Karin Garming Legert, Cecilia Larsson Wexell, Anne Marie Lynge Pedersen, Gita Gale, Victor Tollemar, Hellevi Ruokonen, Saara Kantola and Bente Brokstad Herlofson

Oral manifestations of systemic disorders – part 2

Karin GarmingLegert 

Associate professor, DDS, PhD. Division of Oral Diagnostic and Surgery. Department of Dental Medicine and Department of Orofacial Medicine – University Dental Clinic, Karolinska Institutet, Sweden

Cecilia LarssonWexell 

Associate professor, DDS, PhD. Senior consultant OMFS, Department of Oral and Maxillofacial Surgery, Skåne University Hospital, Lund, Department of Oral and Maxillofacial Surgery and Oral medicine, Faculty of Odontology, Malmö University and Department of Biomaterials, Sahlgrenska academy, University of Gothenburg, Sweden

Anne Marie LyngePedersen 

Professor, DDS, PhD. Section of Oral Medicine and Pathology/Oral Biology and Immunopathology, Department of Odontology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark


DDS, PhD. Department. of Oral Medicine and Pathology, Institute of Odontology, The Sahlgrenska Academy at University of Gothenburg, Sweden


Lecturer, DDS, PhD. Division of Oral Diagnostic and Surgey. Department of Dental Medicine, Karolinska Institutet, Sweden


Adjunct professor, DDS, PhD, eMBA. Oral and Maxillofacial Diseases and Surgery, Head and Neck Center, Helsinki University Hospital and University of Helsinki, Finland


Head, DDS, PhD, Dental Training Clinic, Wellbeing Services County of North Ostrobothnia, Oulu, Finland

Bente BrokstadHerlofson 

Professor, DDS, PhD. Department of Oral Surgery and Oral Medicine, Faculty of Dentistry, University of Oslo, Norway, and Consultant, Unit of Oral Surgery and Maxillofacial Surgery, Department of Otorhinolaryngology – Head, Neck and Reconstructive Surgery, Oslo University Hospital, Norway.

Treatment- and medication-related side effects can affect the oral cavity and occur for both benign and malignant conditions. Immunocompromised individuals are predisposed to oral infections because the immune system plays a specialized role in host defense. Defects in specific functions of the immune system lead to increased susceptibility to specific pathogens. In this article, we address the impact of osteonecrosis of the jaw, osteoradionecrosis, treatment with monoclonal antibodies, chronic graft versus host disease, and viral infections. All these factors are of importance, especially in cancer treatment and/or allogeneic stem cell transplantation.

Treatment-related oral side effects and diseases

Osteonecrosis of the jaw (ONJ)

Osteonecrosis of the jaw (ONJ) is a rare but serious condition characterized by parts of the jawbone becoming necrotic and infected. The two most common causes of ONJ are related to antiresorptive medications, i.e., bisphosphonates, denosumab and antiangiogenic agents (designated medication-related osteonecrosis of the jaw, MRONJ), and radiotherapy involving the jawbone (designated osteoradionecrosis, ORN).

Medication-related osteonecrosis of the jaw (MRONJ)

The first reports of MRONJ were published in the beginning of 2000 after the introduction and approval of a new class of nitrogen-containing bisphosphonates for the prevention of bone complications in adults with advanced cancer [1][2]. Bisphosphonates are a class of inorganic drugs with various chemical structures. Bis­phosphonates bind to the bone surface and accumulate in the bone where they are released by osteoclasts. In 2011, treatment with a monoclonal antibody, denosumab, was approved for the same indications [3]. Denosumab is an inhibitor of RANKL (receptor activator of nuclear factor kappa-B ligand) and inhibits the maturation of osteoclasts by binding to RANKL. In 2019, romosozumab (Evenity®), a humanized monoclonal antibody that targets sclerostin, was approved for postmenopausal osteoporosis [4]. Sclerostin is inhibited, which allows Wnt signalling in osteoblasts to promote bone formation and allows for the inhibition of RANKL.


