Introduction
Solitary plasmacytomas are tumors of plasma cell origin
that constitute less than 10% of all plasma cell neoplasms. These tumors
are categorized as extramedullary plasmacytomas (non-osseous) or solitary
plasmacytomas of bone (osseous). Extramedullary plasmacytomas frequently
remain localized and usually can be treated effectively with radiation
therapy, whereas solitary plasmacytomas of bone frequently convert to multiple
myeloma.
We report an unusual presentation of solitary plasmacytoma
involving the cervical vertebrae and left petrous bone in a patient with dysphagia. Following radiation therapy and adjuvant chemotherapy,
the patient improved clinically and his monoclonal spike disappeared.
Sixteen months later, however, he progressed to multiple myeloma and presented
with lytic lesions in his right hip and femur.
Case Report
A 68-year-old man with a medical history significant
for coronary artery disease, hypertension, and cigar smoking sought medical
assistance in November 1996 for neck pain that he attributed to arthritis
in his neck. Radiological examination showed considerable degenerative
disease at the level of C5-6 and C6-7 vertebrae, and he was placed on a
physical therapy program. The neck pain continued into the spring, and at the same time, he gradually
developed progressive difficulty with swallowing over a duration of four
weeks. Evaluation for dysphagia was in progress when he developed complete
inability to swallow and was brought to the emergency room. Review of systems
revealed a weight loss of 27 lbs in four weeks, slurred speech for the
previous two weeks, but no other systemic complaints. Personal history
was negative for alcoholic abuse.
Pertinent findings on physical examination included
mild tenderness on the posterior aspect of the neck and limited range of
movement of the cervical spine. The pharynx had pooled secretions, but
no obvious lesion or bulging of nasopharyngeal or oropharyngeal walls was
seen. The thyroid was not enlarged. Neurological examination demonstrated
an absent gag reflex, paralysis of the vocal cords, protrusion of the tongue
to the left, and slurred speech. The remainder of the cranial nerves were
intact. Motor and sensory examination of the limbs was unremarkable, deep
tendon reflexes were +2, and gait was normal.
Laboratory studies revealed mild anemia (hemoglobin
level, 13 g/dL), normal white blood cell and platelet counts, serum creatinine
of 1.9 mg/dL, elevated serum calcium of 11.5 mg/dL, total serum protein
of 7.9 g/dL, and lactate dehydrogenase of 482 IU/L. Serum immunoelectrophoresis
showed a monoclonal IgG spike (Table 1). Agarose electrophoresis and immunofixation
studies of the patient’s urine revealed the presence of free kappa (Bence-Jones)
protein migrating in the gamma region with an estimated concentration of
124 mg/dL.
Table 1. -- Results of Serum
Immunoelectrophoresis |
| Immunoglobulin |
Results |
Normal Values |
| IgG |
1946 |
800-1700 mg/dL |
| IgA |
35 |
100-490 mg/dL |
| IgM |
<29 |
50-320 mg/dL |
A modified swallowing study showed an abnormal oral
phase and weakening of the pharyngeal constrictors. These resulted in a
buildup of thickened liquid in the pyriform sinuses that could not be propelled
into the esophagus. Radiographs of the soft tissue of the neck showed no
evidence of a soft-tissue mass.
Magnetic resonance imaging (MRI) revealed a large
mass involving the base of the skull on the left extending into the left
petrous bone and clivus (Figs 1A-B). The mass appeared to extend to the
cervical spine at the level of C1-2 with narrowing of the ventral aspect
and slight posterior displacement of the lower brainstem and proximal cervical
cord. The majority of the mass appeared to be extracranial. It was thought
to be most likely a metastatic lesion, but a primary malignancy could not
be excluded. Computed tomography scan of the neck showed the same mass
identified on the MRI. This mass was primarily situated in the left parapharyngeal
space with involvement of the posterior triangle on the left. Bone windows
demonstrated destruction of the left petrous bone, lateral aspect of the
body of C1, and the pedicle of C2. There appeared to be involvement of
the left posterolateral nasopharyngeal and upper oropharyngeal walls, with
no obvious adenopathy.
Long bone survey showed merely normal variations
in bone density. Laryngoscopy revealed a normal-appearing larynx with immobile
vocal cords. Esophagoscopy was normal except for some brown material refluxing
from the stomach. Bronchoscopy was unremarkable, and a biopsy of the underlying
soft tissue at the level of the uvula showed sheets of plasma cells consistent
with a diagnosis of a plasmacytoma.
Bone marrow contained 4% plasma cells and no evidence
of metastatic tumor or granuloma. The patient appeared to have a solitary
plasmacytoma of bone (left petrous bone and the clivus extending to the
cervical spine at the level of C1-2) at the time of initial staging, which
resulted in lateral medullary syndrome.
