Oral Lymphoproliferative Disorders
Kristin K. McNamara
Carl M. Allen
Lymphoproliferative diseases (LPDs) that affect the oral region are incredibly diverse. The clinicopathologic spectrum ranges from reactive lymphoid hyperplasia to relentlessly aggressive forms of lymphoma. Though relatively uncommon, lymphoid malignancies are ranked third in incidence of oral malignant disease, following squamous cell carcinoma and salivary gland neoplasms. This chapter will explore a selection of the most common and significant LPDs affecting the oral soft and hard tissues. Important elements of clinical presentation, histopathologic findings, and patient management will be discussed, with emphasis on oral cavity manifestations of these disease processes.
Leukemia represents a group of disorders that result from the uncontrolled proliferation of a clone of hematopoietic stem cells, initially occupying bone marrow and eventually overflowing into the peripheral blood. The disease is generally classified according to histogenetic origin (myeloid or lymphoid) and clinical behavior (acute or chronic). Thus, the four primary categories of leukemia are acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), and chronic lymphocytic leukemia (CLL), although multiple subclassifications are recognized within this diagnostic framework.1,2
The annual incidence of leukemia in the United States is over 52,000, representing ∼4% of the overall cancer burden.3 Although the acute leukemias are diagnosed across a broad age range, ALL is generally a childhood disease and AML is more often seen in adults. Chronic leukemia is primarily seen in adults, and CLL, the most common type of leukemia, is typically diagnosed in men over 50 years of age.1,2 If untreated, acute leukemia is expected to follow an aggressive clinical course resulting in death in a matter of months, but chronic leukemia is typically more indolent and expected to slowly progress over many years. The clinical course, however, is quite variable.
The etiology of leukemia is uncertain, although both environmental and genetic factors seem to contribute. Viral infection, ionizing radiation, and chemical exposure to benzene and pesticides have been associated with increased risk.1,2 Multiple genetic syndromes, such as Down syndrome, Bloom syndrome, neurofibromatosis type I, and Fanconi anemia, are also known risk factors.1 A variety of specific cytogenetic abnormalities have been linked with most forms of leukemia, with the Philadelphia chromosome associated with CML being the first chromosomal abnormality detected.4 Early genetic alterations in hematopoietic stem cells may lead to myelodysplastic syndrome, a rare group of hematologic disorders thought to represent a precursor stage in the evolution of AML.5,6
Given the diverse and complex nature of leukemias, as well as the varied treatment approaches and prognoses associated with each of the many subclassifications, this discussion is limited to aspects of the disease that relate to the oral cavity and head and neck region.
The presenting signs and symptoms of an acute leukemia are generally related to bone marrow suppression. Malignant leukemic cells replace normal hematopoietic cells in the marrow, causing myelophthisic anemia. Resultant pancytopenia may manifest as fatigue, dyspnea, easy bruising/bleeding, and infection. Patients may also experience flu-like symptoms with bone and/or joint pain secondary to bone marrow expansion.1,2 The development of a chronic leukemia is typically more insidious and ∼50% of patients will be diagnosed incidentally on the basis of blood studies performed for unrelated purposes.1 Although constitutional symptoms are uncommon in this group, hepatosplenomegaly and lymphadenopathy may be found on physical examination.
