Oral and tertiary.(1) Leukemia is a common

Oral lesions/pathologies associated
with leukemia

Šembera1, Radovan Slezák1, Jakub Radocha2,
Vladimíra Radochová1

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Charles University in Prague, Faculty
of Medicine and University Hospital Hradec Králové, Czech Republic: Department
of Dentistry1, Second Department of Internal Medicine2

Sokolska 581

50005 Hradec

Czech Republic



e-mail: [email protected]


Key words:

Conflict of
interest statement:


aim of this paper is to identify orofacial manifestation of leukemia.


results from the proliferation of a clone of abnormal hematopoietic cells with
impaired differentiation, regulation, and programmed cell death. Leukemic cell multiplication at
the expense of normal hematopoetic cell lines causes marrow failure, depressed
blood cell count and death as a result of infection, bleeding, or both.(3, A) Based on clinical behavior we distinguish acute and chronic
leukemia and according to which hematopoietic cell line is primary affected
myleoid and lymphoid leukemia. The four principal diagnostic categories are
acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), chronic
myelogenous leukemia (CML) and chronic lymphocytic leukemia (CLL).(3) Acute leukemia occurs at all ages,
but ALL is more common in children, whereas AML is more common in adults.
Chronic leukemia is generally an adult disease. (KNIHA) Oral lesions arise in both acute and chronic forms of all
types of leukemia. They occur frequently and may point out the initial evidence
of the disease or of its relapse.(2) Orofacial manifestation of
leukemia are primary, secundary and tertiary.(1)


is a common malignancy accounting for about 30% of all cancers diagnosed for
children aged under 15 years.  (20)

Systemic  disease often
presents associated with associated oral manifestations, which can often occur
at the beginning of the disease. Oral manifestations can sometimes precedes
systemic manifestations and reveals undetected and severe disease, like
leukemia. Dentists and physicans should be aware of these oral
manifestations  and take into account
specific aditional tests , which can lead into diagnosis a possible associated
systemic disease. (B)


manifestation, primary

Primary manifestation include lesions caused by the extramedullary
neoplastic infiltration of oral mucosal and maxillofacial tissues.

Gingival enlargement

Gingival enlargement can have various causes. For example,
acute or chronic infection may cause enlargement involving mainly marginal and
interproximal gingiva. Specific drugs such as calcium channel blockers,
phenytoin, and cyclosporine are associated with gingival enlargement. More
importantly, gingival enlargement may be an early manifestation of underlying
systemic disease, such as acute leukemia. (C)
Diffuse, boggy gingival
enlargement is especially associated with the monocytic variety (A) Histologically, the lesions
consisted of extravasated and proliferating monocytoid or myeloid cells and regional
blood vessels are compressed by the infiltrate (D) Gingival infiltration represents a 5% frequency as the initial
presentation complication of AML. (BOOK
1) In retrospective study of 1076 patients with acute leukemia acute
monocytic leukemia had the greatest incidence of gingival infiltrates (66.7 %)
followed by acute myelomonocytic leukemia 
(18.5 %) and acute myeloblastic leukemia (3.7 %). (D) Gingival enlargement in leukemic
patients is known to disappear without any specific periodontal treatment after
chemotherapy. However, enlarged gingiva facilitates plaque accumulation which
may lead to gingival inflammation with secondary gingival swelling. Gingival
enlargement does not generally develop in edentulous patients. (C, D, E) In retrospective study of
 477 children with AML the presence of extramedullary infiltrates at
diagnosis had no significant effect on eventfree survival. In a stepwise
multiple regression analysis only favourable cytogenetic findings remained
significant. (G)

Granulocytic sarcoma (chloroma) is a localized extramedullary
tumor composed of immature cells of the granulocytic series was observed with
AML and also with the onset of blast crisis in CML. Choroma may precede
the manifestations of AML by months or years on  variety of sites including the skin, lymph
nodes, gingiva, bone, soft tissue, and visceral organs.  (13) Chloroma of the oral
cavity associated with AML is rare, it presents as tumurous solitary mass
typicaly on mandibular and maxillar gingiva or mucosa of hard palate, often
well in advance of other clinical and laboratory findings indicating leukemia. (13, 14, 15)

Leukemia cutis. Cutaneous
manifestations (including orofacial) sites are presented as solitary or
multiple papules, plaques, and nodules or as a generalized erythematous
maculopapular eruption generaly seen only with AML, rarely with CML. (Q) Leukemia cutis presenting only as ulcerative leukemia
labialis was reported in a 52-year-old female with AML. (P)