The patient was given a course of radiation therapy
to the upper parapharyngeal tissues and the base of skull to a total dose
of 48.6 Gy. Although there were no lytic lesions on skeletal imaging studies,
he also subsequently received chemotherapy (melphalan and prednisone) to
achieve the highest likelihood of long-term control. The treatment resulted
in markedly improved swallowing, better voice quality, and a reduction
of the IgG peak to 1335 mg/dL. A follow-up MRI showed a significant reduction
of abnormalities at six months. Follow-up studies after one year revealed
stability of myeloma protein level and an unchanged MRI.
In March 1998, the patient returned with a pathological
fracture of the right femur, back pain localized to the upper lumbar and
lower thoracic spine, and fatigue. Swallowing and vocalization were normal.
Laboratory findings included anemia (hemoglobin, 9.1 g/dL), hypercalcemia
(10.2 mg/dL), elevated serum creatinine (8.7 mg/ dL), serum total protein
of 6.5 g/ dL; platelet count of 109,000/mm3, white blood cell
count of 4,200/ mm3, and lactate dehydrogenase of 714 IU/L.
Serum immunoelectrophoresis showed a monoclonal peak
of 2161 mg/dL of IgG (IgA = 33 mg/dL, IgM = 41 mg/dL). Radiographic skeletal
survey showed mild demineralization of the skeleton and a large lytic defect
in the lesser trochanter and subtrochanteric portion of the right femur.
Bone marrow showed 60% plasma cells (Fig 2). Internal fixation was performed,
and palliative radiation therapy (4 Gy x 5 fractions) was given to the
lesion in the proximal right femur.
Discussion
The incidence of multiple myeloma is approximately 3.5
per 100,000 people per annum, with a median age at diagnosis of 69 years.
1
Solitary plasmacytomas constitute less than 10% of all plasma cell neoplasms
2
with a slightly lower median age of approximately 63 years.
1
Most patients with solitary plasmacytomas are men, with a reported man-to-woman
ratio of 3:1. Approximately half of these patients have a monoclonal gammopathy
detected on serum or urine electrophoresis.
3
Plasmacytoma is further classified into two groups:
osseous and non-osseous (extramedullary) primary lesions. Osseous lesions
constitute approximately 70% of all plasmacytomas. They involve primarily
marrow-containing bones, with a predilection for the vertebrae, femurs,
and pelvis. Of the extramedullary lesions, approximately 80% occur in the
head and neck region and frequently involve the upper respiratory tract.3
In patients with solitary plasmacytomas, progression
to multiple myeloma is common, and approximately 5% of all patients with
multiple myeloma have an initial diagnosis of solitary plasmacytoma.3
Moreover, studies have shown a higher tendency for multiple myeloma to
develop in patients with osseous tumors compared to those with extra-medullary
tumors.4 The prognosis after progression to multiple myeloma
is also poorer for osseous plasmacytoma than for extra-medullary plasmacytoma
as evidenced by multiple retrospective studies. These differences suggest
a difference in the biological behavior of the two types of tumor,
which is further augmented by immunohistochemical staining and flow cytometry
analysis. The biological differences found in such studies include higher
population of aneuploid cells, proliferating cell-nuclear antigen index,
and S-phase fraction.4-6
Prognostic factors that are harbingers for ultimate
conversion into multiple myeloma include lesion size (a large-sized lesion
correlates with a more ominous prognosis), total serum protein levels,
and the presence of a monoclonal spike on serum electrophoresis. The persistence
of myeloma protein after radiation can serve to identify patients who are
at high risk of early progression.5,7 MRI studies can detect
patients with occult myeloma.8,9
Due to the difficulty in predicting survival, patients
with an apparently solitary plasmacytoma of bone deserve aggressive radiotherapeutic
and appropriate orthopedic management. Radiation therapy is the primary
modality of treatment. The recommended dose of radiation is 50 to 60 Gy
in five to seven weeks.10-12 Surgical intervention may include
fixation of pathologic fractures,
prophylactic fixation to prevent fracture, and decompression and stabilization
of spine lesions.13
The use of adjuvant chemo-therapy for osseous plasmacytoma
may prevent progression to multiple myeloma.14 Holland et al15
found that adjuvant cytotoxic therapy delayed the median time of progression
from 29 months to 59 months, but this did not affect the overall rate of
progression to myeloma or the survival rates after the development of myeloma.
Adjuvant chemotherapy may be beneficial in patients with either persistent
myeloma protein or nonsecretory disease who are at a high risk for developing
multiple myeloma. Many prognostic factors have been suggested, but none
has clearly predicted the ultimate conversion to multiple myeloma. Immunohistochemical
markers and flow cytometry analysis may enable the use of cytotoxic therapy
on a more selective basis. Any advantage incurred by a delay in progression
to multiple myeloma must be compared with the side effects of chemotherapy
involving an alkylating agent that can be leukemogenic.14-17
Interferon alpha has shown promise in the clinical
activity in newly diagnosed disease18 and may prolong remission
time.19 The role of interferon alpha in selected patients who
are most likely to progress to multiple myeloma after radiotherapy for
osseous solitary plasmacytoma requires further investigation.
