Orthopedics

Systemic Mastocytosis

Harry Griffiths, MD; Edward Steiner, MD

Abstract

RADIOLOGIC CASE STUDY

1. Brunning RD, McKenna RW, Rosai J, et al: Systemic mastocytosis. Extracutaneous manifestations. Am J Surg Path 1983; 7:425-438.

2. Webb TA, Li C-Y, Yam LT: Systemic mast cell disease: A clinical and hcmatopathologic study of 26 cases. Cancer 1982; 49:927-938.

3. Sagher F, Evan-Paz Z: Mastocytosis and !he Mast Cell. Chicago, Year Book Medical Publishers, 1967.

4 . Hills E, Dunstan CR . Evans RA: Bone metabolism in systemic mastocytosis . J Bone Joint Surg 1981; 63A:665-669.

5. Rafii M, Firooznia H, Golimbu C, et al: Pathologic fracture in systemic mastocytosis. Clin Orthop 1983; 180:260-267.

6. Korenblat PE, Wedner HJ, Whyte MP, et al: Systemic mastocytosis. Arch tntern Med 1984; 144:2249-2253.

7. Rosenbaum RC. Frieri M . Metcalfe DD: Patterns of skeletal scintigraphy and their relationship to plasma and urinary histamine levels in systemic mastocytosis. J Nuci Med 1984; 25:859-864.

8. Fine JD: Mastocytosis. Int J Dermatol 1980; 19:117-123.

Section Editor: Terrence C. Demos, MD

TABLE

CAUSES OF ADULT OSTEOSCLEROSIS…

RADIOLOGIC CASE STUDY

Fig. IA, IB: Case 1. This man of 45, who was otherwise well, was admitted complaining of right sided lower abdominal pain. The diagnosis of acute appendicitis was made and an inflamed appendix successfully removed. A routine chest x-ray and an abdominal series revealed these skeletal changes. What conditions would be in your differential diagnosis for his skeletal changes and how would you work him up?

Case Reports

The differential diagnosis of diffuse increased bone density includes a number of anemias, myelosclerosis and myelofibrosis, diffuse metastatic spread, fluoride and other heavy metal poisoning, some of the rare sclerosing bone dysplasias and possibly Pagets disease (Table). In an asymptomatic man of 45 it is possible to exclude most of these conditions. On closer perusal of the abdominal radiograph an enlarged liver and spleen can be seen, and thus it was thought that this patient suffered from one of the anemias such as thalassemia. However a peripheral blood smear was found to be normal so a bone marrow aspiration was performed which was diagnostic.

A second patient with the same condition but a totally different presentation was also seen. This girl of 23 was three months pregnant and started complaining of pain in the region of her left hip. Films were taken (Fig. 2A, 2B) and a poorly defined lucency was found in the upper femur. It appeared to contain some discrete calcifications and since the lesion was thought to be benign (possibly an area of healing fibrous dysplasia or a residual enchondroma) it was elected to leave it alone until after the pregnancy. Approximately nine months later the patient was admitted and a bone scan performed which was found to be essentially negative. A work-up including peripheral blood smear was normal and a biopsy was taken from the center of the lucent area. Once again a diagnosis was made which was later confirmed on bone marrow biopsy.

Systemic Mastocytosis

Urticaria pigmentosum is a relatively common, usually benign and often asymptomatic skin condition first described in 1869 by Nettleship. It accounts for 99% of all of the mastocytoses and for 1 in 8,000 patients seen at a dermatological clinic.1 On the other hand, systemic mastocytosis is a rare disease which can manifest itself in a number of different ways.13 In fact, five distinct clinical syndromes are now recognized: 1) Urticaria pigmentosum, 2) cutaneous involvement associated with bone disease, 3) systemic mastocytosis with both cutaneous lesions and widespread organ involvement including spleen, liver, lymph nodes and bone, 4) systemic mastocytosis without urticaria pigmentosum (rare, less than 1% of all mastocytoses and the condition from which both these patients are suffering), 5) leukemic mastocytosis.

Systemic mastocytosis is a disease of unknown etiology characterized by the abnormal accumulation of mast cells in the skin and other organs: GI tract, liver, spleen, lymph nodes and bone.4 Systemic effects are due to release of vasoactive substances (probably histamine) leading to flushing, headache, bronchospasm and diarrhea. Urticaria pigmentosum appears to progress to systemic involvement in few children but in about 5% to 10% of the adult onset disease of whom 5% to 6% undergo malignant transformation. Thirty percent of these patients die eventually of some complication of systemic mastocytosis.5

Clinically

The age range of patients with systemic mastocytosis is from 25 to 88 years with a median age of about 60. It is equally common in men and women.0 The signs and symptoms depend to some extent on which organs are involved, but fatigue, night sweats and weakness are common (50% to 60%), diarrhea occurs in 40% and weight loss in 20%, arthralgias and generalized bone pain occur in 10% to 20% of patients. On examination, splenomegaly occurs in 50% to 60% of patients, hepatomegaly in 50% to 70%, generalized lymphadenopathy in 40% and skin lesions are apparent in 60%.

