Hematologic Disorders

CLINICAL FEATURES: Lymphoid hyperplasia may affect the lymph nodes, the lymphoid tissue of Waldeyer’s ring, or the aggregates of lymphoid tissue that are normally scattered throughout the oral cavity, particularly in the oropharynx, the soft palate, the lateral tongue, and the floor of the mouth. When lymphoid hyperplasia affects the lymph nodes, usually the site that the lymph node drains can be identified as a source of active or recent infection. In the head and neck region, the anterior cervical chain of lymph nodes is most commonly involved, although any lymph node in the area may be affected.

With acute infections, the lymphadenopathy appears as enlarged, tender, relatively soft, freely movable nodules. Chronic inflammatory conditions produce enlarged, rubbery firm, nontender, freely movable nodes. Sometimes these chronic hyperplastic lymph nodes may be difficult to distinguish clinically from lymphoma, and a history of a preceding inflammatory process and lack of progressive enlargement are helpful clues that are consistent with a reactive process. Another condition, however, that should be considered in the differential diagnosis of multiple, persistently enlarged, nontender lymph nodes is human immunodeficiency virus (HIV) infection (see page 271).

Tonsillar size is variable from one person to the next, but lymphoid tissue is normally more prominent in younger individuals, usually reaching its peak early during the second decade of life and gradually diminishing thereafter. Some patients have such large tonsils that it seems as if they would occlude the airway (so-called kissing tonsils). Often, however, these patients have no symptoms and are unaware of a problem. As long as the large tonsils are symmetrical and asymptomatic (Fig. 13-1), it is likely that they are normal for that particular patient. Tonsillar asymmetry is a potentially serious sign that should be evaluated further to rule out the presence of a metastatic tumor or lymphoma.

Hyperplastic intraoral lymphoid aggregates appear as discrete, nontender, submucosal swellings, usually less than 1 cm in diameter, which may appear normal or dark pink in color if the aggregate is deeper; they may have a creamy yellow-orange hue if the collection of lymphocytes is closer to the surface (Figs. 13-2 and 13-3). Lymphoid hyperplasia commonly involves the posterior lateral tongue, where it may appear somewhat ominous. The enlargement is usually bilaterally symmetrical, however, which helps to distinguish the condition from a malignancy. The buccal lymph node may also become hyperplastic and appear as a nontender, solitary, freely movable nodule, usually less than 1 cm in diameter, within the substance of the cheek. Infrequently, a more diffuse lymphoid hyperplasia involves the posterior hard palate, producing a slowly growing, nontender, boggy swelling with an intact mucosal surface and little color change. These palatal lesions may be clinically impossible to distinguish from extranodal lymphoma and would, therefore, necessitate biopsy.

HISTOPATHOLOGIC FEATURES: The microscopic features of lymphoid hyperplasia include sheets of small, well-differentiated lymphocytes with numerous interspersed, sharply demarcated collections of reactive lymphoblasts called germinal centers. The cells that comprise the germinal centers are primarily transformed B lymphocytes that may demonstrate numerous mitoses. Macrophages can also be identified by the presence of phagocytized material (tingible bodies) in their cytoplasm as they engulf nuclear debris from the proliferating lymphocytes. In some instances, immunohistochemical studies and clonality assays must be performed to rule out the possibility of follicular lymphoma.

TREATMENT AND PROGNOSIS: Once the diagnosis of lymphoid hyperplasia is confirmed, no treatment is usually required because it is a completely benign process. For those patients with palatal lymphoid hyperplasia that may interfere with a dental prosthesis, complete excision of the lesion is recommended.

CLINICAL FEATURES: Hemophilia A is an X-linked disorder. Females typically carry the trait, but it is expressed primarily in males. Approximately 1 in 5000 males is born with this genetic disease, with about 30% of the cases representing new mutations. Failure of normal hemostasis after circumcision is typically one of the first signs that a bleeding disorder is present.

The severity of the bleeding disorder depends on the extent of the clotting factor deficiency. Hemophilia A is a heterogeneous disorder that is caused by any one of a variety of mutations associated with the gene for factor VIII. Because the mutations occur at different sites in the factor VIII gene (more than 900 different mutations have been identified), a clinical spectrum of deficiency of factor VIII is seen. This results in varying degrees of disease expression, with those mutations affecting more significant or larger portions of the factor VIII gene causing more severe clinical disease. Not all patients have an absolute lack of the particular clotting factor; rather, the deficiency may be a percentage of the normal value in a given patient. For example, a patient with only 25% of normal factor VIII levels may be able to function normally under most circumstances; one with less than 5% commonly manifests a marked tendency to bruise with only minor trauma.

In infants, oral lacerations and ecchymoses that involve the lips and tongue are a frequent occurrence as a result of the common falls and bumps experienced by this age group. If not treated appropriately, then such lacerations may result in significant blood loss in more severely affected patients. Sometimes deep hemorrhage occurs during normal activity and may involve the muscles, soft tissues, and weight-bearing joints (hemarthrosis), especially the knees (Fig. 13-4). The result of such uncontrolled bleeding is the formation of scar tissue as the body removes the extravasated blood. This often causes a crippling deformity of the knee joints secondary to arthritis and ankylosis. Sometimes the tissue hemorrhage results in the formation of a tumorlike mass, which has been called pseudotumor of hemophilia. Such lesions have been reported in the oral regions.

An increased coagulation time (delay in blood clotting), of course, is the hallmark feature of this group of conditions. Uncontrollable or delayed hemorrhage may result from any laceration; this includes surgical incisions, dental extractions, and periodontal curettage (Fig. 13-5). Measurements of the platelet count, bleeding time, prothrombin time (PT), and partial thromboplastin time (PTT) should be ordered as screening tests for any patient with a possible bleeding disorder.

TREATMENT AND PROGNOSIS: The treatment of clotting factor deficiencies essentially consists of replacement therapy with the appropriate clotting factor. Whether treatment is instituted depends on the severity of the clotting factor deficiency.

Patients who have greater than 25% of normal values of factor VIII may function normally. For patients with mild hemophilia (5% to 40% of normal levels of factor VIII), no special treatment is typically required for normal activities. If surgery is to be performed, then clotting factor replacement therapy may be indicated.

For patients with severe deficiencies (<1% of normal levels of factor VIII), injections with the clotting factor must be performed as soon as a hemorrhagic episode occurs to prevent such complications as the crippling joint deformities of the knees.

The use of aspirin is strictly contraindicated because of its adverse effect on blood platelet function. Severe hemorrhage may result if these patients use aspirin-containing medications.

Genetic counseling should be provided to these patients and their families to help them understand the mechanism of inheritance. Using molecular techniques, women who are carriers can be confirmed. In addition, affected male fetuses can now be identified, and the severity of the factor VIII mutation can be assessed.

Optimal dental care is strongly encouraged for these patients to prevent oral problems that might require surgery. If oral or periodontal surgery is necessary, then consultation with the patient’s physician is mandatory. The patient is usually prepared for the procedure by the administration of clotting factor just before the surgery. With an extensive surgical procedure, additional doses of clotting factor may be needed subsequently. In addition, epsilon-aminocaproic acid (EACA), an antifibrinolytic agent that inhibits clot degradation, should be given 1 day before the surgery and continued for 7 to 10 days afterward. Alternative therapy for patients who have levels of factor VIII greater than 5% of normal is desmopressin, which can be given just before surgery. This drug causes the release of bound factor VIII, producing a temporary increase in the plasma levels of the clotting factor. Desmopressin may also be used to manage most patients affected by type 1 von Willebrand’s disease, which represents approximately 70% to 80% of the cases of that disorder.

Although it saved many lives, clotting factor replacement therapy has also resulted in a tragic complication for many of these patients. Cryoprecipitation, the traditional method of concentrating clotting factors from the serum, also resulted in the concentration of several viruses, including the hepatitis viruses and human immunodeficiency virus (HIV). Currently more than 40% of hemophilia A and B patients in the United States are estimated to be infected with hepatitis C virus. In addition, as many as 80% to 90% of hemophiliac patients treated with multiple doses of factor VIII cryoprecipitate were infected with HIV. The methods of preparing the clotting factors have been modified to eliminate the risk of acquiring HIV from the preparation; however, many hemophiliac patients who were infected developed acquired immunodeficiency syndrome (AIDS). Recombinant DNA technology now provides a source of factor VIII that is manufactured by inserting the human factor VIII gene into bacteria that then synthesize the protein. Therefore, this product can now be manufactured without contamination by any viral organisms, and young people affected by hemophilia have minimal risk of contracting these infections.

Other problems must occasionally be confronted, however. Approximately 6% of patients with hemophilia A may develop antibodies directed against factor VIII, and this is a very serious complication. Because the antibodies react with the factor VIII molecule, the result is an inhibition of the activity of the clotting factor, and these patients are once more faced with the prospect of uncontrolled bleeding. Patients with factor IX deficiency can develop similar inhibitory antibodies to factor IX, but this appears to occur much less frequently. Attempts to induce immune tolerance may help some individuals, although more immediate care has generally centered on bypassing the factor VIII–related portion of the clotting cascade by administration of recombinant factor VIIa. Research has shown this approach to be effective, although costly.

