critical to employ a genome-wide approach in which the entire genome is screened for statistically significantly altered allele frequencies based on the linkage disequilibrium concept. The genome-wide approach is essential to enable reliable interpretation of study findings, especially if these findings are to be translated into biomarkers and used to determine personalized radiotherapy strategy (66). Despite the identification of an association of individual genes and SNPs with radiation sensitivity and related tissue damage, our understanding of the pathobiology of RIF remains incomplete at best. This is due in part to the involvement of numerous pathways, many of which have yet to be fully explored, the intricacy of the interactions between pathways and their positive and negative regulators, and the added complexity derived from human variability. Pathways yet to be thoroughly investigated that could be hypothetically involved in normal tissue radiosensitivity include oxidative stress responses, activation of cell cycle checkpoints, inflammation, and apoptosis, among others (67). Clinical Presentation: Head and Neck Lymphedema and Fibrosis Due to the multimodal tissue insult experienced by HNC patients, LEF may coexist. A primary fibrotic process is readily identified clinically because of the general lack of overt swelling in the tissues. Unfortunately, the lack of tissue swelling cannot exclude the possibility of subclinical lymphedema. Conversely, the presence of tissue swelling indicative of lymphedema does not exclude the possibility of concurrent prototypical fibrosis. Because it is clinically difficult to distinguish the relative contribution of LEF in most patients, these two physiological processes have been combined into the term LEF. LEF encompasses the clinical spectrum from prominent reducible swelling with minimal fibrosis all the way through those patients with fibrosis associated with tissue contracture and atrophy (Table 1). Incidence and Prevalence All data on the incidence and prevalence of LEF are based on clinical physical exams using available measurement tools. Previously available tools are conceptually flawed (68); thus, much of the available data underrepresent the incidence and severity of both LEF. To address this unmet need, new methods for measuring LEF in the head and neck population are under development (69). Whereas early studies suggested that the incidence of secondary lymphedema after HNC treatment varies from 12% to 54% (70), a more rigorous cross-sectional report found that 75% of HNC patients after more than 3 months of posttreatment had secondary lymphedema (71). The high incidence of LEF has been confirmed by a recent prospective report indicating that almost 100% of HNC patients develop LEF at some point during HNC treatment and recovery. Location and Anatomical Sites LEF affects both external structures (eg, face, neck, shoulders) (72,73) and internal structures (eg, larynx, pharynx) (74,75). LEF may be confined to internal or external structures, or it may involve both (combined LEF) (71). Because radiation therapy and some surgical procedures may cause a pan-tissue inflammatory process, it is not surprising that a statistically significant percentage of patients have combined LEF. HNC patients frequently manifest lymphedema at one site and fibrosis at another. For example, patients frequently develop facial and submental lymphedema concurrent with neck fibrosis. Whether this reflects the propensity of specific tissue to respond to damage in a specific way, or whether it is a reflection of the density, behavior, or sensitivity of lymphatics within a select anatomical site is unknown. To parse this out, it is critical to carefully document and evaluate soft tissue findings based on the sites involved. Contributing Factors Several studies have reported factors contributing to the development of LEF in the HNC population. Two early studies suggested that radiation dose, positive lymph nodes, tumor stage, and surgery might be related to the development of secondary lymphedema in