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Macroscopically, the tumors are firm or even hard, with some cystic areas. They are lobulated, partially encapsulated, fibrofatty masses, within which are cystic spaces containing chalky white fluid and granules of calcium (Fig. 29.1). They vary in size from 1x1 cm to 15x10 cm or more. The small tumors can be recognized histologically before they can be imaged radiologically, although they may be detected earlier by scintigraphy. Some tumors are so large that their boundary becomes unrecognizable and at surgery there seems to be direct involvement of the surrounding muscle. In some patients, the skin is involved and there may be discharging sinuses through which the white milky fluid escapes. Secondary infection is a common complication of discharging sinuses. At least one patient had extension into a knee joint, but tumoral calcinosis does not usually involve a joint.

Histologically the central calcium material is surrounded by a foreign body reaction. The site of origin has been disputed: originally thought to arise in the periarticular bursae, there are some tumors which arise where there are no bursae. Thus, some histologists have stated emphatically that there is no bursal tissue but others suggest that bursal tissue may be destroyed as the reaction extends to fascia. Many of the tumors are deep in fibrofatty tissue and blend with surrounding tissues as they expand. This explains the varying impression of encapsulation. The "capsule" is composed of fibroblasts and compressed collagen fibers: there are numerous septa extending inwards, from 30 to 60 Am thick and having central capillaries. The fibrous capsule may infiltrate and in some lesions replace the adjacent muscle fibers. Then the muscle fibers show varying stages of degeneration and there will be inflammatory cells (mostly lymphocytes, but also some plasma cells, eosinophils, and neutrophils) around the tumor. The spaces between the trabeculae vary considerably in size; they are filled with a granular basophilic material containing fine and coarse calcium granules. They are lined by epithelioid cells and giant cells. Occasionally, there are fat-containing macrophages and in some parts of the tumor there are large, irregularly rounded, eosinophilic plaques which are probably degenerating collagen. Despite the amount of fibrous tissue and degeneration, there is remarkably little chronic inflammation within the majority of tumors. Calcium may be deposited focally, unassociated with cellular reaction. It has been suggested that where there are well-formed lymphoid follicles in the connective tissue, the tumor is likely to recur after excision.

The amount of activity shown histopathologically varies with each tumor. Some of the cysts are lined only with fibrous tissue, but others are lined with irregular layers of inflammatory cells. The tumors grow at different rates and, in those which progress most rapidly, the arterioles will be more numerous, be thicker walled, and have narrow lumens. If active, the cystic spaces contain fluid with calcific granules at the edge of the spaces. Electron microscopy and crystallography show that the crystals are hydroxyapatite. In the center of the rapidly growing areas there is edema and there are giant cells with foamy cytoplasm. All the published histopathological reports record the breakdown of small cysts into larger ones, but necrosis does not occur. In other specimens, the microscopic appearance is that of inactivity without cellular change, but still with cavities full of calcium. The inactive appearance is marked by collagen sclerosis without edema fluid. There may be active and inactive areas within the same tumor. There is no relationship between the activity of the lesion and the age of the patient or the duration of the disease.

Bone (but not cartilage) has been described in the tumors arising from the stroma rather than from the calcium content of the cysts. The general appearance suggests that the central portion of the tumor is older, because there are few capillaries and there is more marked hyalinization of the stroma. There is an insignificant amount of hemosiderin. In sum, three histological stages have been noted:

1. Collagen degeneration with cellular activity but no calcification.
2. Collagen degeneration with cellular activity and calcification.
3. Calcification with no cellular activity and apparently no continuous collagen degeneration.

There are other anatomical changes which, at least in some patients, suggest that the tumors of tumoral calcinosis may be part of a syndrome or more generalized entity. Bone marrow, teeth, and perhaps skin and intervertebral cartilage (discs) may be involved.

Inflammation of bone marrow, with calcific deposits, htas been described as "calcific myelitis" and may be recognized by scintigraphy and, occasionally, radiography. Periosteal reaction is reported in some patients. Dental abnormalities include widened, bulbous roots, calcific deposits in the dental pulp (pulp stones), and obliteration of the tooth cavity. In the skull, dural and diploic calcification has been described, and the facial bones have also shown myelitis. It has even been suggested that diffuse systemic, vascular, and cerebral calcification, with hand and wrist arthropathy, is part of this syndrome. Some of these descriptions have been based on a small number of patients who have been very extensively investigated in research institutions; just how common these associated abnormalities may be in the numerous patients seen in clinical practice in Africa or elsewhere is unknown. While not all laboratory tests may be available, it should be possible to obtain dental (or oblique mandibular) radiographs to learn whether the dental abnormalities are always present or occur only rarely. Departments of nuclear medicine should be able to check for bone marrow or tissue activity.