CLINICAL FEATURES: The most striking aspect of plasminogen deficiency is the development of thick, creamy yellow to erythematous, firm plaques and nodules involving primarily the conjunctival mucosa of the upper eyelid. Typically the condition is detected during the first decade of life, but lesions can develop later as well. Even though this is an autosomal recessive condition, there is a tendency for the disease to present more often in women, although the reason for this is unknown.

In addition to the conjunctival lesions, other mucosal surfaces can be affected, including the oral mucosa, laryngeal mucosa, and vaginal mucosa. In a recent series of 50 patients with this condition, ocular lesions were documented in 80%, gingival lesions in 34%, respiratory tract lesions in 16%, and vaginal lesions in 8%. Laryngeal mucosal involvement often includes the vocal cords, which will typically cause a raspy, hoarse voice.

Oral lesions of plasminogen deficiency primarily involve the gingivae, presenting as patchy ulcerated papules and nodules with a very irregular surface (Fig. 13-6). These lesions may be few in number or distributed diffusely in all quadrants, and they tend to wax and wane in severity.

HISTOPATHOLOGIC FEATURES: The microscopic features of the lesions associated with this condition can be very confusing for the pathologist who is not familiar with the disease. The accumulation of fibrin appears as diffuse sheets of acellular eosinophilic material that bears a close resemblance to amyloid (Fig. 13-7). Special stains for amyloid (such as Congo red) are negative, however, because this material represents fibrin. Confirmation that the eosinophilic material is fibrin can be done using the Fraser-Lendrum histochemical staining method. Variable numbers of inflammatory cells are seen, and granulation tissue is usually seen adjacent to the fibrin deposits.

TREATMENT AND PROGNOSIS: Treatment of plasminogen deficiency remains a problem. Damage to the mucosal tissues, including surgical trauma, should be minimized to reduce the likelihood of fibrin accumulation. Careful, thorough oral hygiene practices should be encouraged to diminish the effect of local inflammation. Sporadic reports describe resolution of the conjunctival lesions with either topical or systemic plasminogen; however, this agent is not available commercially. Some patients have experienced spontaneous regression of their lesions over time. Currently topical heparin combined with prednisone may be the most reasonable approach until replacement plasminogen is marketed or gene therapy is feasible. Interestingly, these patients do not have any unusual problems with intravascular thrombus formation, and their lifespan does not appear to be shortened.

CLINICAL FEATURES: The symptoms of anemia are typically related to the reduced oxygen-carrying capacity of the blood, which is a result of the reduced numbers of erythrocytes. Symptoms such as tiredness, headache, or lightheadedness are often present.

Pallor of the mucous membranes may be observed in severe cases of anemia. The palpebral conjunctiva is often the site where this paleness is most easily appreciated, but the oral mucosa may show similar signs.

TREATMENT AND PROGNOSIS: The treatment of anemia depends on determining the underlying cause of the anemia and correcting that problem, if possible.

CLINICAL AND RADIOGRAPHIC FEATURES: Virtually any tissue or organ may be affected in sickle cell disease. The clinical spectrum of involvement can vary tremendously, with approximately one third of patients exhibiting severe manifestations. Perhaps the most dramatic sign of this disease is the sickle cell crisis, a situation in which the sickling of the erythrocytes becomes severe. Hypoxia, infection, hypothermia, or dehydration may precipitate a crisis; however, for most crises there is no identifiable predisposing factor. Patients who experience a crisis suffer extreme pain from ischemia and infarction of the affected tissue. The long bones, lungs, and abdomen are among the most commonly affected sites, and each episode lasts 3 to 10 days. Pulmonary involvement, known as acute chest syndrome, is particularly serious, and one large study indicated that this is frequently precipitated by fat embolism or community-acquired pneumonia. Some patients may experience such crises monthly; others may go for 1 year or longer without problems. Often fever accompanies the crisis; therefore, infection must be considered in the differential diagnosis.

Patients with sickle cell disease are susceptible to infections, especially those caused by Streptococcus pneumoniae, probably because of the destruction of the spleen at an early age by repeated infarctions. Such infections are the most common cause of death among children affected by sickle cell disease in the United States.

Other problems include delayed growth and development in most patients. Impaired kidney function and ocular abnormalities develop secondary to the damage caused by vaso-occlusive episodes in the capillary networks of those organs. If the patient lives long enough, then renal failure may eventually develop. In addition, approximately 5% to 8% of these patients will experience central nervous system (CNS) damage in the form of a stroke, which occurs at an average age of about 8 years.

The oral radiographic features of sickle cell disease are relatively nonspecific. They consist of a reduced trabecular pattern of the mandible because of increased hematopoiesis occurring in the marrow spaces. Occasionally, a “hair-on-end” appearance is seen on the skull radiograph, although this is less prominent than that seen in thalassemia (Fig. 13-8). Other oral problems that have been reported include an increased prevalence of osteomyelitis of the mandible, prolonged paresthesia of the mandibular nerve, and asymptomatic pulpal necrosis.

HISTOPATHOLOGIC FEATURES: In homozygous sickle cell disease, a peripheral blood smear shows a peculiar curved distortion of the erythrocytes, resembling a sickle or boomerang shape.

TREATMENT AND PROGNOSIS: The patient experiencing a sickle cell crisis should be managed with supportive care, including fluids, rest, and appropriate analgesic therapy (usually narcotic preparations). It is important, but often difficult, to rule out the possibility of infection.

All 50 states now screen for this hemoglobin disorder as part of their newborn infant health care system to identify affected individuals as soon as possible so that appropriate therapy can be instituted. For children with a diagnosis of sickle cell disease, continuous prophylactic penicillin therapy is indicated until at least 5 years of age. In addition, the child should be given polyvalent pneumococcal vaccinations. Situations that might precipitate a crisis, such as strenuous exercise, dehydration, or exposure to cold, should be avoided. For adults with relatively severe disease, hydroxyurea has been approved for treatment. This drug increases the fetal form of hemoglobin (hemoglobin F), which may inhibit polymerization of hemoglobin S and may also reduce the adherence of erythrocytes to the vessel walls. Unfortunately, hydroxyurea has a number of potential side effects and should be used judiciously. Bone marrow transplantation is curative, but this is a procedure with multiple potential complications and is used primarily for severely affected patients having a histocompatibility antigen (HLA)-matched donor sibling. Only about 1% of sickle cell anemia patients currently meet these criteria.

When surgery is necessary, local anesthesia, if possible, is usually preferred. If general anesthesia is indicated, then precautions should be taken to avoid conditions that might induce a crisis, such as hypoxia, vascular stasis, acidosis, infection, reduced body temperature, or dehydration.

For patients who have either the sickle cell trait or the disease, genetic counseling is appropriate. DNA diagnostic techniques have been used for several years to assess whether a fetus is affected by sickle cell disease, permitting consideration of termination of the pregnancy. Molecular evaluation of the DNA from a single cell obtained from an embryo that was fertilized in vitro has allowed selection of a nonaffected embryo for uterine implantation. For parents who are carriers of the sickle cell trait, this is one method to ensure that their offspring do not have sickle cell disease.

Although the mortality rate for sickle cell disease in developed countries has improved dramatically over the past few years, the prognosis is variable because of the wide spectrum of disease activity. Those who are severely affected, however, often are quite disabled because of the many complications of the disease and have a decreased life span.

CLINICAL AND RADIOGRAPHIC FEATURES:

TREATMENT AND PROGNOSIS: Thalassemia major is treated today primarily by means of blood transfusions. These should be administered every 2 to 3 weeks to simulate the normal hematologic state. Unfortunately, with repeated blood transfusions, iron overload inevitably develops because of the constant infusion of exogenous red blood cells. This is a serious problem, and often death is due to hemochromatosis, an abnormal deposition of iron throughout the tissues of the body. The heart, liver, and endocrine glands are particularly affected by the toxic accumulation of iron. To combat this problem, an iron-chelating agent, deferoxamine (also known as desferrioxamine), must be given. If such therapy is used steadfastly, patients with β-thalassemia may have a relatively normal life span; however, problems may arise with patient compliance because this medication must be infused parenterally over several hours for at least 250 nights each year. Hematopoietic stem cell transplantation has also been used with considerable success for individuals who are relatively young, have little organ damage, and have an HLA-matched donor.

Clinicians can now identify α-thalassemia, with its attendant hydrops fetalis (historically considered a fatal condition), in utero by molecular testing, and the fetus can be given intrauterine umbilical vein transfusions. An 80% survival rate has been reported for these infants, although they will require either lifelong transfusion therapy or hematopoietic stem cell transplantation.

For patients who have developed an abnormal facial appearance caused by thalassemia, surgical correction can be performed in many cases. Prevention of thalassemia also is desirable, either by screening for carriers of the genetic trait or by prenatal diagnosis.

CLINICAL FEATURES: Because all of the formed elements of the blood are decreased in patients with aplastic anemia, the initial symptoms may be related to any one or several of the deficiencies. The erythrocyte deficiency produces signs and symptoms related to a decreased oxygen-carrying capacity of the blood; therefore, patients may experience fatigue, lightheadedness, tachycardia, or weakness. The platelet deficiency (thrombocytopenia) is seen as a marked tendency for bruising and bleeding, which affects a variety of sites. Retinal and cerebral hemorrhages are some of the more devastating manifestations of this bleeding tendency. Deficiency of white blood cells (neutropenia, leukopenia, or granulocytopenia) is the most significant complication of this disease, predisposing the patient to bacterial and fungal infections that often are the cause of death.

