The etiology of deep fibromatoses is almost certainly multifactorial because genetic, endocrine, and physical factors seem to play important pathogenetic roles. Features suggesting an underlying genetic basis are the occasional occurence in siblings and in patients with familial adenomatous polyposis and Gardner syndrome (see below). Mutations of the adenomatous polyposis coli (APC)/β-catenin pathway are identified in most sporadic and FAP-associated deep fibromatoses. ^,

Endocrine factors are clearly implicated by the frequent occurrence of this tumor in the abdominal wall, during or after pregnancy, and by reports of these tumors regressing with menopause. The reported inhibitory effect of antiestrogenic agents, such as tamoxifen and raloxifene, also supports the role of hormonal factors in tumor development. ^, Endocrine factors may also contribute to the development of fibromatoses of the somatic soft tissues.

Trauma or therapeutic irradiation may also serve as trigger mechanisms, as fibromatoses have been reported in the chest wall following trauma and reconstructive mammoplasty. ^, An antecedent history of trauma has been reported in up to 28% of cases in some series. ^, Fibromatoses have also been reported in association with radical nephrectomy sites, peritoneal dialysis catheters, and various types of abdominal surgery sites. ^, It has been suggested that pregnancy-associated stretching of the abdominal wall and minute muscle tears may contribute to the development of abdominal wall fibromatoses. FAP/Gardner-associated fibromatoses commonly arise following intestinal surgery. ^,

Clinical Features.

Fibromatoses of the somatic soft tissue occur in patients between puberty and 40, with a peak incidence between 25 and 35 years. In the Mankin study of 234 patients, the mean age was 37 years, and 61% were female. Children are affected infrequently; only 5% of patients in a series from the Mayo Clinic were 10 years or younger. Almost all large studies have found a definite female predilection. ^,

Most patients present with a deeply situated, firm, poorly circumscribed mass that has grown insidiously and causes little or no pain. Decreased mobility of an adjacent joint may occur. Neurologic symptoms, including numbness, tingling, stabbing or shooting pain, or motor weakness, may occur when the lesion compresses nearby nerves.

Fibromatoses of the somatic soft tissue most often involve the musculature of the shoulder, followed by the chest wall and back, thigh, and head and neck. In the shoulder region, the growth presents most often in the deltoid, scapular region, supraclavicular fossa, or posterior cervical triangle, where it may extend into the anterior or posterior portion of the axilla and upper arm. Because of the numerous vital structures at this site, including nerves of the brachial plexus and large vessels, complete surgical excision of tumors in this location is often not possible. Fibromatoses in the region of the pelvic girdle primarily affect the gluteus muscle. In contrast, those in the region of the thigh affect the quadriceps muscle and muscles of the popliteal fossa. Fibromatoses of the breast may arise in the mammary gland or represent an extension of a lesion arising in the aponeurosis of the chest wall or shoulder girdle. Although an association between fibromatoses involving the breast and breast implants has been suggested, a detailed review of this subject by Balzer and Weiss did not show evidence for a causal relationship.

Fibromatoses are also common in the head and neck. Overall, roughly 25% occur in these locations, ^, including nearly one-third of cases occurring in children. ^, Clinically, fibromatoses of the head and neck are often more aggressive than those arising elsewhere and are capable of massive destruction of adjacent bone and erosion of the base of the skull. They occasionally encroach on the trachea, sometimes with a fatal outcome.

Up to 5% of somatic soft tissue fibromatoses are multicentric, ^, usually involving the same anatomic region. In most cases, the second growth develops proximal to the primary lesion. Less often, multicentric tumors may arise in both soft tissue and intraabdominal locations.

Radiographically, soft tissue fibromatoses appear as a mass that interrupts the adjacent intermuscular and soft tissue planes; they may encroach on adjacent bone, resulting in pressure erosion or superficial cortical defects. Up to 80% of affected patients have multiple minor bony anomalies of the mandible, chest, and long bones, including cortical thickening, exostoses, and areas of cystic translucence or compact islands in the femur (or both). As with other soft tissue tumors, computed tomography (CT) and magnetic resonance imaging (MRI) are extremely helpful in assessing tumor extent before surgery. ^, The use of advanced imaging techniques prior to surgery has been noted to result in lower rates of local recurrence.

Fibromatoses of the abdominal wall usually occur in young, gravid, or parous women during gestation or, more frequently, during the first year following childbirth. Rare examples have been reported in children of both genders (especially boys) and adult men. They arise from the musculoaponeurotic structures of the abdominal wall, especially the rectus and internal oblique muscles and their fascial coverings. Most tumors measure 3–10 cm in greatest dimension and tend not to cross the abdominal midline.

Mesenteric fibromatosis represents the most common primary tumor of the mesentery and accounts for approximately 8% of all fibromatoses. Although most cases are sporadic, some are associated with familial adenomatous polyposis (FAP)/Gardner syndrome, trauma, or hyperestrogenic states. Most often, these tumors are located in the mesentery of the small bowel, but some originate from the ileocolic mesentery, gastrocolic ligament, omentum, or retroperitoneum ( Fig. 9.1 ). Most patients with mesenteric fibromatosis present with an asymptomatic abdominal mass, although some have mild abdominal pain. Less often, patients present with gastrointestinal bleeding or an acute abdomen secondary to bowel perforation. ^, Occasionally, the tumor is found incidentally at laparotomy performed for some other reason, including patients undergoing a bowel resection for FAP. Most are large at the time of excision, with the majority measuring 10 cm or more. Many have an initial phase of rapid growth, and complications may be caused by compression of the ureter, development of a ureteral fistula, or compression of the small or large intestine, sometimes complicated by intestinal perforation. ^,

( A ) Mesenteric fibromatosis is grossly often more edematous. Low-power view of mesenteric fibromatosis in Gardner syndrome showing uniform fibrocollagenous growth infiltrating wall of small bowel ( B ).