The definition consists of three criteria: a) exposed bone or bone that can be probed through an intraoral or extraoral fistula (e) in the maxillofacial region that has persisted for more than eight weeks; b) current or previous treatment with antiresorptive therapy alone or in combination with immune modulators or antiangiogenic medication; and c) no history of radiation therapy to the jaws or obvious metastatic disease to the jaws [5].

Age and incidence

MRONJ affects adult patients at all ages treated with antiresorptive agents, bisphosphonates and denosumab. Postmenopausal women with primary breast cancer have also been shown to have a beneficial reduction in breast cancer recurrence and death from treatment with adjuvant bisphosphonate therapy, i.e., zoledronate 4 mg/ml every 6 months for 3–5 years [6]. The incidence rate of MRONJ in this group is unknown. A Scandinavian 5-year study followed 2900 patients with cancer who were treated with denosumab or zoledronate. MRONJ affects between 1.4% and 6.6% of patients [2]. The risk for developing MRONJ in patients treated with bisphosphonates and denosumab for osteoporosis indication and osteo­porosis prophylaxis is very low [5].

Risk factors

Local and systemic risk factors (table 1) increase the risk for the development of MRONJ, and after 4 years of treatment, the risk is doubled [5]. For treatment with denosumab, there is a steep increase in the risk.

Risk Factors





Type of agent (nitrogen-containing BP, denosumab or/and anti-angiogenic agent), duration of treatment, cumulative dose, potency, route of adminstration (intravenous, subcutaneous, per oral, intramuscular), other medication (chemo­therapy, steroids, thalidomide and biological agents

Poor health status, chronic inflammatory disease, comorbidities, lifestyle (smoking, alcohol and high age)

Odontogenic infections, dento-alveolar surgery (e.g. tooth removal), implant surgery, ill-fitting dentures, exostosis e.g. mandibular and palatal tori, poor dental health and poor oral hygiene

Clinical features

MRONJ lesions present as areas of exposed bone, ranging from a few millimeters to larger areas involving a half jaw, often starting as a nonhealing alveolus following tooth extraction. In other cases, exposed bone occurs spontaneously, often lingually in the molar region of the mandible or related to a mandibular torus. The soft tissue and necrotic bone become infected, and the inflammatory reaction can vary from mild to severe. The symptoms can vary from mild to intense pain (figure 1) [5].

Figure 1 A-E. Patient with multiple myeloma treated with bisphosphonate (Zometa®) for 24 infusions during a 2-year period. Seven months after the last dose, the patient experienced pain related to the bone-anchored implants in the molar area. Both implants were installed several years before bisphosphonate treatment started. A: Before removal of the implant crown in the lower left second molar region. B: After removal of the implant crown in the lower left second molar region showing exposed necrotic bone. C-E: CBCT images demonstrate sclerosis and ostelytic areas involving a larger part of the mandible, including the body and ramus. The dental implants lost bone anchorage (axial, coronal and sagittal views).


The etiopathogenesis is still not clearly defined. Exposure to antiresorptive agents in combination with bone remodelling inhibition, inflammation and infection, angiogenesis inhibition, innate or acquired immune dysfunction, and genetic predisposition have been proposed as hypotheses [5].


MRONJ is a clinical diagnosis. Panoramic X-ray can provide an overview and serve as a basis for confirming the diagnosis and determining whether further imaging techniques are needed. Cone-beam computed tomography (CBCT) or conventional CT, with and without contrast, are valuable techniques commonly used in more complex investigations to evaluate the extent of the disease. A biopsy of the affected area can contribute to support the clinical diagnosis, but the main indication for histopathological analysis of a lesion is to exclude malignancy.

Differential diagnostics

The most important differential diagnoses are secondary chronic osteomyelitis and primary malignant tumour or metastasis in the jawbone or surrounding tissues.


The treatment of MRONJ may be nonsurgical or surgical. Nonsurgical treatment, often referred to as conservative treatment, includes maintenance of good oral hygiene and reduction of local soft tissue inflammation. Nonsurgical treatment may also include prolonged antibiotic therapy, similar to treatment for osteomyelitis. Surgical treatment ranges from sequestrectomy and block resections to segmental (continuity) resections and the insertion of reconstruction plates and is recommended for eligible patients.