Oral manifestations are more often observed in association with acute forms of leukemia, but may also arise in the setting of a chronic leukemia. The most common oral manifestations include petechial hemorrhage of the hard and soft palate, which may be accompanied by spontaneous gingival hemorrhage.2,7 Oral mucosal ulcerations, secondary to neutropenia or local infection, may also be seen.2 Oral candidiasis and herpetic infections are common. Herpetic infections typically represent reactivation of the latent virus and may involve any oral mucosa surface, which is in contrast to the clinical distribution of lesions in immunocompetent individuals that are limited to keratinized surfaces of the hard palate and attached gingiva. Leukemic infiltration of salivary glands, tonsils, and lymph nodes may lead to clinical enlargement of these structures, a manifestation most often seen with CLL7 (Fig. 73-1). This infiltrate may be referred to as small lymphocytic lymphoma (SLL), particularly in the absence of a known leukemic (CLL) setting. Given identical morphologic and immunophenotypic profiles, SLL and CLL are thought to represent different manifestations of the same disease process. SLL/CLL may also occasionally result in palatal enlargement.7 Leukemic infiltration of the oral mucosa is most often seen in association with the monocytic subtype of AML. This generally results in diffuse, boggy, nontender gingival enlargement.2,8 Occasionally, a solitary tumorlike growth will develop and this is referred to as myeloid sarcoma (MS) (previously termed granulocytic sarcoma). Historically, this has been called “chloroma” owing to a greenish color observed on the freshly cut surface of the tumor.9
MS is an extramedullary collection of malignant myeloid cells that clinically forms a mass and is strongly associated with myeloid leukemia. It can occur in virtually any anatomic region, but most commonly involves subperiosteal bone and soft tissues, skin, lymph nodes, gastrointestinal tract, and upper respiratory tract.9,10 It is estimated that ∼16% of MS cases occur in the head and neck region, involving soft tissues of the orbit, nasal cavity, and paranasal sinuses. Intraoral involvement is rare, but it is strongly associated with AML and may be the initial manifestation of the disease.10,11,12 A few cases of intraoral MS have been reported in association with CML.13 Oral mucosal sites include the gingiva, palate, buccal mucosa, tongue, and lips. The typical clinical presentation is a solitary, possibly ulcerated, mass that ranges in color from normal (pink) to red, purple, or bluish-black14,15,16 (Fig. 73-2). Bony involvement of the mandible and maxilla may occur, which has been reported in the setting of nonhealing extraction sites or mimicking periapical inflammatory disease.14,15
FIGURE 73-2. Myeloid sarcoma. The ulcerated soft tissue mass of the mandibular gingiva represents an extramedullary collection of malignant myeloid cells.
Histopathologic assessment of tissues infiltrated by a leukemic cell population reveals destruction of normal tissue architecture by a diffuse proliferation of immature cells with either myeloid or lymphoid features (Figs. 73-3 and 73-4). Classifying the type of leukemia requires immunophenotyping, performed on solid tissue and/or flow cytometry (Fig. 73-5). Cytogenetic and molecular testing has also played an increasingly vital role from a diagnostic and risk-stratification standpoint.
FIGURE 73-3. Myeloid sarcoma. A diffuse malignant mononuclear infiltrate presenting in the gingiva of a 100-year-old female, consistent with MS (A and B: H&E; 100× and 200×).
FIGURE 73-5. Myeloid sarcoma—IHC. The malignant cells are positive for CD43 (A), CD4 (B), lysozyme (C), and a subset is positive for myeloperoxidase (D).
Patient management and prognosis are highly variable and dependent on multiple factors, including patient age and presence of comorbid conditions, type of leukemia, and associated cytogenetic alterations. Treatment strategies may include various forms of chemotherapy, monoclonal antibodies, tyrosine kinase inhibitors, radiation, or hematopoietic stem cell transplantation (HSCT). One of the major success stories in cancer management is related to the treatment of ALL of childhood. This condition used to be uniformly fatal, but now most centers are reporting over 80% overall survival rate.17 In contrast, AML is still associated with significant morbidity and mortality.18 Recent introduction of tyrosine kinase inhibitors in therapeutic management of CML has been associated with dramatic improvement in 5-year survival rates, with most centers reporting up to 85% long-term survival.4 Despite dramatic advancements in treatment strategies, CLL remains an incurable disease outside the setting of hematologic stem cell transplantation. The clinical course of CLL is highly variable, with median survival at diagnosis ranging between 1 and more than 10 years.19
Oral mucosal treatment-related complications often arise secondary to myeloablative therapy. Oral mucositis may develop a few days after the start of chemotherapy and slowly resolve within 2 to 3 weeks following cessation of the cytotoxic drugs. Sites of involvement typically include nonkeratinized surfaces, such as the labial mucosa, buccal mucosa, ventrolateral tongue, soft palate, and floor of mouth. Lesions clinically present as patchy areas of erythema and atrophy that evolve to form ulcerations. Neutropenic ulcerations and oral infections may also occur secondary to treatment-related myelosuppression. The significance of such lesions, in addition to causing considerable pain and discomfort, is that breakdown in the mucosal barrier may allow entryway for systemic bacterial, fungal, and viral infections. Additionally, the presence of severe oral lesions may significantly delay or alter the designed treatment regimen, thus impacting cancer control and overall prognosis. Meticulous oral hygiene, antimicrobials, and