Plasma cell dyscrasias and the head and neck

REVIEW ARTICLE

Plasma Cell Dyscrasias and the Head and Neck John G. Batsakis, Jeffrey L. Medeiros, Mario A. Luna, and Adel K. El-Naggar Structures in the head and neck (bones, soft tissues, lymph nodes, mucosa) are variably affected by plasma cell dyscrasias. Involvement can be manifested by localized lesions (extramedullary plasmacytoma or solitary plasmacytoma of bone) or by more diffuse disease (multiple myeloma). We present a contemporary review of these disorders with emphasis on patient outcomes. Ann Diagn Pathol 6: 129-140, 2002. Copyright 2002, Elsevier Science (USA). All rights reserved.

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HE PLASMA cell neoplastic disorders may be classified into (1) multiple myeloma, (2) myelomatosis, (3) myeloma leukemia (4) extramedullary plasmacytoma, and (5) solitary plasmacytoma of bone. The last two have also been categorized as localized and although all have different natural histories, all have been thought, by some, to be part of the same disease spectrum. Current concepts for interdisciplinary management use the foregoing classification.1 Plasmacytoma is the accepted nomenclature for a solitary tumor of plasma cells, located either in bone marrow (medullary plasmacytoma), the solitary plasmacytoma of bone, or outside of bone, the extramedullary plasmacytoma. If there are multiple plasma cell tumors or if there is a diffuse infiltration of the bone marrow, the terms myelomatosis and multiple myeloma, respectively, apply. We use myelomatosis for the often metastatic-like spread of nodular masses of plasma cells to soft tissues, parenchymal organs, and bone.2 This is seen most often with extramedullary plasmacytomas, but is not limited to that form of the plasma cell dyscrasias. If there are more than 2,000 plasma cell/␮1 of peripheral blood, plasma cell leukemia is said to exist.1,3 Plasma cell leukemia occurs in about 20% of patients with multiple myeloma where it is secondary as part of the terminal phase of multiple myeloma; it is primary in 10% of instances.3

From the Department of Pathology, University of Texas M. D. Anderson Cancer Center, Houston, TX. Address reprint requests to John G. Batsakis, MD, 1701 Hermann Dr, Houston, TX 77004. Copyright 2002, Elsevier Science (USA). All rights reserved. 1092-9134/02/0602-0009$35.00/0 doi:10.1053/adpa.2002.33458

Taken separately, the lesions exhibit different survival rates. Plasma cell leukemia is the most rapidly life consuming, with a median survival of approximately 6 months. Multiple myeloma, treated with conventional chemotherapy, has an approximately 3- to 4-year median survival; extramedullary plasmacytoma, over 10 years.1 Patients with myelomatosis usually fare better than patients with multiple myeloma but may have survival intervals between myeloma and plasmacytomas. The immunoglobulins have importance in all of the different forms except for nonsecretory myeloma, characterized by an absence of detectable monoclonal protein in serum and urine, and which accounts for approximately 2% of all myeloma cases. However, if there is a monoclonal protein present in serum/urine but the histology, cytology, radiologic evidence, and clinical criteria for multiple myeloma are not sufficient for the diagnosis, a “monoclonal gammopathy of undetermined significance” is diagnosed. Patients with this finding must be monitored because up to 20% will eventually develop multiple myeloma. Some cases of multiple myeloma will have only an incomplete secretion of immunoglobulins by the myeloma clone, usually a free light chain (Bence Jones protein). IgD myeloma falls into this category.3 It may be considered as a variant of Bence Jones myeloma in which the presence of IgD-M protein and the light chain are the only distinctive features. Primary radiotherapy of an extramedullary plasmacytoma with its lymphatic drainage can lead to a local control rate of about 85%.4 Because only about 20% of extramedullary plasmacytomas evolve into multiple myeloma, a 10-year survival of 70% can be achieved. Primary radiotherapy of solitary

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plasmacytoma of bone can also achieve local control. Survival rates, however, are much lower (20%) because of the higher conversion rates to multiple myeloma. Multiple Myeloma Multiple myeloma is a B-cell malignancy originating from preswitched, follicle center B-lymphocytes which differentiate into plasma cells accumulating in the bone marrow.6 The cells of multiple myeloma are characterized by a profound genetic instability resulting in a complex set of numerical and structural chromosomal abnormalities. Among these abnormalities, translocations involving 14q32 and the immunoglobulin heavy-chain locus are the most frequent, but translocation partners are remarkably heterogeneous.6 Chromosome 13q14 may harbor a critical tumor suppressor gene because patients with multiple myeloma with deletion of the chromosome have an overall short survival after conventional dose and high-dose chemotherapy. Drach et al6 also report a markedly increased bone marrow vascularity in patients with active myeloma. This is considered to help the marrow’s microenvironment to support growth and survival of the myeloma cells. The malignant, terminally differentiated B-cells (ie, plasma cells in the marrow) not only produce an abnormal immunoglobulin, the laboratory hallmark of multiple myeloma, but also cytokines which stimulate cells of the marrow microenvironment. In addition, factors secreted by myeloma cells activate osteoclasts thus leading to one of the osseous complications of the disease.6 The malignant cells of multiple myeloma have many features of normal long-lived plasma cells. These include expression of CD138 (syndecan-1) high expression of CD38 and other heterogeneous immunophenotypic markers.6 The neoplastic clone of the B cells in multiple myeloma appears to have undergone antigen selection of Ig affinity maturation (which points to derivation from a nonswitched B cell that has left the germinal center). The incidence of multiple myeloma is 3:100,000 and blacks are more often affected that whites.7 There is no sex preference. Median age at diagnosis is 60 years. In a typical case, bone marrow biopsy shows more than 10% of plasma cells arranged in sheets and often at several levels of maturity. The verte-

brae (66%) are the most commonly affected, followed by the ribs (44%), skull (41%), and pelvis (28%). More than 90% are in red bone marrow.6 Anemia, recurrent infections, and chronic renal insufficiency are other morbid manifestations.6 Multiple myeloma may be graded according to a three-tiered system8,9: ● ●

●

Low-grade with plasma cells indistinguishable from normal. Intermediate-grade, an asynchronous type (ie, marked discrepancy of maturation between nucleus and cytoplasm). At least 50% of all cells have enlarged nuclei with prominent nucleoli; cytoplasmic nuclear ratio is low, but a small perinuclear is usually present. High-grade, a plasmablastic type with large nuclei and very prominent centrally located nucleoli. The cytoplasm is restricted to a narrow rim and the perinuclear is inconspicuous or absent.