Radiologcally

Skeletal radiographic changes in systemic mastocytosis are common, occurring in approximately 70% of all patients who have the systemic disease.3-6 However, the findings are heterogenous and include either diffuse or localized osteoblastic or osteolytic lesions. In a recent review of 29 patients in the literature Rafii5 found that 13 patients (45%) had generalized osteosclerosis, eight patients (27%) had a pattern of mixed osteosclerosis with osteolytic areas, five patients (17%) presented with generalized osteoporosis, one patient had patchy areas of osteosclerosis and two patients were normal. These authors were only able to find four reported cases of pathological fracture in systemic mastocytosis in the literature.5 Sagher and Even-Paz3 reviewed 71 patients and found that 56% of these patients had diffuse skeletal changes and 6% were localized. In two more recent papers, Brunning1 reviewed the clinical, radiological and pathological changes in 14 patients with systemic mastocytosis; six of these patients had skeletal changes (43%), three patients had osteoblastic lesions (one localized), one had a localized osteolytic area and two patients had mixed osteoblastic-osteolytic areas. Both the patients with focal lesions also had generalized osteoporosis. Webb2 recently reviewed 26 patients with systemic mastocytosis; 76% of his patients had skeletal involvement, 33% osteoporosis, 16% osteosclerosis, 20% mixed lesions, 24% were negative and there were focal lesions in two patients. Thus the most frequent skeletal manifestation of systemic mastocytosis is diffuse osteosclerosis with or wimout lytic areas (Rg. 1, 3). A localized osteolytic area is really quite rare (Fig. 2).

Fig. 24.

Fig. 24.

Fig.2B.

Fig.2B.

Bone scanning in patients with systemic mastocytosis provides some help in the diagnosis although bone scans do not correlate well with the radiographic findings. Rosenbaum7 found four different scintigraphic patterns in ten patients with systemic mastocytosis, normal (two patients), unifocal (three patients), multifocal (two patients) and diffuse increased uptake (three patients).

Pathological Findings

Bone marrow biopsy is the definitive diagnostic procedure for systemic mastocytosis. Peripheral blood smears are often negative apart from demonstrating anemia in approximately 40% of patients. Eosinophilie occurs in 10% to 20%, leukopenia in 15%, leukocytosis in 20% to 30%. Brunning1 found positive bone marrow biopsies in all 13 of his patients and Webb2 in 100% of his 26 patients. Aggregates of mast cells are found with various degrees of cytoplasmic granulation frequently associated with granulocytic hyperplasia and eosinophilia. Mast cells were often paratrabecular and perivascular. Mast cells are fairly characteristic microscopically and exhibit prominent metachromasia with a toludine blue stain. They have a characteristic ultrastructural appearance. Mast cells are now believed to be of perivascular mesenchymal origin and contain histamine, heparin and various proteolytic enzymes.8

Bone metabolism is altered in patients with systemic mastocytosis, there is an increase in the area of cancellous bone, an increased rate of bone formation, and increased rate of bone mineralization. The osteoblasts and osteoclasts are larger than normal and there is frequently increased osteoclastic activity. Mast cells are found to occupy over one quarter of each microscopic section.4 The increased bone density is probably due to an increased conversion of precursor cells to osteoblasts.4

Treatment

Antihistamines are used in mild forms of the condition to relieve the allergic symptoms. Steroids have been tried as has Cimetidine. Chemotherapy, radiotherapy and PUVA have also been used in severe cases and miüiramycin has been found to reduce bone pain.8

Fig. 3A, B: Chest and abdominal films in a man of 45 with mastocytosis who was largely asymptomatic. Note the patchy increase in bone density with a coarse trabecular pattern. Extramedullary haematopofesis accounts for the masses in the right lower thorax (courtesy of Dr. James Polga, Springfield, MA).

Fig. 3A, B: Chest and abdominal films in a man of 45 with mastocytosis who was largely asymptomatic. Note the patchy increase in bone density with a coarse trabecular pattern. Extramedullary haematopofesis accounts for the masses in the right lower thorax (courtesy of Dr. James Polga, Springfield, MA).