systemic antibiotics are of paramount importance, which may be used in conjunction with systemic analgesics and topical agents for palliative care. In addition to topical anesthetics, various bioadherent oral rinses are available to coat, hydrate, and lubricate the oral mucosa. Prophylactic cryotherapy is also frequently used. Numerous novel agents, such as keratinocyte growth factor-1, fibroblast growth factor-7, transforming growth factor-β3, granulocyte-macrophage colony-stimulating factor, and interleukin-11 are also being evaluated for their protective properties.2,20,21 Additionally, patients who have undergone allogenic bone marrow transplantation will be at risk for development of lichenoid oral mucosal lesions and oral ulcerations associated with graft-versus-host disease. These lesions clinically mimic lichen planus and are associated with increased risk for development of oral epithelial dysplasia and oral squamous cell carcinoma.22
LANGERHANS CELL HISTIOCYTOSIS
Synonyms: Histiocytosis X, Langerhans cell disease, idiopathic histiocytosis, eosinophilic granuloma
Langerhans cell histiocytosis (LCH) is a rare group of disorders characterized by proliferation of histiocytic cells phenotypically similar to Langerhans cells. It has long been debated whether LCH is a malignant or reactive condition, but clonality studies have shown the proliferation to be monoclonal, consistent with a neoplastic process. Nonetheless, the natural history of the disease ranges from rapidly progressive and fatal, to chronic and relapsing, to spontaneously regressing.23 The clinical presentation is also quite variable, but single-organ system disease is most common and typically presents as solitary or multifocal osteolytic bone lesions (“eosinophilic granuloma”).24 This disease is generally seen in older children and young adults, with the majority of patients diagnosed before age 20.23 Multiorgan system disease is less common and has traditionally been designated as Lettere–Siwe disease (acute disseminated histiocytosis), occurring in infants, and Hand–Schüller–Christian disease (chronic disseminated histiocytosis), occurring in children. However, it is now understood that significant clinical overlap exists between these multisystem designations and the classification has largely been dismissed. In addition to bone, multisystem disease often involves skin as an eczematous exanthem, with possible visceral sites to include liver, lungs, pituitary, spleen, lymph nodes, and bone marrow.23,24 Visceral involvement is uncommon in adult patients, but when present is a sign of poor prognosis.24,25 LCH can involve virtually any bone; however, skull, ribs, vertebrae, and mandible are most often affected.23,26
Oral and maxillofacial lesions are frequently encountered in LCH, particularly in adult patients, with involvement of the jaws in up to 30% of cases.23 Pain or tenderness is often the initial clinical finding; however, bone lesions may also be discovered incidentally on dental radiographs taken for routine dental care. The condition typically presents with punched-out radiolucencies that lack a corticated rim, although they may also be ill-defined. The posterior mandible is most commonly affected, and lesions have classically been described as appearing “scooped out” with “teeth floating in air” owing to the tendency for superficial alveolar bone destruction.23,27,28 This disease pattern and resultant loosening of teeth may clinically mimic severe periodontitis (Fig. 73-6). Lesions occurring within the body of the mandible or maxilla may also radiographically resemble periapical inflammatory disease. Ulcerative or exophytic lesions of the overlying oral mucosa may occur if the disease breaks out of bone, but occasionally LCH may be limited to oral soft tissues.29
The histopathologic features of LCH consist of a diffuse infiltrate of large, pale-staining mononuclear cells with abundant eosinophilic to amphophilic cytoplasm and indistinct borders, resembling histiocytes. Vesicular nuclei appear rounded to reniform, with deep indentations or grooves. The presence of eosinophils is characteristic, but varies from a prominent infiltrate to sparse or even absent. Lymphocytes, plasma cells, and occasional multinucleated giant cells may also be observed (Fig. 73-7). Hemorrhage and necrosis within this lesion are not unusual; however, mitotic activity tends to be low to moderate and without atypical mitoses.23,25 The gold standard for diagnosis has traditionally been electron microscopic identification of rod-shaped cytoplasmic structures known as Birbeck granules, which differentiate Langerhans cells from other mononuclear cells. Although this technique may still prove helpful in difficult-to-characterize tumors, it is rarely necessary today.23 Immunohistochemistry (IHC) is generally used to identify lesional Langerhans cells on the basis of their reactivity to antibodies directed against either CD1a or CD207 (langerin), the latter being quite sensitive and specific for Langerhans cells. Lesional cells will also show affinity for antibodies directed against S100 protein; however, this marker shows less specificity and is generally not used for diagnostic purposes.23,25
Following histopathologic diagnosis of gnathic or oral mucosal LCH, patients must undergo full medical evaluation and staging. The initial assessment should include physical examination, hematologic panel and coagulation studies, liver function tests, urine osmolality, chest radiographs, and radiographic skeletal survey.25 If the disease is limited to the jaws, the prognosis is excellent. Curettage is generally curative, although intralesional corticosteroid injection, oral indomethacin, or low-dose radiation may be employed if bone lesions are not readily accessible for surgery.23,25,30 While a favorable outcome would be anticipated, dissemination of the disease may occur, particularly when multiple bones are involved.