Myeloma with multilobated nuclei also appears to follow an aggressive course with a shorter survival. Skull and Jaw Involvement Skull involvement in multiple myeloma is common and can be found in about 45% of cases. Most of the lesions are osteolytic. Witt et al10 found that 36 of 77 patients with multiple myeloma had lesions in the skull. Mandibular involvement is found less often (15.6%) and is almost always seen in association with lesions of the skull. In 17% of multiple myeloma involvement of the jaws, the jaw disease is the first manifestation of systemic disease.10 Nevertheless, the frequency of jaw involvement is largely dependent on the stage of disease and, in that light, may be as high as 95%. Multiple myeloma affecting the jaw bones has a characteristic distribution.11 The mandible is more often involved than the maxilla and the posterior oral cavity is more commonly involved than the anterior oral cavity. Oral manifestations of multiple myeloma, besides the incidence of bone involvement, include jaw pain, tooth pain, migration of teeth, hemorrhage, and fractures. Radiographic features are usually two of the four most often encountered bone changes (namely, radiolucent lesions of the jaws or a generalized osteoparoticlike cortical thinning, see Table 1).11

Plasma Cell Dyscrasias and the Head and Neck Table 1. Radiologic Signs of Bone Destruction in Multiple Myeloma of Jaws Solitary osteolytic lesion not unlike a bone cyst.* Multiple osteolytic lesions without marginal sclerosis (central and peripheral).* Diffuse osteoporosis with generalized involvement. Diffuse osteosclerosis. *The osteolytic lesions can appear in periapical locations or be superimposed over the root apices of adjacent teeth. Data from Pisano et al.11

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bone) or a single tumor involving soft tissue (most often as an extramedullary plasmacytoma of the upper aerodigestive tract) in the absence of significant bone marrow plasma cell infiltration, as well as absence of anemia, hypercalcemia, renal failure, and multiple sites of bone destruction.13 These localized plasmacytomas comprise 2% to 10% of plasma cell malignancies and, in contrast to multiple myeloma, occur most frequently in males and in a younger age group.14,15 The relative frequency of the localized forms compared with that of multiple myeloma is 1:40.16

Waldenstrom’s Macroblobulinemia Waldenstrom’s macroglobulinemia, a lymphoplasmacytoid lymphoma, should not pose problems in the differential diagnosis. Patients with this disease usually present with anemia and lymphadenopathy or splenomegaly. The disease also has unique clinical and laboratory features that only rarely occur in other lymphoproliferative disorders, including extramedullary plasmacytoma. Hyperviscosity, cryoglobulinemia, peripheral neuropathy, and cold agglutinin disease may be early and presenting features or develop during the course of the disease in a significant number of patients. Less common complications include amyloidosis and renal disease. Classified under the category of lymphoplasmacytoid lymphoma/immunocytoma, Waldenstrom’s macroglobulinemia affects approximately 1,500 Americans per year and is 10% to 20% as common as multiple myeloma.12 The malignant B cells in this disease express monoclonal surface and cytoplasmic IgM. A variable proportion may coexpress IgD.11 The levels of surface Ig follow the cytologic pleomorphism of the constituent cells with small lymphocytes having high levels, the lymphoplasmacytoid, lower levels, and plasma cells that are negative for the protein. There is also a reciprocal pattern of CD38 and PCA1 antigen expression.11 There is always involvement of the bone marrow but there is an absence of local MRI patterns, which is in keeping with the rarity of lytic bone lesions in Waldenstrom’s macroglobulinemia.11 Localized Plasmacytomas We define a localized plasmacytoma as a form of plasma cell dyscrasias characterized by either a single lytic lesion of bone (solitary plasmacytoma of

Solitary Plasmacytoma of Bone Although both solitary plasmacytoma of bone and extramedullary plasmacytoma are initially restricted to a single area, the former tends to disseminate and evolve into multiple myeloma much more often than the latter. Galieni et al13 postulate this diversity in progression could be because of different sites of primary localization (osseous v extraosseous). These investigators also raise the question of occult myeloma being already present in the putative solitary osseous forms because dissemination occurred in a relatively short time (3 years after diagnosis). It is studies like those of Galieni et al13 that forcefully bring to mind the deficiencies of early case studies in which the presence of an occult generalized disease was unable to be defined. In a series of 822 patients with plasma cell dyscrasias seen at a single institution between 1958 and 1980, 25 patients (3%) presented with a solitary plasmacytoma of the bone.17 In this cohort, myeloma protein was detected in 12 patients (48%). These patients were usually 10 years younger than those who presented with multiple myeloma. The plasma cell lesions occurred primarily in the axial skeleton and were lytic more often than sclerotic. These data conform well with those collected in five series (N ⫽ 187 patients with solitary plasmacytoma of bone; median age, 56.6 years; 68.8% males; 46.6% of lesions being spinal in location; monoclonal protein detection, 56.5%).18 Arguments continue as to whether solitary plasmacytoma of bone should be classified as a separate entity rather than as an early form of multiple myeloma. This is reflected in the different criteria used to define a solitary plasmacytoma of bone. Table 2 presents criteria used by Frassica et al.19