The oral findings related to thrombocytopenia include gingival hemorrhage (Fig. 13-11), oral mucosal petechiae, purpura, and ecchymoses. The oral mucosa may appear pale because of the decreased numbers of red blood cells. Oral ulcerations associated with infection, particularly those that involve the gingival tissues, may be present. Minimal erythema is usually associated with the periphery of the ulcers. Gingival hyperplasia has also been reported in association with aplastic anemia.

HISTOPATHOLOGIC FEATURES: A bone marrow biopsy specimen usually demonstrates a relatively acellular marrow with extensive fatty infiltration. The histopathologic features of an oral ulceration in a patient with aplastic anemia show numerous microorganisms in addition to a remarkable lack of inflammatory cells in the ulcer bed.

DIAGNOSIS: The diagnosis of aplastic anemia is usually established by laboratory studies. A pancytopenia is characterized by at least two of the following findings:

TREATMENT AND PROGNOSIS: The course for patients with aplastic anemia is unpredictable. For the milder forms of the disease, spontaneous recovery of the marrow may occur in some instances; progression to severe aplastic anemia may be seen in others. Generally, in severe cases, the chances of spontaneous recovery are slim. If a particular environmental toxin or drug is associated with the process, then withdrawal of the offending agent may sometimes result in recovery.

The treatment is initially supportive. Appropriate antibiotics are given for the infections that develop, and transfusions of packed red blood cells or platelets are administered for symptomatic treatment of anemia and bleeding problems, respectively.

Definitive therapy for aplastic anemia is to replace the defective marrow with normal marrow, either by bone marrow transplantation or peripheral blood stem cell transplantation from a matched donor. Patients must be carefully selected; patients younger than 40 years of age and those with an HLA-matched donor (usually a sibling) have the best prognosis, but unfortunately only about 30% of patients meet these criteria.

For those patients who would not be a good prospect for bone marrow transplantation because of their advanced age or no matched donor, immunosuppressive therapy is recommended. Antithymocyte globulin (in the United States) or antilymphocyte globulin (in Europe) combined with cyclosporine produces a response in the majority of these patients. Compared with treatment results from only 25 years ago, the prognosis for this condition has markedly improved. In the past, for patients with severe aplastic anemia treated with only antibiotics and transfusions, the mortality rate was greater than 80% in the first year after the diagnosis. Currently, an overall long-term survival of 75% of these patients can be achieved with either bone marrow transplant or immunosuppressive therapy. However, even if the disease is controlled, then these patients remain at risk for recurrent marrow aplasia and are at increased risk for acute leukemia.

CLINICAL FEATURES: Most patients with neutropenia have some form of bacterial infection rather than a viral or fungal infection, particularly if the other elements of the immune system (lymphocytes, plasma cells, and monocytes) are still intact. Staphylococcus aureus and gram-negative organisms seem to cause the most problems for patients with neutropenia. The suppuration and abscess formation normally associated with such infections may be markedly reduced because of the lack of neutrophils. The most common sites of infection include the middle ear, the oral cavity, and the perirectal area. When neutrophil counts drop below 500/mm³, however, pulmonary infections often develop.

The oral lesions of neutropenia consist of ulcerations that usually involve the gingival mucosa, probably because of the heavy bacterial colonization of this area and the chronic trauma that it receives. These ulcers characteristically lack an erythematous periphery, although this finding has been variable. Premature periodontal bone loss with exfoliation of the deciduous dentition has been described.

HISTOPATHOLOGIC FEATURES: A biopsy specimen of a neutropenic ulceration usually shows a reduced number or the absence of neutrophils. Bacterial invasion of the host tissue may be apparent in some instances.

TREATMENT AND PROGNOSIS: Infections related to neutropenia are managed with appropriate antibiotic therapy. The patient should be encouraged to maintain optimal oral hygiene to decrease the bacterial load in the oral cavity. Studies using recombinant human granulocyte colony-stimulating factor (G-CSF), a cytokine that promotes the growth and differentiation of neutrophils, have shown remarkable results. Patients with severe neutropenia have a significant increase in neutrophil counts and resolution of infections after treatment with this agent. Patients who do not respond to G-CSF may have to be considered for hematopoietic stem cell transplantation, depending on the severity of the neutropenia and subsequent infections.

CLINICAL FEATURES: Agranulocytosis typically develops within a few days after a person ingests the offending drug. Because of the lack of granulocytes (especially neutrophils), bacterial infections often develop and patients may show signs and symptoms of malaise, sore throat, swelling, fever, chills, bone pain, pneumonia, and shock. The erythrocyte and platelet counts are usually normal or only slightly depressed.

Oral lesions are common and include necrotizing, deep, punched-out ulcerations of the buccal mucosa, tongue, and palate. The gingivae are especially susceptible to infection, often resembling the pattern of necrotizing ulcerative gingivitis (NUG) (see page 157).

HISTOPATHOLOGIC FEATURES: Microscopic examination of a biopsy specimen from one of the oral ulcerations in agranulocytosis characteristically shows abundant bacterial organisms, both on the surface and within the tissue. The host inflammatory response is relatively sparse, with few granulocytes, particularly neutrophils, seen in the ulcer bed.

TREATMENT AND PROGNOSIS: If the clinician believes that a particular drug has caused the agranulocytosis, the medication should be discontinued as soon as is reasonably possible. In many instances, the granulocyte count returns to normal within 10 to 14 days after cessation of the offending agent. For patients who have agranulocytosis secondary to cancer chemotherapy, oral hygiene should be meticulous to foster an immaculate oral environment. In addition, the use of chlorhexidine-containing mouth rinses seems to reduce the severity of the oral lesions. Active infections are treated with appropriate antibiotic medications.

If the agranulocytosis is related to cancer treatment, the white blood cell count usually returns to normal after a period of weeks. For patients whose granulocyte counts do not recover, administration of G-CSF or granulocyte-macrophage colony-stimulating factor (GM-CSF) may be beneficial. The overall mortality rate for this condition in the past was 20% to 30%, although cytokine therapy and the newer broad-spectrum antibiotics have improved the outlook for these patients.

CLINICAL AND RADIOGRAPHIC FEATURES: The signs and symptoms of cyclic neutropenia occur in rather uniformly spaced episodes, which usually have a 21-day cycle. Patients typically complain of recurrent episodes of fever, anorexia, cervical lymphadenopathy, malaise, pharyngitis, and oral mucosal ulcerations. Other gastrointestinal mucosal areas, including the colon, rectum, and anus, may be affected by recurrent ulcerations.

The oral ulcerations develop on any oral mucosal surface that is exposed to even minor trauma, particularly the lips, tongue, buccal mucosa, and oropharynx (Fig. 13-12). An erythematous halo is variably present at the periphery of the ulcers. The gingiva is the most severely affected region of the oral cavity. Severe periodontal bone loss with marked gingival recession and tooth mobility are also characteristic (Fig. 13-13).

DIAGNOSIS: The diagnosis of cyclic neutropenia should be established by sequential complete blood counts (typically two to three times per week for 8 weeks) to determine whether cycling of the neutrophil levels occurs. The neutrophil count should be less than 500/mm³ for 3 to 5 days during each of at least three successive cycles to make this diagnosis.

HISTOPATHOLOGIC FEATURES: The histopathologic features of cyclic neutropenia are similar to those of the other neutropenic and granulocytopenic ulcerations if the biopsy is performed during the nadir of the neutrophil count.

TREATMENT AND PROGNOSIS: Supportive care for the patient with cyclic neutropenia includes antibiotic therapy for significant infections that might occur while the neutrophil count is at its lowest. Unfortunately, this approach cannot be considered a permanent treatment. Other methods that have been used with marginal success include splenectomy, corticosteroid therapy, and nutritional supplementation. Studies have shown that administration of the cytokine granulocyte colony-stimulating factor (G-CSF) several times weekly seems to correct the lack of production of neutrophils. This treatment results in a decrease in the time of neutropenia from 5 days to 1 day, which improves the clinical course of the disease. The cycles are reduced from 18 to 21 days to 11 to 13 days, and the severity of mucositis and infection are reduced.

Supportive care in the form of optimal oral hygiene should be maintained to reduce the number and severity of oral infections and improve the prognosis of the periodontal structures. Fortunately, for many of these patients, the severity of symptoms related to cyclic neutropenia seems to diminish after the second decade of life, despite the fact that the cycling of the neutrophils continues.

CLINICAL FEATURES: Clinical evidence of thrombocytopenia is not usually seen until the platelet levels drop below 100,000/mm³. The severity of involvement is directly related to the extent of platelet reduction. The condition often is initially detected because of the presence of oral lesions. Minor traumatic events are continuously inflicted on the oral mucosa during chewing and swallowing of food. The small capillaries that are damaged during this process are normally sealed off with microscopic thrombi. In a patient with thrombocytopenia, however, the thrombi do not form properly. This results in a leakage of blood from the small vessels. Clinically, this usually produces pinpoint hemorrhagic lesions known as petechiae. If a larger quantity of blood is extravasated, then an ecchymosis or bruise results (Fig. 13-14). With even larger amounts of extravasated blood, a hematoma (hemat = blood; oma = tumor) will develop (Fig. 13-15). Spontaneous gingival hemorrhage often occurs in these patients, as does bleeding from sites of minor trauma.