patients with HNC (76,77). Another cross-sectional study including 81 patients 3 months post HNC treatment identified the following factors associated with the presence of secondary external and internal lymphedema, including location of tumor (ie, tumors in the pharynx), total dosage of radiation therapy, number of days of radiation, radiation status of surgical bed (ie, surgery with postoperative radiation and salvage surgery in the irradiated field), number of treatment modalities, and time since end of HNC treatment (78). Available evidence indicates that select tumor and treatment parameters are associated with increased occurrence of lymphedema in the HNC population. Studies are ongoing to further explore causative risk factors for the development of lymphedema in this population. Clinician Assessment and Reporting: Characterizing Soft Tissue Abnormalities Characterizing the soft tissue abnormalities associated with HNC therapy is an ongoing challenge. Historically, soft tissue changes have been assessed by clinicians using physical examinations. There are multiple clinician-reported tools that assess external lymphedema or fibrosis; unfortunately, most of these tools are not specifically directed at the HNC patient population. Furthermore, many of the older tools are conceptually flawed and provide incomplete data. An effective tool would capture the dominant type of soft tissue abnormality, the severity of soft tissue abnormalities, and the anatomic sites. We have developed a clinical assessment tool in which four types of soft tissue change were defined based on the tissue characteristic noted on physical examination: (1) dermal thickening without soft tissue swelling or fibrosis (early-stage tissue damage); (2) visible tissue swelling that is reducible, soft, and fluctuating in nature; (3) visible tissue swelling that is firm, nonreducible, and without fluctuations; and (4) hard tissue without swelling. The reporting system allows for documentation of the type and severity of abnormalities within nine defined anatomical sites in the head and neck region (69). There is only one clinician-reported grading system for internal lymphedema: the Patterson scale (79). The Patterson scale uses an endoscopic examination to assess pharynx and larynx. This includes 11 sites and two spaces. Each anatomic site is graded with regards to severity based on a four-point system of none, mild, moderate, or severe. Ideally, it would be useful to have objective measures of LEF to compliment clinician-reported measures. Unfortunately, objective techniques for assessment of LEF are lacking. To address this unmet need, investigators are developing radiographic imaging methods to provide qualitative and quantitative measurement of LEF (4). Imaging modalities under instigation include CT, MRI, and ultrasound measurement techniques. Impact on Symptomology, Function, and Quality of Life It may be hypothesized that many late effects of therapy are due to soft tissue abnormalities caused by LEF. First, LEF causes unique sensory abnormalities that have been poorly described in the historical literature. This includes symptoms such as tightness, numbness, heaviness, and warmth (80). In addition, LEF is associated with loss of tissue compliance and plasticity resulting in statistically significant functional deficits. The manifestations of LEF vary based on the tissue involved. For example, when pharyngeal structures are involved, patients may experience dysphagia. Swelling of the laryngeal tissues secondary to LEF may result in shortness of breath and airway compromise. Fibrosis of the muscles and tissues involved in mastication may result in profound trismus and difficulty with chewing, speech, and oral care. Decreased range of motion and poor posture may occur when LEF involves the structures of the neck. Finally, alterations in function and cosmesis may lead to statistically significant body image issues, which result in depression, poor socialization (81), financial burden, and employment challenges (75). Management: Head and Neck Lymphedema and