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Table 2. Criteria for Diagnosis of Solitary Plasmacytoma of Bone as Proposed by Mayo Clinic A solitary lytic lesion on skeletal survey. Histologic confirmation of plasmacytoma. Bone marrow plasmacytosis of 10% or less. Appropriate serum and urine protein studies.* *Patients with abnormalities of serum proteins of Bence Jones proteinuria of less than 1 gm/24 hours at first presentation are not excluded if they meet other criteria. Also not excluded are patients who fail within 12 months of diagnosis or whose protein abnormalities did not resolve after treatment. Data from Frassica et al.19

Most clinicians would agree without argument on the first three criteria; it is with the serum and urine protein studies where there is a lack of agreement. With few exceptions, it has been shown that patients with an apparent solitary osseous lesion at the time of first presentation to a physician have an overall survival that is considerably better than patients who present with classic multiple myeloma. The 5-year survival of 74% in a Mayo clinic series of patients is dramatically superior to the 18% 5-year survival of patients with multiple myeloma reported from the same institution.19 It is also notable that the Mayo Clinic investigators (Rochester, MN) reported a 41% 5-year survival with disease progression after treatment failure. Chak et al20 have reported similar findings. These data indicate solitary plasmacytoma of bone may often have a long clinical history, even after an initial therapeutic failure. Table 3 reports outcome of patients after radiotherapy as reported in five series. The majority of patients will progress to multiple myeloma, but apparently one fourth can be disease-free at 10 years. Neither Frassica et al19 or Chak et al20 were able to identify any prognostic factors associated with disease progression. Other investigators have

commented that a presence of an M-protein after treatment is an indication of residual tumor or occult spread.21 An increased incidence of multiple myeloma has also been associated with high concentrations of beta 2 microlobulins and immunoparesis (defined as a depression of at least two immunoglobulin classes to below normal levels) at the time of initial diagnosis.21 The treatment of solitary plasmacytoma of bone is radiation therapy with dose recommendations usually ranging between 35 and 50 Gy. Frassica et al,19 while reporting an 11% overall local failure rate, indicate that a 15% incidence was seen with doses less than 45 Gy as compared with no local failure after treatment with 45 Gy or more. Local therapeutic failures tend to be more frequent with lesions of the spine. The most common patterns of relapse in nearly all reports is a progression to multiple myeloma; this applies equally to extramedullary plasmacytoma. However, correlations between total radiation dose and the subsequent development of systemic disease have not been consistent.22 Solitary plasmacytoma of bone may convert to multiple myeloma more readily than extramedullary plasmacytoma, and this liability can continue even after 17 years. Holland et al23 have reported a postconversion median survival rate of 24 months. This is similar to survival times of patients in whom multiple myeloma is diagnosed initially. It is the apparent continual conversion by solitary plasmacytoma of bone that has prompted considerations that the lesion is actually an in-evolution multiple myeloma. Table 4 presents conversion rates and median survivals for the two localized (solitary osseous and extramedullary plasmacytomas) as reported in three separate series of patients.14,23,24

Table 3. Patient Outcome After Radiotherapy of Solitary Plasmacytoma of Bone Study

Outcomes

Galieni et al13

Frassica et al19

Jackson & Scarffe21

Dimopoulos et al17

Holland et al23

Local recurrence rate (%) Ten-year disease-free survival (%) Survival (median, yrs)

9 35 10

44 25 9.3

6 25 9.87

8 42 13

NA 50 11

Data from Dimopoulos et al.17

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Table 4. Conversion to Multiple Myeloma and Survival of Plasmacytomas Washington University Medical Center23

Median survival (mos) % Conversion to myeloma

Princess Margaret Hospital14

M. D. Anderson Cancer Center24

SPB

EP

SPB

EP

SPB

EP

50⫹ 53

63⫹ 36

86 48

101 8

43⫹ 50

124 17

Abbreviations: SPB, solitary plasmacytoma of bone; EP, extramedullary plasmacytoma. Data from Holland et al.23

Jaws and Skull Involvement In contrast to extramedullary plasmacytomas, solitary plasmacytomas of bone are uncommon in the head and neck.25-27 They have, however, been reported in the mandible, clivus, sphenoid, and petrous bone. In the temporal bones and skull, radiographs show the lesions to be trabeculated and multicystic, or purely destructive with sharply demarcated margins. Solitary plasmacytoma of the osseous mandible represents only about 4% of all myelomatous diseases.26 Like myeloma involvement, which is far more common, the site of predilection is the posterior mandible. At this location, the lesion presents as an unpainful swelling of relatively long duration. The radiologic appearance is not specific. A monoclonal immunoglobulinemia is initially detected in about 40% of patients.26 Treatment has consisted of radiation with or without surgery. In follow-up periods of 4 months to 12 years, approximately 15% of patients progressed to multiple myeloma in the series reported by Kanazawa et al.26 Progression may occur over a 20- or 30-year period, but most reported cases have “converted,” usually within a year (suggesting coexistence with occult multiple myeloma). The strong implication is that mandibular plasmacytomas are not separate and distinct entities.27 Plasmacytomas of the temporal bone may be either primary in bone or extramedullary. Both can be associated with cranial nerve dysfunction. Because of a location within a relatively small space containing multiple functional elements, plasmacytomas of the temporal bone tend to be rapidly symptomatic. They may be misleading in early stages, when they suggest inflammatory disease of the middle ear. Whereas solitary plasmacytoma of bone and multiple myeloma rise from the marrow-rich area of

