This chapter discusses a heterogeneous group of benign tumors or pseudotumors, many of which are characterized by abundant myxoid stroma (intramuscular myxoma, juxta-articular myxoma, cutaneous myxoma, ganglion). Evidence indicates that the cells in these lesions are fibroblastic or have some features of myofibroblasts.
Tumoral calcinosis is a distinct clinical and histologic entity characterized by tumorlike periarticular deposits of calcium hydroxyapatite that are found mainly in the regions of the hip, shoulder, and elbow. The disorder occurs predominantly in otherwise healthy children, adolescents, and young adults; is more often multiple than solitary; and can affect two or more siblings of the same family. Unlike similar calcifications associated with renal insufficiency, hypervitaminosis D, and milk-alkali syndrome, there are no demonstrable abnormalities in calcium metabolism.
The term tumoral calcinosis was coined by Inclan in 1943, but this condition was recognized as an entity much earlier. In 1899, Duret observed this process in siblings, a 17-year-old girl and her younger brother, who had multiple calcifications in the vicinity of the hip and elbow joint. Later, in 1935, Teutschlaender gave a detailed account of another typical case, an 11-year-old girl with multiple lesions in the shoulder and elbow regions that had onset at age 2 years. He thought this process was secondary to fat necrosis and used the term lipid calcinosis . Since these descriptions, numerous other acceptable examples of this growth have been reported under various names, including calcifying bursitis , calcareous tendinitis , and “Kikuyu bursa.” In New Guinea, the natives aptly refer to it as “hip stones.”
There are essentially three forms of tumoral calcinosis ( Fig. 31.1 ): sporadic, familial, and secondary. Most common is the sporadic ( nonfamilial ) and idiopathic form, with onset during the first and second decades of life and rare in patients older than 50. It affects whites and blacks about equally, and there is a slight female preponderance. Most patients present with a solitary large, firm, subcutaneous calcified mass that is slowly growing and usually asymptomatic, typically located in the vicinity of a large joint, especially the trochanteric and gluteal regions of the hip and the lateral portion of the shoulder and the posterior elbow ( Table 31.1 ). The lesion is firmly attached to the underlying fascia, muscle, or tendon and may even infiltrate these structures, but it is unrelated to bone, and the underlying joints are unaffected. Most of these patients are in otherwise good health.
|Site||No. of Cases||Percentage (%)|
The familial form of tumoral calcinosis has two variants, hyperphosphatemic and normophosphatemic, both inherited in an autosomal recessive manner but characterized by distinct genetic mutations. The hyperphosphatemic form, which appears to lie on a spectrum with the so-called hyperostosis-hyperphosphatemic syndrome, is characterized by mutations in GALNT3 , FGF23 , or the KL gene. Biallelic mutations in GALNT3 prevent degradation of the phosphaturic hormone fibroblast growth factor 23 (FGF23), but defective function of any of these three genes results in hyperphosphatemia and ectopic calcifications. In contrast, the normophosphatemic variant is associated with absence of functional SAMD9 , a putative tumor suppressor gene.
Both hereditary forms of tumoral calcinosis have a predilection for young males, especially African Americans. These patients characteristically have elevation of serum phosphate and vitamin D, unless they have the normophosphatemic variant. The lesions are often multifocal and may be associated with a number of other bony abnormalities, including calcifications in the shaft of long bones and cranium as well as ocular and dental abnormalities.
There is also a secondary form of tumoral calcinosis resulting from conditions that promote ectopic calcifications. This encompasses a wide range of disorders, including chronic renal failure (typically associated with secondary hyperparathyroidism), systemic sclerosis, sarcoidosis, and primary hyperparathyroidism. A history of trauma is also often elicited, particularly in those cases presenting in the distal extremities. Treatment of the calcific lesions is best done by treating the underlying disorder.
Radiographic, CT, and MRI examination reveals a subcutaneous conglomerate of multiple, rounded opacities separated by radiolucent lines (fibrous septa) imparting a chicken-wire pattern of lucencies with distinct fluid levels in some of the nodules ( Figs. 31.2 and 31.3 ). Despite the large amounts of calcium in these lesions in patients with idiopathic tumoral calcinosis, there is no evidence of osteoporosis in the skeleton, as seen in patients with renal insufficiency and secondary hyperparathyroidism.
Study of the gross specimen discloses a firm, rubbery mass that is unencapsulated, extends into the adjacent muscles and tendons, and is usually 5 to 15 cm in greatest diameter. On sectioning, the mass consists of a framework of dense fibrous tissue containing spaces filled with yellow-gray, pasty, calcareous material or chalky, milky liquid that is easily washed out, resulting in irregular cystic cavities.