Similar hemorrhagic events occur throughout the body. With severe thrombocytopenia (<10,000 platelets/mm³), massive bleeding from the gastrointestinal or urinary tract may be fatal. Epistaxis is often present in these patients, and hemoptosis indicates signifi-cant pulmonary hemorrhage. Intracranial hemorrhage is also a potentially fatal complication of severe thrombocytopenia.

Special types of thrombocytopenia include idiopathic (immune) thrombocytopenic purpura (ITP) and TTP. ITP usually occurs during childhood, classically after a nonspecific viral infection. The symptoms of thrombocytopenia appear quickly and may be severe. Most cases, however, resolve spontaneously within 4 to 6 weeks, and 90% of patients recover by 3 to 6 months.

TTP is a serious disorder of coagulation and is thought to be caused by some form of endothelial damage that appears to trigger the formation of numerous thrombi within the small blood vessels of the body.

HISTOPATHOLOGIC FEATURES: Gingival biopsy may be performed for diagnostic purposes in patients with suspected TTP. Approximately 30% to 40% of such biopsy specimens show the presence of fibrin deposits in the small vessels. These deposits are more readily appreciated after staining the tissue section using the periodic acid-Schiff (PAS) method.

TREATMENT AND PROGNOSIS: If the clinician believes the thrombocytopenia to be drug-related, the drug should be discontinued immediately. In most instances, the platelet count returns to normal after several days. Platelet transfusions and corticosteroid therapy may be necessary if life-threatening hemorrhage occurs. As mentioned earlier, ITP often resolves spontaneously, but those cases that are more severe may require corticosteroid therapy or intravenous immunoglobulin (IVIG) therapy. For some forms of thrombocytopenia, such as TTP, the patient’s prognosis is relatively guarded. In the past, the condition was almost uniformly fatal, although the outlook has improved since therapy with plasmapheresis or plasma exchange transfusions became available. More than 70% of these patients now survive with proper treatment.

CLINICAL FEATURES: Polycythemia vera typically affects older adults. The median age at diagnosis is 60 years. Only 5% of cases are diagnosed before the age of 40 years. No sex predilection is seen, and the annual incidence estimates of the condition have ranged widely, from 0.2 to 28.0 cases per million population. Recent evidence suggests that an acquired mutation of one of the tyrosine kinase genes, Janus kinase 2 (JAK2), may play a significant role in the development of this disorder, because more than 95% of patients with polycythemia vera have been shown to have this mutation.

The initial symptoms of the disease are nonspecific and include the following:

A ruddy complexion may be evident on physical examination. One relatively characteristic complaint, described in about 40% of affected patients, is that of generalized pruritus (itching), particularly after bathing, without evidence of a rash.

The problems caused by thrombus formation, which would be expected with the increased viscosity of the blood and the increased platelet numbers, include transient ischemic attacks, cerebrovascular accidents, and myocardial infarctions. Hypertension and splenomegaly are also common.

A peculiar peripheral vascular event called erythromelalgia affects the hands and feet. Patients experience a painful burning sensation accompanied by erythema and warmth. This may eventually lead to thrombotic occlusion of the vessels that supply the digits. Digital gangrene and necrosis may result. Erythromelalgia is probably caused by excessive platelets, and its onset seems to be precipitated by exercise, standing, or warm temperatures.

Strangely enough, these patients may also have problems with excess hemorrhage. Epistaxis and ecchymoses are often a problem, and gingival hemorrhage has been described.

TREATMENT AND PROGNOSIS: With the initial diagnosis of polycythemia vera, an immediate attempt is made to reduce the red blood cell mass. The first treatment is usually phlebotomy, with as much as 500 mL of blood removed daily. If thrombotic events are an immediate problem, then treatment with low-dose aspirin should be started. To control the platelet levels, anagrelide hydrochloride, a selective inhibitor of megakaryocyte maturation and platelet production, may be prescribed. Antihistamines are used to help control the symptoms of pruritus.

Long-term management may include intermittent phlebotomy, although myelosuppressive therapy has also been advocated. Each has disadvantages. An increased risk of thrombosis is associated with phlebotomy, and an increased risk of leukemia is associated with some chemotherapeutic drugs. Hydroxyurea is one chemotherapeutic agent that may not pose an increased risk of leukemia, however, because it acts as an antimetabolite and does not appear to have any mutagenic properties. Nevertheless, in 2% to 10% of patients with polycythemia vera, acute leukemia ultimately develops.

Overall, the prognosis is fair; patients with polycythemia vera survive an average of 10 to 12 years after the diagnosis, if treated. Given the fact that the median age at diagnosis is 60 years, the majority of affected patients do not seem to have a markedly higher death rate compared with their unaffected peers.

CLINICAL FEATURES: If all types of leukemia are considered, this condition occurs at a rate of 13 cases per 100,000 population annually. Slightly more males than females are affected. The myeloid leukemias generally affect an adult population; acute myeloid leukemia affects a broader age range, which includes children. Chronic myeloid leukemia shows a peak incidence during the third and fourth decades of life. Acute lymphoblastic leukemia, in contrast, occurs predominantly in children and represents one of the more common childhood malignancies. Chronic lymphocytic leukemia, the most common type of leukemia, primarily affects older adults.

Many of the clinical signs and symptoms of leukemia are related to the marked reduction in the numbers of normal white and red blood cells, a phenomenon that results from the crowding out of the normal hematopoietic stem cells by the malignant proliferation (myelophthisic anemia). Because of the reduced red blood cell count and subsequent reduction in oxygen-carrying capacity of the blood, patients complain of fatigue, easy tiring, and dyspnea on mild exertion. The malignant cells may also infiltrate other organs and often cause splenomegaly, hepatomegaly, and lymphadenopathy.

Leukemic patients may also complain of easy bruising and bleeding, problems that are caused by a lack of blood platelets (thrombocytopenia), the result of megakaryocytes being crowded out of the marrow. Petechial hemorrhages of the posterior hard palate and the soft palate may be observed, and these may be accompanied by spontaneous gingival hemorrhage, especially with platelet counts less than 10,000 to 20,000/mm³. Because disturbances in stem cell differentiation accompany the myelodysplasia syndromes, thrombocytopenia is often present in these patients, and gingival hemorrhage has been reported in this setting. Serious hemorrhagic complications may result from bleeding into the central nervous system or the lungs.

A fever associated with infection may be the initial sign of the leukemic process. Perirectal infections, pneumonia, urinary tract infections, and septicemia are common infectious complications. The microorganisms that are typically involved include gram-negative bacteria, gram-positive cocci, and certain Candida species.

Ulceration of the oral mucosa is often present as a result of the impaired ability of the host to combat the normal microbial flora. Usually, the gingival mucosa is the most severely affected because of the abundant bacteria normally present around the teeth. The neutropenic ulcers that are produced are typically deep, punched-out lesions with a gray-white necrotic base. Oral candidiasis is often a complication of leukemia, involving the oral mucosa diffusely. Herpetic infections are the most common viral lesions, and these may involve any area of the oral mucosa rather than being confined to the keratinized mucosa, as in immunocompetent patients.

Occasionally, the leukemic cells infiltrate the oral soft tissues and produce a diffuse, boggy, nontender swelling that may or may not be ulcerated. This occurs most frequently with the myelomonocytic types of leukemia, and it may result in diffuse gingival enlargement (Figs. 13-16 and 13-17) or a prominent tumorlike growth (Fig. 13-18). The tumorlike collection of leukemic cells is known as granulocytic sarcoma or extramedullary myeloid tumor, and historically the term chloroma has been used because it is often greenish (chlor = green; oma = tumor) on fresh-cut sections. Other oral manifestations include infiltration of the periapical tissues, simulating periapical inflammatory disease both clinically and radiographically.

HISTOPATHOLOGIC FEATURES: Microscopic examination of leukemia-affected tissue shows diffuse infiltration and destruction of the normal host tissue by sheets of poorly differentiated cells with either myelomonocytic characteristics or lymphoid features.

DIAGNOSIS: The diagnosis is usually established by confirming the presence of poorly differentiated leukemic cells in the peripheral blood and bone marrow. Bone marrow biopsy is normally performed in conjunction with the peripheral blood studies because some patients may go through an aleukemic phase in which the atypical cells are absent from the circulation. Classifying the type of leukemia requires establishing the immunophenotype by using immunohistochemical markers to identify cell surface antigens expressed by the tumor cells. Immunohistochemical confirmation of certain characteristic enzymes (e.g., myeloperoxidase, lysozyme) is necessary to identify and classify the myeloid leukemias. In addition, cytogenetic and molecular characterization of the lesional cells is typically necessary. In many cases, the results of these various studies will be significant because the patient’s prognosis is directly affected.

TREATMENT AND PROGNOSIS: The treatment of a patient with leukemia consists of various forms of chemotherapy; the type of leukemia dictates the chemotherapeutic regimen. In most cases the purpose of chemotherapy is to destroy as many of the atypical cells as possible in a short time, thus inducing a remission. For this reason, this technique has been termed induction chemotherapy. Usually, this phase of chemotherapy requires high doses of toxic chemotherapeutic agents; often, the patient experiences a number of unpleasant side effects during treatment. Once remission has been induced, this state must be maintained. This is the purpose of maintenance chemotherapy, which typically requires lower doses of chemotherapeutic drugs given over a longer period.