the petrous bone, extramedullary plasmacytoma develops from the mucosal lining of the middle ear and mastoid air cells.25,28 Involvement of the temporal bone by the plasma cell neoplasm can course hearing loss, vertigo, tinnitus, otalgia, or facial nerve paralysis. With extensive skull base lesions, there may be other cranial nerve deficits (III, V, VI, X, XII).29 Even subjects without otologic complaints will have bone marrow infiltration of the temporal bone in advanced stages of multiple myeloma.29 Extramedullary Plasmacytoma Between 1905 and 1997 there had been more than 400 published reports addressing extramedullary plasmacytomas.5 From these, Alexiou et al5 culled 714 cases (82.2%) that were found in the upper aerodigestive tract. Other regions of the body accounted for the sites in 155 cases (17.8%). Tabular data for major sites in the upper aerodigestive tract and for sites in nonupper aerodigestive tract locations are presented in Tables 5 and 6. Typical extramedullary plasmacytoma of the upper aerodigestive tract is a solitary, submucosal, reddish, sessile or polypoid tumor that is rarely ulcerated. Pedunculated lesions are more often seen in the larynx and pharynx, while sessile tumors have a sinonasal predilection. Friability and softness may indicate a more aggressive lesion. There may be more than one mucosal plasmacytoma in the same anatomic region. Invasion of underlying bone is considered an adverse factor by some; other have not found this to be true.30 Light-optic examination shows a diffuse monotonous and monoclonal proliferation of plasma cells, all set in sparse matrix that is quite vascular. Mitosis are few or absent. Cells range in maturity but are in a pure culture (absent lymphoid cells), except cells in relation to necrosis and secondary

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Table 5. Selected Upper Aerodigestive Tract Sites of Extramedullary Plasmacytomas Site

Percent*

Sinonasal tract Nasal cavity Maxillary sinus Nasopharynx Oropharynx Palantine tonsil or soft palate Larynx Hypopharynx Glands of upper aerodigestive tract Parotid Submandibular Thyroid Trachea Cervical lymph nodes Middle ear and mastoid

43.8 21.5 15.2 18.3 17.8 10.5 11.0 0.6 4.1 2.0 0.7 1.4 1.0 1.7 1.0

*Total percent does not equal 100 because sites with considerably lower incidences are not listed. Data from Alexiou et al.5

infection. Amyloid can be found in 15% to 40% of cases (without clinical significance).30 Some investigators have found a correlation between the histologic grade and local aggressiveness, but not for overall survival.31 Wiltshaw’s proposed three stages are more prognostic: Stage I, localized to an extramedullary site; Stage II, regional lymph nodes are involved; and Stage III, multiple areas of spread/conversion to multiple myeloma.15 In their literature search, Alexiou et al5 found a 7.6% frequency of regional lymph node involvement in the extramedullary plasmacytomas of the upper aerodigestive tract, as opposed to 2.6% for nonupper aerodigestive tract tumors. In the upper air passages, the majority of extramedullary plasma cell tumors occur as single lesions. Approximately 10% are multiple, but there may be moderately extensive superficial mucosal speared. Reactive plasma cell lesions are also most often solitary.3 The sinonasal tract is, by far, the favorite localization for extramedullary plasmacytoma of the upper aerodigestive tract, accounting for nearly 44% of reported cases.5 Subsites with the highest prevalence are the nasal cavity and maxillary sinus. The nasopharynx and oropharynx are nearly equal in incidence, and are followed by the larynx. In the latter, it appears that there is no subsite predilec-

tion with the subglottis epiglottis area; the aryepiglottic area and glottis having between 1.4% and 1.0% of laryngeal plasmacytomas.5 Plasmacytomas replace tissue, unlike inflammatory, reactive lesions which infiltrate by a disposition of plasma cells and other reactive cells through the involved tissue. This growth pattern, stromal prominence, mixed cellularity, and polyclonality should separate true plasmacytomas from inflammatory plasmacytic lesions. There also is a relative paucity, or even absence, of Russell bodies in plasmacytomas. The so-called plasma cell granulomas in the oral cavity are usually exophytic and most often affect the gingiva. The maxillary and mandibular gingiva are equally involved.3 The lesions are found on the marginal, interdental, and attached gingiva. Bone loss may or may not be present. There is no sex predilection and the lesion can occur at any age.3 Although the quasi-meta-analysis by Alexiou et al5 suffers from including data when clinical and laboratory investigations were not optimal, the study is, nevertheless, informative. Regional lymph node involvement was found with 7.6% of the aerodigestive tract tumors; 2.6% with plasmacytomas outside of the head and neck regions. With the exception of qualitative immunoglobulin (Ig) determinations, the extramedullary plasmacytomas’ laboratory findings were not exceptional. At the time of diagnosis of an extramedullary (nonosseous) plasmacytoma, a monoclonal gammopathy is said to be present in one quarter of the cases; disappearing with successful treatment.5 Most investigators exclude tumors that arise in bone and insist on having a normal bone marrow biopsy result and an absence of lytic bone lesions to exclude multiple myeloma. Magnetic resonance is probably the most sensitive method for serving this

Table 6. Selected Nonupper Aerodigestive Tract Sites of Extramedullary Plasmacytomas Site

Percent*

Gastrointestinal tract Genitourinary tract Skin Lung

40 25.2 16.8 9.7

*Total percent does not equal 100 because sites with considerably lower incidences are not listed. Data from Alexiou et al.5

Plasma Cell Dyscrasias and the Head and Neck Table 7. Patterns of Progression in Extramedullary Plasmacytomas After Radiotherapy (n ⴝ 128) Failure Pattern

Percent

Local failure Recurrence in adjacent lymph nodes Evolution of multiple myeloma Multifocal (extramedullary) relapse