Fibrosis The core components of lymphedema management include patient education, completed decongestive therapy, exercises and stretching, and skin care (82–84). Education should include discussion of the chronic nature of LEF and the need for life-long self-care, the role of posture and body position in reducible lymphedema, the influence of diet and medication on tissue swelling, the need to monitor for infection, the need to monitor for function loss, and issues that should be brought to the attention of the health-care team. Complete decongestive therapy may involve manual lymph drainage and compression therapy. Exercise and stretching may improve both lymph flow and range of motion, thereby potentially limiting long-term functional deficits. Although these techniques are considered standard of care, data supporting their use are limited. The relative contribution of each of these interventions to long-term functionality and symptom burden is unclear. Clinical experience would indicate that early implementation of adequate lymphedema therapy may result in regression of lymphedema and minimization of late effects. That being said, prospective studies are lacking. Surgical revascularization is an emerging and effective treatment for selected patients with lymphedema. Reports in the HNC population are lacking. The combination of LEF may hinder investigation of this modality in the HNC population. It is often thought that fibrosis and loss of range of motion are intrinsically intertwined. However, clinical experience would indicate that early intervention with exercise and stretching may ameliorate some of the late effects of fibrosis, thereby retaining function. Once again, unfortunately, prospective studies defining the optimal therapeutic techniques are lacking. A number of studies have been conducted looking at pharmacologic and nonpharmacological techniques for improving or preventing fibrosis. To date, none of these techniques has been demonstrated to be unequivocally effective. Future Directions for Research Advances in our understanding of the cellular and molecular mechanisms regulating the pathobiology of lymphedema may lead to the development or testing of targeted anti-inflammatory or antifibrotic agents effective for prevention and treatment of lymphedema or fibrosis. Studies are needed to establish consistent and useful biomarkers that indicate the early development of LEF. This would potentially allow early detection of latent disease at a point along the trajectory where interventions may be more effective. Studies are needed to identify patients who are genetically predisposed to the development of soft tissue complications from treatment. This could potentially allow tailoring of therapy to the patient’s risk and benefit profile. In addition, this would allow preventive strategies to be tested in a high-risk population. Studies using promising pharmacologic therapies for prevention and treatment of lymphedema are warranted. For example, as noted above, T cells play an important role in lymphedema. Tacrolimus is a T cell inhibitor approved for fibrotic dermal processes such as atopic dermatitis and psoriasis. Animals studies with topical tacrolimus demonstrated improved lymphatic function (85). Studies investigating the prophylactic use of this agent in high-risk patients may result in attenuation or mitigation of LEF. Additional potential mechanisms that might be addressed based on the known pathophysiology include the use of anti-inflammatories, reduction of reactive oxygen species (86), inhibition of the 5-lipoxygenase metabolite leukotriene B4 (87), local inhibition of elastase (88), and photobiomodulation (89). Development of imaging modalities that can objectively measure both LEF are needed. This will facilitate interventional trials by providing sensitive and specific tools to assess LEF as an outcome. Studies are needed to clearly delineate optimal therapeutic methods, timing, and dosing to prevent and treat LEF. Notes Affiliations of authors: School of Nursing, University of Pennsylvania, Philadelphia, PA (JD); University of Kansas Medical Center, Kansas City, KS (EMW-B); Vanderbilt-Ingram Cancer Center, Nashville, TN (BAM). The authors declare that they have no conflicts of interest. For support see Funding Acknowledgement section of Monograph. References 1 Murphy BA , Deng J. Advances in supportive care for late effects of head and neck cancer . J Clin Oncol . 