If the bcr-abl fusion is identified in the leukemic cells of a patient with chronic myeloid leukemia, then treatment with a tyrosine kinase inhibitor is appropriate. The first tyrosine kinase inhibitor to be developed and marketed was imatinib mesylate, and a significant proportion of patients will respond dramatically to this therapy. Imatinib must be taken continuously, because relapses develop quickly if the drug is stopped. Other tyrosine kinase inhibitors are currently being investigated as well.

Newer treatments for chronic lymphocytic leukemia include monoclonal antibodies directed against cell surface antigens, such as CD20, a B-lymphocyte antigen. Rituximab is one such agent that is now being investigated in the treatment of hematologic malignancies of B-cell differentiation.

Drug therapy may be combined with radiation therapy to the CNS because the chemotherapeutic drugs often do not cross the blood-brain barrier effectively. Therefore, the leukemic cells may survive in this site and cause a relapse of the leukemia. Direct intrathecal infusion of the chemotherapeutic agent may be performed to circumvent the problem of the blood-brain barrier. If this strategy succeeds in inducing a remission, then a bone marrow transplant may be considered as a therapeutic option, particularly for the types of leukemia that tend to relapse. This option often is reserved for patients younger than 45 years of age because the success rate is less favorable in older patients.

Supportive care is often necessary if these patients are to survive their leukemia. For patients with bleeding problems, transfusions with platelets may be necessary. If severe anemia is present, packed red blood cells may be required. Infections, of course, should be evaluated with respect to the causative organism, and appropriate antibiotics must be prescribed. Support must be maintained from an oral perspective because many of these patients experience infections of the oral mucosa during the course of their disease. Optimal oral hygiene should be encouraged, and aggressive investigation of any oral complaint should be performed as soon as possible to prevent potentially serious oral infectious complications.

The prognosis of a particular patient depends on a number of variables, including the type of leukemia, the age of the patient, and the cytogenetic alterations associated with the disease. In children with acute lymphoblastic leukemia, more than 80% of these patients are now considered to be cured after appropriate treatment. In an adult with the same diagnosis, even though the rate of initial remission induction is 80%, the 5-year survival rate is generally much lower in most reported series.

Patients younger than 60 years of age with acute myeloid leukemia have a 5-year survival rate of approximately 40% today. This form of leukemia in a patient older than 60 years, however, has a much poorer prognosis, with less than a 10% chance of survival seen in that population. Similarly, patients with a previous history of myelodysplasia have an unfavorable prognosis.

Even though an indolent period is experienced with chronic myeloid leukemia, eventually the neoplastic cells undergo a process known as blast transformation, in which they become less differentiated, proliferate wildly, and cause the patient’s death within 3 to 6 months. In the past, the 5-year survival rate for chronic myeloid leukemia was in the 20% range. Today, most centers are reporting 5-year survival rates of approximately 80%, a dramatic improvement presumably because of the effect of tyrosine kinase inhibitor therapy. Additional factors that may play a role in improved survival include diagnosis of the disease at an earlier stage and the availability of better supportive care. Attempts to control chronic myeloid leukemia by bone marrow transplantation from an HLA-matched donor have resulted in 5-year survival rates of 60% to 70% in younger patients with this disease. This may be an option for those patients who do not respond to tyrosine kinase inhibitor therapy.

Chronic lymphocytic leukemia is considered to be incurable, but its course is highly variable and depends on the stage of the disease. Patients with limited disease have an average survival time of more than 10 years. Those with more advanced disease survive an average of only 2 years.

CLINICAL AND RADIOGRAPHIC FEATURES: The clinicopathologic spectrum traditionally considered under the designation of Langerhans cell histiocytosis includes the following:

It is difficult to categorize many patients into one of these classic designations because of overlapping clinical features. The often-cited Hand-Schüller-Christian triad—bone lesions, exophthalmos, and diabetes insipidus—is present in only a few patients with chronic disseminated disease. It is widely believed that the traditional designations of Hand-Schüller-Christian and Letterer-Siwe disease serve no useful purpose and should be discontinued. Many cases reported as Letterer-Siwe disease in the older literature probably included obscure infections, immunodeficiency syndromes, and malignant histiocytic lesions. Pulmonary Langerhans cell histiocytosis has also been described, but this probably is unrelated to the condition that affects the jaws. Patients who develop pulmonary Langerhans cell histiocytosis are usually adults with a history of smoking, and clonality studies suggest that this is probably a reactive process.

Although Langerhans cell histiocytosis may be encountered in patients over a wide age range, more than 50% of all cases are seen in patients younger than age 15. Although some series have reported a male predilection, overall the sexes appear to be equally affected. Bone lesions, either solitary or multiple, are the most common clinical presentation. Lesions may be found in almost any bone, but the skull, ribs, vertebrae, and mandible are among the most frequent sites. Children younger than age 10 most often have skull and femoral lesions; patients older than age 20 more often have lesions in the ribs, shoulder girdle, and mandible. Adult patients with solitary or multiple bone lesions may have lymphadenopathy but usually do not have significant visceral involvement.

The jaws are affected in 10% to 20% of all cases. Dull pain and tenderness often accompany bone lesions. Radiographically, the lesions often appear as sharply punched-out radiolucencies without a corticated rim, but occasionally an ill-defined radiolucency is seen. Bone involvement in the mandible usually occurs in the posterior areas, and a characteristic “scooped out” appearance may be evident when the superficial alveolar bone is destroyed. The resulting bone destruction and loosening of the teeth clinically may resemble severe periodontitis (Fig. 13-19). Extensive alveolar involvement causes the teeth to appear as if they are “floating in air” (Fig. 13-20).

Ulcerative or proliferative mucosal lesions or a proliferative gingival mass may develop if the disease breaks out of bone (Fig. 13-21). Occasionally, this process may involve only the oral soft tissues. Lesions also can occur within the body of the mandible or maxilla, where they may simulate a periapical inflammatory condition.

HISTOPATHOLOGIC FEATURES: The bone lesions of patients with Langerhans cell histiocytosis show a diffuse infiltration of large, pale-staining mononuclear cells that resemble histiocytes. These cells have indistinct cytoplasmic borders and rounded or indented vesicular nuclei. Varying numbers of eosinophils are typically interspersed among the histiocyte-like cells (Fig. 13-22). Plasma cells, lymphocytes, and multinucleated giant cells are often seen, and areas of necrosis and hemorrhage may be present.

The identification of lesional Langerhans cells is necessary to confirm the diagnosis. Because Langerhans cells cannot be differentiated from other histiocytes by routine histologic staining, additional diagnostic methods are required. Electron microscopic evaluation of lesional tissue has been the gold standard for many years because, ultrastructurally, Langerhans cells contain rod-shaped cytoplasmic structures known as Birbeck granules, which differentiate them from other mononuclear phagocytes (Fig. 13-23). Most laboratories now rely on immunohistochemical procedures to identify the lesional Langerhans cells because of their immunoreactivity with antibodies directed against either CD-1a or CD-207, the latter marker being even more specific for Langerhans cells. To a lesser extent, the lesional cells have S-100 protein immunoreactivity, and they also may show affinity for peanut agglutinin (PNA).

TREATMENT AND PROGNOSIS: Accessible bone lesions, such as those in the maxilla and mandible, are usually treated by curettage. Low doses of radiation may be used for less accessible bone lesions, although the potential for induction of malignancy secondary to this treatment is a concern in younger patients. Intralesional injection with corticosteroid agents has also been reported to be effective in some patients with localized bone lesions. Infrequently, the apparent spontaneous regression of localized Langerhans cell histiocytosis has been reported. The prognosis for bone lesions in the absence of significant visceral involvement is generally good; however, progression or dissemination of the disease may occur, particularly for patients who have three or more bones affected.

Chronic disseminated disease is often associated with considerable morbidity, but few patients die as a result of the disease. Because of the relative rarity of disseminated cases, the ideal treatment has yet to be identified. Single-agent chemotherapy using prednisolone, etoposide, vincristine, or cyclosporine has produced a good response in a significant percentage of such patients, although recurrence is typically seen in over half of the cases. A combination of vincristine and prednisone seems to reduce this risk of recurrence. The acute disseminated form of the disease seen in infants and young children may not respond to these more conservative approaches, and multiple chemotherapeutic agents are given in that situation. Diffuse involvement with compromise of multiple organs is associated with a poor prognosis and is often fatal. In general, the prognosis is poorer for patients in whom the first sign of the disease develops at a very young age and somewhat better for patients who are older at the time of onset.

CLINICAL FEATURES: Hodgkin’s lymphoma almost always begins in the lymph nodes, and any lymph node group is susceptible. The most common sites of initial presentation are the cervical and supraclavicular nodes (70% to 75%) or the axillary and mediastinal nodes (5% to 10% each). The disease initially appears less than 5% of the time in the abdominal and inguinal lymph nodes.

Overall, a male predilection is observed, and a bimodal pattern is noted with respect to the patient’s age at diagnosis. One peak is observed between 15 and 35 years of age; another peak is seen after the age of 50.

