Bone Manifestations of Hematologic Disorders

Bone Manifestations of Hematologic Disorders LELAND E. KELLERHOUSE, M.D. * LOUIS R. LIMARZI, M.D., F.A.C.P.**

The skeletal system is just one of the many organs affected by various hematologic disorders. Since most blood disorders by virtue of their pathogenesis are widespread, it is not surprising to see the many various types and locations of bone lesions. Although generally not necessary for diagnosis, x-ray changes can be helpful in evaluating the progress or treatment of these diseases. It is, therefore, necessary to understand the various bone manifestations to help the physician administer optimal care of his patient. The blood dyscrasias associated with skeletal involvement are listed in Table 1.

BONE MANIFESTATIONS OF ANEMIA

Anemias produce bone changes because high red cell turnover with consequent marked erythroid hyperplasia exists over an extended period of time. The degree of bone change seems to be directly related to age of onset, duration, and severity of erythroid hyperplasia (Fig. 1). Anemias associated with marked chronic erythroid hyperplasia are the hereditary hemolytic anemias, i.e., sickle cell disease, hereditary spherocytosis and thalassemia. Iron deficiency anemia of infants may demonstrate bony From the Department of Medicine, University of Illinois College of Medicine and Research and Educational Hospitals of the University of Illinois * Research Assistant in the Department of Medicine, University of Illinois College of Medicine; U.S.P.H.S. Fellow in Cancer Chemotherapy ** Professor of Medicine, University of Illinois College of Medicine; Attending Staff and Hematologist, Augustana Hospital, Chicago, Illinois Aided by grants from the National Institute of Health: CYP-4912, Midwest Cooperative Chemotherapy Group and CYP-4985, Acute Leukemia Cooperative Chemotherapy Study Group A

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Table 1.

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Blood Dyscrasias Associated with Skeletal Involvement

A. Anemia 1. Congenital aplastic anemia (Fanconi syndrome) 2. Hereditary hemolytic anemias a. Sickle cell disease b. Thalassemia c. Hereditary spherocytosis 3. Iron deficiency anemia of infancy B. H emophilia 1. Antihemophilic globulin deficiency 2. Plasma thromboplastic component deficiency 3. Plasma thromboplastic antecedent deficiency

C. Reticuloendothelial Malignancie8 1. Acute leukemia 2. Hodgkin's disease 3. Lymphosarcoma a. Giant follicle lymphosarcoma b. Small cell lymphosarcoma c. Reticulum cell sarcoma 4. Plasmacytic myeloma (multiple myeloma) D. Primary Reticulum Cell Sarcoma of Bone E. Myel08clerosis F. Osteopetr08is (Alber8-Schonberg's disease or marble bone disease) G. Reticuloendotheli08e8 1. Histiocytosis X a. Eosinophilic granuloma b. Schuller-Christian disease c. Letterer-Siwe's syndrome 2. Gaucher's disease 3. Niemann-Pick's disease H. M i8cellaneou8*

Felty's syndrome-Still's disease; secondary gout; polycythemia-primary and secondary; thrombocythemia, infectious mononucleosis; amyloidosis and arthritis; Henoch-Schoenlein purpura

ment.

* Many of these conditions have bone or joint symptoms without bone involve-

lesions secondary to erythroid hyperplasia but to a lesser degree than the hemolytic anemias. The bone changes in iron deficiency anemia of adulthood or pernicious anemia are not usually evident since bone formation has taken place long before the disease becomes manifest. Increased erythroid hyperplasia does occur, of course, and some conversion of fatty to red marrow takes place but generally not enough to cause significant bone changes. Since the degree of bone change is related to erythroid hyperplasia, a more critical look at the pathogenesis is warranted. As erythroid hyperplasia increases, the medullary portion of the bone increases, usually with a diminution of cortical thickness; this gives the roentgenologic appearance of a swollen, radiolucent marrow cavity with a thin cortex and altered trabecu-

BONE MANIFESTATIONS OF HEMATOLOGIC DISORDERS

~

Childhood

~

Adulthood

•

Infancy

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Characteristic location of bone lesions in hemolytic anemias according to age

Figure 1. This figure demonstrates the bony areas likely to be affected for a given age group in thalassemia major. Although other hemolytic anemias have less severe bone changes, the pattern of progression is the same.

lar pattern (Fig. 2). These changes usually occur in areas of most active erythropoiesis consistent with the patient's age. Since the age of onset influences the degree of bone change, all of the hereditary hemolytic anemias may demonstrate changes as early as infancy. The most marked changes in infancy are in the small tubular bones of the hands and feet, in early childhood the skull, and in late childhood and adulthood the pelvis and spine (Fig. 1). These areas correspond to the most active areas of hemopoiesis for a given age group. The degree of bony change depends upon the severity of the anemia. Therefore, the radiologic bone changes are more pronounced in thalassemia major than in hereditary spherocytosis (Table 2).

Thalassemia Major Usually the skeletal changes are not evident clinically or by x-ray until after the first year of life. 35 The first changes, noted in infancy, are medullary widening and cortical thinning of the metatarsals and metacarpals. The trabecular pattern appears coarse, often producing a honeycomb appearance on x-ray (Fig. 2). In early childhood similar changes are

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Figure 2. Thalassemia major. There is generalized overgrowth of bone and soft tissue with trabecular coarsening and cortical thinning to give a honeycomb pattern to the bones of this hand. Although this is a 5 year old child, one could expect changes of this degree as early as infancy.

Table 2.

Comparison

of Various Bone Changes Among the Anemias SICKLE CELL DISEASE

SPHEROCYTOSIS

IRON DEFICIENCY ANEMIA OF INFANCY

4+

3+

2+

+

3+ 3+ 2+ 2+ 3+

2+ 3+

2+

+

2:

±

±

±

THALASSEMIA

1. Anemia ................ 2. Osteoporosis a. Skull ............... b. Spine and pelvis .. c. Long bones .......... d. Hands and feet ...... e. Facial bones ....... 3. Periosteal reaction .... 4. Bone infection of femoral and humeral heads ................. 5. Cortical thickening of long bones ...........