Overall outcome of LCH is dependent on the number of organs involved, the presence of organ dysfunction, and the age at diagnosis.25 In general, the prognosis is poorer for individuals who develop the disease at a very young age. Overall 5-year survival for children with LCH is 71%; however, this figure drops to just 25% in patients with liver or spleen involvement.25 Involvement of the liver, lungs, spleen, or hematopoietic system translates to a poor prognosis and signifies the need for chemotherapy; however, because of the relative rarity of disseminated LCH, the ideal treatment has not been elucidated.23,25 Single-agent chemotherapy using prednisolone, etoposide, vincristine, or cyclosporine produces a good response, but recurrence is frequently encountered. Several studies have shown that sustained multiagent chemotherapy results in greater response with fewer recurrences. Novel therapies currently under investigation include monoclonal antibody therapy using antibodies directed against CD1a or CD207, cytokine inhibitors, and a relatively new agent called 2-chlorodeoxyadenosine.25,30,31 Even with successful treatment, survivors of disseminated LCH may be faced with significant long-term sequelae owing to organ system dysfunction, disease recurrence, and increased risk for second malignancies.24,25
Synonym: Hodgkin disease
Hodgkin lymphoma (HL) is an uncommon B-cell derived lymphoma characterized by the presence of the neoplastic Hodgkin and Reed–Sternberg (HRS) cells. The pathogenesis of the disease is not fully understood; however, up to 40% of cases are associated with Epstein–Barr virus (EBV) infection.32 In addition, genetic factors seem to play a role, as same-sex siblings of a patient with HL are at a 10-fold increased risk for developing the disease, and a monozygotic twin is at significantly greater risk than a dizygotic twin.33
Over 9,000 new cases of HL are diagnosed annually in the United States, which represents ∼11% of all lymphomas.3,33 A male predilection and bimodal age distribution is seen, with most patients being diagnosed either between the ages of 15 and 35 or after age 55.33 On the basis of histologic features and the immunophenotypic profile of tumor cells, HL is categorized as either classic HL or the more rare nodular lymphocyte-predominant HL. Nodular sclerosis, mixed cellularity, lymphocyte-rich, and lymphocyte-depleted are subtypes under the designation of classic HL.32
Regardless of subtype, the overwhelming majority of cases present with nodal disease; only rarely will HL arise in extranodal sites.33,34 A nontender enlarging lymph node or mass in a lymph node region is a typical clinical presentation. The cervical and supraclavicular lymph nodes are the most common sites of initial involvement, followed by the axillary and mediastinal nodes. Abdominal and inguinal lymph nodes are less frequently involved.33 Up to 40% of patients will present with constitutional “B symptoms,” including fever, night sweats, and weight loss.32 Many patients will also experience generalized chronic pruritis. As the disease progresses, involved lymph nodes may become matted or fixed to surrounding tissues. The disease spreads contiguously along lymphatic channels to other lymph node groups and may ultimately involve extranodal sites, such as the spleen, bone marrow, liver, and lungs.32,33
HL arising within the oral mucosa is quite uncommon.35,36 Oral sites of involvement include the tongue, palate, palatine tonsils, and floor of mouth, with most extranodal head and neck cases associated with Waldeyer ring, a designation applied to lymphoid tissues involving the base of tongue, tonsillar fauces, oropharynx, and nasopharynx.34 A few cases of primary HL arising within the maxilla or mandible have also been reported.35 Primary parotid gland HL is extremely rare.37
The diagnosis of HL relies upon open biopsy, as fine-needle aspiration and core-needle biopsies do not allow for adequate evaluation of important architectural features. In addition, unlike most malignancies, the neoplastic cells constitute a minority of the cell population, representing less than 3% of cells within a prominent mixed population of reactive lymphocytes, eosinophils, and histiocytes.33 Thus, a small sample size may fail to capture the malignant cell component and preclude an accurate diagnosis.