Alveolar bone
destruction with tooth mobility (16)

alveolar bone destruction has been described as initial manifestation of acute
lymphoblastic leukemia in a 14-year-old boy. While the radiographs showed
severe alveolar bone loss which extended to apical thirds of many teeth,
the microbiologic analysis revealed that the patient did not harbor major
periodontopathogenic bacteria species. (J)
Osteolytic lesion of the mandibule accompanied with dull pain were reported
in a 35-year-old male with acute lymphoblastic leukemia. A panoramic radiograph
taken 4 months ago showed no bony involvement. (K)

lymphadenopathy The
most common manifestations or clinical signs of acute leukemia at initial
presentation are lymphadenopathy (71.4 % in All; 45 % in AML). (3) More than 25% of malignant tumors in
children occur in the head and neck, and the cervical lymph nodes are the most
common site. During the first 6 years of life, neuroblastoma and leukemia are
the most common tumors associated with cervical lymphadenopathy. (O)


Clinical manifestations of ALL are similar to those of AML
but with a high incidence of central nervous system (CNS) disease (A) Pathologies due to increased
cerebrospinal fluid pressure, intercranial hemorrhage or localized leukemic
infiltration of the central nervous system or around peripheral nerves.  (1)
An autopsy study conducted
on 100 subjects who died of active leukemia suggested that CNS involvement is
more common in acute than chronic leukemia. In the study, 81% of acute
lymphoblastic leukemia (ALL) and 46% of acute myelogenous leukemia (AML) cases
revealed CNS infiltration in autopsy. (19) Cranial nerve symptomatology
involvement is known to disappear after chemotherapy or radiotherapy. (11, 12, 18, 9)

Facial nerve paralysis
Symptomatic otologic
involvement by leukemic infiltration is unusual, most often occurring in the
already-diagnosed leukemic patient as postauricular mass, acute hemorrhagic
otitis media, mastoiditis, cranial neuropathy, vertigo, hearing loss, or
leptomeningitis. (17)
Mastoiditis accompanied with cranial neurapathies especially of facial nerve
could be due to leukemic infiltration of central nervous system or presence of
granulotic sarcoma, associated mainy with AML, leading to facial nerve
paralysis. (11, 18) Facial nerve paralysis in ALL
has been reported in medical literature and in many cases there is accompanying
meningeal involvement due to blast cells in cerebrospinal fluid. (12)

Trigeminal neuralgia Beside
facial nerve paralysis leukemic blasts in cerebrospinal fluid in ALL can cause
trigeminal neuralgia with typical symtomatology of painful sharp electric
shocklike transient spasms triggered by light touch and activities such as
brushing teeth, talking, and blowing his nose. (9)

Numb chin syndrome Numb
chin syndrome is recognized to occur in association with tumors, inflammatory
disorders, traumas, and cysts in the mandible and is also iatrogenically caused
by dental anesthesia. It is characterized by hypostezia, anestezia or pain over
the chin in the region supplied by mental nerve and its branches. The neuropahy
is purely sensory because inferion alveolar nerve has no motor fibres. (6) Numb chin syndrome is an uncommon
but well documented neurological manifestation of metastatic malignancy
particulary breast cancer and malignant lymphomas. Mental neuropathy has been
discribed as an initial symptom of ALL. (7)

Tooth ache due to the
leukemic infiltration of the pulp, inability to protrude the tongue, difficulty
in swallowing, weakness in biting, paraesthesia or anesthesia of the face, lips
or tongue (1)


manifestation, secondary

Secondary manifestation are due to the suppression of normal
hematopoietic bone marrow (anemia, leucopenia, trombocytopenia) with general
symptoms like weakness, constant fatigue, dyspnea, pallor, fever, infection,
weight loss, spontaneous bleeding, petechiae, ecchymoses, epistaxes,
menorrhagia and bruising. Anemia is
a disordered process in which the rate of red cell production fails to match
the rate of destruction, resulting in a reduction in hemoglobin concentration. (3) Intraorally generalized mucosal
pallor, non-specific oral erythema or cyanosis may be present. (1) Specifis entities like angular
cheilitis, glossitis with different degrees of atrophy of fungiform and
filliform papillae, oral candidiasis, recurrent aphthous stomatitis,
erythematous mucositis and burning mouth syndrome may be present. (3) Trombocytopenia is a condition
characterized by abnormally low levels of thrombocytes, and manifastates as spontaneous
prolonged and profuse mucosal hemorrhage or after trivial trauma.  Typical localization of profuse bleeding is
gingiva. Leukopenia is a decrease in
the number of white blood cells. Generally, quantitative polymorfonuclear
deficiencies (neutropenia) are accompanied by recurrent gingivitis, generalized
periodontal destruction and oral ulceration. (3, 16) Erosions and painful or necrotic ulcerations occur as a
result of infection by normal oral flora in the setting of neutropenia of as
direct leukemic infiltration (A) Increased
susceptibility to opportunistic infection due to leukopenia is well documented
e.g. viral (herpes simplex stomatitis HSV, cytomegaloviral stomatitis CMV varicella zoster virus,
Epstein-Barr virus, respiratory viral infections, hepatitis viral infections,
and gastrointestinal infection??) fungal (oral candidiasis) and
bacterial infections (acute necrotizing ulceratice gingivostomatitis) or
reactivation of latent infections such as osteomyelitis, pericoronitis,
periodontal, or periapical persistent and prominently painful inflammations. Healing
responses after tooth extraction can be altered. (A) Palatal ulcerations and necrosis can be caused by acute opportunistic fungal infection mucormicosis, which usually begins in the
nose and paranasal sinuses. This fungus invades the arteries, forms thrombi
within the blood vessels that reduce blood supply and cause necrosis of hard
and soft tissues. Numerous predisposing risk factors are associated with
mucormycosis, although most cases have been reported in poorly controlled
diabetics or in patients with hematological malignancies such as acute leukemia. (4, 5)