3+ 2+ +

±

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noted in the skull with widening of the diploid space, thinning and outer displacement of the outer table, and rearrangement of the trabecular pattern to give a "hair-on-end" appearance. Skull changes are the most frequent radiologic bone changes found in all hereditary hemolytic anemias. Medullary widening and cortical thinning in the humerus, femur and spine producing kyphosis, scoliosis or saber shins also occur in early childhood. Facial abnormalities produced by bone changes are a characteristic feature of thalassemia. 7 Incomplete pneumatization of the sinuses may occur from the marked medullary swelling. Enlargement of the medullary space of the maxillary bones produces malocclusion and "rodent facies," seen in early adult thalassemia. These changes rarely occur in sickle cell disease, spherocytosis, or iron deficiency anemia of infancy. In late childhood and adulthood the skull, spine and pelvis demonstrate progressive, more osteoporotic involvement concurrent with less and less involvement of the peripheral skeleton as a patient matures. 7 This is consistent with the normal decrease of active marrow in the peripheral skeleton concurrent with the normal increase of active marrow in the central skeleton (Fig. 1). In the above outline we have spoken of the most severe changes noted in thalassemia major. The bone changes in thalassemia minor are correspondingly less severe and tend to vary in degree as the severity of the anemia. Hereditary Spherocytosis

Hereditary spherocytosis demonstrates the least severe bone changes of the hereditary hemolytic anemias, probably because the severity of the anemia is, in general, the least. These changes are similar but less severe than those in thalassemia and are usually confined to the skull. Ultimately, malformation such as a tower-shaped skull or central skeletal changes may occur.21 Following splenectomy, the bony lesions may improve. 49 Although splenectomy does not correct the basic defect of the spherocytic red cell, the hemolytic process is markedly reduced, red cell production is correspondingly reduced, and medullary bone mass shrinks. Iron Deficiency of Infancy Iron deficiency may produce skull changes in the infant similar to those of spherocytosis and thalassemia. Facial and long bone changes, however, have not been reported in this condition. 85 Sickle Cell Disease

A discussion of sickle cell disease has not been presented until now, since in addition to the medullary widening from erythroblastic hyperplasia, changes from ischemic necrosis are also found. Medullary widening produces bone changes similar to those seen in thalassemia and spherocytosis, i.e., tower-shaped skull, kyphosis, scoliosis and saber shins. Thrombosis and/or

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Figure 3. A, Sickle cell disease. Healed osteomyelitis in the fibula demonstrating marked deformity (arrow). B, Sickle cell disease. Salmonella osteomyelitis of tibia and fibula demonstrating marked bone reaction and deformity.

bone infarction from either thrombus formation of sickled cells or decreased oxygen-carrying power of sickled red cells produces lesions of ischemic necrosis which differ from those seen in the other hemolytic anemias. The earliest bone changes result from ischemia and consist of periosteal elevation of the metatarsals and metacarpals of infants.·5 Roentgenologic evidence often occurs several days after soft tissue swelling of the hands and feet. These changes are similar to those seen in periosteal tuberculosis, syphilis, osteomyelitis, hypervitaminosis A, Caffey's infantile cortical hyperostosis, and trauma, which must therefore be ruled out; however, the occurrence of periosteal elevation in a Negro infant should alert the physician to the possibility of sickle cell disease. In children severe periosteal reaction in the larger tubular bones often occurs (Fig. 3, A). This may be difficult to differentiate from osteomyelitis save for sterile blood cultures and less prolonged toxic manifestations, i.e., fever and leukocytosis. 6 .16 The increased frequency of salmonella osteomyelitis in sickle cell disease further complicates this differentiation (Fig. 3, B).15. 24 In early childhood a ground-glass appearance of the skull may occur. Later, trabecular changes produce the "hair-on-end" appearance, and still later, thickening of the diploe occurs.

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In late childhood and early adulthood bone infarctions tend to involve the ends of large bones near the weight-bearing surfaces. The lesions are initially lytic, but owing to their location they become sclerotic and secondary hypertrophic arthritic changes eventually occur. Other changes resembling aseptic necrosis of the femoral or humeral head also occur and may not be different from the appearance seen in Legg-Perthes' disease or Gaucher's disease. A differentiating point, however, is that the long bones of late childhood sickle cell disease often demonstrate diffuse cortical thickening coupled with medullary narrowing. This finding of aseptic necrosis associated with cortical thickening of the long bones is almost exclusively associated with sickle cell disease or one of the sickle cell variants such as S-thalassemia or SC disease. Aseptic necrosis is reported to occur more frequently in SC than in SS disease ;40 however, this may be a function of the normal attrition of SS disease patients. The SC patients, with a less severe disease, live longer and have a much greater chance of developing aseptic necrosis than do those patients with SS disease who generally have a shorter life span. A final important bone change is osteoporosis of the spine associated with cupping of the superior and inferior surfaces of the vertebral bodies secondary to pressure from the nucleus pulposus. 85 Osteoporosis of the spine is also noted in hereditary hemolytic spherocytosis and in thalassemia but does not have vertebral cupping. BONE MANIFESTATIONS OF HEMOPHILIA

Of the various types of bleeding disorders, hemophilia is generally associated with bone and joint changes. There are three types of hemophilia, but only two are severe enough to manifest osteoarticular changes. These are antihemophilic globulin deficiency (AHG) or classical hemophilia and plasma thromboplastin component deficiency (PTC) or Chr~stmas disease. Plasma thromboplastin antecedent (PTA) deficiency rarely involves bones. AHG deficiency comprises most of hemophiliacs, whereas PTC deficiency makes up a smaller percentage. Of the various clinical manifestations of bleeding, hemorrhage into joints is the most characteristic occurrence. The probability of hemorrhage is most likely when the clotting factors are at their lowest levels. The onset is usually sudden and characterized by a warm, painfully swollen joint often fixed in a position of flexion. 60 After repeated intra-articular hemorrhages, permanent joint deformities occur. Only a rare patient reaches adulthood without some joint changes, frequently referred to as hemarthrosis (Fig. 4). The severity of joint deformity is proportional to the degree of clotting factor deficiency. Joint hemorrhages may be precipitated by minor trauma or severe stress. The knees, elbows and ankles are most frequently affected.

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Figure 4. Plasma thromboplastin component (PTC) deficiency. Osteoporosis, trabecular coarsening and enlargement of the epiphysis with thickening of the periarticulal soft tissues are apparent in the left knee (arrows in A and C). Frontal and lateral view of right knee (A and B) are normal.

Initial hemorrhagic episodes are associated with incomplete absorption of blood which results in chronic synovitis8 • 29 and compression of adjacent soft tissues. No bony abnormalities are noted at this stage. Subsequent episOdes of hemorrhage produce villous hyperplasia and subsynovial fibrosis. The thickened synovial membrane causes cartilage destruction followed by subchondral bone erosion and narrowing of the interosseous space. Eventually, multiple juxta-articular cysts and osteophytes develop in the weightbearing joints. 52 These changes are demonstrable on x-ray but are not specific for hemarthroses. The arthropathy of rheumatoid arthritis andhemophilia are quite similar. Some lesions are considered almost specific for hemophilic arthropathy, i.e., chronic hyperemia produces premature ossification of the epiphyses and is most frequently seen at the head of the radius.8& Osteoporosis of the epiphyses is seen in hemophilia (Fig. 4), but this may also occur in rheumatoid and tuberculous arthritis. Genu hemarthrosis at an early age often

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produces a characteristic "squared-off" patella. 28 Subperiosteal and intraosseous hemorrhages may occur which may ultimately lead to destructive changes. BONE MANIFESTATIONS OF RETICULOENDOTHELIAL MALIGNANCIES

Acute Leukemia Skeletal lesions are a frequent complication of acute leukemia. They are usually manifested as bone joint pain which mayor may not be associated with various x-ray changes. Bone pain is a presenting complaint in about 8 per cent of cases. 5 It is virtually never reported with marked hypercalcemiaj however, the following case of leukemia is unusual in that the disease first masqueraded as a primary metabolic disorder of bone. PATIENT G.S: A 15 year old white boy presented with a 5-month history of progressive anorexia, nausea, vomiting, weakness, abdominal pain, polyuria, polydipsia and mildly refractory anemia associated with bone pain and severe back pain secondary to generalized osteoporosis of the central and peripheral skeleton (Fig. 5). Physical examination revealed a markedly emaciated male with a barely

Figure 5. Acute leukemia (Patient G.S.). The intervertebral BpaceB are wider than the vertebrae (arrow) due to marked oBteoporoBiB, cupping and narrowing of the vertebral bodies.