The usual presenting sign is the identification by the patient of a persistently enlarging, nontender, discrete mass or masses in one lymph node region (Fig. 13-24). In the early stages, the involved lymph nodes are often rather movable; as the condition progresses, the nodes become more matted and fixed to the surrounding tissues. If it is untreated, then the condition spreads to other lymph node groups and eventually involves the spleen and other extralymphatic tissues, such as bone, liver, and lung. Oral involvement has been reported, but it is rare. In about 30% of patients with Hodgkin’s disease, other systemic signs and symptoms may be present, such as weight loss, fever, night sweats, and generalized pruritus (itching). The absence of these systemic signs and symptoms is considered to be better in terms of the patient’s prognosis, and this information is used in staging the disease. Patients who have no systemic signs are assigned to category A and those with systemic signs to category B.

The staging of Hodgkin’s lymphoma is important for planning treatment and estimating the prognosis for a given patient. The staging procedure typically includes confirmation of the pathologic diagnosis, careful history and physical examination, abdominal and thoracic computed tomography (CT) scans or magnetic resonance imaging (MRI) studies, chest radiographs, and routine hematologic studies (e.g., complete blood count, serum chemistries, erythrocyte sedimentation rate). Evaluation of the extent of disease involvement using positron emission tomography (PET) scans is becoming part of the standard protocol, particularly at large institutions. Lymphangiography, gallium scan, bone marrow biopsy, exploratory laparotomy, and splenectomy may be necessary if the information that they would provide might have an effect on staging or treatment. A summary of the staging system for Hodgkin’s lymphoma is presented in Table 13-2.

HISTOPATHOLOGIC FEATURES: Hodgkin’s lymphoma is recognized to comprise two main forms, (1) nodular lymphocyte–predominant Hodgkin’s lymphoma and (2) classical Hodgkin’s lymphoma, the latter of which is divided into five subtypes. Although this group of diseases has certain features in common, current immunohistochemical and molecular biologic techniques have allowed distinctions to be made among the various types. The common features include effacement of the normal nodal architecture by a diffuse, often mixed, infiltrate of inflammatory cells that is interspersed with large, atypical neoplastic lymphoid cells. In the case of classical Hodgkin’s lymphoma, this atypical cell is known as a Reed-Sternberg cell (Fig. 13-25). The Reed-Sternberg cell is typically binucleated (“owl-eye” nuclei), although it may be multinucleated (“pennies on a plate”), with prominent nucleoli. The malignant cell in nodular lymphocyte–predominant Hodgkin’s lymphoma is the “popcorn cell,” which is so-named because of the resemblance of the nucleus to a kernel of popped corn. The pathologist must see one of these types of distinctive atypical cells to make a diagnosis of Hodgkin’s lymphoma, although their presence does not automatically imply that diagnosis, because similar cells may be seen in certain viral infections, especially infectious mononucleosis. To summarize, Hodgkin’s lymphoma is currently classified in the following manner:

These names describe the most prominent histopathologic feature of each type, and specific epidemiologic and prognostic characteristics are associated with each type.

Nodular lymphocyte–predominant Hodgkin’s lymphoma constitutes 4% to 5% of all cases of Hodgkin’s lymphoma in the United States. In the past, this form was probably combined with the lymphocyte-rich subtype, but the presence of the characteristic popcorn cells is a significant clue to the diagnosis.

Lymphocyte-rich classical Hodgkin’s lymphoma represents about 6% of all cases. Sheets of small lymphocytes with few Reed-Sternberg cells characterize this form.

The nodular sclerosis subtype makes up 60% to 80% of cases and occurs more frequently in females during the second decade of life. This type gets its name from the broad fibrotic bands that extend from the lymph node capsule into the lesional tissue. Reed-Sternberg cells in the nodular sclerosis form appear to reside in clear spaces and, therefore, are referred to as lacunar cells.

The mixed cellularity form accounts for about 15% to 30% of the cases and is characterized by a mixture of small lymphocytes, plasma cells, eosinophils, and histiocytes with abundant Reed-Sternberg cells.

The lymphocyte depletion subtype, the most aggressive type, makes up less than 1% of the cases in recent reports. Before modern immunohistochemical techniques, many examples of large cell lymphoma or anaplastic T-cell lymphoma were undoubtedly included in this category. In this form of Hodgkin’s lymphoma, numerous bizarre giant Reed-Sternberg cells are present, with few lymphocytes.

Occasionally, examples of Hodgkin’s lymphoma are encountered that really do not fit the criteria for any of the known subtypes, and these are designated as unclassifiable.

TREATMENT AND PROGNOSIS: The treatment of Hodgkin’s lymphoma depends on the stage of involvement. Patients who had limited disease (stages I and II) often were managed by local radiation therapy alone. Recent treatment trends, however, combine less extensive radiotherapy fields with milder multiagent chemotherapy regimens to maximize disease control and minimize long-term complications of therapy. Patients with stage III or IV disease require chemotherapy; radiation therapy is used conjointly if significant mediastinal involvement or residual disease is detected. For many years a regimen known as MOPP (mechlorethamine, Oncovin, procarbazine, prednisone) was widely used to treat Hodgkin’s lymphoma. Because significant long-term side effects can be associated with this chemotherapy, another regimen known as ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine [DTIC]) is now used most often, particularly for early and intermediate stage disease, because it has fewer complications.

Before modern cancer therapy was developed for Hodgkin’s lymphoma, the 5-year survival rate was only 5%. The prognosis for this disease is fairly good today; the best treatment results occur in those who present in the early stages. Patients with stage I and II disease often have an 80% to 90% relapse-free 10-year survival rate; those with stage III and IV disease have a 55% to 75% 10-year survival rate.

The histopathologic subtype also influences the response to therapy. Patients with the lymphocyte-predominant and nodular sclerosis forms have the best prognosis, whereas those with the mixed cellularity form have a less favorable prognosis. In the past, researchers believed that the lymphocyte depletion form had a poor prognosis. However, with newer immunohistochemical studies, clinicians now realize that many of these cases were misdiagnosed; therefore, the available data are probably not reliable. In most instances, however, the stage of disease now plays a more important role in determining the patient’s prognosis than does the histopathologic subtype.

After 15 years posttreatment, patient mortality is due more often to the complications of therapy: either secondary malignancy or cardiovascular disease. Currently, research is focused on the development of treatment regimens that continue to have a superior cure rate, while simultaneously decreasing the risk of treatment-related complications.

CLINICAL AND RADIOGRAPHIC FEATURES: Non-Hodgkin’s lymphoma occurs primarily in adults, although children may be affected, particularly by the more aggressive intermediate- and high-grade lymphomas. The condition most commonly develops in the lymph nodes, but so-called extranodal lymphomas are also found. In the United States, approximately 20% to 40% of lymphomas develop in an extranodal site, but in Asian countries such as Korea and Japan, nearly half of all lymphomas are extranodal.

With a nodal presentation, the patient usually is aware of a nontender mass that has been slowly enlarging for months. The lesion typically involves a local lymph node collection, such as the cervical, axillary, or inguinal nodes; one or two freely movable nodules are noticed initially. As the malignancy progresses, the nodes become more numerous and are fixed to adjacent structures or matted together (Fig. 13-26). Gradually, the process involves other lymph node groups, and invasion of adjoining normal tissues occurs.

In the oral cavity, lymphoma usually appears as extranodal disease. Although the oral lesions of lymphoma are often a component of more widely disseminated disease, at times the lymphoma begins in the oral tissues and has not spread to other sites. The malignancy may develop in the oral soft tissues or centrally within the jaws. Soft tissue lesions appear as nontender, diffuse swellings; they most commonly affect the buccal vestibule, posterior hard palate, or gingiva (Figs. 13-27 and 13-28). Such swellings characteristically have a boggy consistency. The lesion may appear erythematous or purplish, and it may or may not be ulcerated. Patients who wear a denture that contacts the lesional site often complain that their denture does not fit because it feels too tight.

Lymphoma of bone may cause vague pain or discomfort, which might be mistaken for a toothache. The patient may complain of paresthesia, particularly with a mandibular lesion (so-called numb chin syndrome). Radiographs usually show an ill-defined or ragged radiolucency, although in the early stages, the radiographic changes may be subtle or nonexistent. If untreated, then the process typically causes expansion of the bone, eventually perforating the cortical plate and producing a soft tissue swelling. Such lesions have been mistaken for a dental abscess, although a significant amount of pain is not present in most cases.

Clinical staging to determine the extent to which the disease has spread is an important factor in assessing the prognosis for a particular patient. The staging evaluation should include a history, physical examination, complete blood count, liver function studies, routine chest radiographs, CT scans of the pelvic and abdominal regions, lymphangiography, and bone marrow biopsy. The staging system for Hodgkin’s lymphoma (see Table 13-2) has been widely adopted for use with the non-Hodgkin’s lymphomas.

HISTOPATHOLOGIC FEATURES: Non-Hodgkin’s lymphomas are histopathologically characterized by a proliferation of lymphocytic-appearing cells that may show varying degrees of differentiation, depending on the type of lymphoma. Low-grade lesions consist of well-differentiated small lymphocytes. High-grade lesions tend to be composed of less differentiated cells. All lymphomas grow as infiltrative, broad sheets of relatively uniform neoplastic cells that usually show little or no evidence of lesional tissue necrosis (Figs. 13-29 and 13-30). In some lesions, particularly those of B-lymphocyte origin, a vague semblance of germinal center formation may be seen (i.e., a nodular or follicular pattern). Other lymphomas show no evidence of such differentiation, and this pattern is termed diffuse. If the lymphoma arises in a lymph node, then the tumor destroys the normal architecture of the node. An extranodal lymphoma destroys the normal adjacent host tissue by infiltrating throughout the area. In the oral cavity, diffuse large B-cell lymphoma, which is considered to be a high-grade lymphoma, is the most common diagnosis, comprising approximately 60% of the cases.