In classic HL, effacement of normal tissue architecture is seen with a diffuse, often mixed, inflammatory cell infiltrate with occasional large neoplastic HRS cells. HRS cells are typically binucleated with prominent nucleoli (“owl-eye nuclei”), although multinucleation may also be seen. HRS cells are almost always CD30+. Reactivity to CD15 is also often seen, with CD20 being less consistent and of varied intensity.33,38 In contrast, nodular lymphocyte-predominant HL has neoplastic cells with large lobulated nuclear outlines (“popcorn cells”) that have been termed lymphocyte-predominant (LP) cells (formerly termed lymphocytic and histiocytic [L&H] cells). Unlike HRS cells, LP cells are generally negative for CD30, but positive for CD20.33,38
Staging of HL is essential for treatment planning. A routine hematologic panel, physical examination, and imaging studies are typically performed. Computed tomography (CT) scans, magnetic resonance imaging (MRI), or the newer fluorodeoxyglucose–positive emission tomography (FDG-PET) scans can obtain crucial information regarding the extent of disease.33 The staging system is based on the number of involved lymph node regions and whether they are on one or both sides of the diaphragm, the presence of extranodal disease, and history of systemic symptoms.33
The development of modern management strategies for HL has been one of the few victories in cancer therapy in recent history. Depending on stage and clinical risk factors, 65% to 90% of patients can be rendered disease-free after 5 years, with over 80% of newly diagnosed patients under age 60 being cured of their disease.32,33,39 Interestingly, the histologic subtype of HL has diminished in prognostic significance, as patient age and presence of systemic symptoms have proven to be the most important prognostic factors.33,40 Patients with early-stage HL and favorable prognosis typically receive a short course (generally two cycles) of combination ABVD chemotherapy (doxorubicin, bleomycin, vinblastine, dacarbazine) in conjunction with radiation therapy (generally limited to 20 Gy) using narrow fields restricted to involved lymph nodes.33,39 Advanced-stage disease is generally managed using an increased number of cycles of ABVD chemotherapy alone, or alternating with MOPP (mechlorethamine, Oncovin, procarbazine, and prednisone) or BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone). The MOPP and BEACOPP regimens, however, have been associated with significant toxicity.33 At 15 or more years posttreatment, patient mortality is often secondary to complications of therapy, such as development of a secondary malignancy or cardiovascular disease. Thus, the current goal of novel therapeutics is to maximize disease control while minimizing long-term treatment-related complications.