Gardner syndrome (an autosomal dominant disease characterized by intestinal polyposis, osteomas, fibromas, epidermal or sebaceous cysts, and mesenteric fibromatoses) is more common in women than in men and is usually diagnosed in adults 25–35 years of age. Mesenteric fibromatoses occur in roughly 10%–15% of patients with FAP/Gardner syndrome, an estimated 800-fold increased risk, ^, usually arise 1–2 years after excision of a diseased portion of the intestinal tract and represent the most common cause of death in polyposis patients following colectomy. It has been estimated that almost 70% of FAP patients who develop fibromatoses had prior abdominal surgery. Compared with sporadic lesions, FAP-associated mesenteric fibromatoses arise in slightly younger patients (36 vs. 42 years), tend to be larger, and are more often multicentric. A meta-analysis of 10 published studies has shown a positive family history of a desmoid tumor to be the only factor predictive of the development of this lesion in FAP patients. There are no morphologic features that distinguish Gardner syndrome-associated and sporadic fibromatoses.

Fibromatosis of the pelvic region typically involves the iliac fossa and lower portion of the pelvis, where it manifests as a slowly growing palpable mass that is asymptomatic or causes only slight pain. Clinically, it is often mistaken for an ovarian neoplasm or a mesenteric cyst. Large tumors in this location may encroach on the urinary bladder, vagina, or rectum, or they may cause hydronephrosis or compress the iliac vessels. ^, Most occur in young women.

Grossly, fibromatoses are typically confined to the musculature and the overlying aponeurosis or fascia ( Figs. 9.2 and 9.3 ). Large tumors may extend along the fascial plane, infiltrate the overlying subcutaneous tissue ( Fig. 9.4 ), and erode underlying bone. Most tumors measure 5–10 cm in greatest dimension, although lesions as large as 20 cm have been reported. They are usually firm and “gritty,” with a glistening white, coarsely trabeculated cut surface resembling scar tissue (see Figs. 9.2 and 9.3 ). The gross distinction of fibromatoses from areas of scarring may be very challenging.

Extraabdominal fibromatosis involving chest wall. The cut surface reveals a trabecular appearance reminiscent of that seen in uterine leiomyomas.

Extraabdominal fibromatosis involving pectoralis muscle.

( A ) Extraabdominal fibromatosis invading striated muscle tissue. ( B ) Atrophic muscle at periphery of fibromatosis should not be mistaken for cellular atypia. ( C ) Tentacles of fibromatosis invading fat and surrounded by typical lymphoid aggregates.

The morphologic features of deep fibromatoses are essentially identical in all anatomic locations. However, some minor variations may be seen, especially in mesenteric lesions, which are often edematous. All fibromatoses are poorly circumscribed and infiltrate the surrounding tissues ( Fig. 9.4A ) with striking skeletal muscle atrophy and small lymphoid aggregates, a useful diagnostic clue ( Fig. 9.4B and C ). Mesenteric fibromatoses may invade the bowel wall ( Fig. 9.1 ). The tumors grow in long, sweeping fascicles or graceful arcs ( Figs. 9.5 and 9.6 ) composed of uniform, “active-appearing” myofibroblastic spindled cells with tapered nuclei and lightly eosinophilic cytoplasm ( Fig. 9.7 ). The nuclei are small and pale staining with one to three pinpoint nucleoli and lack hyperchromatism or nuclear irregularity ( Figs. 9.8A and 9.9 ). Multinucleated tumor giant cells are occasionally present and can be mistaken for pleomorphic tumor cells ( Fig. 9.7C ). Scattered mitotic figures may be identified, and there is no “maximal” number of mitotic figures that distinguish fibromatoses from fibrosarcomas. Fibromatoses typically contain thin-walled, dilated vessels, often with some perivascular edema, and recognition of this vascular pattern assists in the correct diagnosis of these tumors.

Interlacing bundles of fibroblasts separated by variable amounts of collagen in extraabdominal fibromatosis. Pattern can vary from fascicular ( A ) to vaguely whorled ( B ).

Medium-power view illustrating fascicular growth pattern of fibromatosis.

Wavy, widely spaced cells arranged in parallel fashion often likened to a “school of fish” ( A ). Mitotic figures ( B ) and giant cells ( C ) may be seen in fibromatosis.

( A ) Wavy spindle cell having indistinct cytoplasmic borders and finely stippled nuclear chromatin in fibromatosis. ( B ) Nuclear β-catenin expression and LEF1 expression( C ) in fibromatosis.

Cross section of fascicle of fibromatosis showing rounded cell profiles.

The foregoing describes the typical appearance of a fibromatosis, but these tumors can also vary from highly myxoid to very hyalinized ( Fig. 9.10A ). In myxoid lesions, which are more common in mesenteric locations, the cells are more widely spaced and more randomly arranged ^, ( Fig. 9.10B ). Myxoid change seems to be especially common in Gardner-associated fibromatoses. Hyalinization can be restricted to scattered dense keloidal collagen bundles ( Fig. 9.10C ) or almost completely replace the tumor ( Figs. 9.10D and 9.11 ). Recognition of the characteristic vascular pattern of fibromatoses (dilated vessels with perivascular edema) is quite helpful in the recognition of myxoid or hyalinized tumors.

Stromal variations in fibromatosis ranging from hyalinized ( A ) to myxoid ( B ) to keloid-like( C and D ). Note fascicular pattern is not as apparent in these areas.

Totally hyalinized fibromatosis with ectatic staghorn vessels. The presence of these vessels suggests the diagnosis of fibromatosis as opposed to reactive fibrosis.

The IHC features of all subtypes of deep fibromatoses are similar. The spindle cells show variable staining for smooth muscle actin and muscle-specific actin, typically in a “tram-track” pattern, consistent with fibroblastic/myofibroblastic differentiation. Desmin expression is usually absent, but can occasionally be found in scattered tumor cells, and should not be misinterpreted as evidence of a smooth muscle tumor. H-caldesmon expression is not seen. Approximately 70% of fibromatoses show aberrant nuclear accumulation of β-catenin, although this finding is not perfectly specific for fibromatoses ( Fig. 9.8B ). Interpretation of β-catenin immunostains can be quite challenging, owing to its expression on cell membranes, and in some cases, is confined to only scattered tumor cell nuclei. Lymphoid-enhancer factor 1 (LEF1) has also been found to be expressed in deep fibromatoses ( Fig. 9.8C ), and we have found it a helpful immunohistochemical stain in conjunction with β-catenin. It should be kept in mind, however, that LEF1 staining may be present in scars and other benign tumors including nodular fasciitis and perineurioma. ^, In a recent study by Jobbagy et al., the sensitivity and specificity of LEF1 immunohistochemistry in fibromatoses was 94% and 70%, respectively. However, the combination of LEF1 and β-catenin in fibromatoses improved the specificity to 96% compared to the specificity of β-catenin alone (88%). Although some older studies have reported CD117 (KIT) expression in fibromatoses, ^, this does not seem to be the case with newer antibodies and immunohistochemical techniques. DOG1 expression is not seen.