7 7 15 13

Data from Dimopoulos et al.17

function. Isotopic bone scans are of limited value because the isotopes are taken up only in areas of osteoblastic – not osteolytic – activity. The site distribution, gross and microscopic features, and monoclonality of the extramedullary plasmacytoma have been well characterized.32 This is not so for the requirement of a monoclonal paraprotein. The presence of a monoclonal peak on serum and/or urine electrophoresis was not an exclusionary factor for Hotz et al33; although it was for Aboulafia et al.34 In the 16 series (1952 to 1999) of extramedullary plasmacytoma reviewed by Hotz et al,33 an assessment of monoclonality of the plasma cells was partially achieved in only four. There is, however, no apparent link between detection of monoclonal immunoglobulins or light chains in a patients’ sera and the secondary development of multiple myeloma.35 According to some investigators, myeloma develops more often in patients who produce non-IgG immunoglobulin classes.35 It should be noted that because extramedullary plasmacytomas of the head and neck typically have a low tumor burden, monoclonal paraprotein can be elusively low or apparently not present. The finding of a monoclonal protein in this patient subset could reflect an increased tumor burden and disseminated disease. Patterns of progression of extramedullary plasmacytomas after radiotherapy are presented in Table 7.17 A 10-year diseasefree survival of 74% was reported in 110 patients.18 Treatment modalities recorded for extramedullary plasmacytomas, as identified by Alexiou et al,5 were as follows: radiation alone, 44.3%; surgery plus radiation, 26.9%; and surgery alone, 21.9%. Median overall survival and recurrence-free survival was longer than 300 months for surgery plus radiation. Surgery only yielded a median survival of 156 months, while radiation alone had a median survival of 144 months. Overall, after treatment for upper aerodigestive

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tract plasmacytomas, 61.1% of patients had no recurrences or conversion to a systemic involvement. Twenty-two percent of patients had recurrences and 16.2% converted to multiple myeloma.5 For patients treated for extramedullary plasmacytoma in non-head and neck mucosal areas, there were no recurrences or development of multiple myeloma in 64.7%, recurrences in 21.2%, and a conversion to multiple myeloma in 14.1% of the described cases.5 Most patients with extramedullary plasmacytoma died of unrelated causes. Table 8 offers a clinicopathologic synopsis of five of the plasma cell dyscrasias. Differential Diagnosis Important differential diagnoses are low-grade B-cell non-Hodgkin’s lymphomas and low-grade mucosa associated lymphoid tissue (MALT) lymphomas which may also manifest plasmacytic differentiation and can present in the same anatomic locations. Other than morphologic criteria, immunostaining for perinuclear or cytoplasmic Ig expression (IgM rather than 1gA or IgG), kappa or lambda light-chain restriction, or a lack of B-cell antigens (such as CD20) are of help in distinguishing MALT lymphomas from extramedullary plasmacytoma.35 The type of immunoglobulins synthesized by neoplastic cells of an extramedullary plasmacytoma are primarily IgG, 40% of upper respiratory tract tumors and 54% of the extramedullary cases in the remaining body areas are of the IgG type.35 Because extramedullary plasmacytoma represents a distinctly different lesion from solitary plasmacytoma of bone and multiple myeloma in terms of sex predilection, locations, and tumor progression, overall survival could be related to the homing patterns of lymphocytes.5 Multiple myeloma and solitary plasmacytoma of bone are tumors of B cells that are indigenous to bone marrow and bound to return to it. One the other hand, extramedullary plasmacytomas result from B cells that develop in and home back to the MALT system. These concepts of distinct patterns of lymphocyte traffic serve as underpinning for the thesis that extramedullary plasmacytomas represent a form of marginal zone lymphoma (MZL) that has undergone an extensive degree of plasmacytic differentiation.36 This concept has also been used not only to account for similar sites of involvement of ex-

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Batsakis et al Table 8. The Plasma Cell Dyscrasias: A Comparison

Multiple Myeloma

Site of involvement

Marrow

Median age at Early 60s diagnosis (yrs) Median survival 3 yrs

Usual histopathology

Clinical and laboratory characteristics

Extramedullary Plasmacytoma

Solitary Plasmacytoma of Bone

Anaplastic Plasmacytoma

Large-Cell Lymphoma Immunoblastic Plasmacytoid Type

Usually head and neck

Any bone, but most common in axial skeleton

59

50

Visceral organs, subcutaneous tissues, and rarely skin 60s

Lymph nodes, bone marrow, liver, spleen, and rarely skin 60s

7 yrs; patients 7.2 yrs; most often 1.5 to 13 mos most often died died from multiple because of myeloma unrelated causes Increased plasma Sheets of plasma Sheets of plasma Blastic cells (clusters cells in bone cells confined cells in lytic bone or diffuse) in marrow to soft tissue lesions marrow or extramedullary tissue. Cells range from mature to immunoblasts 97% of cases have M-protein rare; M-protein rare; high M-protein typically M-protein in urine low evolution evolution to IgA lambda. Rapid or serum; anemia, to multiple multiple deterioration with hypercalcemia, myeloma. myeloma. constitutional renal insufficiency, Male:female, Minimal male symptoms in increased beta 2 4:1 predominance approximately microlobulin 50% (claimed to be a poor prognostic factor)

tramedullary plasmacytoma and MZL but also for the common pattern of metastases of these neoplasms to adjacent lymph nodes and soft tissues. With the increase in plasma cell differentiation in MZL, along with a concomitant decrease in other MALT-associated components, a continuum of histologic features is produced that may, in some intermediate stages, make it impossible to classify a tumor of MALT lymphoma with plasmacytic differentiation as opposed to a true plasma cell neoplasm. Similar to the Richter transformation that lowgrade B-cell lymphoproliferative diseases may undergo, myeloma, solitary plasmacytoma of bone, and extramedullary plasmacytoma can transform to a morphologically more immature and clinically more aggressive form; anaplastic myeloma.34 This evolution develops months to years after the original diagnosis and is characterized by a morphologic dedifferentiation of the bone-marrow plasma cells to plasmablasts or immunoblasts that may

Occasional long survivors; otherwise not well defined Morphologically not distinguishable from anaplastic plasmacytoma

M-protein typically IgM kappa. Constitutional symptoms in approximately 50%

resemble cells of immunoblastic or plasmacytoid large-cell lymphoma. Unlike the typical localized plasmacytomas, which are, in general, quite responsive to radiotherapy and chemotherapy, patients with anaplastic myeloma are rapidly consumed by their disease, despite aggressive therapeutic efforts (median survival, 3 to 4 years).34 Most afflicted patients have marrow involvement and large tumor burdens (extensive soft tissue involvement and retroperitoneal masses).37 Immunoblastic or plasmacytoid large-cell lymphoma is also a transformation that can occur in the setting of multiple myeloma.37 Tumor characteristics include histomorphologic features that are similar to its aplastic myeloma counterpart, but with predominantly IgM rather than IgG and kappa rather than lambda. Patients with these lymphomas respond more favorably to combined modality treatment and there have been occasional long-term survivors.37

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Human Immunodeficiency Virus and Plasma Cell Disorders

to 16 months despite chemotherapy with or without radiation therapy.