Reports about the success rate of treatment of MRONJ often combine different MRONJ stages, underlying diseases, and drug treatments. In a recent review, extensive missing data and a lack of consensus were reported to be problems [7]. Optimal prevention of MRONJ includes regular dental check-ups, maintenance of good oral health and treatment of odontogenic infections and pathology in the jawbone and surrounding tissues before and during the treatment. It has been demonstrated that tooth extractions during/after antiresorptive therapy with low MRONJ incidences are possible provided that the following preventive measures are taken considering antibiotic therapy, alveoplasty, and primary wound closure [8].

Osteoradionecrosis (ORN)

In 1922, Regaud reported bone necrosis of the mandible after radio­therapy (RT) of cancer in the buccal mucosa [9]. Since then, numerous terms and definitions have been proposed for this feared and debilitating effect of RT.


The most frequently used definition of osteoradionecrosis (ORN) is exposed bone in a radiated field without healing over a period of 3 months without evidence of persisting or recurrent tumors [10][11]. However, some ORN cases appear to have necrotic bone (even to the extent of fracture) on radiology in the presence of intact skin and oral mucosa [12]. Radiology is thus an important tool for dia­gnosis and for describing the extent of the ORN condition.

Age and incidence

All patients treated with RT to the jaws run a life-long risk for developing ORN. The higher the amount of RT, the higher the risk for developing ORN. After the introduction of intensity-modulated RT (IMRT), the incidence of ORN was hypothesized to be reduced, but it persists with an incidence between 5-10% and argu­ably seems to increase, particularly in oropharyngeal cancer patients. The highest incidence of spontaneous ORN is seen in the first 2 or 3 years after RT, although cases have been reported more than 10 to 15 years after RT. Trauma-induced ORN (ORN secondary to, e.g., tooth extraction) has the highest incidence 2-5 years after RT [13].

Risk factors

The risk factors for ORN can be divided into treatment- and patient-related factors (table 2). Recently, an association between the development of ORN and the sites of pre-RT tooth extractions and other pre-RT-performed surgical procedures has been reported [14].

Risk Factors

Treatment- related




Radiation dose > 55Grey, radiation field, radiation involving molars and teeth close to tumour, time to radio therapy < 14 days after removal of teeth especially molars i the mandible, chemotherapy

Poor health status, older age, male gender, immune-deficiency, malnutrition, peripheral vascular disease, smoking, alcohol

Site and size of tumour, poor oral hygiene, poor dental health and periodontal status, dry mouth, reduced mouth opening, ill-fitting dentures, dento-alveolar surgery (e.g. tooth removal), trauma to the oral tissues after radio therapy

Clinical features

The clinical features of ORN are exposed bone, pain, swelling, trismus, oro-cutaneous fistula, and suppuration. Early radiographic features of ORN include widening of the periodontal ligament, coarsening of the trabecular pattern, osteolytic and sclerotic areas, and periosteal reaction, and further progression may show sequestration and pathological fracture (figure 2) [15]. These changes with­out any clinical features of ORN should not be diagnosed as ORN and require no treatment but should be regularly assessed since they could be a sign of early ORN.

Figure 2 A-B. A: Patient with tongue cancer, treated twice with radiotherapy due to recurrence of the cancer, developed pain and discomfort in the right lower jaw 7 years after radiotherapy. The lower right first molar was endodontically treated and later removed. The patient developed bone necrosis with an exposed jawbone. B: An orthopantomogram displayed an osteolytic and irregular appearance in the mandibular area. Four years later and 13 years after radiotherapy, a pathological fracture occurred.


The cause of ORN is most likely multifactorial. The most accepted current theories are the hypoxia, hypocellular, and hypovascular theory (3H theory), followed by the radiation-induced fibrosis theory (RIF theory) [16][17].


The diagnosis of ORN is based on the history of RT, clinical signs and symptoms and radiological findings. Several imaging techniques may be used for ORN detection, such as panoramic radiography, CT or cone beam CT (BCT), MRI, positron emission tomo­graphy (PET) and single-photon emission computed tomography (SPECT). Panoramic radiography and CT/CBCT are most commonly used.