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Figure 6. (patient G.S.). Acute leukemia. A, A transverse radiolucent line (arrows) extends across the metaphysis of all the long bones adjacent to the epiphyseal plate as shown in this distaI tibia.. B, Bone marrow biopsy demonstrating densely packed marrow consisting mostly of blast cells. (Hematoxylineosin, X500.) palpable spleen. Blood counts were normal save for a mild anemia and slight lymphocytosis. Moderately severe hypercalcemia and hypercalciuria were prsesnt with normal serum phosphorus and alkaline phosphatase levels. X-rays of the lower extremities demonstrated a radiolucent band proximal to the metaphysis (Fig. 6, A). Bone marrow could not be successfully aspirated, but bone biopsy revealed a thin cortex with a marrow packed with blast cells (Fig. 6, B). Shortly before institution of treatment the peripheral blood demonstrated a rare blast cell (Fig. 7, A) and occasional normoblasts with normal blood platelets. The patient was started on 6-mercaptopurine and prednisone with prompt reversal of symptoms and normalization of the bone marrow within a month (Fig. 7, B).

Comment. This case is cited to illustrate an unusual presentation of acute leukemia. The gastrointestinal symptoms, polyuria, and polydipsia associated with generalized osteoporosis, hypercalcemia and hypercalciuria suggested hyperparathyroidism as a probable diagnosis. However, the normal serum inorganic phosphorus and normal alkaline phosphatase tended to rule against hyperparathyroidism. The mild anemia, barely palpable spleen and the proximal metaphyseal radiolucent band (Fig. 6, A) were the only clues to a possible acute leukemia. Marrow could not be aspirated because it was packed with blast cells. Biopsy established the diagnosis. The demineralization and calcium mobilization are the result of marrow expansion with blast cells. Although osteoporosis is a frequent occurrence in acute leukemia,23 it is rarely a presenting symptom. It is also important to note that the patient received no steroids. The frequency of hypercalcemia is not known mainly because its presence is rarely looked for in the usual management of patients with leukemia. Bone pain, unrelated to the joints, has been demonstrated in 59 per cent of children and 50 per cent of adults" with acute leukemia. It is usually

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located in the peripheral skeleton of children and in the central skeleton of adults. Joint pains are much less frequent in acute leukemia, occurring in about 13 per cent of children and 3 per cent of adult patients. 45 • 54 The lower extremities are affected twice as often as the upper extremities. The knees are the major site of involvement. Of the patients with joint pain, 50 per cent have migratory arthralgia which is frequently associated with fever, making it difficult to differentiate from rheumatic fever. Monoarticular arthralgia occurs in about 6 per cent of patients. 45 Gouty arthropathy appears to be rare in acute leukemia53 despite the high blood uric acid levels. This paradox is probably related to the shortened survival time of the patient with leukemia. The incidence of x-ray-demonstrable bone involvement in childhood leukemia varies between 50 and 70 per cent in most series.a• 44. 59 The incidence in adult leukemia is usually quoted as 8 to 10 per cent.l1 A marked difference in incidence between adults and children is therefore apparent. In fact, Jaffe27 feels that the incidence in adults is much lower since it includes many cases of lymphosarcoma in which the terminal blood picture presents as lymphoblastic leukemia. Probably the main reason for the difference between adults and children is the increased growth rate in children. In the extensive review of 85 patients with acute leukemia by Thomas et al.,54 generalized osteoporosis was noted in all of the children and in 43 per cent of the adults. Osteolytic lesions occurred in 90 per cent of children and 57 per cent of adults in the same series. In fact, generalized osteoporosis and osteolytic lesions are about the only bone

A Figure 7. (Patient, G.S.). Acute leukemia. A, Peripheral blood smear demon strating large blast cell with nucleoli flanked by monocyte and small lymphocyte. (Wright's stain X 1500.) R, Recovery stage. Bone marrow smear demonstrating normal maturation of granulocytic series and normoblastic erythroid elements. (Wright's stain, X 1000.)

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Figure 8. Acute leukemia. Demonstra ting two parallel transverse radiolucent lines of the distal radius (arrows) separated by a calcified growth arrest line. Other calcified growth arrest lines may be noted. Note also the increased osteoporosis and trabecular coarsening in the hand. (Compare similarity of hand but difference in the distal radius with Figure 2.)

lesions described in acute adult leukemia. The marked difference in observable bone lesions in earlier and more recent studies could be due to the frequent present-day use of corticosteroids. In the same review, however, frequent osteolytic lesions not attributable to steroids were also noted in adults. The incidence of bone involvement in chronic adult leukemia is probably more rare, although this area has not been well studied to our knowledge. The most frequently described x-ray lesion of acute leukemia is a radiolucent band adjacent and parallel to the epiphyseal line in the metaphyses (Figs. 6, A, and 8). It rarely occurs in adults but has been described in over 80 per cent of children. 54 , 69 It is practically diagnostic of acute leukemia if it occurs in a child older than two years. Scurvy and syphilis can produce similar lesions; however, they are generally seen in infants under two years of age. This lesion is most frequently seen in the metaphyses of the femur, tibia, fibula or humerus. It may also be noted in flat bones such as the ilium and ischium. The location of these lesions in children is probably related to disturbances of endochondreal bone formation during periods of longitudinal bone growth. Often radiolucent bands will be interspersed with calcified growth arrest lines (Fig. 8). X-ray-demonstrable periosteal reaction

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occurs in 32 to 50 per cent of children.'" 64, 69 It is most frequently observed in the long bones, especially the femur, but can occur in the short tubular bones and ribs as well. This type of bone lesion seems to be most closely correlated with bone pain. This observation seems to be well supported, since bone pain is equally well correlated with leukemic cell infiltration of the periosteum at postmortem examination. Also the fact that small doses of x-ray relieve pain is added incriminating evidence that periosteal involvement is the chief cause of pain. As with bone pain, x-ray evidence of bony lesions of any type correlates well with therapeutic success or failure. Remissions are generally associated with bone healing and the longer the remission the more complete the healing. The persistence or reappearance of bone or joint pain indicates the presence of active disease.