Microscopically, active and inactive phases of the disease can be distinguished, often coexisting in the same lesion ( Figs. 31.4 and 31.5 ). Slavin et al. proposed a three-stage classification scheme to describe these lesions, spanning from cellular examples devoid of calcification to cellular cystic lesions with calcification to hypocellular calcified lesions. In the active (cellular) phase, a central mass of amorphous or granular calcified material is bordered by a florid proliferation of mononucleated or multinucleated macrophages, osteoclast-like giant cells, fibroblasts, and chronic inflammatory elements. Fibrohistiocytic nodules may be seen during the early proliferative phase and are characterized by fibroblast-like cells, foamy histiocytes, occasional multinucleated macrophages, and hemosiderin-laden macrophages. During the inactive phase, there is merely calcified material surrounded by dense fibrous material extending into the adjacent tissues, or a cystic space surrounded by calcium deposits.
Morphologically, the lesions of tumoral calcinosis are identical regardless of whether they are idiopathic, familial, or secondary. Patients with chronic renal disease and secondary hyperparathyroidism are usually older than those with idiopathic tumoral calcinosis, have additional calcifications in visceral organs (e.g., kidney, lung, heart, stomach), and may have abnormally low calcium levels. Similar calcifying soft tissue lesions, but associated with hypercalcemia, occur in patients with primary hyperparathyroidism and milk-alkali syndrome (Burnett syndrome), a rare condition associated with prolonged antacid therapy for peptic ulcer. Patients with excessive osteolysis and mobilization of calcium in destructive neoplastic and infectious process of bone may also develop lesions that can resemble tumoral calcinosis. Laskin et al. described a group of tumoral calcinosis–like lesions that arise in an acral location and are smaller in size and seem to be pathogenetically distinct from tumoral calcinosis. In all these lesions, a detailed clinical history and laboratory data aid in reaching a reliable diagnosis. Some of these cases could represent “tenosynovitis with psammomatous calcifications.” This lesion arises in the distal extremities, predominantly the fingers and toes, mostly in young to middle-aged females, possibly secondary to trauma or repetitive injury. Histologically, the lesion shows tendinous degeneration associated with psammomatous calcifications and a histiocyte-rich infiltrate.
Calcinosis cutis universalis and calcinosis cutis circumscripta likewise are located in the skin and subcutis and are associated with normal serum calcium and phosphorus levels. Calcinosis universalis forms multiple nodules or plaques mainly in children and in about half the cases associated with manifestations of scleroderma, systemic lupus erythematosus, or dermatomyositis. It may ultimately lead to limited mobility, contractures, and ankylosis. Calcinosis circumscripta , on the other hand, chiefly affects middle-aged women and typically involves the hand and wrist, including tendon sheaths. It is associated in a large percentage of cases with Raynaud disease or scleroderma, sclerodactyly, or polymyositis. A related condition is CREST syndrome (calcinosis cutis, Raynaud phenomenon, esophageal hypomotility, sclerodactyly, telangiectasia).
There are also dystrophic calcifications, as in calcareous tendinitis or tenosynovitis, that show a similar microscopic picture but are smaller and develop in damaged tissue secondary to minor injury, ischemic necrosis, or a necrotizing infectious process. Calcifications of tendons and ligaments have also been reported in patients undergoing long-term therapy with etretinate, a synthetic vitamin A derivative prescribed for acne, psoriasis, and various keratinization disorders. Other forms of calcification, such as those of the scrotal skin, are not uncommon, but the exact cause is not clear.
Although there are different familial and nonfamilial causes of tumoral calcinosis, the constellation of histologic features is fairly consistent. The largest study in the literature, by Pakasa and Kalengayi, encompassed patients with familial, idiopathic, and secondary tumoral calcinosis, and therefore the observations are not restricted to a single entity. Minor repeated trauma and tissue injury seem to play a role in the calcifying process in some cases, serving as a trigger mechanism in genetically susceptible individuals, leading to a chain of events that begins with hemorrhage, fat necrosis, fibrosis, and collagenization and ends with collagenolysis and ultimately calcification.
For familial and idiopathic lesions, surgical excision is the treatment of choice. Although the majority of patients with idiopathic lesions are cured, familial lesions have a propensity to recur locally. Medical therapies have included intravenous sodium thiosulfate (effective for calciphylaxis related to end-stage renal disease), with limited success. Treatment of the underlying systemic cause in patients with secondary tumoral calcinosis is critical for effective management.