Laboratory Diagnosis

Biochemical investigations have been disappointing and inconsistent. Sophisticated studies have been undertaken, including calcium, phosphorus, and nitrogen balances before and after surgery. There is probably a high rate of calcium exchange within the tumors, yet skeletal calcium turnover is normal. Some patients have hyperphosphatemia, an elevated renal phosphate absorption threshold, and an elevated serum 1,25-dihydroxyvitamin D; in others, moderate fluctuations in serum calcium and phosphorus have been noted. In the majority the serum calcium, parathyroid hormones, renal function, serum alkaline phosphatase, and other biochemical tests have been normal. There are no significant hematological findings or alterations in any other renal chemistry. Analysis of the creamy contents of the masses has varied in the same way. Some show almost pure calcium carbonate, others a mixture of calcium carbonate and calcium phosphate. The tumors have contained magnesium and traces of ammonia, carbonate, and cystine, but no oxalates or urates. Electron microscopy and crystallography have shown that the "crystals" in the tissues or fluid are hydroxyapatite, and may be the cause of the tissue and marrow inflammatory reaction.

It must be concluded that without histopathology the laboratory investigations do not establish the diagnosis.

Clinical Characteristics

The clinical history is not helpful; the patient will have no related complaints of general ill health or other significant symptoms. There is no polydypsia, polyuria, lethargy, weakness, arthritis, muscle pain, or vascular disturbance. There is no history of renal calculi, and seldom has there been any history of trauma related to the soft tissue tumor. Milk intake is normal or may be low compared with that in Europe and North America. There is no abnormal intake of vitamins, antacids, or other medicines.

The majority of tumors present as a swelling near a joint: the elbows, hips, and shoulders are most commonly affected. Tumors in the hands, knees, ankles, and soles of the feet beneath the metatarsal heads are less common. Tumoral calcinosis also may be found without any relationship to a joint and has been described in the anterior abdominal wall, on the medial aspect of the thigh, in the perineum, and over the lower part of the scapula. (After careful histopathological examination many pathologists have been unable to demonstrate any evidence of a bursa associated with the tumor: others believe that bursal and synovial tissue have been destroyed as the tumor enlarges.)

The smaller masses are usually mobile beneath the skin and subcutaneous tissues, firm (even hard) or cystic, painless, and lobulated or discrete. They may be single or multiple and in different parts of the body. Patients cannot always describe accurately how long the mass has been present, but some tumors have certainly grown rapidly within a few months, whereas others have been present for years and changed very little. Ulceration of the skin and sinus formation can occur, particularly as the tumor enlarges and exerts pressure on the overlying stretched skin. The sinuses may become secondarily infected, but even when there is no discharge from sinuses, the size of the tumor may fluctuate.
Joint movement is seldom restricted, unless the tumor is of considerable size or in a position that impedes normal movement. Some tumors have been reported in which the clinical diagnosis was "carpal tunnel syndrome." One patient, a 41-year-old African woman, had a typical small lobulated mass in a carpal tunnel: removal cured her discomfort.

Some local bone pain and localized soft tissue swelling have been associated with low fever and general malaise in patients in whom active bone marrow is shown by scintigraphy. Clinically this is unusual, because pain is not part of the tumoral calcinosis syndrome unless there is pressure on a nerve or artery, giving rise to referred pain. Such pressure symptoms usually arise late in the development of the tumors. It is probable that clinical examination will not show any other abnormality, unless there are other previously unsuspected similar tumors.

At surgery, the masses are usually well circumscribed although not encapsulated (Fig. 29.1). They have a nodular or lobulated surface which is gray or white. They are not vascular, but may have to be dissected from around a nerve or vessel which has been surrounded, but not invaded. Other tumors have a less clear plane of separation and seem to infiltrate the nearby muscle. Surgery can then be very difficult and complete removal impossible. When the skin has become involved or is ulcerated, secondary infection usually follows and will add to the difficulties of surgery. It is important that the whole tumor be removed, because recurrence at the site of surgery occurs frequently and further removal becomes increasingly difficult: one patient had seven recurrences in 8-1/2 years. It is therefore wise to make a radiological check of both the surgical specimen and the tumor site to be certain there is no remaining calcification before the operation is completed. The optimistic statement in one report that "the prognosis (of tumoral calcinosis) is good" needs to be viewed with caution and related to each tumor.

Incision of the tumor will show multiple cysts of various sizes, containing a chalky liquid under pressure. The tissue is gritty, and the fluid is visually and radiographically opaque because of its high calcium content (Fig. 29.1 D).

Numerous attempts have been made to treat the tumors "conservatively", which seems to mean either doing nothing or embarking on various regimens of low-calcium diets and endocrine and drug therapy, including calcitonin. None have been very satisfactory: doing nothing allows the tumors to grow, usually slowly but sometimes quite quickly. Surgery is the only successful way of treating these masses, but may need to be extensive when the mass is large, and may be difficult because of adjacent vital tissues. Witchcraft and radiotherapy have both been tried (independently), but neither has been successful. Hemorrhage or persistent infection has killed some patients. Microscopically, the tumors have all remained benign. The only exception is a massive tumor in which a mycotic infection developed and metaplastic neoplasia occurred in the granulation tissue. It is probable that this was a complication and not malignant degeneration of tumoral calcinosis.



Fig. 29.1 A-F. The surgical pathology of tumoral calcinosis. A At operation, the tumor surrounded but did not involvethe nerve. B The tumor was divided into two parts to facilitate removal. C Radiography of the specimen to make sure that it has been fully removed. D When the specimen is cut open it contains a milky fluid with a high calcium content. E Another, more necrotic tumor removed from the buttock of a middle-aged African woman. F The typical histological findings.

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