Standard of care demands that appropriate immunohistochemical and cytogenetic studies be performed for a tumor diagnosed as lymphoma. In general, these studies can become quite involved and, therefore, are beyond the scope of this text.

TREATMENT AND PROGNOSIS: The treatment of a patient with non-Hodgkin’s lymphoma is based on several factors, including the stage and grade of the lymphoma, the overall health of the patient, and the patient’s pertinent past medical history. The patient’s health must be considered because many of the chemotherapeutic regimens are quite debilitating. Surgical management is not usually indicated.

Low-grade lymphomas are perhaps the most controversial in terms of treatment. Some authorities recommend no particular treatment because these tumors are slow growing and tend to recur despite chemotherapy. Given the fact that low-grade lymphomas arise in older adults and the median survival without treatment is 8 to 10 years, many clinicians opt for a “watch and wait” strategy, treating the patient only if symptoms develop. Unfortunately, approximately 40% of low-grade lymphomas eventually transform to a high-grade lymphoma, leading to the patient’s demise. Because these low-grade lymphomas have been considered “incurable,” new treatments are being investigated. Most of these lesions are of B-cell differentiation, so treatment strategies using monoclonal antibodies directed against CD20, a B-cell surface antigen, are now being evaluated. Rituximab is one of the agents being examined in clinical trials.

For the intermediate-grade and high-grade lymphomas, the treatment of localized disease consists of radiation plus chemotherapy. With more advanced and disseminated disease, chemotherapy alone usually is implemented. Multiagent chemotherapy is used routinely, and new combinations are being evaluated continuously. Unfortunately, although the response rate of many lesions is good and much progress has been made in this area, the cure rate is not high. For intermediate-grade lesions, a failure rate of 30% to 50% can be expected. High-grade lymphomas are associated with a 60% mortality rate at 5 years after diagnosis and treatment.

CLINICAL FEATURES: Mycosis fungoides is a condition that usually affects middle-aged adult men; there is a 2:1 male-to-female ratio and a mean age at diagnosis of 55 to 60 years. The disease progresses through three stages, usually over the course of several years.

The first stage, known as the eczematous (erythematous) stage, is often mistaken for psoriasis of the skin because of the well-demarcated, scaly, erythematous patches that characterize these lesions. Patients may complain of pruritus. With time, the erythematous patches evolve into slightly elevated, red lesions (plaque stage). These plaques tend to grow and become distinct papules and nodules. At this time, the disease has entered the tumor stage (Fig. 13-31). Visceral involvement is also seen at this point.

Approximately 35 cases of mycosis fungoides with oral involvement have been reported. The most commonly affected sites are the tongue, hard and soft palates, and gingiva (Fig. 13-32). The buccal mucosa, tonsils, lips, sinuses, and nasopharynx may also be affected. The oral lesions present as erythematous, indurated plaques or nodules that are typically ulcerated. Generally, these lesions appear late in the course of the disease and develop after the cutaneous lesions.

Sézary syndrome is an aggressive expression of mycosis fungoides that essentially represents a dermatopathic T-cell leukemia. The patient has a generalized exfoliative erythroderma, as well as lymphadenopathy, hepatomegaly, and splenomegaly. The lung, kidneys, and CNS can also be involved. This condition follows a fulminant course and typically results in the patient’s death within a short period of time; the median survival for this form of the disease is 2 to 3 years.

HISTOPATHOLOGIC FEATURES:

TREATMENT AND PROGNOSIS: Topical nitrogen mustard, topical carmustine, superpotent topical corticosteroids, electron beam therapy, or photochemotherapy (PUVA [8-methoxy-psoralen + ultraviolet A]) are effective in controlling mycosis fungoides during the early stages. Ultimately, the topical forms of therapy fail, and aggressive chemotherapy is necessary, particularly if there is visceral involvement. Newer agents that may be added to the chemotherapy regimen include monoclonal antibodies directed against the cell surface marker CD52, certain retinoid compounds, and specific interferon compounds. Another new agent that may be used for advanced disease is known as denileukin diftitox, which is derived from diphtheria toxin and targets the interleukin-2 receptor on the neoplastic lymphocytes. If Sézary syndrome develops, then extracorporeal photopheresis or chemotherapy is used as a treatment modality. Extracorporeal photopheresis involves the ingestion of the photoactive drug 8-methoxypsoralen, followed by the removal of a portion of the patient’s blood and a separation of red and white blood cells. The red blood cells are returned to the patient immediately. The white blood cells are irradiated outside the body (extracorporeal) with ultraviolet A. These altered white cells are then infused back into the patient. Their altered state may help generate an immunologic response to the patient’s own abnormal lymphocytes.

Although mycosis fungoides is not considered to be curable, the disease is usually slowly progressive. As a result, there is a median survival time of 8 to 10 years, and patients may die of causes unrelated to their lymphoma. Once the disease progresses beyond the cutaneous involvement, the course becomes much worse. The patient usually dies of organ failure or sepsis within 1 year.

CLINICAL AND RADIOGRAPHIC FEATURES: As many as 50% to 70% of the cases of endemic Burkitt’s lymphoma present in the jaws. The malignancy usually affects children (peak prevalence, about 7 years of age) who live in Central Africa, and a male predilection is usually reported. The posterior segments of the jaws are more commonly affected, and the maxilla is involved more commonly than the mandible (a 2:1 ratio). Sometimes all four quadrants of the jaws show tumor involvement.

The tendency for jaw involvement seems to be age related; nearly 90% of 3-year-old patients have jaw lesions, in contrast to only 25% of patients older than age 15. Sporadic Burkitt’s lymphoma tends to affect patients over a greater age range than is noted for the African tumor. Although the abdominal region is typically affected, jaw lesions have been reported in sporadic Burkitt’s lymphoma (Fig. 13-35).

The growth of the tumor mass may produce facial swelling and proptosis. Pain, tenderness, and paresthesia are usually minimal, although marked tooth mobility may be present because of the aggressive destruction of the alveolar bone. Premature exfoliation of deciduous teeth and enlargement of the gingiva or alveolar process may also be seen.

The radiographic features are consistent with a malignant process and include a radiolucent destruction of the bone with ragged, ill-defined margins (Fig. 13-36). This process may begin as several smaller sites, which eventually enlarge and coalesce. Patchy loss of the lamina dura has been mentioned as an early sign of Burkitt’s lymphoma.

HISTOPATHOLOGIC FEATURES: Burkitt’s lymphoma histopathologically represents an undifferentiated, small, noncleaved B-cell lymphoma. The lesion invades as broad sheets of tumor cells that exhibit round nuclei with minimal cytoplasm. Each tumor nucleus often has several prominent nucleoli, and numerous mitoses are seen. Immunohistochemical studies using markers that identify proliferating cells (e.g., Ki-67) typically indicate that almost 100% of the tumor cells are in the process of replicating. On viewing the lesion on low-power magnification, a classic “starry-sky” pattern is often appreciated—a phenomenon that is caused by the presence of macrophages within the tumor tissue (Fig. 13-37). These macrophages have abundant cytoplasm, which microscopically appears less intensely stained in comparison with the surrounding process. Thus these cells tend to stand out as “stars” set against the “night sky” of deeply hyperchromatic neoplastic lymphoid cells (Fig. 13-38).

Because the histopathologic features of Burkitt’s lymphoma can appear similar to some cases of diffuse large B-cell lymphoma, standard of care now dictates that, in addition to immunohistochemical studies, molecular genetic analysis of the tumor tissue should be performed. This distinction is important because these two malignancies are treated differently. Burkitt’s lymphoma is characterized by one of several specific translocations, the most common being t(8;14), that results in overexpression of the oncogene c-myc, an event that presumably drives the neoplastic proliferation.

TREATMENT AND PROGNOSIS: Burkitt’s lymphoma is an aggressive malignancy that usually results in the death of the patient within 4 to 6 months after diagnosis if it is not treated. Treatment generally consists of an intensive chemotherapeutic regimen, which emphasizes the use of high doses of cyclophosphamide. More than 90% of the patients respond to this treatment.

The prognosis for Burkitt’s lymphoma in the past was poor, with a median survival time of only 10½ months. More recent trials with more intensive, multi-agent chemotherapeutic protocols have shown an 85% to 95% event-free (no evidence of recurrence) survival rate 3 to 5 years after treatment for patients with stage I or II disease. Even for advanced stage (III and IV) Burkitt’s lymphoma, the event-free survival has improved to 75% to 85%.

CLINICAL FEATURES: Extranodal NK/T-cell lymphoma is typically observed in adults. The initial signs and symptoms are often localized to the nasal region and include nasal stuffiness or epistaxis. Pain may accompany the nasal symptoms. Swelling of the soft palate or posterior hard palate may precede the formation of a deep, necrotic ulceration, which usually occupies a midline position. This ulceration enlarges and destroys the palatal tissues, which typically creates an oronasal fistula (Fig. 13-39). Secondary infection may complicate the course of the disease, and life-threatening hemorrhage is a potential problem in some instances.