2015 ; 33 29 : 3314 – 3321 . Google Scholar Crossref Search ADS PubMed WorldCat 2 Ringash J. Survivorship and quality of life in head and neck cancer . J Clin Oncol . 2015 ; 33 29 : 3322 – 3327 . Google Scholar Crossref Search ADS PubMed WorldCat 3 O'Sullivan B , Levin W. Late radiation-related fibrosis: pathogenesis, manifestations, and current management . Semin Radiat Oncol . 2003 ; 13 3 : 274 – 289 . Google Scholar Crossref Search ADS PubMed WorldCat 4 Deng J , Ridner SH , Aulino JM. Measurement of head and neck lymphedema and fibrosis: a comprehensive review . Oral Oncol . 2015 ; 51 5 : 431 – 437 . Google Scholar Crossref Search ADS PubMed WorldCat 5 Smith BG , Lewin JS. Lymphedema management in head and neck cancer . Curr Opin Otolaryngol Head Neck Surg . 2010 ; 18 3 : 153 – 158 . Google Scholar Crossref Search ADS PubMed WorldCat 6 Lee B-B , Bergan JJ , Rockson SG , 2011 . Lymphedema: A Concise Compendium of the Theory and Practice . London : Springer; 2011 . Google Preview WorldCat COPAC 7 Földi M , Földi E , Strössenreuther RHK , Kubik S , editors. Földi's Textbook of Lymphology: For Physicians and Lymphedema Therapists . 2nd ed . Munchen, Germany : Mosby ; 2006 . Google Preview WorldCat COPAC 8 Mortimer PS , Rockson SG. New developments in clinical aspects of lymphatic disease . J Clin Invest . 2014 ; 124 3 : 915 – 921 . Google Scholar Crossref Search ADS PubMed WorldCat 9 Yarbro CH , Wujcik D , Gobel BH. Cancer Symptom Management . 4th ed . Burlington, MA : Jones & Bartlett Learning, LLC ; 2014 . Google Preview WorldCat COPAC 10 Carlson JA. Lymphedema and subclinical lymphostasis (microlymphedema) facilitate cutaneous infection, inflammatory dermatoses, and neoplasia: a locus minoris resistentiae . Clin Dermatol . 2014 ; 32 5 : 599 – 615 . Google Scholar Crossref Search ADS PubMed WorldCat 11 Avraham T , Zampell JC , Yan A. Th2 differentiation is necessary for soft tissue fibrosis and lymphatic dysfunction resulting from lymphedema . Faseb J . 2013 ; 27 3 : 1114 – 1126 . Google Scholar Crossref Search ADS PubMed WorldCat 12 Ridner SH , Dietrich MS , Niermann K , Cmelak A , Mannion K , Murphy B. A prospective study of the lymphedema and fibrosis continuum in patients with head and neck cancer . Lymphat Res Biol . 2016 ; 14 4 : 198 – 205 . Google Scholar Crossref Search ADS PubMed WorldCat 13 Rockson SG , editor. Lymphatic Continuum Revisited . 1st ed . New York : Wiley-Blackwell ; 2008 . Google Preview WorldCat COPAC 14 Lin S , Kim J , Lee MJ. Prospective transcriptomic pathway analysis of human lymphatic vascular insufficiency: identification and validation of a circulating biomarker panel . PLoS One . 2012 ; 7 12 : e52021. Google Scholar Crossref Search ADS PubMed WorldCat 15 Rockson SG. Update on the biology and treatment of lymphedema . Curr Treat Options Cardiovasc Med . 2012 ; 14 2 : 184 – 192 . Google Scholar Crossref Search ADS PubMed WorldCat 16 Zampell JC , Yan A , Elhadad S. CD4(+) cells regulate fibrosis and lymphangiogenesis in response to lymphatic fluid stasis . PLoS One . 2012 ; 7 11 : e49940. Google Scholar Crossref Search ADS PubMed WorldCat 17 Ghanta S , Cuzzone DA , Torrisi JS , et al. . Regulation of inflammation and fibrosis by macrophages in lymphedema . Am J Physiol Heart Circ Physiol . 2015 ; 308 9 : H1065 – H1077 . Google Scholar Crossref Search ADS PubMed WorldCat 18 Scavelli C , Weber E , Agliano M , et al. . Lymphatics at the crossroads of angiogenesis and lymphangiogenesis . J Anat . 2004 ; 204 6 : 433 – 449 . Google Scholar Crossref Search ADS PubMed WorldCat 19 Zheng W , Aspelund A , Alitalo K. Lymphangiogenic factors, mechanisms, and applications . J Clin Invest . 