A dizzying array of benign mesenchymal lesions are characterized by abundant myxoid matrix, inconspicuous stellate- or spindle-shaped cells, and a poorly developed vascular pattern. Most are composed of modified fibroblasts that produce excessive amounts of glycosaminoglycans rich in hyaluronic acid and with little collagen. Intramuscular myxoma, a benign mesenchymal lesion, is of particular importance because it is almost always cured by local excision yet is easily mistaken for a low-grade myxoid sarcoma.
Intramuscular myxoma is a tumor of adult life that occurs primarily in patients 40 to 70 years old. It is rare in young adults and virtually nonexistent in children and adolescents. About two-thirds of the patients are women. There is no evidence of increased familial incidence.
The clinical manifestations are nonspecific, and it is difficult to diagnose this tumor before biopsy and microscopic examination. In most patients the sole presenting sign is a painless, palpable mass that is slightly movable and often fluctuant. As one would expect, pain and occasional numbness, paresthesia, and muscle weakness distal to the lesion are mostly associated with tumors of large size. Because of the relative lack of symptoms, most lesions are present for several months or even years before they are excised. A history of trauma is rarely given, and the tumor is not etiologically related to thyroid dysfunction, as in myxedema.
By far the most common sites of the tumor are the large muscles of the thigh, shoulder, buttocks, and upper arm ( Fig. 31.6 ). Unusual examples have been reported in the muscles of the head and neck, the forearm, scrotum, and small muscles of the hand. The exact location in the musculature varies; some tumors are completely surrounded by skeletal muscle tissue, whereas others are firmly attached on one side to muscle fascia. There are also myxomas of identical appearance that arise from the periosteum, subchondral epiphysis, and joint capsule, discussed later. Angiographic examination reveals a poorly vascularized soft tissue mass surrounded by well-vascularized muscle tissue. Magnetic resonance imaging (MRI) reveals a well-defined, usually homogeneous tumor exhibiting low signal intensity relative to skeletal muscle on T1-weighted images and a hyperintense appearance relative to muscle on T2-weighted images.
Multiple Intramuscular Myxomas and Fibrous Dysplasia
Although most intramuscular myxomas are solitary, there are occasional patients in whom two or more myxomas are present, usually in the same region of the body. Microscopically, these tumors are no different from the solitary myxomas. Almost all are associated with monostotic or polyostotic fibrous dysplasia of bone, generally in the same anatomic region where the myxomas are located ( Mazabraud syndrome ) ( Fig. 31.7 ). In this setting, females are affected much more frequently than males, even more so than in solitary cases. Often there is a long interval between the appearances of the two processes. In most cases the fibrous dysplasia is noted during the growth period, whereas the multiple myxomas, as with their solitary counterparts, become apparent many years later during adult life. On occasion, multiple intramuscular myxomas are detected before the osseous lesions. If specifically sought, radiologically evident bone abnormalities are seen in many patients with intramuscular myxomas.
In the case originally reported by Mazabraud et al., an osteosarcoma developed in a patient with fibrous dysplasia and multiple myxomas, a phenomenon that others have noted. Activating missense mutations in the Arg201 codon of the gene encoding the alpha subunit of G S ( GNAS1 ), the G protein that stimulates cAMP formation, have been recognized in fibrous dysplasia of bone and McCune-Albright syndrome , consisting of polyostotic fibrous dysplasia, sexual precocity, and café au lait spots. Subsequently, these same mutations were identified in sporadic intramuscular myxomas and fibrous dysplasias. Delaney et al. found that 8 of 28 (29%) sporadic intramuscular myxomas had GNAS1 mutations, using a conventional polymerase chain reaction (PCR) technique. However, using a more sensitive COLD ( co amplification at l ower d enaturation temperature) PCR technique, 17 of 28 (61%) sporadic lesions harbored this mutation, which was not detected in any of the low-grade myxofibrosarcomas. In a similar study by Walther et al., only 23 of 63 (36.5%) intramuscular myxomas had detectable mutations of GNAS1 .
The gross appearance is characteristic and varies little from case to case. Most tumors are ovoid or globular and have a glistening gray-white or white appearance, depending on the relative amounts of collagen and myxoid material ( Fig. 31.8 ). They consist of a mass of stringy, gelatinous material with occasional small, fluid-filled, cystlike spaces, often covered by bundles of skeletal muscle or fascial tissue ( Fig. 31.9 ). Although on gross examination most tumors appear to be well circumscribed, many infiltrate the adjacent musculature or are surrounded by edematous muscle tissue, which may serve as a natural cleavage plane for the surgeon. The size varies greatly; the majority measure 5 to 10 cm in greatest diameter, but some lesions are 20 cm or larger.