Hodgkin's Disease In a collection of several series, bone involvement with Hodgkin's disease occurred in about 14 per cent of the patients.10, 14,17,18, 61 The range varies considerably, however, and has been noted between 0 and 26 per cent. 2, 16, 19, 20, 60 On the other hand, when the frequency of osseous involvement is based on autopsy findings, the incidence is considerably higher and has been reported as between 30 and 78 per cent.I6, 25, 60, 57 In fact, it is the opinion of some pathologists that every case of Hodgkin's disease will have demonstrable bone involvement if looked for with enough diligence,60 The prognosis of clinically demonstrable bone lesions is even more difficult to evaluate. In general, the appearance of osseous involvement is not considered to have any prognostic significance in Hodgkin's disease. 57 However, in the series of 25 patients with bone involvement studied by Fischer et aI., 20 died within two years of the discovery.17 Bony lesions can involve any area of the skeleton, and again, discovery is largely dependent on the diligence of the physician. They may be solitary or multiple, but usually more than half of the cases demonstrating bone involvement show multiple lesions.l7· 67 Without much question the most frequent site of involvement is the spine, particularly the lumbosacral spine. In a collection of three series involving 115 patients with demonstrable bone lesions, the distribution was as follows: spine 82 per cent, pelvis 57 per cent, ribs 44 per cent, proximal femur 34 per cent, sternum 18 per cent.14. 18. 67 The most frequent clue to discovering bone involvement is local pain. Local bone pain may precede x-ray evidence of bone involvement by several months. Pressure tenderness on physical examination can sometimes be elicited except where involved bones are inaccessible. Neurologic complications are an occasional manifestation of bone involvement. Sclerotic overgrowth of vertebrae may cause pressure on nerve roots and sheaths. It is interesting that cord compression secondary to vertebral collapse is not particularly common. Of 62 patients with Hodgkin's disease who presented with signs of spinal cord compression, in the series of Williams et aI., 58 none was directly attributable to vertebral collapse. Paravertebral disease was

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Figure 9. Hodgkin's disea.se. Marked sclerosis of the thoracic and lumbar vertebrae (lower arrow) is seen a.ssociated with a lytic area of the left 11th rib (upper arrow). The scoliosis ha.s resulted from lysis and partial vertebral collapse which ha.s preceded the current sclerotic process.

the apparent cause in 66 per cent of these patients. Among this latter group bony overgrowth was a possible contributing factor in about a third of the patients. Skeletal x-rays can yield a great deal when bony lesions are suspected. The lesions may be osteolytic, osteosclerotic, or a mixture of both. The mixed lesion is most frequently seen according to Moseley35 and the lytic lesions most frequent according to Fucilla. 18 However, the most distinctive lesion is osteosclerosis, particularly the "ivory vertebrae" (Fig. 9) which may be a strikingly radiopaque vertebral body isolated between two normal vertebrae. Bony sclerosis is also frequently seen involving the iliac bone near the sacroiliac junction. The other particularly characteristic lesion of bone involvement with Hodgkin's disease is anterior marginal erosion of vertebrae. When this finding is associated with mixed osteolytic and sclerotic lesions of the spine, the diagnosis of Hodgkin's disease is nearly certain. Periosteal reaction is also seen in Hodgkin's disease. lo Metastatic carcinoma of breast or prostate may demonstrate mixed or sclerotic lesions but usually they do not show anterior marginal erosion or evidence of periosteal involvement. Recently, osteosclerotic bone lesions have been reported with carcinoma of the lung and gastrointestinal tract, although the frequency of this occurrence is not well known as yet. 66 The sclerotic lesion of Paget's disease may also be difficult to differentiate from Hodgkin's disease except that there are roentgenologic features such as the double contour or "pictureframe" appearance of vertebrae and other obvious clinical differences that will usually settle the issue.

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The diagnostic potential of serum calcium and phosphorus levels in determining bone involvement has not been fully exploited. In Moses and Spencer's recent series,86 about one-third of their 18 Hodgkin's patients with proven bone involvement had hypercalcemia, usually associated with low phosphorus values. In these patients the characteristic symptoms of hypercalcemia, i.e., anorexia, constipation, lethargy, confusion, polyuria and polydipsia, were often manifested. Alkaline phosphatase levels were normal in this series. Others, however,67, 61 have noted that alkaline phosphatase elevations are quite frequent. The incidence of alkaline phosphatase elevation in patients with bone pain but absent x-ray findings has been reported as between 50 and 60 per cent. With x-ray-demonstrable lesions the incidence is about 75 per cent. In this series elevated alkaline phosphatase values were more often found in patients demonstrating osteosclerotic lesions accompanied by osteoblastic reaction, as opposed to patients with osteolytic lesions in whom osteoblasts were weakly reactive. In any patient demonstrating elevated serum alkaline phosphatase values obstructive liver disease must, or course, be ruled out. Bone marrow aspiration will, on occasion, demonstrate the presence of Reed-Sternberg cells but the diagnostic yield of this procedure is poor. There is no characteristic pattern seen on routine bone marrow smears of proven Hodgkin's patients except for the occasional report of increased megakaryocytes. 16 ,88 The discovery of bone involvement does not, in general, alter the type of therapy used except when, by virtue of its presence, it demonstrates generalized disease. In these situations the patient is usually a candidate for systemic therapy as opposed to local radiation. 84 Occasionally, however, radiation is used to help control local pain even in the face of widespread disease. Lymphosarcoma

The term lymphosarcoma includes all the malignant lymphomas except Hodgkin's disease. It generally refers to three basic types: reticulum cell sarcoma, small cell lymphosarcoma, and giant follicle lymphoma (BrillSymmer's disease). These three not only differ in histology, but also in the malignant nature of their course. A fourth disease, primary reticulum cell sarcoma of bone, will also be mentioned in this discussion. Whether it is a separate disease or a precursor of systemic reticulum cell sarcoma is not yet known. As currently understood it is considered to be a relatively benign localized disease occurring in a younger age group and demonstrating radio curability. The overall incidence of clinically demonstrable bone involvement is about 10 per cent.D, 12, 40, 61, 67 This incidence seems to be well correlated with the cell type. Giant follicle lymphoma rarely involves bones except in the terminal stage of disease. Conversely, reticulum cell sarcoma, the most malignant of the group, has a 21 per cent incidence of clinically evident

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Comparison of Clinical Features of Bone Changes in Hodgkin's Disease with L-pmphosarcoma HODGKIN'S

DISEASE

1. Incidence ...................... 14%

2. Prognosis of bone involvement ... No significance 3. Type of lesion .................. Mixed or sclerotic 4. Site ........................... Spine