Gardner syndrome is a genetically determined, autosomal dominant disease caused by a germline abnormality of the APC gene on the long arm of chromosome 5. ^, Tumors arising in the setting of FAP/Gardner syndrome harbor inactivating mutations of APC . Up to 85% of sporadic lesions harbor mutations in the gene that codes for β-catenin ( CTNNB1 ). Molecular assays for CTNNB1 mutations using paraffin-embedded tissue may be extremely useful in difficult-to-diagnose lesions, particularly in distinguishing recurrent/residual fibromatosis from scar tissue. Mutations of this gene are not found in the spindle cell lesions likely to enter the differential diagnosis. CTNNB1 mutations result in intranuclear accumulation of β-catenin protein, detectable by IHC.

Deep fibromatoses in any location are nonmetastasizing tumors with no risk of malignant progression. Thus, the treatment of these lesions was historically directed toward complete surgical resection, which often resulted in significant morbidity or was impossible to achieve due to local anatomic constraints. Additionally, despite aggressive surgery, local recurrences were common, with up to 76% local recurrence, for example, in a series of 203 consecutive patients treated with surgery over a 35-year period at a single large cancer hospital. As might be expected, the rate of local recurrence is closely related to anatomic location, with a large review by Easter and Halasz noting local recurrence rates of 24%, 43%, and 77% in abdominal wall, somatic soft tissue, and intraabdominal/pelvic tumors, respectively. A more recent, large, retrospective series from Memorial Sloan Kettering Cancer Center, showed local recurrence-free survival of 90% for abdominal wall tumors, as compared with 60% for extremity tumors and 76% for intraabdominal tumors. As might be expected, the risk of local recurrence has been shown to be closely associated with margin status, with a “meta-analysis” by Leithner and co-workers finding a 27% local recurrence rate in tumors excised with wide or radical microscopic margins, as compared to 72% of tumors resected in a marginal or intralesional fashion. The risk of local recurrence is also higher in younger patients and for larger tumors. The risk for local recurrence is significantly higher for intraabdominal tumors occurring in patients with FAP (90%) as compared to sporadic tumors (12%), likely reflecting the frequent multicentricity of FAP-associated fibromatoses.

Over the past 20 years, however, the paradigm for treating patients with desmoid tumors has undergone a dramatic change, beginning with the seminal study of Bonvalot et al., demonstrating that a significant percentage of primary, resectable fibromatoses either stabilized or regressed, without any therapy. This finding has subsequently been confirmed in several studies. Several large clinical trials have convincingly demonstrated that patients with fibromatoses may be managed primarily with active surveillance, with 3-year progression-free survival figures ranging from 53% to 58%. In fact, in one of these series, spontaneous regression was observed initially in 25% of patients and in 31% of patients following a period of progression. Current treatment guidelines recommend surgery in patients with mesenteric fibromatoses at risk for hemorrhage or gastrointestinal complications or for patients who progress while under surveillance or while on medical therapy, in particular for those with abdominal wall tumors.

There is somewhat conflicting data on whether the specific mutational event present in fibromatoses impacts prognosis. There is data to suggest that CTNNB1 -mutated tumors have a worse recurrence-free survival than wild-type tumors, ^, and that patients with APC mutations have worse overall survival. Although it has been suggested that certain CTNNB1 mutations, in particular the S45F mutation in exon 3, are associated with a worse prognosis, this has not been confirmed in other studies. Possibly, differences in the relative proportions of tumors in different anatomic locations may explain these different findings.

A wide variety of adjuvant therapies are now available for patients with recurrent or progressive fibromatoses, including radiotherapy, cryoablation, and a wide variety of medical therapies, including new, exciting agents such as the gamma-secretase inhibitor nirogacestat, which targets the Notch signaling pathway, and tegavivint, a transducin beta-like protein one inhibitor involved in beta-catenin degradation.

Fibromatosis most closely resembles adult-type fibrosarcoma on the one extreme and benign fibroblastic processes on the other. Adult-type fibrosarcoma is more uniformly cellular, and the cells are arranged in a more consistent, sweeping fascicular (herringbone) growth pattern. Unlike fibromatosis, the cells are often overlapping and separated by less collagen. The nuclei are more hyperchromatic and atypical and have more prominent nucleoli than those found in fibromatosis. Although it is important to remember that there can be considerable overlap in levels of mitotic activity between fibromatosis and adult-type fibrosarcoma, high mitotic counts (>1 mitotic figure per 10 high-power fields [hpf]) throughout a tumor should at least arouse some suspicion of fibrosarcoma. A small biopsy specimen may lead to a misdiagnosis because some examples of adult-type fibrosarcoma have areas that are indistinguishable from fibromatosis and vice versa.

Fibromatosis can also be difficult to distinguish from reactive fibroblastic/myofibroblastic proliferations following injuries such as trauma, minor muscle tear, or intramuscular injection. Cytologically, these reactive proliferations are composed of cells that are essentially indistinguishable from those found in fibromatosis. The low-magnification appearance is much more helpful in distinguishing these entities because reactive processes have a more variable growth pattern and frequently have focal hemorrhage or hemosiderin deposition, often situated along vascular structures. In some cases, iron stains highlight hemosiderin that is difficult to identify on hematoxylin-eosin–stained sections. In addition, an infiltrative growth pattern is much more characteristic of fibromatosis. β-Catenin and LEF1 immunohistochemistry (IHC) may be of some value in this distinction, although these are not perfect ancillary tests.

Confusion with myxoma is possible, particularly if only a small biopsy is available for examination. Myxomas are usually paucicellular, with the cells separated by an abundant myxoid matrix. In contrast, fibromatosis always displays a greater degree of cellularity and more interstitial collagen than myxoma.