2014 ; 124 3 : 878 – 887 . Google Scholar Crossref Search ADS PubMed WorldCat 20 Zampell JC , Avraham T , Yoder N , et al. . Lymphatic function is regulated by a coordinated expression of lymphangiogenic and anti-lymphangiogenic cytokines . Am J Physiol Cell Physiol . 2012 ; 302 2 : C392 – C404 . Google Scholar Crossref Search ADS PubMed WorldCat 21 Harvey NL , Srinivasan RS , Dillard ME , et al. . Lymphatic vascular defects promoted by Prox1 haploinsufficiency cause adult-onset obesity . Nat Genet . 2005 ; 37 10 : 1072 – 1081 . Google Scholar Crossref Search ADS PubMed WorldCat 22 Zampell JC , Aschen S , Weitman ES , et al. . Regulation of adipogenesis by lymphatic fluid stasis: part I. adipogenesis, fibrosis, and inflammation . Plast Reconstr Surg . 2012 ; 129 4 : 825 – 834 . Google Scholar Crossref Search ADS PubMed WorldCat 23 Sell H , Eckel J. Adipose tissue inflammation: novel insight into the role of macrophages and lymphocytes . Curr Opin Clin Nutr Metab Care . 2010 ; 13 4 : 366 – 370 . Google Scholar Crossref Search ADS PubMed WorldCat 24 Medina M , Orgill DP. Discussion: regulation of adipogenesis by lymphatic fluid stasis: part I. Adipogenesis, fibrosis, and inflammation . Plast Reconstr Surg . 2012 ; 129 4 : 835 – 837 . Google Scholar Crossref Search ADS PubMed WorldCat 25 Weisberg SP , McCann D , Desai M , et al. . Obesity is associated with macrophage accumulation in adipose tissue . J Clin Invest . 2003 ; 112 12 : 1796 – 1808 . Google Scholar Crossref Search ADS PubMed WorldCat 26 Savetsky IL , Torrisi JS , Cuzzone DA , et al. . Obesity increases inflammation and impairs lymphatic function in a mouse model of lymphedema . Am J Physiol Heart Circ Physiol . 2014 ; 307 2 : H165 – H172 . Google Scholar Crossref Search ADS PubMed WorldCat 27 Cuzzone DA , Weitman ES , Albano NJ , et al. . IL-6 regulates adipose deposition and homeostasis in lymphedema . Am J Physiol Heart Circ Physiol . 2014 ; 306 10 : H1426 – H1434 . Google Scholar Crossref Search ADS PubMed WorldCat 28 Finegold DN , Schacht V , Kimak MA , et al. . HGF and MET mutations in primary and secondary lymphedema . Lymphat Res Biol . 2008 ; 6 2 : 65 – 68 . Google Scholar Crossref Search ADS PubMed WorldCat 29 Finegold DN , Baty CJ , Knickelbein KZ , et al. . Connexin 47 mutations increase risk for secondary lymphedema following breast cancer treatment . Clin Cancer Res . 2012 ; 18 8 : 2382 – 2390 . Google Scholar Crossref Search ADS PubMed WorldCat 30 Miaskowski C , Dodd M , Paul SM , et al. . Lymphatic and angiogenic candidate genes predict the development of secondary lymphedema following breast cancer surgery . PLoS One . 2013 ; 8 4 : e60164. Google Scholar Crossref Search ADS PubMed WorldCat 31 Leung G , Baggott C , West C , et al. . Cytokine candidate genes predict the development of secondary lymphedema following breast cancer surgery . Lymphat Res Biol . 2014 ; 12 1 : 10 – 22 . Google Scholar Crossref Search ADS PubMed WorldCat 32 Rockey DC , Bell PD , Hill JA. Fibrosis: a common pathway to organ injury and failure . N Engl J Med . 2015 ; 372 12 : 1138 – 1149 . Google Scholar Crossref Search ADS PubMed WorldCat 33 Shaw SM , Skoretz SA , O'Sullivan B , et al. . Valid and reliable techniques for measuring fibrosis in patients with head and neck cancer postradiotherapy: a systematic review . Head & Neck . 2016 ; 38(suppl 1) : E2322 – E2334 . Google Scholar Crossref Search ADS PubMed WorldCat 34 Travis EL. Organizational response of normal tissues to irradiation . Semin Radiat Oncol . 2001 ; 11 3 : 184 – 196 . Google Scholar Crossref Search ADS PubMed WorldCat 35 Khan MA , Van Dyk J , Yeung IW , Hill RP. Partial volume rat lung irradiation; assessment of early DNA damage in different lung regions and effect of radical scavengers . Radiother Oncol . 2003 ; 66 1 : 95 – 102 . Google Scholar Crossref Search ADS PubMed WorldCat 36 Straub JM , New J , Hamilton CD , et al. . Radiation-induced fibrosis: Mechanisms and implications for therapy . J Cancer Res Clin Oncol . 2015 ; 141 11 : 1985 – 1994 . Google Scholar Crossref Search ADS PubMed WorldCat 37 Terasaki Y , Ohsawa I , Terasaki M , et al. . Hydrogen therapy attenuates irradiation-induced lung damage by reducing oxidative stress . Am J Physiol Lung Cell Mol Physiol . 