Applied Radiology

CASE SUMMARY:

A 37-year-old male of Eastern European, Jewish ancestry presented to an orthopedic surgeon for pain in his shoulder and neck. A plain radiograph of the right shoulder (figure 1A) showed an extensive, well defined bubbly lesion occupying the medullary cavity of the proximal shaft of the humerus. Expansion of the humeral shaft and endosteal scalloping was noted. MRI of the shoulder and proximal humerus (figures 1B,C) showed the lesion to be confined entirely to the marrow space and to have a mix of low and intermediate signal on both T1 and gradient echo images.

FIGURE 1. (A) Radiograph of the right shoulder shows multiple areas of medullary lucency in the humeral head and proximal shaft. Note the prominent cortical trabeculations in the shaft and the endosteal scalloping. (B,C) Coronal T7-weighted MR images of the right proximal humerus show multiple well defined lesions of low to intermediate signal of the humeral head and proximal shaft. The lesions are confined entirely to the marrow space.

Additional history revealed that the onset of shoulder (and neck) pain occurred acutely while the patient was "rough-housing" with one of his children. At the request of the radiologist, a cervical MR examination was performed, and an acute C-6 disc herniation was encountered. During subsequent anterior discectomy and cervical fusion, an open biopsy of the humeral lesion was performed.

Pathologically, the lesion consisted of small fragments of yellowish-brown-to-red soft tissue. Histologic sections demonstrated a xanthomatous lesion with large, foamy macrophages interspersed with areas of normal marrow elements (figure 2A). The iron stain was strongly positive. An electron microscopic study showed numerous intracytoplasmic twisted tubules consistent with Gaucher cells (figure 2B).

FIGURE 2. (A) Histologic section showing the bone marrow space filled with cells of 20 to 100 microns in diameter with "wrinkled tissue paper" cytoplasm, characteristic of Gaucher cells (hematoxylin and eosin, 400X). (B) Electron micrograph of a Gaucher cell containing intracytoplasmic deposits of twisted membranous bilayers measuring 60 nanometers (uranyl acetate and lead citrate 31,000X).

DIAGNOSIS:

Gaucher disease.

The radiologic differential diagnosis suggested a variant of fibrous dysplasia. The lesions were too well defined for a malignancy such as leukemia, lymphoma, or metastatic disease to be considered. A skeletal survey showed numerous well-defined, lytic lesions within the long bones, identical to those encountered in the humerus. Despite the multiple skeletal lesions, the patient remains asymptomatic from his disease.

DISCUSSION:

Gaucher disease is one of the lipid storage disorders that also includes Niemann-Pick disease and TaySachs disease. It is a rare familial disorder that is inherited as an autosomal recessive trait and affects males and females equally. The condition was originally described by Gaucher in 1882 as a chronic progressive disorder that produced hepatosplenomegaly. ^1,2 The disease is now recognized to be the result of a disorder of cerebroside metabolism in which a deficiency of the enzyme glucocerebroside hydrolase produces excess deposits of lipid materials within the macrophages of the reticuloendothelial system. ^2,3 The affected cells, referred to as Gaucher cells, are 20 to 100 microns in diameter, are found predominantly in the liver, spleen, and bone marrow, and have a cytoplasm that stains pale pink with PAS and pale blue with Mallory analine blue stain. Characteristically, the cytoplasm either has a foamy appearance or has the appearance of "crumpled tissue paper" (figure 2A). Iron deposits also are commonly found in the cells. On electron microscopy, intracytoplasmic deposits of twisted membranous layers can be found (figure 2B); these are considered characteristic of the Gaucher cell. ^4,5 Proliferation of Gaucher cells within the liver, spleen, and lymph nodes produces hepatosplenomegaly and lymphadenopathy, respectively. Other infiltrations occur in the kidneys, lungs, thyroid, adrenals, and bone marrow. It is the marrow involvement that produces the characteristic bony lesions. ²

Three clinical forms of Gaucher disease are recognized: type 1, termed the "adult" or chronic nonneuropathic form, is most common. There is a predominance, although not exclusive, among Jews of Ashkenazic heritage. Patients with this form of the disease often present in the first decade of life with symptoms referable to splenomegaly. Occasionally, as in the case we present here, the symptoms are so mild that diagnosis is delayed until the third or fourth decade of life. In the more typical case, the replacement of hematopoietic cells with Gaucher cells produces various degrees of anemia, leukopenia, and/or thrombocytopenia which often are relieved by splenectomy. ² While 75% of these patients have radiographically demonstrable skeletal lesions, only about one-third show symptoms. ^2,6-8

Type II, the "infantile" or acute neuropathic type, is generally fatal within two years of onset. ³ This form has no ethnic predilection and generally presents within the first six months of life. There are a large number of neurologic manifestations, including mental retardation, strabismus, seizures, and spasticity. Hepatosplenomegaly also may be present. ^2,3 Skeletal manifestations are rare.

Type III, the "juvenile" or subacute neuropathic form, is the rarest form and is characterized by hepatosplenomegaly and delayed onset of neurologic and skeletal manifestations. ^2,3

Radiographically, the long tubular bones (especially the femur), vertebral column, hip, shoulder, and pelvis are the most frequently involved sites. Infiltration of the marrow spaces with Gaucher cells and resorption of bony trabeculae result in osteopenia and patchy lytic areas, with foci of reparative bony sclerosis (figure 1). Pathologic fractures are known to occur in these areas. Bone marrow infiltration and endosteal cortical erosion frequently produce modeling deformities that result in the "Erlenmeyer flask" appearance of the distal femur, one of the most characteristic bony manifestations of the disease. The epiphyses in adjacent joints are usually spared. Findings are often bilateral. ^2,3,6-8 In the vertebral column, infiltration of the central marrow frequently results in a "fish-type" deformity of the vertebrae similar to that seen in sickle-cell disease and other hemoglobinopathies. ^2,8 Ischemic necrosis may occur, particularly in the femoral and humeral heads.

Occasionally, the diagnosis of Gaucher disease may be made when the skeletal manifestations are found as an incidental finding, as in this case. A careful search of the patient's medical history should reveal some evidence of hepatosplenomegaly. Our patient related an episode of blunt abdominal trauma twenty years previously, during which time hepatosplenomegaly was found. This reminds us to be cognizant of the old dictum which states that patients are allowed to have more than one disease at the same time.

A variety of neoplastic, hematologic, and metabolic disorders, including metastatic disease, solitary or multiple myeloma, leukemia, sickle-cell disease, and fibrous dysplasia should be considered in the differential diagnosis. ² Since the radiographic manifestations overlap so many other disorders, Gaucher disease should be considered in patients who have hepatosplenomegaly combined with osteopenia with a coarsened trabecular pattern, focal osteosclerosis, Erlenrneyer flask deformities of the distal femora, and ischemic necrosis of the femoral heads. ² CT-guided biopsy of one or more skeletal lesions may be necessary to confirm the diagnosis. The histologic features, particularly the electron microscopic picture, is considered characteristic.