In the breast, fibromatosis should be distinguished from metaplastic carcinoma, malignant phyllodes tumor, and benign processes such as nodular fasciitis and keloid. In general, IHC for keratins, in particular high-molecular-weight keratins, β-catenin, and LEF1 helps distinguish fibromatosis from metaplastic carcinoma . Metaplastic carcinomas also tend to show greater nuclear atypia and often contain small foci of cellular clustering (“proliferation centers”), a helpful morphologic feature. Interestingly, there is a higher rate of APC mutations and a lower rate of CTNNB1 mutations in desmoid-type fibromatosis of the breast. Phyllodes tumors can usually be identified with extensive sampling to reveal foci of epithelial proliferation. Identification of MED12 mutations may also be helpful in the diagnosis of phyllodes tumors, although this test is not yet widely available.

The differential diagnosis for intraabdominal fibromatosis also includes sclerosing mesenteritis , a lesion also sometimes referred to as mesenteric panniculitis and mesenteric lipodystrophy . As with mesenteric fibromatosis, sclerosing mesenteritis typically involves the small bowel mesentery and presents as a large solitary mass, although multiple lesions or diffuse mesenteric thickening may also be seen. Histologically, sclerosing mesenteritis is composed of variable amounts of fibrosis, chronic inflammation, and fat necrosis. Any of these three components may predominate in a given lesion. In difficult cases, IHC staining for β-catenin and LEF1 can be helpful because mesenteric fibromatosis consistently shows strong nuclear β-catenin and LEF1 staining, whereas sclerosing mesenteritis does not express these antigens ( Table 9.1 ).

Inflammatory myofibroblastic tumor (IMT) of the mesentery and retroperitoneum is also a diagnostic consideration, but this lesion is more cellular, has more pronounced cytologic atypia, and is more inflamed than mesenteric fibromatosis. Moreover, many (but not all) cases of IMT express ALK-1 protein, which is not found in mesenteric fibromatosis.

Also included in the differential diagnosis is idiopathic retroperitoneal fibrosis , also known as Ormond disease . This is an uncommon fibroinflammatory process characterized by diffuse or localized fibroblastic proliferation and a chronic lymphoplasmacytic infiltrate in the retroperitoneum, causing compression or obstruction of the ureters, aorta, or other vascular structures. It is more common in men, and most patients present in the fifth or sixth decade of life. ^, Most patients present with vague, nonspecific abdominal symptoms, but some have weight loss, nausea and vomiting, anorexia, or fever. Although many cases are idiopathic, some are clearly drug-related (methysergide, pergolide), and up to 50% of cases are immunoglobulin G4 (IgG4) related (see later). Grossly, idiopathic retroperitoneal fibrosis is dense, white, and plaque-like, usually arising at or just below the aortic bifurcation. With progression, it surrounds the aorta and inferior vena cava and spreads through the retroperitoneum in a perivascular distribution. Histologically, broad anastomosing bands of hyalinized collagen are associated with fibroblastic proliferation and lymphoplasmacytic infiltrate with occasional germinal centers. The aorta, which is surrounded by the proliferation, usually shows severe atherosclerosis, with protrusion of atherosclerotic debris through the media into the adventitia with intramural chronic inflammation. In some cases, a large number of IgG4-immunoreactive cells are found within the infiltrate, suggesting (in up to 50% of cases) that it is part of a larger group of IgG4-related sclerosing diseases. ^, Immunosuppressive agents are effective in the treatment of this condition.

Distinguishing mesenteric fibromatosis from mesenteric gastrointestinal stromal tumor (GIST) can be difficult in some cases. ^{, ,} Distinguishing between these lesions is of clinical significance because of their vastly different therapeutic and prognostic implications. In a study of 25 cases of mesenteric fibromatosis, Rodriguez et al. found that GIST was by far the most common misdiagnosis, occurring in 52% of the cases. The histologic features of GIST are heterogeneous and can range from bland spindle cell tumors to highly cellular and overtly malignant epithelioid tumors. The confusion between these entities is compounded by and, in large part, may have arisen because of reports of KIT (CD117) expression in mesenteric fibromatosis. Regardless of the immunophenotypic findings, mesenteric fibromatosis is sufficiently distinct from GIST on a morphologic basis that IHC may not be necessary for diagnostic purposes in most cases ( Table 9.2 ).

The principal manifestation of the disease is a nontender, painless swelling or mass that ranges from 1 to 20 cm. Up to one-third of the tumors are present at birth; in most cases the mass becomes evident during the first year of life. In the Armed Forces Institute of Pathology (AFIP) series, 20 of 53 tumors (38%) were present at birth, and 27 (51%) were noted before age 3 months. Similarly, 40 of 110 cases (36%) reported by Soule and Pritchard were congenital. Males are affected slightly more often than females. The principal sites of involvement are the extremities, especially the regions of the foot, ankle, and lower leg and the hand, wrist, and forearm. The next most common sites of involvement are the trunk and head and neck regions, although these tumors have also been reported in virtually every anatomic site. ^,

Radiographic examination may show, in addition to a soft tissue mass, cortical thickening, bending deformities, and rarely extensive destruction of the underlying bone ^, ( Fig. 9.12 ). Both MRI and ultrasound are useful in the evaluation of these tumors, including the detection of congenital tumors in utero. Interestingly, some newborns with this tumor show evidence of hypercalcemia, ^, presumably caused by the production of parathormone-related protein. ^,

Radiograph ( A ) and clinical photograph ( B ) of infantile fibrosarcoma in 1-day-old infant.

The tumors vary considerably in size. Some are only a few centimeters when first detected, whereas others are extremely large and may replace the entire distal portion of the involved limb. Some patients present with a large exophytic mass that ulcerates the overlying skin. Most are poorly demarcated, fusiform or disk-shaped, and have a gray-white or pale-pink cut surface. Large tumors may be greatly distorted by central necrosis or hemorrhage ( Fig. 9.13 ), whereas others show extensive myxoid or cystic change.

Infantile fibrosarcoma of right shoulder in 1-month-old boy, showing marked interstitial hemorrhage.