5. Symptom ...................... Local pain

6. Pathological fractures ........... Rare

LYMPHOSARCOlllA

10% Poor Lytic Equal distribution between central and peripheral skeleton Local pain and occasional swelling Common

bone involvement, according to Cole and Schultz. 9 A 12 per cent incidence of small cell lymphosarcoma was noted by the same group. Rosenberg4° was able to demonstrate a higher incidence when postmortem findings were combined with x-ray evidence of bone involvement. An overall incidence of 25 per cent was demonstrated with a 33 per cent incidence in reticulum cell sarcoma and 15 per cent incidence in small cell lymphosarcoma. This is still much less than the postmortem incidence in Hodgkin's disease. However, it was Rosenberg's opinion that even these figures were low estimates and that most patients with lymphosarcoma have bone involvement. Bone lesions secondary to lymphosarcoma are considered to indicate a very poor prognosis. This is quite different from Hodgkin's disease, in which bone involvement is considered to have no prognostic signifi~nce. In Vieta's&7 series the average survival after discovery of bony lesions was 5.8 months in lymphosarcoma as compared to 17.6 months in Hodgkin's disease. As in Hodgkin's disease, bone lesions in lymphosarcoma are most often found in the vertebrae and pelvis; however, there is more general distribution with less concentration in the central skeleton than in Hodgkin's disease. In primary reticulum cell sarcoma of bone the lesions predominate in the peripheral skeleton, especially the lower extremities. The patient's usual complaint is either boring pain or local swelling of the involved skeletal area. As in Hodgkin's disease, local pain is often present, months before bone destruction is sufficient to be discovered on x-ray examination. Probably because bone involvement tends to occur in the end stages of lymphosarcoma when the disease is more widely disseminated and more rapidly invasive, osseous lesions tend to be more destructive and progress at a greater rate when present (Fig. 10). The lesions are almost always osteolytic and quite patchy, with only rare mixed or sclerotic lesions as are so commonly seen in Hodgkin's disease&7 (Table 3). Elliptical, linear or round discrete lytic areas with their long axes running parallel ,to the long

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axis of the shaft are a rather common feature of lymphosarcoma. However, these changes are also seen in Hodgkin's disease and leukemia. Cortical thinning is prominent and periosteal reaction has been noted in over half of the long bone lesions in lymphosarcoma. When bone involvement is evident, pathologic fractures are quite frequent compared to their much less common incidence in Hodgkin's disease.3• Neurologic complications secondary to vertebral collapse, however, are no more frequent than in Hodgkin's disease. 58 As in Hodgkin's disease, calcium and phosphorus determinations have not been performed often enough to evaluate their diagnostic potential. Three out of 11 of Moses and Spencer's36 patients with reticulum cell sarcoma and lymphosarcoma demonstrated hypercalcemia. One of the patients with hypercalcemia had no x-ray evidence of bone involvement, although bone pain was present and the 24-hour urinary calcium output was markedly high. It has been noted that urinary calcium excretion in patients with hypercalcemia is present for a relatively long time before elevation of serum calcium occurs, and that the urinary calcium output is proportional to the mineral content of bone. 39 As in Hodgkin's disease, alkaline phosphatase elevation in lymphosarcoma is often seen with bone involvement. Rosenberg4° noted elevation of greater than 5.0 Bodansky units in 47.8 per cent of 409 patients who had this determination performed. Oddly enough, alkaline phosphatase elevations were more frequent in giant

Figure 10. Lymphosarcoma. Marked osteolytic destruction of the left ilium (arrow) and symphysis pubis has resulted in upward displacement of the left hemipelvis.

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follicle lymphosarcoma than in small celllymphasarcoma or reticulum cell sarcoma. As in Woodward studies,61 Rosenberg noted that the incidence of elevation was greater in patients who demonstrated osteoblastic lesions. He also noted that extremely high values were more often indicative of obstructive liver disease than bone involvement. Bone marrow examination will occasionally reveal marked infiltration with smalllymphocytes. When this occurs in conjunction with a peripheral blood lymphocytosis, the diagnosis of chronic lymphocytic leukemia is generally made. The pathogenesis and treatment of chronic lymphocytic leukemia and lymphosarcoma are often considered to be the same. 34 Reticulum cell sarcoma is usually excluded from this close association with chronic lymphatic leukemia. Therapy of bone involvement is similar to that applied to the bone lesions of Hodgkin's disease. As noted before, by the time bone lesions are clinically evident in lymphosarcoma, the disease is widely disseminated and systemic therapy such as Cytoxan, triethylene melamine or chlorambucil is generally indicated. 34 However, when local bone pain is evident without demonstrable activity elsewhere, x-ray therapy may be helpful. Because bone pain may be the only clue to disease activity, systemic or local therapy should probably not be withheld until objective evidence is apparent.

Plasmacytic Myeloma (Multiple Myeloma) Multiple myeloma is a reticuloendothelial malignancy characterized by the malignant transformation of plasma cells with corresponding production of abnormal proteins and bone destruction. The marked skeletal infiltration produces pain, a number of x-ray changes, and complications secondary to bone involvement. The most frequent presenting symptom of multiple myeloma is bone pain which occurs in 90 per cent of patients. 32 • 38 The pain may start out mild but usually becomes quite severe and agonizing. 4 In even later stages, with widespread disease, patients may be pain-free and sternal aspirations may be performed without anesthesia. 32 The site of pain is most frequently reported to be the lower back or rib cage, but also the hips and legs. The onset of pain may be gradual and migratory in nature, or abrupt, secondary to pathologic fractures. More than one-half of the patients demonstrate pathologic fractures and of these about one-half are of the lower thoracic and lumbar spine. 48 The incidence of vertebral collapse has been quoted as 73 per cent in Heiser and Schwartzman's series. 22 Fractures of the ribs are also quite frequent, occurring in about one-fifth of cases. 48 Vertebral collapse has the serious possibility of cord compression with consequent paraplegia. Next to metastatic carcinoma, multiple myeloma is said to be the most frequent noninflammatory cause of cord compression. 41 Less severe complications such as nerve root pain or kyphoscoliosis also may be present. X-ray changes correlate quite well with bone pain and are most fre-

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quently located in the spine, ribs and sternum, i.e., the bones containing red marrow in an adult. However, as in other reticuloendothelial malignancies, x-ray evidence of disease may lag behind the onset of bone pain by months. The most characteristic lesion is the "punched-out" defect usually described in the spine, pelvis and skull (Fig. 11). The lesion is usually a well circumscribed, round or oval osteolytic lesion which may be seen in any size or may occur in any number. When the lesions become very large, they may coalesce and become difficult to differentiate from osteoporosis circumscripta of Paget's disease. 35 In 25 per cent of cases the initial x-ray manifestations may be merely those of simple diffuse osteoporosis. 3s The overall incidence of osteoporosis is even higher since it is often associated with osteolytic lesions. The pathogenesis of osteoporosis in multiple myeloma seems to be similar to that in the other hematologic malignancies in that the osteoporosis is probably due to diffuse infiltration of the marrow with plasma cells. Osteoporosis is most frequent in the lumbar spine and is the major cause of vertebral collapse. The incidence of solitary plasmacytoma of bone ranges from 2 to 10 per cent.3S This tumor is usually less discrete, has a cystic or soap-bubble appearance on x-ray,36 and may be difficult to differentiate from the typical isolated osseous metastases described with metastatic hypernephroma or thyroid carcinoma. 42 • 43 Though generally considered benign, dissemination may eventually occur. Although Osserman3S considers solitary plasmacytoma of bone to be more frequent than solitary plasmacytoma of soft tissue. Best et al,4 found no instances of solitary bone tumor in a review of 190

Figure 11. Multiple myeloma. Multiple well-circumscribed punched-out osteolytic lesions are evident in this skull, radius, ulna and hand.