2011 ; 301 4 : L415 – 426 . Google Scholar Crossref Search ADS PubMed WorldCat 38 Zhao W , Robbins M. Inflammation and chronic oxidative stress in radiation-induced late normal tissue injury: therapeutic implications . CMC . 2009 ; 16 2 : 130 – 143 . Google Scholar Crossref Search ADS WorldCat 39 Denham JW , Hauer-Jensen M. The radiotherapeutic injury--a complex ‘wound’ . Radiother Oncol . 2002 ; 63 2 : 129 – 145 . Google Scholar Crossref Search ADS PubMed WorldCat 40 Stubblefield M , O'Dell M. Cancer Rehabilitation: Principles and Practice . New York : Demos Medical Publishing ; 2009 . Google Preview WorldCat COPAC 41 Calveley VL , Khan MA , Yeung IWT , Vandyk J , Hill RP. Partial volume rat lung irradiation: temporal fluctuations of in-field and out-of-field DNA damage and inflammatory cytokines following irradiation . Int J Radiat Biol . 2005 ; 81 12 : 887 – 899 . Google Scholar Crossref Search ADS PubMed WorldCat 42 Porter DW , Ye J , Ma J , et al. . Time course of pulmonary response of rats to inhalation of crystalline silica: NF-kappa B activation, inflammation, cytokine production, and damage . Inhal Toxicol . 2002 ; 14 4 : 349 – 367 . Google Scholar Crossref Search ADS PubMed WorldCat 43 Sica A , Mantovani A. Macrophage plasticity and polarization: in vivo veritas . J Clin Invest . 2012 ; 122 3 : 787 – 795 . Google Scholar Crossref Search ADS PubMed WorldCat 44 Li M , Jendrossek V , Belka C. The role of PDGF in radiation oncology . Radiat Oncol . 2007 ; 2 2 : 5. Google Scholar Crossref Search ADS PubMed WorldCat 45 Bray FN , Simmons BJ , Wolfson AH , Nouri K. Acute and chronic cutaneous reactions to ionizing radiation therapy . Dermatol Ther (Heidelb) . 2016 ; 6 2 : 185 – 206 . doi: 10.1007/s13555-016-0120-y. Google Scholar Crossref Search ADS PubMed WorldCat 46 Canney PA , Dean S. Transforming growth factor beta: a promotor of late connective tissue injury following radiotherapy? BJR . 1990 ; 63 752 : 620 – 623 . Google Scholar Crossref Search ADS PubMed WorldCat 47 Singh M , Alavi A , Wong R , Akita S. Radiodermatitis: a review of our current understanding . Am J Clin Dermatol . 2016 ; 17 3 : 277 – 292 . Google Scholar Crossref Search ADS PubMed WorldCat 48 Akita S , Yoshimoto H , Akino K , et al. . Early experiences with stem cells in treating chronic wounds . Clin Plastic Surg . 2012 ; 39 3 : 281 – 292 . Google Scholar Crossref Search ADS WorldCat 49 Rattay T , Talbot CJ. Finding the genetic determinants of adverse reactions to radiotherapy . Clin Oncol (Royal College of Radiologists) . 2014 ; 26 5 : 301 – 308 . Google Scholar Crossref Search ADS WorldCat 50 Martin M , Lefaix J , Delanian S. TGF-Beta1 radiation fibrosis: a master switch and a specific therapeutic target? Int J Radiat Oncol Biol Phys . 2000 ; 47 2 : 277 – 290 . Google Scholar Crossref Search ADS PubMed WorldCat 51 Terrazzino S , La Mattina P , Gambaro G , et al. . Common variants of GSTP1, GSTA1, and TGFβ1 are associated with the risk of radiation-induced fibrosis in breast cancer patients . Int J Radiat Oncol Biol Phys . 2012 ; 83 2 : 504 – 511 . Google Scholar Crossref Search ADS PubMed WorldCat 52 Andreassen CN , Grau C , Alsner J , Overgaard J , editors. Are TGF-Beta 1 Polymorphisms Potential Predictors of Fibrosis Risk after Radiotherapy? - A Subset Analysis from the DAHANCA 6 and 7 Protocols . ECGO ; 2007 . Google Preview WorldCat COPAC 53 Spiegelberg L , Swagemakers SMA , van Ijcken WFJ , et al. . Gene expression analysis reveals inhibition of radiation-induced TGFβ-signaling by hyperbaric oxygen therapy in mouse salivary glands . Mol Med . 2014 ; 20 1 : 257 – 269 . Google Scholar Crossref Search ADS PubMed WorldCat 54 Li H , You Y , Lin C , et al. . XRCC1 codon 399Gln polymorphism is associated with radiotherapy-induced acute dermatitis and mucositis in nasopharyngeal carcinoma patients . Radiat Oncol . 2013 ; 8 1 : 31. Google Scholar Crossref Search ADS PubMed WorldCat 55 Azria D , Ozsahin M , Kramar A , et al. . Single nucleotide polymorphisms, apoptosis, and the development of severe late adverse effects after radiotherapy . Clin Cancer Res . 