Histologically, most infantile fibrosarcomas are composed of sheets of solidly packed, spindle-shaped cells that are relatively uniform in appearance and arranged in bundles or fascicles, imparting a herringbone appearance. The cells show minimal nuclear pleomorphism and are mitotically active, but their numbers vary from area to area in the same tumor. Tumors with abundant collagen tend to be more fasciculated and often approach the appearance of an adult-type fibrosarcoma (sometimes referred to as the desmoplastic type). Tumors with minimal amounts of collagen, on the other hand, show a lesser degree of cellular polarity and consist of small, more rounded, immature-appearing cells with only focal evidence of fibroblastic differentiation ( medullary type) ( Figs. 9.14–9.16 ). Bizarre cells and multinucleated giant cells are rare. Scattered chronic inflammatory cells, particularly lymphocytes, are another common, sometimes striking feature of infantile fibrosarcoma. A branching, “staghorn” vascular pattern may be prominent ( Fig. 9.17 ).

Infantile fibrosarcoma composed of uniform, well-oriented fibroblasts arranged in fascicular growth pattern.

Infantile fibrosarcoma with immature-appearing fibroblasts and intralesional lymphocytes.

High-power view of immature-appearing fibroblasts with a prominent lymphocytic infiltrate, characteristic of infantile fibrosarcoma.

Infantile fibrosarcoma composed of immature-appearing fibroblasts arranged around a prominent hemangiopericytoma-like vascular pattern.

By IHC the spindle cells of infantile fibrosarcoma stain variably for muscle markers, including muscle-specific actin (MSA), smooth muscle actin (SMA), and h-caldesmon. ^, The more primitive-appearing ovoid cells tend not to express these muscle markers. As discussed later, NTRK3 aberrations are characteristic of this tumor, and immunoreactivity with the Pan-Trk antibody correlates well with the presence of NTRK3 fusions. ^,

Numerous studies have noted nonrandom gains of chromosomes 11, 20, 17, and 8 (in descending order of frequency) in infantile fibrosarcomas. Using fluorescence in situ hybridization (FISH), Schofield et al. found gains of these chromosomes (in various combinations) in 11 of 12 infantile fibrosarcomas in patients younger than 2 years, but not in morphologically similar tumors occurring in older children. Interestingly, one of three cases of “cellular fibromatosis” also showed these cytogenetic abnormalities, suggesting that some infantile fibrosarcomas may mimic fibromatosis.

Most infantile fibrosarcomas and cellular mesoblastic nephromas have the same diagnostic chromosomal translocation: t(12; 15) (p13; q25). ^, This translocation results in a fusion of the ETV6 gene on chromosome 12 with the neurotrophin-3 receptor NTRK3 (also known as TRKC ) gene on chromosome 15. Although this translocation is difficult to detect by conventional cytogenetics, it can be readily demonstrated by reverse-transcriptase polymerase chain reaction (RT-PCR) or FISH. Given the similar histologic and genetic findings in infantile fibrosarcoma and cellular mesoblastic nephroma, these two lesions likely represent slightly different manifestations of the same entity in different locations. Interestingly, a number of other tumors, including secretory breast carcinoma, rare subtypes of acute myeloid leukemia, and mammary-type secretory carcinoma of skin and salivary glands, also harbor this same translocation. Rare cases of infantile fibrosarcoma with an EML4::NTRK3 fusion or an LMNA::NTRK1 fusion have also been reported. ^,

With more widespread use of molecular genetic testing, infantile fibrosarcoma-like tumors harboring rearrangements of genes other than NTRK3 are increasingly recognized. For example, Kao et al. recently identified a small group of infantile fibrosarcoma-like, BRAF -rearranged spindle cell sarcomas. Similar tumors, harboring FGFR1 rearrangements, have also been reported by Warmke et al. It is not yet clear whether these tumors should be considered molecular genetic variants of infantile fibrosarcoma or distinct entities, and it is anticipated that the list of similar tumors will only grow.

Despite often-alarming clinical presentation and morphology, the clinical course of infantile fibrosarcoma is favorable. Of the 48 patients with follow-up in the Chung and Enzinger study, only eight (17%) developed one or more local recurrences 6 weeks to 10 years after the initial excision. Only four (8%) patients died of metastatic disease, and one patient was living 6.5 years after a lobectomy for a metastatic tumor. The 5-year survival rate in this series was 84%. The recurrent and nonrecurrent groups showed no demonstrable differences regarding tumor site, age at onset, or tumor size. However, the initial therapy was more radical for the tumors that neither recurred nor metastasized. Most studies have found that cellularity, mitotic counts, and extent of tumor necrosis do not correlate well with clinical behavior. ^, Some have found that tumors in the axial skeleton behaved more aggressively than those found peripherally. There are reports of incompletely excised infantile fibrosarcomas that have not recurred or metastasized after several years, as well as sporadic reports of spontaneous regression.

Despite rapid growth and a high degree of cellularity, most infantile fibrosarcomas are cured by wide local excision. For patients with unresectable disease, adjuvant cytotoxic agents of various types have been shown to be of value. ^, More recently, however, adjuvant treatment with the TRK inhibitor Larotrectinib has resulted in a very high rate of complete, sustained response in children with NTRK -rearranged tumors, with generally low toxicity. It is anticipated that TRK inhibition will become the new standard of care for patients with this disease.

Infantile fibrosarcomas may be confused with a variety of other pediatric mesenchymal neoplasms. However, in most cases the clinical presentation, cellular uniformity, solid growth pattern, fascicular arrangement, stromal lymphocytes, and absence of any other form of cellular differentiation permit a reliable diagnosis. In the appropriate histologic context, of course, molecular genetic confirmation of ETV6::NTRK3 is diagnostic.

Spindle cell rhabdomyosarcomas harboring VGLL3 or NCOA2 rearrangements may be difficult to distinguish from infantile fibrosarcomas. These tumors are most often encountered in the paratesticular region and the head and neck, but may also occur at other sites, including the extremities. Histologically, they may be almost indistinguishable from infantile fibrosarcoma, although close inspection often identifies scattered tumor cells with distinctly eosinophilic cytoplasm, suggesting skeletal muscle differentiation. IHC for skeletal muscle markers (e.g., desmin, myogenin, and MYOD1) and next-generation sequencing studies will allow these distinctions without great difficulty.

Primitive myxoid mesenchymal tumor of infancy, another rare pediatric tumor composed of primitive cells deposited in an abundant myxoid stroma, can also resemble infantile fibrosarcoma. Recently, this tumor has been found to be characterized by recurrent BCOR internal tandem duplications; expression of BCOR and BCL6, and absent TRK expression allows for its distinction from infantile fibrosarcoma. ^,

IMTs have been reported in virtually every anatomic site. The most common sites of extrapulmonary IMT are the mesentery and omentum. ^, In a seminal study by Coffin et al., 36 of 84 (43%) extrapulmonary lesions arose at these sites. Unusual sites of involvement include the thyroid, central nervous system, uterus, and various parts of the gastrointestinal tract. ^, Although the age range is broad, extrapulmonary IMTs show a predilection for children, with a mean age of approximately 10 years. Females are affected slightly more often than males.