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cases of plasmacytic myeloma. However, there were three soft tissue plasmacytomas of the nasopharyngeal area in this series. The prognosis of bone involvement is difficult to establish because of the frequency of x-ray-demonstrable lesions at the time diagnosis is made. On the one hand, discretely isolated plasmacytomas may be demonstrable long before systemic evidence of disease, e.g., anemia, Bence-Jones proteinemia or hypergammaglobulinemia, becomes manifest. On the other hand, Osserman37 believes that x-ray-evident disease is indicative of a faradvanced stage. Generalized osteoporosis is reported to be indicative of a poor prognosis. 37 Hypercalcemia, a frequent consequence of bone involvement, occurs in approximately 30 per cent of the patients. 41 This is frequently associated with osteoporosis and reflects advanced disease. 38 The absence of hypophosphatemia and elevated alkaline phosphatase differentiates the hypercalcemia in multiple myeloma from primary hyperparathyroidism. MYELOSCLEROSIS

Myelosclerosis and myelofibrosis are terms applied to the fibrous or bony replacement of normal bone marrow. This is usually associated with extramedullary hemopoiesis in the spleen, liver and lymph nodes. The natural consequence is hepatosplenomegaly, anemia, and many immature red and white cell forms in the peripheral blood. The prime defect in bones seems to be thickening and increases in number of bony trabeculae which replace the marrow spaces to the point of obliterating any source of hemopoietic tissue. Occasional islands of hemopoiesis frequently exist and are difficult to find even at postmortem examination. Therefore, bone marrow aspiration usually results in a "dry tap." Inadvertently, if an island of hemopoiesis is aspirated, marrow hyperplasia will be found which may obscure the diagnosis. Usually surgical biopsy is necessary for final confirmation. Radiologic lesions are present in a third to a half of cases. 26 , 30 Lesions are usually found in the spine, pelvis, ribs, sternum and proximal humerus and femur, which are the areas of normal red marrow distribution in an adult. The peripheral skeleton may also be involved but the skull is rarely affected. The most frequent characteristic reported is a diffusely dense ground-glass appearance which is attributed to medullary condensation by calcified trabeculae. Although the increased density is usually quite homogeneous, scattered osteolytic areas may be found. Long bones often demonstrate increased cortical thickening as the inner cortex encroaches upon the medullary cavity. This appearance may be identical to the bone changes seen in the latter stages of sickle cell disease. Another feature, described by Moseley,35 is periosteal reaction of the long bones, particularly along the medial aspects of the distal femora, the lateral aspects of the proximal tibial shafts, and the ankles.

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Differential diagnosis includes osteopetrosis, metastatic carcinoma and mast cell disease. Osteopetrosis generally is no problem because it is a childhood disease displaying greater bone density, often involving the skull, and predominantly affecting the metaphyseal ends of long bones. Osteoblastic metastatic carcinoma usually demonstrates localized lesions rather than the generalized lesion associated with myelosclerosis and it, of course, does not have the blood and splenic changes. Tissue mast cell disease can also demonstrate diffuse osteosclerosis of the central skeleton. However, the skin manifestations of urticaria pigmentosa and subsequent demonstration of mast cells on bone marrow biopsy would usually differentiate it. OSTEOPETROSIS OR ALBERS-SCHONBERG'S DISEASE (MARBLE BONE DISEASE)

Osteopetrosis is a rare disease of childhood characterized by hard brittle bones, splenomegaly and a myelophthisic anemia. It is usually a congenital disorder which may be hereditary. Frequently, the same osseous pattern is noted in various affected members of the same family. Osteopetrosis is generally considered a highly malignant disease of infants and young children although a more benign form, seen in older children and adults, is also described. 35 Osteopetrosis is generally thought to result from a marked decrease of resorption of calcified cartilage which results in islands of calcified ground substance to account for the medullary narrowing and increased bone density apparent on x-ray. Obliteration of the marrow cavity results in extremedullary hemopoiesis with consequent enlargement of the reticuloendothelial organs. Faulty resportion also causes modeling defects which produce widened metaphyses. The normal architectural mosaic that results from absorption and apposition does not develop so that the patient is subject to a greater incidence of fractures. Bone manifestations are symmetrical and at birth consist of increased homogeneous density of all bones with obliteration of normal architecture. As the disease progresses and new bone is laid down, a surrounding shadow of bone can be seen around the original sclerotic core that gives a typical "bone-within-bone" appearance. This is most apparent in the long bones but may also occur in the central skeleton. Even later, the metaphyseal ends of the long bones become widened and blunt. In contrast to osteosclerosis, osteopetrosis frequently involves the skull. Sclerotic lesions, usually seen at the base of the skull, are characterized by thickening of the dorsum sellae and posterior clinoid processes. The foraminae at the base of the skull become narrowed, resulting in cranial nerve compression which most frequently produces deafness and optic atrophy. The benign form of osteopetrosis exhibits similar changes which are

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much less severe. There is no way of differentiating the benign form from the malignant except by age. According to Hinkel and Beiler,2s any patient surviving beyond infancy has the benign form. BONE MANIFESTATIONS OF THE RETICULOENDOTHELIOSES The reticuloendothelioses are a group of diseases characterized by the presence of malignant-appearing histiocytic or monocytoid cells of the reticuloendothelial system. This results in enlargement of the spleen, liver and lymph nodes, various peripheral blood aberrations, and frequent bone involvement. Histiocytosis X

Histiocytosis X is a general term applied to three diseases of young individuals characterized by invasive histiocytic granulomas of varying extent.S1 They range from the localized, relatively benign histiocytic granulomas of bone known as eosinophilic granuloma, to the highly malignant, widely disseminated Letterer-Siwe syndrome. A more chronic disseminated form of histiocytosis X is known as Schuller-Christian disease. All three diseases have similar lesions in bone except for the Letterer-Siwe syndrome which can be so rapidly fulminating that clinical or x-ray evidence of bone involvement never becomes manifest. Generalized lymphadenopathy, hepatosplenomegaly, and widespread soft-tissue infiltration more accurately characterize this disease. Bone involvement is usually evident in Schuller-Christian disease some time during its course, although a number of cases only have soft tissue lesions. Eosinophilic granuloma, by definition, however, must involve bone. Histologically the lesions are granulomatous and characterized by marked histiocytic proliferation which mayor may not exhibit eosinophilic infiltration.31 More active lesions may appear "foamy" and fat stains are positive. In older, "healed" lesions there is a tendency toward fibrosis. Bone involvement is manifest as a single or multiple discrete lesion. Only about one-quarter of the cases of eosinophilic granuloma are multiple, whereas most cases of Schuller-Christian disease show multiple lesionsY The skull is most frequently involved, although lesions of the pelvis, femur, ribs and vertebrae are also described. The presenting complaint is often local pain and swelling of the affected bone associated with malaise, fever, weight loss and leukocytosis. Pathologic fractures may also be a presenting problem. Because of the destructive nature of histiocytosis X, x-my lesions are usually osteolytic. They are frequently seen as large, well circumscribed, radiolucent areas of the calvarium which may have a maplike appearance. This accounts for the term "geographic skull," which is considered highly diagnostic of Schuller-Christian disease and Letterer-Siwe's disease. 86