Differential diagnostics

Diseases and conditions that may show similar clinical and radiographical features as described for ORN include MRONJ (due to antiresorptives, antiangiogenics or immunosuppressants), bone infections (i.e., herpes zoster, tuberculosis or osteomyelitis), genetic diseases (i.e., sickle cell anemia), and environmental exposure (i.e., to phosphorous or radium).

Management and treatment

Oral and maxillofacial surgeons and head and neck surgeons take care of patients with ORN, often at the same hospital where the can­cer treatment was performed. Currently, there are no consensus statements or guidelines for the management of ORN.

The treatment of ORN may be nonsurgical or surgical. Nonsurgical treatment, often referred to as conservative treatment, includes maintenance of good oral hygiene and reduction of local soft tissue inflammation primarily for symptom relief and prevention of disease progression. Nonsurgical treatment may also include longer periods of antibiotic treatment, corresponding to the protocol for osteomyelitis treatment. PENTO (PentoxifyllinTocoferol) or PENTOCLO (PentoxifyllinTocoferolClodronate) have been suggested as pharmacological treatments to influence red blood cells and inhibit the inflammatory response [17]. Infection control prior to and during such treatment is key to achieving a high rate of healing [18]. Surgical treatment ranges from sequestrectomy and block resections to segmental (continuity) resections and extensive surgical intervention, such as resection with or without vascularized free tissue flaps. Hyperbaric oxygen therapy (HBO) is still included in the protocol in some areas/countries when surgical treatment is indicated for ORN and when tooth removal after RT is needed.


Patients treated with radiotherapy for head and neck cancers have a life-long, and with time, increasing risk of developing ORN. Since tooth extraction in the irradiated jawbone is one of the most important risk factors for the development of ORN, this should be done at hospitals by specialists with knowledge in treating these patients.

Advanced therapy medicinal products (biologics)


A biopharmaceutical is any drug manufactured from a biological source made from complex molecules. Many biological drugs are produced using recombinant DNA technology. The European Medicines Agency (EMA) uses the term advanced therapy medicinal products (ATMP) for medicines for human use that are “based on genes, cells, or tissue engineering”, i.e., manufactured using liv­ing microorganisms, plants, human or animal cells [19].


During the last decade, ATMPs have become a valuable contribution and a new opportunity for the treatment of different diseases [20][21]. They can be classified into three main types: 1) gene therapy medicines, 2) somatic-cell therapy medicines and 3) tissue-­engineered medicines. Combined ATMPs can be both cells and a biodegradable matrix or scaffold (medical device). Examples of conditions treated with gene- and somatic-cell therapy medicines are cancer, rheumatoid arthritis and asthma [19][20][21].

Oral aspects

The oral side effects of ATMPs are poorly characterized, resulting in a lack of guidance for dental practitioners. Case reports describing oral side effects such as oral lichenoid reactions, oral mucosal ulcers and pigmentation are emerging [22][23]. Large multicenter studies will be necessary to further define the oral and dental complications caused by biologic agents [23]. The recommendations regarding oral health and accuracy when handling teeth and oral mucosa are the same as those for antiresorptive agents. The need for preoperative drug cessation varies (1 week - 4 months) and must be discussed with the responsible physician depending on the type of oral intervention. Treatment with ATMPs has been proposed as a possible medication for some oral conditions, i.e., JAK inhibitors for potential future treatment of oral lichen planus. Studies have demonstrated improvement for lichen planopilaris (a lichen affecting the nails) and erosive lichen planus, but the agents need to be further tested in clinical trials [24].

Oral chronic graft versus host disease


Graft versus host disease (GVHD) is a serious multiorgan complication in patients treated with allogeneic hematopoietic stem cell transplantation (HSCT). Patients receive donor cells that can immunologically respond to the host environment as a foreign body, leading to manifestations resembling an autoimmune syndrome such as GVHD [25][26]. GVHD can be acute or chronic based on clinical recognition, but acute (a) GVHD often occurs within the first 100 days post-HSCT. The main organs for aGVHD are the skin, liver, and upper and lower gastrointestinal (GI) tract, whereas oral aGVHD seldom occurs [27]. Chronic (c)GVHD often manifests in multiple organs, including the skin, mouth, liver, GI tract, lungs, eyes, and genitals [28]. Oral cGVHD features three disease presentations: lichenoid-like mucosal lesions, Sjögren’s syndrome-­like sicca symptoms and limited mouth opening due to sclerosis.