Presenting symptoms depend on the site of primary tumor involvement. Patients with intraabdominal tumors typically complain of abdominal pain or an abdominal mass with increased girth, occasionally with signs and symptoms of gastrointestinal obstruction. Some patients have prominent systemic manifestations, including fever, night sweats, weight loss, and malaise, possibly related to the secretion of cytokines, including interleukin (IL)-6. Laboratory abnormalities are present in a small number of patients and include an elevated erythrocyte sedimentation rate, anemia, thrombocytosis, and hypergammaglobulinemia, which often resolve when the lesion is excised. ^,

Grossly, most IMTs are lobular, multinodular, or bosselated with a hard or rubbery cut surface that appears white, gray, tan-yellow, or red ( Fig. 9.19 ). Those with calcifications cut with a gritty sensation. Although most are solitary tumors, multiple nodules generally restricted to the same anatomic location are found in almost one-third of cases. ^, The tumors range in size from 2 to 20 cm, but most are 5–10 cm.

Gross appearance of inflammatory myofibroblastic tumor in left upper lobe of lung of 21-year-old woman.

Various histologic patterns may be seen, and different patterns may be found in the same tumor. Some IMTs are composed predominantly of cytologically bland spindle- or stellate-shaped cells loosely arranged in a myxoid or hyaline stroma with scattered inflammatory cells, somewhat resembling nodular fasciitis. Others are composed of a compact proliferation of spindle-shaped cells arranged in a storiform or fascicular growth pattern ( Figs. 9.20–9.24 ). In these foci, the nuclei tend to be elongated but lack significant hyperchromasia or cytologic atypia. Mitotic figures are variable but not atypical. These foci are usually associated with a prominent lymphoplasmacytic infiltrate, occasionally with the formation of germinal centers. Other foci may be sparsely cellular, with cytologically bland cells deposited in a sclerotic stroma resembling a scar. Lymphocytes and plasma cells are often seen in these foci, and small punctate areas of calcification or metaplastic bone may be observed.

Inflammatory myofibroblastic tumor. (A) Low-power view showing admixture of spindle-shaped and ovoid cells with a prominent inflammatory infiltrate. (B) high-power view of inflammatory myofibroblastic tumor. Note the conspicuous admixture of lymphocytes and plasma cells.

Inflammatory myofibroblastic tumor. Cytologically bland spindle-shaped cells are intimately admixed with a predominantly plasmacytic infiltrate.

High-power view of plump spindle-shaped cells admixed with inflammatory cells in inflammatory myofibroblastic tumor.

Less cellular inflammatory myofibroblastic tumor than depicted in Figs. 9.21 and 9.22 . Plate-like collagen is present.

Hypocellular inflammatory myofibroblastic tumor composed of predominantly sclerotic fibrous tissue with scattered spindle-shaped and inflammatory cells.

In some lesions, there is pronounced cytologic atypia, with cells containing large nuclei and distinct nucleoli ( Figs. 9.25–9.27 ). Some tumors have large histiocytoid cells resembling ganglion cells or Reed-Sternberg cells. In 2011, Mariño-Enriquez et al. described 11 IMTs arising within the abdomen (mesentery or omentum) with prominent epithelioid morphology, a unique pattern of nuclear membrane or perinuclear ALK immunoreactivity ( Fig. 9.28A ), and aggressive clinical behavior, coining the term epithelioid inflammatory myofibroblastic sarcoma. Subsequently, other similar-appearing cases have been reported in the literature.

Epithelioid inflammatory myofibroblastic sarcoma composed of sheets of atypical ganglion-like cells.

Atypical spindled areas within an epithelioid inflammatory myofibroblastic tumor.

High-power view of atypical ganglion-like cells in epithelioid inflammatory myofibroblastic sarcoma.

Immunostaining in epithelioid inflammatory myofibroblastic sarcoma showing circumferential accentuation of ALK1 expression ( A ) and diffuse actin staining ( B ).

The tumor cells variably express myoid markers, including SMA ( Fig. 9.28B ), MSA, and desmin. Meis and Enzinger found that SMA and MSA were present in 90% and 83% of cases, respectively. In contrast, there was equivocal desmin staining in only 1 of 11 cases (9%). Coffin et al. found staining for SMA, MSA, and desmin in 92%, 89%, and 69%, respectively. Focal keratin immunoreactivity was noted in 36% and 77% of cases in the studies by Coffin and Meis and Enzinger, respectively.

A high percentage of IMTs are associated with ALK mutations, and as such, many are also immunoreactive for ALK. A wide range of ALK positivity is reported, ranging from 36% to 60% of cases. Thus, this marker lacks sensitivity, and there is an imperfect correlation with ALK mutations. Evidence suggests that different fusion partners result in different patterns of ALK immunoreactivity. For example, Chen and Lee described an IMT with a RANBP2::ALK fusion that was associated with round cell transformation and an unusual pattern of nuclear membrane ALK expression. Similarly, Mariño-Enriquez reported epithelioid inflammatory myofibroblastic sarcomas with RANBP2::ALK fusions that also showed nuclear membrane staining for ALK, although some showed perinuclear ALK staining. Others have also noted this correlation between a fusion partner (in this case, RANBP2 ) and the pattern of ALK staining. Diffuse cytoplasmic staining for ALK is typically seen with TPM3 , TPM4 , ATIC , SEC31L1 , and CARS fusions, whereas granular cytoplasmic staining is seen with CLTC fusions.