There is an increasing scrutiny being applied to the role of human immunodeficiency virus in the various neoplastic plasma cell disorders. Questions are also raised as to whether plasmacytomagenesis is an acquired immunodeficiency syndrome (AIDS)-associated illness.38 Both immunosuppressed allograft recipients and patients with AIDS can manifest aggressive forms of polyclonal lymphoproliferative disease. A shift in clonality, affected by AIDS-impaired cell-mediated immunity, can follow. A decrease in CD4 and T cells and in the CD4⫹ and/CD8⫹ ratio has been described in examples of Waldenstrom’s macroglobulinemia as well as overt multiple myeloma.38 Plasmacytoma is more frequently diagnosed in human immunodeficiency virus patients than in allograft recipients.38 Impaired immunosurveillance may also explain the aggressive features of plasmacytomas and multiple myeloma in a setting of human immunodeficiency virus infection. The AIDS-related plasmablastic lymphomas of the oral cavity and jaws are a novel category of AIDS-related non-Hodgkin’s lymphomas derived from B cells.39 They have been defined as plasmablastic on the basis of morphologic and immunophenotypic features. The lymphomas involve mucosa and submucosa and there is often ulceration by a diffuse cohesive growth of relatively monomorphic, large neoplastic cells. Apoptotic figures and single-cell necrosis are common. There are only a few lymphocytes to mar the monocellular character of the plasmablastic neoplastic infiltrate. The AIDS-related plasmablastic lymphoma fails to express the most common B-cell–associated antigens, whereas it consistently expresses high levels of plasma-cell–associated markers, including VS38c and CD138/syndecanI.39 About one third of cases also express a monotypic light-chain expression but no patient has shown monoclonal immunoglobulinemia. All of these AIDS-related lymphomas are very aggressive and all are extranodal, initially localized in the oral mucosa, and often involving the gingiva. In the latter stages, or even shortly after primary diagnosis, there are abdominal, retroperitoneal, and other (ovary, bones) organ involvement.39 The prognosis is uniformly very poor with a survival of 1

Other Plasma Cell Lesions in the Head and Neck The ubiquity of plasma cells and related lineages in the head and neck is, in part, accountable for a number of clinicopathologic entities, often unrelated to those in the previous discussion. The lesions are most often clinically and biologically benign; a precis of several follow. Lymph Node Plasmacytomas Most nodal plasmacytomas are attributable to metastases from multiple myeloma or from another extramedullary plasmacytoma. The tumors considered primary in the lymph nodes are rare with fewer than 20 reported cases as of 1997.40 Diagnosis is based on the morphologic and immunophenotypical findings of a localized tumorous collection of monoclonal plasma cells without an associated component of a malignant lymphoma (eg, low-grade B cell lymphoma with plasmacytic differentiation). There is a characteristic immunophenotype expression in 85% of cases (ie, light-chain restriction with a monoclonal heavy chain [10 with IgG, 4 with IgM, and 2 with IgA]).40 Except in unusual and contested cases, the lesions are probably not related to localized or systemic Castelman’s disease. There is also no support for the notion that primary plasmacytomas of lymph nodes are related to other malignant lymphomas. Patients with nodal plasmacytomas have responded well to surgical excision, with or without adjuvant chemotherapy or radiotherapy. Some patients have had paraproteinemia or paraproteinuria, but none have developed multiple myeloma during follow-up periods of varying lengths.40 Three patients have died, however, of disseminated nodal disease (myelomatosis) and two others developed plasmacytomas of bone.40 Parotid Plasmacytoma Extramedullary plasmacytoma of the parotid gland is as rare as solitary plasmacytoma of the mandible. In a worldwide survey of the literature since the publication of the first case in 1965, 12 more examples had been added; eight of which involved the parotid gland.41 Three of the tumors had parapharyngeal extension. Three other pa-

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tients manifested widespread dissemination with death of two of the three. Immunoglobulin Crystallization and Plasma Cell Lesions Plasma cell dyscrasias may have crystallization of immunoglobulins in the rough endoplasmic reticulum of plasma cells where they are synthesized or in the Golgi apparatus where carbohydrate moieties are added to facilitate their secretion through the plasma membrane.42,43 By electron-optic examination, the immunoglobulin crystals manifest a laminar periodicity of 4 to 10 nm and a honeycomb lattice network in crosssection seen during digital imaging.42 The presence of the crystals in any cell other than plasma cells is rare, but as the plasma cell’s storage capacity is overwhelmed the crystals are extruded into the interstitium where histiocytes phagocytose them. The latter, in turn, can become considerably distended and in extreme situations can form masses. There is also an association of crystal-storing histiocytes with low-grade B-cell lymphoplasmacytic neoplasms, multiple myeloma, and immunocytomas of the skin.42 The term immunocytoma is analogous to lymphoplasmacytoid lymphoma and probably also to MZL or mucosa-associated lymphomas of the Revised European American Lymphoma classification.43 There is probably more than one mechanism responsible for the accumulation of the intra-cytoplasmic crystallized immunoglobulin. Variation in size and shape of the crystals speaks to this point.42 When associated with lymphoplasmacytic lymphomas, they can appear as rod-like structures in rough endoplasmic reticulum or in the perinuclear cisternae.42,43 In plasma cell dyscrasias, the crystals may be rectangular, square or finely uniform, or globular. In instances where immunohistochemical studies have been performed, the majority of crystals can be stained using anti-light and/or anti-heavy chains of immunoglobulins.42 They often manifest light-chain restriction. The crystals seem to contain whole or fragmented portions of immunoglobulin and are different from Russell bodies which do not show an internal stratification.42 To date, the crystals have tended to appear in B-cell lymphomas which have a prominent plasma cell differentiation. Although similar crystals may occasionally be found in nonlymphomatous plas-