2008 ; 14 19 : 6284 – 6288 . Google Scholar Crossref Search ADS PubMed WorldCat 56 Borgmann K , Röper B , El-Awady R , et al. . Indicators of late normal tissue response after radiotherapy for head and neck cancer: fibroblasts, lymphocytes, genetics, DNA repair, and chromosome aberrations . Radiother Oncol . 2002 ; 64 2 : 141 – 152 . Google Scholar Crossref Search ADS PubMed WorldCat 57 Cheuk IW , Yip SP , Kwong DL , Wu VW. Association of XRCC1 and XRCC3 gene haplotypes with the development of radiation-induced fibrosis in patients with nasopharyngeal carcinoma . Mol Clin Oncol . 2014 ; 2 4 : 553 – 558 . Google Scholar Crossref Search ADS PubMed WorldCat 58 Alsbeih G , El-Sebaie M , Al-Harbi N , et al. . SNPs in genes implicated in radiation response are associated with radiotoxicity and evoke roles as predictive and prognostic biomarkers . Radiat Oncol . 2013 ; 8 : 125. Google Scholar Crossref Search ADS PubMed WorldCat 59 Krisciunas GP , Platt M , Trojanowska M , et al. . A novel in vivo protocol for molecular study of radiation-induced fibrosis in head and neck cancer patients . Ann Otol Rhinol Laryngol . 2016 ; 125 3 : 228 – 234 . Google Scholar Crossref Search ADS PubMed WorldCat 60 Koerdt S , Rohleder NH , Rommel N , et al. . An expression analysis of markers of radiation-induced skin fibrosis and angiogenesis in wound healing disorders of the head and neck . Radiat Oncol . 2015 ; 10 : 202. Google Scholar Crossref Search ADS PubMed WorldCat 61 Alam A , Mukhopadhyay ND , Ning Y , et al. . A preliminary study on racial differences in HMOX1, NFE2L2, and TGFβ1 gene polymorphisms and radiation-induced late normal tissue toxicity . Int J Radiat Oncol Biol Phys . 2015 ; 93 2 : 436 – 443 . Google Scholar Crossref Search ADS PubMed WorldCat 62 Lyons AJ , Crichton S , Pezier T. Trismus following radiotherapy to the head and neck is likely to have distinct genotype dependent cause . Oral Oncol . 2013 ; 49 9 : 932 – 936 . Google Scholar Crossref Search ADS PubMed WorldCat 63 Pratesi N , Mangoni M , Mancini I , et al. . Association between single nucleotide polymorphisms in the XRCC1 and RAD51 genes and clinical radiosensitivity in head and neck cancer . Radiot Oncol . 2011 ; 99 3 : 356 – 361 . Google Scholar Crossref Search ADS WorldCat 64 Alsbeih G , Al-Harbi N , Al-Hadyan K , El-Sebaie M , Al-Rajhi N. Association between normal tissue complications after radiotherapy and polymorphic variations in TGFB1 and XRCC1 genes . Radiat Res . 2010 ; 173 4 : 505 – 511 . Google Scholar Crossref Search ADS PubMed WorldCat 65 Alsbeih GA , Al-Harbi NM , El-Sebaie MM , et al. . Involvement of mitochondrial DNA sequence variations and respiratory activity in late complications following radiotherapy . Clin Cancer Res . 2009 ; 15 23 : 7352 – 7360 . Google Scholar Crossref Search ADS PubMed WorldCat 66 Ghazali N , Shaw RJ , Rogers SN , Risk JM. Genomic determinants of normal tissue toxicity after radiotherapy for head and neck malignancy: a systematic review . Oral Oncol . 2012 ; 48 11 : 1090 – 1100 . Google Scholar Crossref Search ADS PubMed WorldCat 67 Strauss J , Small W , Woloschak GE. Breast Cancer Biology for the Radiation Oncologist . Berlin, Heidelberg : Springer Verlag ; 2015 . Google Preview WorldCat COPAC 68 Deng J , Ridner SH , Dietrich MS , et al. . Assessment of external lymphedema in patients with head and neck cancer: a comparison of four scales . Oncol Nurs Forum . 2013 ; 40 5 : 501 – 506 . Google Scholar Crossref Search ADS PubMed WorldCat 69 Deng J , Ridner SH , Wells N , Dietrich MS , Murphy BA. Development and preliminary testing of a head and neck cancer related external lymphedema and fibrosis assessment criteria . Eur J Oncol Nurs . 2015 ; 19 1 : 75 – 80 . Google Scholar Crossref Search ADS PubMed WorldCat 70 Deng J , Ridner SH , Murphy BA. Lymphedema in patients with head and neck cancer . Oncol Nurs Forum . 2011 ; 38 1 : E1 – E10 . 