Approximately 50%–70% of IMTs, particularly those arising in children and young adults, harbor clonal rearrangements of the ALK gene at 2p23. This gene codes for a tyrosine kinase receptor that is a member of the insulin-like growth factor receptor superfamily. ALK rearrangements result in constitutive expression and activation of this gene with abnormal phosphorylation of cellular substrates. This gene has innumerable fusion partners, including EML4 , TPM3 , TPM4 , CLTC , CARS , HNRNPA1 , ATIC , SEC31L1 , RANBP2 , DES , FN1 , THBS1, SQSTM1, CASC15, NRP2, and IGFBP5 . ^{, ,}

Next-generation sequencing has shown that some ALK -negative IMTs have alterations of ROS1 and PDGFRB . ^, Hornick et al. found positivity with the ROS1 antibody to be a reliable indication of ROS1 gene rearrangement, and useful in recognizing a subset of ALK -negative IMTs. Interestingly, a recent report found evidence of an ETV6::NTRK3 fusion (a fusion found in a variety of tumors, including infantile fibrosarcoma and congenital mesoblastic nephroma) in a case of pulmonary IMT. Several additional cases of ETV6 -rearranged tumors were found among a group of 15 ALK -negative IMTs. These findings raise intriguing questions regarding a possible relationship between IMT and infantile fibrosarcoma. In a large study of IMTs, 68% of cases showed evidence of a kinase fusion, supporting the role of targeted therapy with tyrosine kinase inhibitors, including crizotinib. ^{, ,}

ALK rearrangements are, of course, not at all specific for IMT, and have been reported in a wide variety of other tumors, including anaplastic lymphomas, various types of carcinoma, melanomas, neuroblastoma, and other mesenchymal tumors. Among mesenchymal tumors, a morphologically distinctive, CD34 and S100 protein-positive, ALK -rearranged, myxoid spindle cell tumor of the superficial soft tissues has recently been reported by Dermawan et al.

Despite previous controversy, there is compelling evidence that these lesions are true neoplasms rather than pseudotumors. Many have been associated with aggressive local behavior that has resulted in patient death.

Based on the two largest studies of abdominal and retroperitoneal lesions, tumors in this location have a propensity for more aggressive behavior than their extraabdominal counterparts, with recurrence rates of 23%–37%. ^, The major question seems to be whether IMTs have metastatic potential or whether multiple lesions in a single patient represent multifocal disease. The Coffin series of 53 cases with follow-up reported no instances of metastasis, whereas 3 of 27 patients in the Meis and Enzinger series developed metastasis to the lung and brain. The reasons for this discrepancy are not clear. In at least one patient (case 26), the simultaneous presentation of histologically bland mediastinal and cerebral lesions with no evidence of disease almost 4 years after surgery suggests that these lesions may be multifocal. However, other reports clearly indicate that some examples of this tumor metastasize and can result in patient death. Debelenko et al. reported a primary lesion and metastasis with identical CARS::ALK fusions, supporting a metastasis as opposed to multifocal disease.

There is an imperfect correlation between the clinicopathologic features of these tumors and prognosis. Traditional features, including tumor size, nuclear atypia, mitotic activity, and necrosis, do not correlate well with clinical outcome. There are rare examples of IMTs with usual features that have behaved aggressively. ^, Another group of tumors have undergone histologic progression with so-called round cell transformation, characterized by highly atypical spindled or epithelioid cells with vesicular nuclei, prominent nucleoli, and increased mitotic activity, including atypical mitotic figures. ^{, ,} As mentioned earlier, a subgroup of IMTs with RANBP2::ALK fusion and a distinctive pattern of ALK nuclear membrane immunoreactivity behave aggressively. ^{, , ,} For uterine tumors, a two-tier-risk stratification model (low-risk vs. high-risk) has been proposed.

The mainstay of therapy is surgical resection with reexcision of recurrent tumors. Some advocate chemotherapy and radiation therapy in recurrent or metastatic cases. Over the past few years, tyrosine kinase inhibitors have been found to be highly efficacious in the treatment of aggressive IMTs. Therefore, accurate recognition of this entity, including the ALK -negative variants, has become increasingly important.

The differential diagnosis of IMT depends on the clinicopathologic setting, including the patient’s age and gender, tumor location, and number of lesions. For tumors composed of elongated spindled cells with eosinophilic cytoplasm arranged in a fascicular growth pattern, differentiation from inflammatory rhabdomyoblastic tumor may pose a problem. However, IMTs lack the deeply eosinophilic, angulated, bizarre-appearing cells seen in inflammatory rhabdomyoblastic tumor, and are negative for skeletal muscle markers. Rare IMTs have a conspicuous population of large, multinucleated tumor cells with prominent nucleoli resembling the Reed-Sternberg cells of Hodgkin lymphoma . Expression of actins and ALK and negativity for CD15 and CD30 assist in distinguishing these two entities. IMT can occasionally arise in the gastrointestinal tract and can be confused with an inflammatory fibroid polyp . The latter is a benign lesion often occurring in the stomach and ileum as a solitary submucosal polyp. Histologically, this lesion is dominated by stellate-shaped cells deposited in a myxoid stroma with reactive blood vessels and mixed inflammatory cells, particularly eosinophils. GIST occasionally may closely resemble an IMT, but consistently express CD117 and DOG1 and are ALK-negative. In the uterus, IMTs can histologically resemble a smooth muscle tumor, and the possibility of an IMT should be considered in any unusual uterine smooth muscle tumor or in the setting of recurrent disease. Although they share some histologic similarities, IMTs can be distinguished from the group of inflammatory fibrosclerosing lesions (e.g., sclerosing mediastinitis, idiopathic retroperitoneal fibrosis, and Riedel thyroiditis) and IgG4 sclerosing disease by paying close attention to the clinical setting and gross and microscopic findings. IgG4 sclerosing disease is typically a poorly defined, mass-producing lesion of older patients marked by alternating sclerotic and mixed inflammatory areas ( Figs. 9.29 and 9.30 ). Eosinophils and endophlebitis are typically seen, but a discrete population of plump myofibroblasts is conspicuously absent. Although some studies have found IgG4-positive plasma cells in IMTs, Yamamoto et al. found significantly fewer IgG4-positive plasma cells and a lower IgG4/IgG ratio than found in IgG4-related sclerosing diseases. Other fibroinflammatory processes that occur in this location, including xanthogranulomatous inflammation secondary to Erdheim-Chester disease and pseudotumor resulting from atypical mycobacterial infection, also may be in the differential diagnosis and can be distinguished by their distinct clinicopathologic setting.

IgG4 sclerosing disease with mats of dense collagen punctuated with foci of chronic inflammation ( A ) consisting of plasma cells, lymphocytes, and occasionally eosinophils ( B ).