The involvement of the nervous system is a common
complication of plasma cell neoplasms. Cranial myelomas (osseous, such
as skull bones) and intracranial myelomas (other than bones, ie, extramedullary,
such as hypothalamus) can be broadly classified into three clinical groups10,20
as shown in Table 2.
Table 2. -- Involvement of
Nervous System in Plasma Cell Neoplasms |
| Group |
Syndrome |
Involvement |
Clinical Picture |
| I |
cranial nerve palsies |
base of the skull |
single or multiple cranial nerve palsies |
| II |
intracranial tumor |
- cranial myeloma extending intracranially |
similar to a primary brain tumor |
| - lesions that are entirely intracranial |
| III |
intraorbital tumor |
orbit |
orbital space-occupying lesion |
This patient falls into clinical group I suggesting
cranial myeloma that involved the left petrous bone and cervical vertebrae.
This caused dysphagia secondary to lateral medullary syndrome and resulted
in paralysis of the 10th and 12th cranial nerves. Lateral medullary syndrome
is one of the brainstem vascular syndromes that occur due to the occlusion
of posterior inferior cerebellar artery or one vertebral artery, which
may lead to dysphagia, vertigo, vomiting, ipsilateral paralysis of soft
palate, ipsilateral Horner’s syndrome, ipsilateral hypotonia and ataxia,
and dissociated sensory loss. The body of the sphenoid and the apex of
the petrous bone are the most common sites of involvement. The tumors may
be either small or discrete, or they may grow to large dimensions. These
lesions have a greater tendency to expand locally rather than to disseminate,
a property that may be controlled by specific cytokines.7 The
bone is probably the site of origin; however, they may arise from mucosa
contained within the sphenoid and petrous bones, since non-osseous myelomas
are common.
The cranial nerves can be affected either by local
distortion or by direct destruction, such as that which occurs with invasion
of the cavernous sinus or jugular foramen region, or the effect could be
secondary to a "toxin" and therefore similar to the polyneuritis that occurs
in approximately 5% of patients with myelomatous diseases (POEMS). POEMS
is an acronym applied to the constellation of clinical findings in addition
to polyneuropathy in which M designates the presence of the monoclonal
protein: P = polyneuropathy, O = organomegaly (hepatomegaly and adenopathy),
E = endocrinopathy (decreased testosterone level, hypercalcemia, impotence,
hyperprolactinemia, hyperglycemia), M = monoclonal protein, and S = skin
lesion (hyperpigmentation, white nails, and hypertrichosis). The neuropathy
is chronic and slowly progressive and appears to be an axonopathy with
secondary demyelination. High titers of anti-MAG (myelin-associated glycoproteins)
are seen in patients with neuropathy. Effective radiotherapy of solitary
plasmacytomas may be accompanied by the reversal of neuropathy in addition
to the nonneurological manifestations of the disease. Similar but less
dramatic effects also have been achieved in patients with disseminated
disease treated with chemotherapy. Involvement of the 5th, 6th, and 8th
cranial nerves is most common.10,20
The differential diagnosis for our patient’s presentation
includes nasopharyngeal carcinoma, extra-sellar extension of a chordoma,
primary malignant neoplasm of sphenoid or petrous bone, metastatic carcinoma,
or eosinophilic granuloma as well as a plasmacytoma. In patients with solitary
plasmacytoma, the 10-year survival is approximately 70%. Approximately
20% develop recurrence by 2 years, and 85% develop multiple myeloma by
10 years. Those who do not progress to myeloma tend to be younger and have
disease in the spine.5,6,11
Conclusions
Our case is unique in its presentation in which a 68-year-old
man presented with dysphagia secondary to a plasmacytoma. In addition to
radiotherapy, he also underwent adjuvant chemotherapy, but even then, he
progressed to multiple myeloma in 16 months. This further underlines the
higher tendency for multiple myeloma to develop in patients with osseous
plasmacytoma, thereby suggesting a difference in the biological behavior
compared to extramedullary plasmacytoma and the failure of chemotherapy
to delay the time to progression.
We suggest that when cranial nerve symptoms similar
to those we observed are associated with lesions in cervical vertebral
bodies or the petrous bone, a solitary plasmacytoma should be considered
in the differential diagnosis. Further clinical, biochemical, and radiological
follow-up of such patients is necessary since the presence of an osseous
solitary plasmacytoma is a harbinger of ultimate development of multiple
myeloma. A definitive analysis of prognostic factors including immunohistochemical
markers, flow cytometry analysis, and therapeutic modalities, particularly
chemotherapy, needs to be conducted on a multi-institutional basis.
Appreciation is expressed to Joe Pallus, librarian at St. Francis
Hospital, Hartford, Connecticut, for his help in providing the medical
literature and to Joyce Fritz and Charlotte Soderberg for their invaluable
assistance in preparation of this manuscript.
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