Prognosis

In reviewing the literature the overall prognosis in patients with systemic mastocytosis appears reasonable with about 70% of patients surviving over ten years.8 In Brunning's group of 14 patients, five died (an incidence of 35%); two patients developed widespread poorly differentiated lymphoreticular tumors and one patient died of acute myelogenous leukemia; two patients died of infectious processes. > Of Webb's 22 patients with adequate follow up 16 were still alive (73%), three had died of neoplasms developed elsewhere (lung and pancreas); two had died of mastocytosis and one patient had died of a lymphoreticular tumor.3

Differential Diagnosis

The radiographic differential diagnosis will depend on the skeletal manifestations of systemic mastocytosis. Generalized osteoporosis has a wide differential including the osteoporosis of aging, osteomalacia, hyperparathyroidism, steroid induced osteoporosis, and other infiltrating disorders. A localized lytic area could be caused by a variety of benign cysts and tumors, fibrous dysplasia, a brown tumor or a metastasis for example. There are many causes of adult osteosclerosis (Table), however metastatic carcinoma (Fig. 4), myelofibrosis (Fig. 5), thalassemia (Fig. 6) and fluorosis (Fig. 7) are probably most similar in appearance to the diffuse patchy increased bone density seen in most patients with skeletal manifestations of systemic mastocytosis.

Table

TABLECAUSES OF ADULT OSTEOSCLEROSIS

TABLE

CAUSES OF ADULT OSTEOSCLEROSIS

Fig. 4: This man of 58 presented with diffuse bone pain, a generalized increase in bone density and a highly elevated acid phosphatase. The diagnosis of prostatic carcinoma with widespread bony metastases was confirmed by biopsy.

Fig. 4: This man of 58 presented with diffuse bone pain, a generalized increase in bone density and a highly elevated acid phosphatase. The diagnosis of prostatic carcinoma with widespread bony metastases was confirmed by biopsy.

Fig. 5: Female of 72 presented with anemia, a history of gallstones, hepatomegaly and generalized increased bone density. The diagnosis of myelofibrosis was confirmed on bone marrow biopsy.

Fig. 5: Female of 72 presented with anemia, a history of gallstones, hepatomegaly and generalized increased bone density. The diagnosis of myelofibrosis was confirmed on bone marrow biopsy.

Fig. 6: This 34 year old man of Mediterranean origin had had thalassemia for many years. The diffuse overall increase in bone density with an exaggerated trabecular pattern is typical of this condition. Note the many soft tissue densities which represent extramedullary haematopoiesis.

Fig. 6: This 34 year old man of Mediterranean origin had had thalassemia for many years. The diffuse overall increase in bone density with an exaggerated trabecular pattern is typical of this condition. Note the many soft tissue densities which represent extramedullary haematopoiesis.

Fig. 7: This 29 year old Indian woman presented with bone pain and lethargy. Radiographically all her bones have increased density with a blurred trabecular pattern. Note however, that there is ossification of the sacro ischial ligaments behind the contrast filled bladder. Ossification of ligaments and tendons in association with dense bones is the hallmark of fluorosis.

Fig. 7: This 29 year old Indian woman presented with bone pain and lethargy. Radiographically all her bones have increased density with a blurred trabecular pattern. Note however, that there is ossification of the sacro ischial ligaments behind the contrast filled bladder. Ossification of ligaments and tendons in association with dense bones is the hallmark of fluorosis.

References

1. Brunning RD, McKenna RW, Rosai J, et al: Systemic mastocytosis. Extracutaneous manifestations. Am J Surg Path 1983; 7:425-438.

2. Webb TA, Li C-Y, Yam LT: Systemic mast cell disease: A clinical and hcmatopathologic study of 26 cases. Cancer 1982; 49:927-938.

3. Sagher F, Evan-Paz Z: Mastocytosis and !he Mast Cell. Chicago, Year Book Medical Publishers, 1967.

4 . Hills E, Dunstan CR . Evans RA: Bone metabolism in systemic mastocytosis . J Bone Joint Surg 1981; 63A:665-669.

5. Rafii M, Firooznia H, Golimbu C, et al: Pathologic fracture in systemic mastocytosis. Clin Orthop 1983; 180:260-267.

6. Korenblat PE, Wedner HJ, Whyte MP, et al: Systemic mastocytosis. Arch tntern Med 1984; 144:2249-2253.

7. Rosenbaum RC. Frieri M . Metcalfe DD: Patterns of skeletal scintigraphy and their relationship to plasma and urinary histamine levels in systemic mastocytosis. J Nuci Med 1984; 25:859-864.

8. Fine JD: Mastocytosis. Int J Dermatol 1980; 19:117-123.

Section Editor: Terrence C. Demos, MD

TABLE

CAUSES OF ADULT OSTEOSCLEROSIS

10.3928/0147-7447-19851001-20

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