Non-Hodgkin lymphoma (NHL) represents a heterogeneous group of malignant LPDs. It accounts for ∼4% of malignancies in the United States, with close to 71,000 new cases diagnosed annually.3 The incidence has been steadily increasing over the last few decades, and while the explanation is unclear, this trend may, to some extent, be a result of the growing immunocompromised and elderly populations.41
More than two-thirds of NHL cases are diagnosed after the age of 60, and a slight male predominance is seen.3,42 Immunosuppression represents a significant risk factor for the development of NHL, which may arise in the clinical setting of hereditary immune dysfunction, HIV, solid organ transplantation (SOT) or HSCT, or immunomodulatory therapy for various autoimmune processes. In addition, infectious agents, such as EBV, human T-cell leukemia/lymphoma virus type 1, and Helicobacter pylori, have each been associated with specific types of NHL.41,42
NHL is categorized by the type of precursor cell from which it arises, with 85% to 90% arising from B lymphocytes.42 Most cases develop within lymph nodes, but NHL may occur in almost any tissue type. While overall it is generally reported that less than 40% of patients present with extranodal disease, a recent series limited to the head and neck found that 62% of cases exhibited extranodal manifestations as the initial sign of disease.42,43 Head and neck are the second most common anatomic sites for extranodal NHL, following the gastrointestinal tract.43
Up to 3% of extranodal cases of NHL arise within the oral cavity and jaws.44 This presentation is often a component of disseminated disease with involvement of regional lymph nodes, but primary oral NHL may also be the only manifestation of disease. Oral lesions frequently present as diffuse, nontender, soft tissue swellings that may or may not be ulcerated. These swellings often exhibit a boggy consistency and may appear erythematous to somewhat purplish in color. The posterior hard palate, attached gingiva, and buccal vestibule are the most frequently involved oral mucosal sites. NHL may also arise centrally within the jaws, causing pain or discomfort that may be mistaken for a toothache. Upon radiographic examination, an ill-defined or ragged radiolucency may be seen; however, early lesions may be associated with minimal to no radiographic alteration. When the mandible is involved, patients may complain of paresthesia in the distribution of the mandibular division of cranial nerve V, an ominous clinical sign often referred to as “numb chin syndrome.” Constitutional symptoms, such as fever, weight loss, fatigue, and malaise, are infrequently reported with primary NHL of the oral cavity.41,44
The World Health Organization 2008 Classification of Haematopoietic and Lymphoid Tissue recognizes more than 40 subtypes of NHL. This discussion will focus on forms that are most commonly encountered in the oral cavity.
Diffuse Large B-Cell Lymphoma
B-cell neoplasms represent the most common subset of NHL that arise within the oral cavity, with diffuse large B-cell lymphoma (DLBCL) comprising ∼60% of oral cases and encompassing nearly all cases arising within the jaws.44 DLBCL is a heterogeneous group of lymphoproliferative malignancies that harbor somatic mutations at variable regions of immunoglobulin heavy and light chains. Though primarily a disease of older adults, rare cases are seen in young adult and pediatric populations.44
DLBCL of the oral cavity typically presents as a soft tissue swelling that may or may not be ulcerated or associated with destruction of underlying bone. Any oral mucosal site can be affected, with the hard palate, gingiva, and buccal mucosa most commonly involved (Fig. 73-8). Primary intrabony lesions within the maxilla or mandible are also seen with some frequency45 (Fig. 73-9). Histopathologic evaluation reveals a diffuse, monomorphic proliferation of large neoplastic B cells that effaces normal tissue architecture. Lesional cells demonstrate large, somewhat irregular nuclei with prominent nucleoli (Fig. 73-10). Immunohistochemical analysis demonstrates positivity to CD45 and pan–B-cell markers, such as CD20 and CD79a. Variable expression of CD30 may be observed, especially in the anaplastic variant of DLBCL. Ki-67 characteristically shows a high proliferation index, which may range from 40% to over 90%.38 Multiple morphologic variants of DLBCL are recognized and are associated with variable immunophenotypic and cytogenetic profiles. On the basis of gene expression, DLBCL has been divided into two subgroups, namely the germinal center B-cell type (GCB) or the activated B-cell type (non–germinal center B-cell type; non-GCB). Immunophenotypic differences between these subgroups have been identified and CD10, BCL-6, and MUM1 are typically used for classification purposes. Studies have shown the non-GCB subtype to be associated with a poorer prognosis, a trend that has also recently been reflected in a small series of oral DLBCL.45,46,47 Likewise, the presence of a MYC break has been linked to unfavorable clinical outcome.38,46 Nonetheless, the clinical impact of risk-stratification efforts seems questionable, because GCB and non-GCB subtypes are currently treated equivalently.38,45 DLBCL is considered an aggressive neoplasm, with combination rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), a mainstay of treatment. A variable clinical course is recognized, with initial remission rates of 60% to 80% and overall 5-year survival of ∼50%.44
WordPress theme by UFO themes