manifestation, tertiary

The goal of treatment is complete remission. First step is remission-induction
therapy, the goal is to eradicate more than 99% of the initial burden of
leukemia cells and to restore normal hematopoesis and a normal performance
status. Complete remission occurs in 80% of patients. Once remission is
achieved, intensification therapy is given. After intensification therapy,
consolidation chemotherapy or hematopoetic stem cell transplantation (HSCT) is
necessary. Reinduction treatment, and repetition of the initial induction
therapy administered during the first few months of remission, has become an
integral component of successful treatment protocols. Although optimal timing
is unclear, HSCT is recommended for high-risk patients in the first complete
remission and low-risk patients in the second complete remission. Tertiary
manifestations of leukemia occur due to the toxicity of chemotherapy or
radiotherapy or to graft versus host disease after allogeneic bone marrow

Oral mucositis

Oral mucositis (OM) is an iatrogenic condition of
erythematous inflammatory changes that tend to occur on the buccal and labial
surfaces, the ventral surface of the tongue, the floor of the mouth, and the
soft palate of patients receiving chemotherapy. As a form of iatrogenic stomatitis, mucositis usually starts
off with aplasia 7–14 days after the initiation of chemotherapy. (A15)

WHO and NCI oral
mucositis scale (A16)

Current literature’s reported incidence of OM is highly
variable, ranging from 75% to 99%

44. Sonis ST, Elting LS,
Keefe D, et al. Perspectives on cancer therapy-induced mucosal injury:
pathogenesis, measurement, epidemiology, and consequences for patients. Cancer. 2004;100(9):1995–2025.PubMed

45. Rubenstein EB,
Peterson DE, Schubert M, et al. Clinical practice guidelines for the prevention
and treatment of cancer therapy-induced oral and gastrointestinal mucositis. Cancer. 2004;100:2026–2046.PubMed



Acute and cGVHD is distinguished by time of onset following
transplantation or by characteristics signs and symptoms. Chronic
graft-versus-host diseas is a major late complication of allogeneic
hematopoietic stem cell transplantation. It is estimated that 40 – 70 % of
engrafted patients surviving the initial transplant will eventually developed
cGVHD. It is more likely to occure
if the graft is from unrelated donor or if the host or donor is older. (B2, B19) To prevent graft rejection,
conditioning chemotherapy is given before transplantation and after the
transplantation immunosuppresive therapy is needed. (B4) This clinical syndrome is characterized by complex
interactions of both autologous and allogeneic immune dysregulation and is the
leading cause of non-relapse-related morbidity and mortality in long-term
transplant survivors. (B12) On the
other hand cGVHD is associated with decresed relapse risk. (B2) Chronic GVHD can persist for months to years and may affect
multiple organ systems. Oral cavity is the second most commonly involved organ
system, behind skin involvement. (B13,
B14) The clinical presentation of oral cGVHD is diverse and can involve any
site in the oral cavity. Oral mucosal lesions are characterized as erythema,
lichenoid changes, sclerosis, ulceration, mucoceles and salivary gland damage. (B1, B2, B4, B15, B16) In many cases,
these manifastation closely resembles clinicaly and histologicaly common
autoimmunie disorders including lichen planus, Sjögrens syndrome, scleroderma,
systemic lupus erythematosus. (B2, B4)

Oral mucosal lesions are estimated to occur in 45 – 83 %
patients.  (B17, B14, B13) Erythema is defined as redness of the oral mucosa
without obvious breakdown and is often a sign of infection or inflamation. It
can be accompanied with musocal atrophy od edema of the musoca. Patients often
complain of oral mucosal sensitivity and burning mouth syndrome. (B8)