Age and incidence

Children and adults may be treated with allogenic HSCT, but children do not develop GVHD to the same degree as adults, possibly due to restored thymus function. Nevertheless, GVHD remains a potential serious oral complication in the pediatric population. In adults, approximately 30-70% of patients surviving HSCT will develop GVHD. The oral cavity is frequently affected (45-83%) in pati­ents with cGVHD [29][30].

Predisposing factors

Risks associated with GVHD development include donor and patient match, gender, age, virus serology and human leukocyte antigen, source of donor stem cells, preparative HSCT treatment regimen (radiotherapy and/or chemotherapy) and underlying disease [31]. Specific cGVHD risk factors include earlier episodes of aGVHD, mismatched donors and the use of peripheral blood stem cells (PBSCs) [32].

Clinical features

Figure 3. cGVHD in the buccal mucosa with lichenoid striations and ulcerations.

Figure 4. cGVHD on the dorsum of the tongue presenting with lichenoid striations, plaques and ulcerations.

Figure 5. cGVHD on the tongue with lichenoid striations and ulcerations.

Figure 6. Mucoceles in the soft palate in a patient with cGVHD.

Figure 7. Mucoceles in a patient with cGVHD who also suffered from dry mouth.

Oral cGVHD manifests as oral lichen planus-like lesions, including white striations, erythema, and ulcerations [33] (figure 3-5). Xerosto­mia and hyposalivation are common in patients undergoing HSCT due to polypharmacy, radiotherapy, chemotherapy and cGVHD (figure 6-7). Salivary gland cGVHD lacks validated diagnostic criteria, but persistent xerostomia, hyposalivation and mucoceles may be indications of cGVHD and are regarded as distinctive, but not diagnostic, features of cGVHD [34][35][36]. Chronic GVHD is associated with impaired wound healing, tissue repair and fibrosis. Additional complications of cGVHD include perioral fibrosis leading to limited mouth opening, sensitive, vulnerable, and painful oral mucosa, increased caries activity and aggravation of periodontal dis­ease [37][38][39][40][41].


The pathophysiology of cGVHD is not completely defined, and pathobiological pathways are probably different for the organs and tissue sites involved. Overall, immunocompetent donor T cells respond to genetically different human leukocyte antigens [29]. The acute inflammatory phase is triggered by conditioning-induced pathogen-associated molecules and host tissue damage-associated molecules followed by a chronic expansion of T cells. Macrophages and B cells might also play a role.

Changes in the oral mucosa and minor salivary glands in GVHD may histopathologically resemble those seen in oral lichen planus and Sjögren’s syndrome, respectively. The lichenoid lesions are characterized as a band-like lymphocytic aggregate that accumulates in the basal membrane region with exocytosis and apoptosis [42]. In the minor salivary gland tissue, periductal and acinar lymphocytic infiltration is considered specific for cGVHD [43]. The infiltrate usually comprises both plasma cells and T lymphocytes [43].


The diagnosis is based on clinical recognition, particularly the presence of lichenoid lesions, with a history of allogeneic HSCT.


Patients have systemic calcineurin inhibitors (CNIs) as GVHD prophylaxis. These agents are tapered, aiming for discontinuation postallogenic HSCT. Mild cGVHD is treated with topical cortico­steroids or calcineurin inhibitors, whereas systemic corticosteroids are used for patients with moderate to severe cGVHD [44][45]. As such, first-line treatment often includes a combination of corticosteroids with or without CNIs [45][46]. As many as 50% of cGVHD patients become steroid refractory and demand second-line treatment within the first two years post-HCT [45][46]. Second-line therapies might involve extracorporeal photopheresis, B-cell deplet­ion, antimetabolite immunosuppressants, chemotherapy, and kinase inhibitors [45][46][47].