Table 9. Plasma Cell Mucositis: Presenting Symptoms, Site Distribution and Coexistent Systemic Disease Coexisting Systemic Disease

Presenting Symptoms (n)

Seronegative rheumatoid arthritis Diabetes mellitus Polymyositis

Sore mouth (3) Gingivitis (3) Hoarse voice (9) Dysphagia (2)

Lips (4)

Stridor (2)

Supraglottic larynx (10) Glottic larynx (5) Nose (2) Pharynx (2) Trachea (1)

Raynaud’s phenomenon

Dry cough (1) Dyspnea (1)

Site Distribution (n)

Palate (4) Mouth (3) Gingivae (4)

Data from Smith et al.45

macellular lesions, the frequent reporting of their presence in lymphomas may possibly serve as a marker for these malignancies.43 Plasma Cell Mucosities Plasma cell mucosities, also known as mucous membrane plasmacytosis, is a distinctive upper aerodigestive tract lesion whose name encompasses the clinical and pathologic features that define it.44,45 This disorder is also found in the external genitalia. Smith et al45 reviewed the reported cases that had simultaneous oral and upper airway lesions. Table 9 records the principal clinical features of aerodigestive tract plasma cell mucosities. There is no sex preference and the age range of patients is 32 to 70 years. The lesions show a bright red erythema combined with well-demarcated warty or lobulated surface plaques. There may be a coexisting fissured tongue. Endoscopic examination shows that the most frequently affected site is the supraglottic larynx. It also confirms multiple site involvement in the upper airway and oral cavity. An observed paucity of abnormal clinical laboratory data (serum proteins, anti-neutrophil cytoplasmic antibodies, blood count, serum angiotensin converting enzyme) leaves the substantiation of the diagnosis to the clinical and biopsy finding. The primary histopathologic features are a combination of epithelial hyperplasia and a dense plas-

Plasma Cell Dyscrasias and the Head and Neck

macytic infiltrate in the superficial lamina propria. The epithelium may be psoriasiform or manifest pseudoepitheliomatous hyperplasia. Suprapapillary tinning and dyskeratosis may also be seen. The plasmacellular infiltrate is diffuse, but the plasma cells are not atypical. Secondary ulceration accounts for microabscesses and polymorphonuclear leukocytes. The plasma cells are polyclonal with no kappa or lambda light-chain restriction. IgG plasma cells predominate over IgA. Stains for infective agents are negative. While there is a range of coexistent immunologically mediated and autoimmune disease, no single disease has been consistently associated. There is no history of allergy in most cases. If should be noted, however, that if plasma cell gingivitis (result of hypersensitivity to chewing gum or toothpaste) is included in the spectrum of plasma cell mucosities, other environmental antigens, including bacteria, should be investigated.46 Treatment is not established with a variety of methods including antibiotics, systemic steroids, or CD2 laser resection being used to shrink the lesions. To date, none of the cases have shown signs of disease regression, but long-term survival is good.44,45 References 1. Cremer FW, Goldschmidt H: Multiple myeloma – Current concepts for an interdisciplinary management. J Cancer Res Clin Oncol 2000;136:181-184 2. Batsakis JG: Plasma cell tumors of the head and neck. Ann Otol Rhinol Laryngol 1983;92:311-313 3. Blade´ J, Kyle RA: Nonsecretory myeloma, immunoglobulin D myeloma, and plasma cell leukemia. Hematol Oncol Clin North Am 1999;13:1259-1272 4. Brinch L, Hannisdal E, Foss AA, et al: Extramedullary plasmacytomas and solitary plasma cell tumours of bone. Eur J Hematol 1990;44:131-134 5. Alexiou C, Kau RJ, Dietzfelbinger H, et al: Extramedullary plasmacytoma. Tumor occurrence and therapeutic concepts. Cancer 1999;85:2305-2314 6. Drach J, Kaufmann H, Urbauer E, et al: The biology of multiple myeloma. J Cancer Res Clin Oncol 2000;126:441-447 7. Ryder C, Naclerio RM: Multiple myeloma presenting as proptosis. Ann Otol Rhinol Laryngol 1999;108:211-213 8. Hokamp HG, Grundmann E: Histological grading in clinical staging of plasmacytoma. J Cancer Res Clin Oncol 1983;105107 9. Sukpanichnant S, Cousar JB, Leelasiri A, et al: Diagnostic criteria and histologic grading in multiple myeloma: Histologic and immunohistologic analysis of 176 cases with clinical correlation. Hum Pathol 1994;25:308-318 10. Witt C, Borges AC, Klein K, et al: Radiographic manifes-