On histologic examination, the tumor varies little in its appearance and is composed of relatively small numbers of inconspicuous cells, abundant mucoid material, and a loose meshwork of reticulin fibers ( Figs. 31.10 to 31.14 ). Characteristically, mature collagen fibers and vascular structures are sparse. Fluid-filled cystic spaces may be present ( Fig. 31.15 ), but are rarely a prominent feature. The constituent cells have small, hyperchromatic, pyknotic-appearing nuclei and scanty cytoplasm that sometimes extends along the reticulin fibers with multiple processes, giving the cell a stellate appearance ( Fig. 31.16 ). There is no cellular pleomorphism, and there are no multinucleated giant cells. In some cases, there are also scattered macrophages with small intracellular droplets of lipid material. The small size of these droplets and the absence of nuclear deformation or scalloping afford their distinction from lipoblasts. At the periphery, where the tumor merges with the surrounding muscle, fat cells and atrophic muscle fibers are occasionally scattered in the mucoid substance. These residual muscle fibers can be misinterpreted as evidence of rhabdomyoblastic differentiation, resulting in a misdiagnosis of rhabdomyosarcoma.
Some intramuscular myxomas show focal areas of hypercellularity and hypervascularity, which may cause further confusion with a low-grade myxoid sarcoma ( cellular myxoma ) ( Fig. 31.17 ). Nielsen et al. found that 38 of 51 (76%) cases of intramuscular myxoma had hypercellular zones that comprised 10% to 80% of the tumor. However, even in these hypercellular zones, the cells lack nuclear atypia, and there is a paucity of mitotic figures and an absence of necrosis. Areas of more typical hypocellular intramuscular myxoma are always present and allow their definitive recognition.
On immunohistochemistry (IHC), the cells may stain for actins consistent with focal myofibroblastic differentiation. The macrophages containing lipid droplets are negative for S-100 protein, unlike true lipoblasts. The cells are suspended in large amounts of mucoid material that stains positively with Alcian blue and colloidal iron stains and is depolymerized by prior treatment of the sections with hyaluronidase, although this is of little practical diagnostic value. Ultrastructurally, the cells show evidence of fibroblastic differentiation.
Numerous benign and low-grade malignant myxoid neoplasms are apt to be confused with intramuscular myxoma ( Table 31.2 ). At times, the tumor is difficult to distinguish from myxolipoma, myxoid neurofibroma, nerve sheath myxoma, chondroma with myxoid change, and nodular fasciitis, conditions discussed in previous chapters. More important, intramuscular myxoma may be confused with low-grade myxoid sarcomas of various types. Low-grade myxofibrosarcoma, similar to intramuscular myxoma, predominantly affects adults and most often arises as an irregular infiltrating subcutaneous mass, although it can arise in deeper soft tissues. At the low end of the histologic spectrum, myxofibrosarcoma is a hypocellular neoplasm composed of spindle-shaped cells deposited in an abundant myxoid stroma. However, the cells always demonstrate a greater degree of nuclear hyperchromasia and cytologic atypia than those of intramuscular myxoma. Many of these neoplasms also have prominent curvilinear blood vessels, often with perivascular tumoral condensation, although this latter feature is frequently not seen at the low-grade end of the spectrum. Myxoid liposarcoma is characterized by a regular plexiform (“chicken-wire”) vasculature with spindle-shaped or stellate cells with mild cytologic atypia deposited in a myxoid stroma. In addition, the identification of cells with adipocytic differentiation, including well-formed lipoblasts, is useful for this distinction. Extraskeletal myxoid chondrosarcoma is a multinodular tumor composed of nests and cords of cells with densely eosinophilic cytoplasm deposited in a chondroitin sulfate–rich stroma. Although blood vessels are often not conspicuous, these lesions frequently show areas of hemorrhage and hemosiderin deposition at the periphery of the nodules. Perhaps the most difficult distinction is from a low-grade fibromyxoid sarcoma (Evans tumor) , especially when dealing with a cellular intramuscular myxoma or a small biopsy specimen. Low-grade fibromyxoid sarcoma arises in the deep soft tissues of young adults. Histologically, this tumor is composed of cytologically uniform, spindle-shaped cells deposited in a variably collagenous and myxoid matrix, often with a swirling arrangement of tumor cells around thin-walled capillaries. The transition between fibrous and myxoid zones is often abrupt. In difficult cases, evaluation for evidence of a t(7;16) or MUC4 expression by IHC characteristic of this tumor can be extremely helpful. Paraffin-embedded tissue can be used for evaluation by fluorescence in situ hybridization (FISH) using a probe to the FUS gene, which is characteristically rearranged in low-grade fibromyxoid sarcoma.