Lichenoid oral cGVHD lesions are source of pain and when
significant they can limit nutrition intake and ability to maintain oral
hygiene. Clinicaly they present as
white reticular (resembling Wickham´s strie), erythematous, atrophic, ulcerative
lesions and can affect almost any oral site, with buccal mucosa and tongue
being most frequently affected. (B2,
B16) These oral lesions are considered diagnostic for oral cGVHD. (B16) The ulcerations represent a
breakdown of oral mucosa barrier-immune properties and represent most obvious
route for infection agents to enter bloodstream. (B8)

Mucocele developes when the duct of the minor salivary gland
is physically occluded, forcing the saliva into the surrounding tissues. It is
believed that salivary gland inflammation and decreased salivary fluid
secretion associated with cGVHD and viscosus saliva blocs excretory ducts.
Mucocele is clinicaly presented as fluid-filled, smooth elevation of the
epithelium. Mucocele associated witch cGVHD are seen on the palete and the lips
and are asymptomatic. (B2, B8, B17, B16)

Oral or perioral cGVHD can limit mouth-opening due to
continued inflamation and scarring of the buccal mucosa and perioral skin
sclerosis decreasing patients nutrition intake and ability to maintain oral
hygiene. (B1, B2, B4, B13) Other oral morbidities releated do cGVHD
include muscle wasting, muscle cramping and joint range of motion problems. (B8)

cGVHD salivary gland disease can presents as Sjögren-like
syndrome with lymphocytic infiltration of salivary gland ducts, individual
ductal epithelial necrosis/apoptosis and destruction of acinar tissues leading
to sicca syndrome. (B2, B7, B18)

cell carcinoma ???


Certain organisms, commonly Candida sp., are commensal
residents of the oral cavity in a large proportion of individuals. Normaly
these fungal microorganisms co-exists with immunecompetent individuals and do
not cause disease. In cancer patients receiving chemotherapy and/or radiation the
change in oral enviroment results in an owergrowth and imbalance in the oral
flora. Other factors as hyposalivation and local tissue damagetherapy are
considered predisposing factors to infections, especially fungal. The
prevalence of oral fungal infection from all forms of cancer therapy was about
7.5% before treatment, 49% during treatment, and 33% after treatment. Candida
albicans continues to be leading cause of fungal infection, though Candida
tropicalis and Candida glabrata also represent significant protion of
infections. The most common intraoral candidiasis is erythematous and
pseudomembranous and is associated with burning sensation, oral dyscomfort and
taste change. Extraoraly candida infection manifests manifests as angular
cheilitis causing pain when opening mouth wide, decreasing patients nutrition
intake and ability to maintain oral hygiene. (A11) Non-candida species can cause invasive aspergilosis
associated with high mortality during post-induction aplasia is invasive
aspergillosis. (A12)

Viral infections frequently seen in
patients undergoing chemotherapy include the herpes simplex virus (HSV),
varicella zoster virus (VZV), and cytomegalovirus (CMV). Viral reactivation
(rather than exogennous reinfection) is not uncommon during periods of
myeloimmunosuppression, particularly with HSV infections. With incidence of
recurrent infection reported up to 48%, HSV infected patients often report
severe, painful, and prolonged ulcerations atypical of those discovered in
immunocompetent hosts. (A1)

As mentioned above, HSV infection is commonly reactivated during
treatment of leukemia. Risk factors for reactivation in these patients include
neutropenia and disruption of normal mucosal barriers secondary to
chemotherapy, dental prosthesis and nasogastric intubation. (A3) The HSV lesions become clinically
apparent approximately 17 days after the onset of neutropenia. (A2) Before the onset of these lesions,
patients may develop systemic symptoms, including lymphadenopathy, fever, and
malaise, with focal prodromal symptoms of tingling, burning, itching and pain
several hours before the eruption. The lesions begin as vesicles, which
progress rapidly and spontaneously rupture. This leads to ulcerations that
enlarge, coalesce, and form a crust. (A13)

Oral ulcerations associated with CMV (individually or
synergistically with other herpes viruses) show diversity in terms of clinical
appearance. Most commonly affected oral musoca is of the hard-soft palate. Such
lesions usually present as long-lasting, solitary or numbered, painful or
painless, medium-sized, shallow ulcerations. Their bases can be covered with a
yellow slough or pseudomembrane, and the margins can be rolled, elevated, with
induration or lack of induration . Cervical lymphadenitis and pyrexia are seen
inconsistently. (A14)

Oral hairy leucoplakia (OHL) a result of Epstein-Barr virus infection
is commonly seen in HIV infected individuals. However reports have shown that OHL
can occur in patients under chemotherapy for acute myelogenous leukemia, acute
lymphocytic leukemia. (A15) OHL is a
white patch, which almost exclusively occurs on the lateral surfaces of the
tongue, although rarely it may occur on the buccal mucosa, soft palate, pharynx
or esophagus. (Neville)

Normal oral flora comprises of a
variety of bacteria, some of which may become pathogenic with
immunosuppression. A15