The dentist plays an important role in the management of patients with oral cGVHD since diagnosis and management rely on clinical surveillance, which might be accompanied by a biopsy. Patients with severe disease should be treated by hospital oral disease units or specialists in oral medicine. Treatment should be inserted in collaboration with the medical team around the patient [48].

Prognosis, complications, and prevention

A special focus should be on hyposalivation and the risk of caries development [48]. Prolonged severe oral cGVHD is classified according to the WHO as a potential malignant disorder with an elevated risk for malignant transformation, which needs to be recognized by dental professionals [49].

Viral infections in immunocompromised patients

The most common viral infections affecting the oral cavity belong to the herpesviridae group: herpes simplex virus1 and 2 (HSV-1, HSV-2), human herpes viruses (HHV-3, HHV-4 and HHV-5), human papillomavirus (HPV), enteroviruses (coxsackie virus and enterovirus) and human immunodeficiency virus (HIV). Oral viral infections usually manifest as either solitary or multiple blisters (vesicles) and ulcerations. The onset of primary infection is typically abrupt, and general symptoms such as fever and malaise may be present. HSV-1 and -2, HPV and coxsackie virus are examples of viruses producing primary oral lesions, while oral manifestations of HIV occur due to immunosuppression.

Herpesviruses are a family of DNA viruses. HSV-1 and 2 produce lesions of oral, labial, nasal and/or genital mucosa. The epidemi­ology of HSV-1 infection is undergoing a transition, with less exposure in childhood and more exposure in adulthood [50]. In immunocompromised individuals, herpes infections can have more severe symptoms and more frequent recurrences.

Varicella zoster virus (VZV or HHV-3) causes the classic childhood disease chickenpox infection as a primary infection and establishes latency in nerve ganglia. Reactivation of the virus or recurrent infection is called herpes zoster or shingles and is characterized by painful eruptions in the skin and/or oral cavity. In the trigeminal nerve area, unilateral blisters or vesicles are characteristic signs and are found especially on the palate, gingivae, buccal mucosa, and lateral tongue. For HSV, herpes zoster can have more severe sym­ptoms and more frequent recurrences in immunocompromised hosts.

Epstein‒Barr virus (EBV or HHV-4) infects B cells and is responsible for infectious mononucleosis but is also associated with oral hairy leukoplakia, Burkitt lymphoma and nasopharyngeal carcinoma in immunocompromised patients.

Cytomegalovirus virus (CMV or HHV-5) causes asymptomatic infection in childhood. In immunocompromised patients, it may produce oral ulcerations.

Oral lesions in HIV-infected patients have been observed since the beginning of the epidemic. Approximately 10% of HIV-infected patients have oral manifestations as a first sign of the infection. These manifestations are not specific to HIV but to immunodeficiency due to HIV infection. Oral manifestations are classified as fungal, bacterial (HIV-associated periodontal disease) and viral infections (EBV and hairy leukoplakia, VZV, HSV).


The oral cavity may exhibit manifestations of a wide range of systemic disorders or their treatments. The development of more advanced medical treatments is a specific challenge. Dentists need knowledge regarding variations in the drugs used and their side effects on the oral cavity. Furthermore, with an aging population in Nordic countries, both the prevalence of systemic disorders and the need for treatment increase. There is a lack of guidance for dental practitioners on the oral side effects of new advanced medical therapies, which are poorly characterized and reported. Therefore, oral manifestations may be underdiagnosed.

A close collaboration with the patients’ medical team is important. Careful history taking, detailed drug history and a meticulous clinical examination by dentists may facilitate the determination of the underlying etiology of oral manifestations and allow for earlier diagnosis and intervention in medical health care settings.


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Corresponding author: Karin Garming Legert, Department of Dental Medicine, Karolinska Institutet, PO BOX 4064, SE 14104 Huddinge, Sweden. E-mail: karin.garming.legert@ki.se

Accepted for publication 11.10.2023

The article is peer reviewed

Legert KG, Wexell CL, Pedersen AML, Gale G, Tollemar V, Ruokonen H, et al. Oral manifestations of systemic disorders – Part 2. Nor Tannlegeforen Tid. 2024; 134: 114-22.

Keywords; Oral; systemic; diseases; manifestations