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The temporal bone is often involved near the mastoid and petrous portion, giving rise to otitis media in about 75 per cent of cases with this involvement. 1 When the mandible is involved, lesions often begin around teeth, giving rise to the complaint of "loose teeth." The latter is usually associated with Schuller-Christian disease. As stated before, discrete osteolytic lesions occur in other bones as well. Osteolytic lesions of the iliac bones in a child are highly suggestive of histiocytosis X. Another characteristic feature is a three-dimensional appearance to the lesion, especially in the thicker aspects of bones such as the femur and humerus. This gives rise to a "hole-within-a-hole" appearance not observed in other tumors.35

Gaucher's Disease Gaucher's disease is a familial disorder characterized by outstanding splenomegaly, bone lesions, brownish skin pigmentation, and pingueculae. It occurs in an acute infantile form and a chronic type seen in older children and adults. The condition results from infiltration and proliferation of large kerasin-containing Gaucher cells in the spleen, bone marrow, liver and lymph nodes. Infiltration of the nervous system also occurs in the infantile type. Bone involvement mayor may not be present. Generally, the acute infantile type runs such a rapid course that bone changes are rarely seen. In the chronic type, however, extensive changes may be seen. Bone lesions are a result of Gaucher cell infiltration of the medullary cavity with consequent destruction of bony trabeculae. In most cases bone lesions are not symptomatic but are discovered on x-ray examination. The lesions may involve any bone in the body, although x-ray-demonstrable lesions are most frequently seen in large tubular bones such as the femora. The usual lesion is generalized osteoporosis of the distal end of the femur associated with expansion of this area. The normal concave contour of the medial aspect of this bone is lost and a convex shape eventually results. The overall effect gives a club-shaped or "Erlenmeyer flask" shape to the distal femur. 6o The upper ends of the tibia and humerus may also have a swollen appearance, but this is much less common. A diffuse mottled destructive process of long bones sometimes produces a honeycomb pattern and may simulate osteoporosis. Mottled osteosclerotic lesions of the long bones may occur. Periosteal involvement has also been reported. The generalized nature of this disease and variability of its course result in many different bone lesions.

Niemann-Pick's Disease Niemann-Pick's disease is a familial condition similar to Gaucher's disease with a predilection for Jewish infants.la, 56 It is characterized by early jaundice, marked hepatomegaly, splenomegaly,emaciation, mental retardation and cherry-red spots in the maculae. The condition results

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from widespread sphingomyelin-containing Niemann-Pick cell infiltration of all organs. The disease is generally more malignant in its course than Gaucher's, hence x-ray-evident bone involvement is less often manifest, as in the acute type of Gaucher's disease. Bone is infiltrated, however, and frequently appears strikingly yellow on gross examination. Myelophthisis frequently results in a pancytopenia. The radiologic lesions are similar to those seen in the malignancies. The medullary cavity is widened and the cortex thinned, giving rise to a diffuse osteolytic process, usually of the large tubular bones.

SUMMARY A discussion of the hematologic disorders which are commonly associated with bone involvement has been presented. Most lesions can be attributed to diffuse medullary expansion, periosteal involvement, focal destruction, or a combination of all three. All of the hemolytic anemias are characterized by medullary expansion. In addition to this process, periosteal involvement is frequently a mechanism in sickle cell disease and acute leukemia. Focal lesions are common with Hodgkin's disease, lymphosarcoma, multiple myeloma and hemophilia. As a result of these processes, x-ray-demonstrable lesions may arise which are considered pathognomonic, such as the proximal metaphyseal radiolucent band of acute leukemia or the "ivory vertebrae" of Hodgkin's disease. However, most of the bony lesions seen in diseases of the hemopoietic system are quite nonspecific and may occur with a host of diseases.

REFERENCES 1. Avery, M. E., McAfee, J. G. and Guild, H. G.: Course and prognosis of reticuloendothelioses (eosinophilic granuloma, Schuller-Christian disease and Letterer-Siwe's disease). Am. J. Med. 22: 636, 1957. 2. Baker, C. and Mann, W. N.: Hodgkin's disease. Lancet 1: 23,1940. 3. Baty, J. M. and Vogt, E. C.: Bone changes of leukemia in children. Am. J. Roentgenol. 34: 310, 1935. 4. Best, W. R. and others: Multiple myeloma. J.A.M.A. 188: 741, 1964. 5. Boggs, D. R., Wintrobe, M. M. and Cartwright, G. E.: The actute leukemiaE. Medicine 41: 163,1962. 6. Buckman, J.: Sickle cell disease simulating osteomyelitis. Bull. Hosp. Joint Dis. 10: 239,1949. 7. Caffey, J.: Cooley's anemia: A review of thc roentgenographic findings in the skeleton. Am. J. Roentgenol. & Rad. Therapy 78: 381, 1957. 8. Caffey, J. and Schlesinger, E. R.: Certain effects of hemophilia on the growing skeleton. J. Pediat. 16: 549,1940. 9. Cole, W. C. and Schultz, M. D.: Bone involvement in malignant lymphomas. Radiology 50: 458, 1948. 10. Craver, L. F. and Copland, M. M.: Changes in the bone in Hodgkin's granuloma. Arch. Sur. 28: 1062, 1934. 11. Craver, L. F. and Copland, M. M.: Changes of bones in leukemias. Arch. Surg. 30: 639,1935.