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tations of multiple myeloma in the mandible: A retrospective of 77 patients. J Oral Maxillofac Surg 1997;53:450-453 11. Pisano JJ, Coupland R, Chen S-Y, et al: Plasmacytoma of the oral cavity and jaws. A clinicopathologic study of 13 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997;83: 265-271 12. Dimopoulos MA, Panayiotidis P, Moulopoulos LA, et al: Waldenstrom’s macroglobulinemia: Clinical features, complications and management. J Clin Oncol 2000;18:214-226 13. Galieni P, Cavo M, Avvisati G, et al: Solitary plasmacytoma of bone and extramedullary plasmacytoma: Two different entities? Ann Oncol 1995;6:587-691 14. Knowling MA, Harwood AR, Bergsagel DE: Comparison of extramedullary plasmacytomas with solitary and multiple plasma cell tumors of bone. J Clin Oncol 1983;1:255-262 15. Wiltshaw E: The natural history of extramedullary plasmacytoma and its relation to solitary myeloma of bone and myelomatosis. Medicine 1976;55:245-249 16. Liebross RH, Ha CS, Cox JD, et al: Clinical course of solitary extramedullary plasmacytoma. Radiother Oncol 1999; 52:245-249 17. Dimopoulos MA, Moulopoulos A, Delasalle K, et al: Solitary plasmacytoma of bone and asymptomatic multiple myeloma. Hematol Oncol Clin North Am 1992;6:359-368 18. Dimopoulos MA, Kiamouris C, Moulopoulos LA: Solitary plasmacytoma of bone and extramedullary plasmacytoma. Hematol Oncol Clin North Am 1999;13:1249-1257 19. Frassica DA, Frassica FJ, Schray MF, et al: Solitary plasmacytoma of bone: Mayo Clinic experience. Int J Radiat Oncol Biol Phys 1989;16:43-48 20. Chak LY, Cox RS, Bostwick DG, et al: Solitary plasmacytoma of bone: Treatment, progression and survival. J Clin Oncol 1987;5:1811-1815 21. Jackson A, Scarffe H: Prognostic significance of osteopenia and immunoparesis at presentation in patients with solitary myeloma of bone. Eur J Cancer 1990;26:363-371 22. Jyothirmayi R, Gangadharan VP, Nair MK, et al: Radiotherapy in the treatment of solitary plasmacytoma. Br J Radiol 1997;70:511-516 23. Holland J, Trenker DA, Wasserman TH, et al: Plasmacytoma. Treatment results and conversion to myeloma. Cancer 1992;69:1513-1517 24. Corwin J, Lindberg RD: Solitary plasmacytoma of bone versus extramedullary plasmacytoma and their relationship to multiple myeloma. Cancer 1979;43:1007-1013 25. Chiang SK, Canalis RF, Ishiyama A, et al: Plasmacytoma of the temporal bone. Am J Otolaryngol 1998;19:267-273 26. Kanazawa H, Shoji A, Yokoe H, et al: Solitary plasmacytoma of the mandible. Case report and review of the literature. J Craniomaxillofac Surg 1993;21:202-206 27. Bataille R, Sany J: Solitary myeloma: Clinical and prognostic features of a review of cases. Cancer 1981;48:845-851 28. Nofsinger YC, Mirza N, Rowan RT, et al: Head and neck manifestations of plasma cell neoplasms. Laryngoscope 1997; 107:741-746 29. Wuyi L, Schachern P, Morizano T, et al: The temporal bone in multiple myeloma. Laryngoscope 1994;104-675-680 30. Susnerwala SS, Shanks JH, Banerjee SS, et al: Extrameduallary plasmacytoma of the head and neck regions: Clinicopathology and correlation in 25 cases. Br J Cancer 1997;75:921-927 31. Bart R, Frisch B, Fateh-Moghadan A, et al: Histological

140

Batsakis et al

classification and staging of multiple myeloma. A retrospective and prospective study of 674 cases. Am J Clin Pathol 1987;87: 342-355 32. Kapadia SB, Desai Y, Chen VS: Extramedullary plasmacytoma of the head and neck. Medicine (Baltimore) 1982;61:317329 33. Hotz M-A, Bosq J, Schwaab G, et al: Extramedullary solitary plasmacytoma of the head and neck. A clinicopathological study. Ann Otol Rhinol Laryngol 1999;108:495-500 34. Aboulafia DM, Lee RM, Haferman M, Chu FW-K, Fenski M, et al: Extramedullary facial plasmacytomas with anaplastic features. A diagnostic dilemma with implications for treatment. Am J Clin Oncol 1998;21:401-405 35. Mock RM, Neal GD, Aufdemorte TB: Immunoperoxidase characterization of extramedullary plasmacytoma of the head and neck. Head Neck Surg 1987:9:356-361 36. Hussong JW, Perkin SL, Schnitzer B, et al: Extramedullary plasmacytoma. A form of marginal zone cell lymphoma? Am J Clin Pathol 1999;111:111-116 37. Strand WR, Banks PM, Kyle RA: Anaplastic plasma cell myeloma and immunoblastic lymphoma. Clinical, pathologic and immunologic comparisons. Am J Med 1984;76:861-867 38. Vallisa D, Pagani L, Berte R, et al: Extramedullary plasmacytoma in a patient with AIDS: Report of a case and review of the literature. Tumori 1998; 84:511-514

39. Carbone A, Gaidano G, Gloghini A, et al: AIDS-related plasmablastic lymphomas of the oral cavity and jaw: A diagnostic dilemma. Ann Otol Rhinol Laryngol 1999:108;95-99 40. Lin Bt-Y, Weiss LM: Primary plasmacytoma of lymph nodes. Hum Pathol 1997;28:1083-1090 41. Gonzalez-Garcia J, Chufoor K, Sandu G, et al: Primary extramedullary plasmacytoma of the parotid gland: a case report and review of the literature. J Laryngol Otol 1998;112:179-181 42. Suarez P, El-Naggar AK, Batsakis JG: Intracellular crystalline deposits in lymphoplasmacellular disorders. Ann Otol Rhinol Laryngol 1997:106:170-172 43. Prasad ML, Charney DA, Sarlin J, et al: Pulmonary immunocytoma with massive crystal storing histiocytosis. A case report with review of literature. Am J Surg Pathol 1998; 22:1148-1153 44. Ferreiro JA, Egorshin EV, Olsen KD, et al: Mucous membrane plasmacytosis of the upper aerodigestive tract. Am J Surg Pathol 1994;18:1048-1053 45. Smith ME, Crighton AJ, Chisholm DM, Montain RE, et al: Plasma cell mucosities: A review and case report. J Oral Pathol Med 1999;28:183-186 46. Sollecito TP, Greenberg MS: Plasma cell gingivitis. Report of two cases. Oral Surg Oral Med Oral Pathol 1992; 72:690-693