HISTOPATHOLOGIC FEATURES: Histopathologic examination of one of these lesions shows a mixed infiltrate of a variety of inflammatory cells, often arranged around blood vessels (angiocentric) (Fig. 13-40). The lesional process appears to invade and destroy the normal tissue in the area. Necrosis is often present in some areas of the lesion, presumably secondary to infiltration of the blood vessels by the tumor cells. Large, angular, lymphocytic cells with an atypical appearance are usually identified as a component of the cellular infiltrate. Immunohistochemical evaluation of this infiltrate often shows that the large atypical cells mark with antibodies directed against T-lymphocyte antigens. Molecular genetic studies typically show monoclonal gene rearrangements of the T-lymphocyte receptor, consistent with a lymphoreticular malignancy.

TREATMENT AND PROGNOSIS: Without treatment, extranodal NK/T-cell lymphoma is a relentlessly progressive, highly destructive process that ultimately leads to the patient’s death by secondary infection, massive hemorrhage, or infiltration of vital structures in the area. Lesions that are localized usually respond to radiation therapy, a feature that is similar to that of T-cell lymphomas of other sites. Approximately 4500 cGy is required to control the disease, and many of these patients show no evidence of recurrence or dissemination of the lesion. Five-year sur-vival rates in some series have been reported to be as high as 85%. For patients with more disseminated disease, combination chemotherapy is indicated, and a less favorable prognosis can be expected, with 30% to 50% 5-year survival generally reported.

CLINICAL AND RADIOGRAPHIC FEATURES: Multiple myeloma is typically a disease of adults, with men being affected slightly more often than women. The median age at diagnosis is between 60 and 70 years, and it is rarely diagnosed before age 40. For reasons that are not understood, the disease occurs twice as frequently in blacks as whites, making this the most common hematologic malignancy among black persons in the United States.

Bone pain, particularly in the lumbar spine, is the most characteristic presenting symptom. Some patients experience pathologic fractures caused by tumor destruction of bone. They may also complain of fatigue as a consequence of myelophthisic anemia. Petechial hemorrhages of the skin and oral mucosa may be seen if platelet production has been affected. Fever may be present as a result of neutropenia with increased susceptibility to infection. Metastatic calcifications may involve the soft tissues and are thought to be caused by hypercalcemia secondary to tumor-related osteolysis.

Radiographically, multiple well-defined, punched-out radiolucencies or ragged radiolucent lesions may be seen in multiple myeloma (Fig. 13-41). These may be especially evident on a skull film. Although any bone may be affected, the jaws have been reported to be involved in as many as 30% of cases. The radiolucent areas of the bone contain the abnormal plasma cell proliferations that characterize multiple myeloma.

Renal failure may be a presenting sign in these patients because the kidneys become overburdened with the excess circulating light chain proteins of the tumor cells. These light chain products, which are found in the urine of 30% to 50% of patients with multiple myeloma, are called Bence Jones proteins, after the British physician who first described them in detail.

Approximately 15% of patients with multiple myeloma show deposition of amyloid (see page 822) in various soft tissues of the body, and this may be the initial manifestation of the disease. Amyloid deposits are due to the accumulation of the abnormal light chain proteins. Sites that are classically affected include the oral mucosa, particularly the tongue. The tongue may show diffuse enlargement and firmness or may have more of a nodular appearance. Sometimes the nodules are ulcerated. Another area that is commonly affected is the periorbital skin, with the amyloid deposits appearing as waxy, firm, plaquelike lesions (see Fig. 17-7 on page 823).

HISTOPATHOLOGIC FEATURES: Histopathologic examination of the lesional tissue in multiple myeloma shows diffuse, monotonous sheets of neoplastic, variably differentiated, plasmacytoid cells that invade and replace the normal host tissue (Fig. 13-42). Mitotic activity may be seen with some frequency. The monoclonality of the plasma cell population can be demonstrated using antibodies directed against the lambda and kappa light chain components of the immunoglobulin molecule. In a neoplastic proliferation of plasma cells, virtually all of the lesional cells will mark with only one of these antibodies. In contrast, a reactive plasma cell infiltrate will show a mixture of lambda- and kappa-producing plasma cells. Occasionally, deposition of amyloid may be observed in association with the neoplastic cells. Like other types of amyloid, this material appears homogeneous, eosinophilic, and relatively acellular. It stains metachromatically with crystal violet and shows an affinity for Congo red, demonstrating apple-green birefringence on viewing with polarized light. A biopsy specimen of bone marrow from a patient with multiple myeloma should show at least 10% atypical plasma cells making up the marrow cell population.

TREATMENT AND PROGNOSIS: The goals of treatment related to multiple myeloma include not only controlling the malignancy but also making the patient comfortable and prolonging the patient’s survival. Initial attempts to control multiple myeloma generally consist of chemotherapy. An alkylating agent, such as melphalan or cyclophosphamide, is often used in conjunction with prednisone, and approximately 60% of patients will respond initially to this regimen. However, virtually all patients eventually experience relapse of their disease. More aggressive chemotherapeutic regimens and bone marrow transplantation, either autologous or allogeneic, may be considered in otherwise healthy patients under the age of 55 to 65 years, but these individuals comprise a minority of multiple myeloma patients. Addition of thalidomide to the treatment protocol may improve survival; however, ongoing studies are evaluating the effect of this drug. Radiation therapy is useful only as palliative treatment for painful bone lesions. Any one of several bisphosphonate medications (clodronate, pamidronate, or zoledronic acid) can be prescribed to reduce the possibility of myeloma-related fracture with its attendant pain, but these medications do not appear to increase survival. A small percentage of these patients may experience the complication of bisphosphonate-related osteonecrosis of the jaws (see page 299).

The prognosis is considered poor, but younger patients tend to fare better than older ones. Pretreatment serologic studies examining the levels of b₂-microglobulin and albumin should be performed. With lower levels of b₂-microglobulin (<3.5 mg/L) and higher levels of albumin (>35 g/L), the median survival is approximately 5 years. In contrast, when serum b₂-microglobulin levels are >5.5 mg/L, the 5-year survival rate falls to about 2½ years. A median survival time of about 3 to 4 years can be expected after the onset of symptoms. In the past, a 10% 5-year survival rate was typical; the prognosis today has improved only slightly. Most hematology and oncology centers report a 5-year survival rate of 25%. With aggressive chemotherapy and bone marrow transplantation, the 5-year survival rate may be improved to as high as 50%; however, only a small percentage of multiple myeloma patients can reasonably tolerate this treatment. This approach seems to hold the most promise for control of this aggressive disease, however, and some centers have indicated that as many as 20% of their patients may survive for longer than 10 years.

CLINICAL AND RADIOGRAPHIC FEATURES: The plasmacytoma usually is detected in an adult male, with an average age at diagnosis of 55 years. The male-to-female ratio is 3:1. Most of the lesions present centrally within a single bone, and the spine is the most commonly involved site. About one third of the cases are reported in that location. The initial symptoms often relate to swelling or bone pain; occasionally, however, this lesion is detected on routine radiogra-phic examination. The extramedullary plasmacytoma appears as a relatively nondescript, well-circumscribed, nontender soft tissue mass. An even stronger male predilection is seen with this lesion, approaching a 6:1 male-to-female ratio. Approximately 80% to 90% of extramedullary plasmacytomas develop in the head and neck region, and such lesions have been reported in the tonsils, the nasopharynx, the paranasal sinuses, the nose, and the parotid gland.

Radiographically, the lesion may be seen as a well-defined, unilocular radiolucency with no evidence of sclerotic borders or as a ragged radiolucency similar to the appearance of multiple myeloma (Fig. 13-43). No other lesions should be identifiable by a skeletal survey or careful physical examination, however.

HISTOPATHOLOGIC FEATURES: The histopathologic features of the plasmacytoma are identical to those of multiple myeloma. Sheets of plasma cells show varying degrees of differentiation. Immunohistochemical studies demonstrate that these plasma cells are monoclonal. As many as 25% to 50% of these patients also show a monoclonal gammopathy on evaluation by serum protein immunoelectrophoresis, although the amount of abnormal protein is much less than that seen with multiple myeloma. Solitary plasmacytoma also differs from multiple myeloma in that no evidence of plasma cell infiltration should be seen by a random bone marrow biopsy, and the patient should not show signs of anemia, hypercalcemia, or renal failure. Immunohistochemically, extramedullary plasmacytoma appears to differ from its intrabony counterparts in that it shows a marked decrease or lack of immunoreactivity for antibodies directed against cyclin D1 and CD56.

TREATMENT AND PROGNOSIS: Plasmacytomas are usually treated with radiation therapy, and typically a dose of at least 4000 cGy is delivered to the tumor site. A few lesions have been surgically excised with good results, although this is not the preferred treatment in most instances. Unfortunately, when patients with plasmacytoma of bone are observed on a long-term basis, most will eventually develop multiple myeloma. About 50% show evidence of disseminated disease within 2 to 3 years. However, one third of these patients will not have symptoms of multiple myeloma for as long as 10 years. Extramedullary plasmacytoma seems to have a much better prognosis, with only 30% of these patients showing progression to multiple myeloma and 70% having a 10-year disease-free period after treatment.