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12. Craver, L. F. and Copland, M. M.: Lymphosarcoma in bone. Arch. Surg. 28: 809, 1934. 13. Crocker, A. C. and Farber, S.: Niemann-Pick's disease. Medicine 37: 95, 1949. 14. Dresser, R. and Spencer, J.: Hodgkin's disease and allied conditions of the bone. Am. J. Roentgenol. 36: 809, 1936. 15. Ellenbogen, N. C., Raim, J. and Grossman, L.: Salmonella sp. osteomyelitis. Am. J. Dis. Child. 90: 275, 1955. 16. Falconer, E. H. and Leonard, M. E.: Skeletal lesions in Hodgkin's disease. Ann. Int. Med. 29: 1115-1131, 1948. 17. Fischer, A. M. H., Kendal, B. and VanLeuven, B.: Hodgkin's disease, a radiological survey. Clin. Radiol. 13: 115, 1962. 18. Fucilla, 1. S. and Hamann, A.: Hodgkin's disease in bone. Radiology 77: 53, 1961. 19. Goldman, L. B.: Hodgkin's disease: Analysis of 212 cases. J.A.M.A. 114: 16111616,1940. 20. Goldman, L. B. and Victor, A. W.: Hodgkin's disease: Salient clinical features and relative value of various methods of treatment based upon study of 319 cases. New York J. Med. 45: 1313-1318, 1945. 21. Hansen, K. and Klein, E.: Symptomatology and heredity of hemolytic jaundice Deutsch. Arch. klin. Med. 176: 567, 1934. 22. Heiser, P. and Schwartzmann, J. J.: Variation in the roentgen appearance of the skelet:tl system in myeloma. Radiology 58: 179, 1952. 23. Hinkel, C. L. and Beiler, D. D.: Osteopetrosis in adults. Am. J. Roentgenol. & Rad. Therapy 74: 46, 1955. 24. Hook, E. W., Campbell, C. G., Ween, H. S. and Cooper, G. R.: Salmonella osteomyelitis in patients with sickle cell anemia. New England J. Med. 257: 403, 1957. 25. Jackson, H., Jr. and Parker, F., Jr.: Hodgkin's Disease and Allied Disorders. New York, Oxford, 1947, 177 pp. 26. Jacobson, H. G., F'ateh, H., Shapiro, J. H., Spaet, T. H. and Poppel, M. H.: Agnogenic myeloid metaplasia. Radiology 72: 716, 1959. 27. J affe, H. L.: Skeletal manifestations of leukemia and malignant lymphoma. Bull. Hosp. Joint Dis. 13: 217, 1952. 28. Jordan, H. H.: Hemophilic Arthropathies. Springfield, Ill., C. C Thomas, 1958. 29. Key, J. A.: Hemophilic arthritis (bleeder's joints). Ann. Surg. 95: 198, 1932. 30. Leigh, T. H., Corley, C. C., Jr., Huguley, C. M., Jr. and Rogers, J. V., Jr.: Myelofibrosis. Am. J. Roentgenol. & Rad. Therapy 82: 183, 1959. 31. Lichtenstein, L.: Histiocytosis X: Integration of eosinophilic granuloma of bone, Letterer-Siwe's disease, and Schuller-Christian disease as related manifestations of a single nosologic entity. Arch. Path. 56: 84, 1953. 32. Limarzi, L. R.: Diagnostic and therapeutic aspects of multiple myeloma. M. CLIN. NORTH AMERICA 35: 189-226, 1951. 33. Limarzi, L. R. and Paul, J. T.: Sternal marrow studies in Hodgkin's disease. Am. J. Clin. Path. 19: 929-961, 1949. 34. Louis, J.: Management of reticuloendothelial malignancies. M. CLIN. NORTH AMERICA 46: 171, 1962. 35. Moseley, J. E.: Bone Changes in Hematologic Disorders. New York, Grune & Stratton, 1963. 36. Moses, A. M. and Spencer, H.: Hypercalcemia in patients with a malignant lymphoma. Ann. Int. Med. 59: 531-536, 1963. 37. Osserman, E. F.: Natural history of mUltiple myeloma before radiological evidence of disease. Radiology 71: 157, 1958. 38. Osserman, E. F.: Plasma cell myeloma. New England J. Med. 261: 952,1006,1959. 39. Plirnpton, C. H. and Gellhorn, A.: Hypercalcemia in malignant disease without evidence of bone destruction. Am. J. Med. 21: 750,19,1)6. 40. Rosenberg, S. A., Diamond, H. D., Jaslowitz, B. and Craver, L.: Lymphosarcoma: A review of 1269 cases. Medicine 40: 31, 1961. 41. Shenkin, H. A., Horn, R. C., Jr. and Grant, F. C.: Lesions of the spinal extradural space producing cord compression. Arch. Surg. 51: 125, 1945. 42. Sherman, R. S. and Ivker, M.: Roentgen appearance of thyroid metastasis in bone. Am. J. Roentgenol. & Rad. Therapy 63: 196, 1950. 43. Sherman, R. S. and Pearson, T. A.: Roentgenographic appearance of renal cancer metastases in bone. Cancer 1: 276, 1948.

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44. Silverman, F. N.: The skeletal lesions in leukemias: Clinical and roentgenographic observations in 103 infants and children with a review of the literature. Am. J. Roentgenol. & Rad. Therapy 59: 819, 1948. 45. Silverstein, M. N. and Kelley, P. J.: Leukemia with osteoarticular symptoms and signs. Ann. Int. Med. 59: 637, 1963. 46. Smith, F. W. and Conley, C. L.: Clinical features of the genetic variants of sickle cell disease. Bull. Johns Hopkins Hosp. 94: 289, 1954. 47. Snapper, 1.: Medical Clinics in Bone Disease. New York, Interscience Publishers, 1949. 48. Snapper, 1., Turner, L. B. and Mascovitz, H. L.: Multiple Myeloma. New York, Grune & Stratton, 1953. 49. Snelling, C. E. and Brown, A.: A case of hemolytic jaundice with bone changes. J. Pediat. 8: 330, 1936. 50. Steiner, P. E.: Hodgkin's disease: Incidence, distribution, nature, and possible significance of lymphogranulomatous lesions in bone marrow; review with original data. Arch. Path. 36: 627-637,1943. 51. Sugarbaker, E. D. and Craver, L.: Lymphosarcoma: A study of 196 cases with biopsy. J.A.M.A. 115: 17, 1940. 52. Swanton, M. C.: Pathology of hemarthroses in hemophilia and hemophiloid diseases. International Symposium, University of North Carolina Press, Chapel Hill, 1957. 53. Talbot, J. H.: Gout and blood dyscrasias. Medicine 38: 173, 1959. 54. Thomas, L. B., Forkner, C. E., Jr., Frei, E., Ill, Besse, B. E. and Stabenau, J. R.: Skeletal lesions of acute leukemias. Cancer 14: 608, 1961. 55. Toomey, F. B. and Felson, B.: Osteoblastic bone metastases in gastrointestinal and bronchial carcimoids. Am. J. Roentgenol. & Rad. Therapy 83: 709, 1960. 56. Viedeback, A.: Niemann-Pick's disease. Acta. paediat. 37: 95,1949. 57. Vieta, J. 0., Friedell, H. L. and Craver, L. F.: Survey of Hodgkin's disease and lymphosarcoma in bone. Radiology 39: 1, 1942. 58. Williams, H. M., Giman, H. D., Craver, L. F. and Parson, H.: Neurological Complications of Lymphomas and Leukemias. Springfield, Ill., C. C Thomas, 1959. 59. Willson, J. K. V.: Bone lesions of childhood leukemia. Radiology 72: 672,1959. 60. Wintrobe, M. M.: Clinical Hematology. Philadelphia, Lea & Febiger, 1961. 61. Woodward, H. Q. and Craver, L. F.: Serum phosphatase in lymphomatoid diseases. J. Clin. Invest. 19: 1-7, 1940. 30 North Michigan Avenue Chicago, Illinois 60602 (Dr. Limarzi)