2011; Google Scholar Crossref Search ADS PubMed WorldCat 71 Deng J , Ridner SH , Dietrich MS , et al. . Prevalence of secondary lymphedema in patients with head and neck cancer . J Pain Symptom Manage . 2012 ; 43 2 : 244 – 252 . Google Scholar Crossref Search ADS PubMed WorldCat 72 Hammond T. Symptoms of head and neck edema. http://www.lymphnotes.com/article.php/id/378/. Accessed January 2, 2016. 73 Zimmermann T , Leonhardt H , Kersting S , et al. . Reduction of postoperative lymphedema after oral tumor surgery with sodium selenite . Biol Trace Elem Res . 2005 ; 106 3 : 193 – 203 . Google Scholar Crossref Search ADS PubMed WorldCat 74 Bruns F , Buntzel J , Mucke R , et al. . Selenium in the treatment of head and neck lymphedema . Med Princ Pract . 2004 ; 13 4 : 185 – 190 . Google Scholar Crossref Search ADS PubMed WorldCat 75 Micke O , Bruns F , Mucke R , et al. . Selenium in the treatment of radiation-associated secondary lymphedema . Int J Radiat Oncol . 2003 ; 56 1 : 40 – 49 . Google Scholar Crossref Search ADS WorldCat 76 Sanguineti G , Adapala P , Endres EJ , et al. . Dosimetric predictors of laryngeal edema . Int J Radiat Oncol Biol Phys . 2007 ; 68 3 : 741 – 749 . Google Scholar Crossref Search ADS PubMed WorldCat 77 Warren AG , Slavin SA. Scar lymphedema: fact or fiction? Ann Plastic Surg . 2007 ; 59 1 : 41 – 45 . Google Scholar Crossref Search ADS WorldCat 78 Deng J , Ridner SH , Dietrich MS , et al. . Factors associated with external and internal lymphedema in patients with head-and-neck cancer . Int J Radiat Oncol Biol Phys . 2012 ; 84 3 : e328. WorldCat 79 Patterson JM , Hildreth A , Wilson JA. Measuring edema in irradiated head and neck cancer patients . Ann Otol Rhinol Laryngol . 2007 ; 116 8 : 559 – 564 . Google Scholar Crossref Search ADS PubMed WorldCat 80 Deng J , Murphy BA , Dietrich MS , et al. . Differences of symptoms in head and neck cancer patients with and without lymphedema . Support Care Cancer . 2016 ; 24 3 : 1305 – 1316 . Google Scholar Crossref Search ADS PubMed WorldCat 81 McGarvey AC , Osmotherly PG , Hoffman GR , Chiarelli PE. Lymphoedema following treatment for head and neck cancer: impact on patients, and beliefs of health professionals . Eur J Cancer Care (Engl) . 2014 ; 23 3 : 317 – 327 . Google Scholar Crossref Search ADS PubMed WorldCat 82 Zuther J. Lymphedema Management: The Comprehensive Guide for Practitioners . 2nd ed . New York : Thieme ; 2009 . Google Preview WorldCat COPAC 83 Jeffs E , Huit M. Treatment and outcomes of head and neck oedema referrals to a hospital-based lymphoedema service . Br J Community Nurs . 2015 ;( suppl) : S6 – S13 . Google Scholar Crossref Search ADS PubMed WorldCat 84 Tacani PM , Franceschini JP , Tacani RE , et al. . Retrospective study of the physical therapy modalities applied in head and neck lymphedema treatment . Head Neck . 2016 ; 38 2 : 301 – 308 . Google Scholar Crossref Search ADS PubMed WorldCat 85 Gardenier JC , Kataru RP , Hespe GE , et al. . Topical tacrolimus for the treatment of secondary lymphedema . Nat Commun . 2017 ; 8 : 14345 . Google Scholar Crossref Search ADS PubMed WorldCat 86 Pfister C , Dawzcynski H , Schingale F. Sodium selenite and cancer related lymphedema: biological and pharmacological effects . J Trace Elem Med Biol . 2016 ; 37 : 111 – 116 . Google Scholar Crossref Search ADS PubMed WorldCat 87 Tian W , Rockson SG , Jiang X , et al. . Leukotriene B4 antagonism ameliorates experimental lymphedema . Sci Transl Med . 2017 ; 9 389 . doi:10.1126/scitranslmed.aal3920. WorldCat 88 Pivetta E , Wassermann B , Belluz LDB , et al. . Local inhibition of elastase reduces EMILIN1 cleavage reactivating lymphatic vessel function in a mouse lymphoedema model . Clin Sci . 2016 ; 130 14 : 1221 – 1236 . Google Scholar Crossref Search ADS PubMed WorldCat 89 Baxter GD , Liu L , Petrich S , et al. . Low level laser therapy (photobiomodulation therapy) for breast cancer-related lymphedema: a systematic review . BMC Cancer . 2017 ; 17 1 : 833. Google Scholar Crossref Search ADS PubMed WorldCat © The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Journal

JNCI MonographsOxford University Press

Published: Aug 1, 2019

References