Endophlebitis in IgG4 sclerosing disease.

Definitionally, the cells of a fibrosarcoma recapitulate the appearance of the normal fibroblast. This admittedly broad definition has resulted in great subjectivity as to which spindle cell, collagen-forming tumors are appropriately termed fibrosarcoma and which are better classified as another type of sarcoma. Depending on the era and the accepted criteria at that time, the incidence and behavior of this neoplasm have varied greatly. This trend is well illustrated by a series of studies from the Mayo Clinic over 50 years. In 1974, Pritchard et al. reported that 12% of all soft tissue sarcomas were fibrosarcomas (down from 65% in an earlier Mayo Clinic study), which was revised by Scott et al. to an even lower percentage by 1989. A subsequent study, incorporating immunohistochemical and molecular genetic studies, by Bahrami and Folpe revised this number to less than 1% of all adult soft tissue sarcomas, reflecting a fascinating evolution of diagnostic criteria ( Table 9.3 ).

On closer scrutiny, three major factors are probably responsible for the apparent decline in the incidence of fibrosarcoma. First, many pathologists’ categorization of high-grade, pleomorphic spindle cell tumors with fibroblastic and myofibroblastic differentiation as “malignant fibrous histiocytoma” (MFH) or more recently “undifferentiated pleomorphic sarcoma,” as opposed to fibrosarcoma, certainly has contributed to this trend. Second, a refinement of histologic criteria resulted in the segregation of deep fibromatoses (desmoid tumors) as a unique group of tumors distinct from fibrosarcoma. Third, with the advent of IHC, cytogenetic, and molecular genetic techniques, it became possible to more reproducibly recognize monophasic fibrous synovial sarcoma and malignant peripheral nerve sheath tumors (MPNST), which were undoubtedly frequently misclassified as fibrosarcomas. Despite significant progress in this area, the differential diagnosis of spindle cell tumors remains a difficult, challenging, and sometimes unsolvable problem, especially when only a small biopsy specimen is available for microscopic examination.

As a result of these trends, the following general statements can be made about the diagnosis of fibrosarcoma:

• 1.

  The tumor previously known simply as “fibrosarcoma,” and now referred to more specifically as “adult-type fibrosarcoma” has largely become a diagnosis of exclusion. It presupposes that other fibrosarcoma subtypes (discussed in detail below) and diagnoses such as monophasic fibrous synovial sarcoma and MPNST have been excluded by the appropriate IHC or cytogenetic/molecular genetic studies.

• 2.

  Adult-type fibrosarcoma, like other fibroblastic tumors (e.g., fibromatosis), may have a variable component of neoplastic cells with myofibroblastic features. Therefore, the finding of various actin isoforms within these tumors does not mitigate against the diagnosis of fibrosarcoma. On the other hand, some spindle cell sarcomas are composed predominantly of cells with myofibroblastic differentiation, and the entity of myofibrosarcoma (myofibroblastic sarcoma) has become accepted.

• 3.

  Collagen-forming spindle cell tumors of high nuclear grade showing fibroblastic differentiation are, by convention, classified as undifferentiated pleomorphic sarcomas (see Chapter 12 ). Consequently, lesions diagnosed as adult-type fibrosarcoma mostly occupy the low-grade end (grades 1 and 2) of a spectrum that includes undifferentiated pleomorphic sarcoma at the high-grade end.

Despite the incidence of adult-type fibrosarcoma greatly decreasing in recent years, there have been renewed efforts to identify unique subsets or variants within this group of lesions. Although it is still not clear to what extent these variants are biologically different from one another, they certainly have distinct histologic and sometimes molecular genetic features that allow their identification in a consistent fashion. These variants include myxofibrosarcoma (discussed in Chapters XX [high-grade myxofibrosarcoma] and XX [low-grade myxofibrosarcoma]), low-grade fibromyxoid sarcoma , sclerosing epithelioid fibrosarcoma, and fibrosarcomas arising in dermatofibrosarcoma protuberans ( Box 9.1 ). This chapter also includes sarcomas that are composed predominantly of myofibroblasts ( myofibroblastic sarcoma ), an entity that has only begun to gain acceptance over the past 15 years.

As with most other sarcomas, adult-type fibrosarcoma causes no characteristic symptoms and is difficult to diagnose clinically. Most patients present with a solitary palpable mass ranging from 3 to 8 cm in greatest dimension. They are slowly growing and usually painless; pain is encountered more often with synovial sarcoma and MPNST than with fibrosarcoma.

The skin overlying the tumor is generally intact, although more superficially located neoplasms that grow rapidly or have been traumatized may result in ulceration of the skin. Such tumors, particularly when clinically neglected, may form large fungating masses in the areas of ulceration. The preoperative duration of symptoms varies greatly and ranges from as short as a few weeks to as long as 20 years. Adult-type fibrosarcoma is most common in the third through fifth decades of life. In the Bahrami and Folpe study, patient age ranged from 6 to 74 years (median: 50). In a separate study of fibrosarcomas that rigidly excluded other lesions and apparently comprised a uniform group of tumors, the median age was 56 years.

The tumor may occur in any soft tissue site but is most common in the deep soft tissues of the lower extremities, particularly the thigh and knee, followed by the trunk, upper extremities, and head and neck. Rare examples of this tumor have been reported in virtually every anatomic site.

Adult-type fibrosarcomas predominantly involve deep structures, where they tend to originate from the intramuscular and intermuscular fibrous tissue, fascial envelopes, aponeuroses, and tendons. Deeply situated tumors may even encircle bone and cause radiographically demonstrable periosteal and cortical thickening; in such cases, distinction from parosteal osteosarcoma may be difficult. Other radiographic findings, in addition to a soft tissue mass, include occasional foci of calcification and ossification, although this feature is much more common with synovial sarcoma than adult-type fibrosarcoma. Fibrosarcomas arising from the subcutis, excluding those that arise in dermatofibrosarcoma protuberans (DFSP), are incredibly rare and tend to originate in tissues damaged by radiation, heat, or scarring. In the recent Mayo Clinic study, only 5 of 26 tumors arose in a suprafascial location.

Considering the prominent role of fibroblasts in posttraumatic repair, it is not surprising that trauma has been implicated repeatedly as a possible and even likely causative factor. Stout, for example, reported 36 cases of fibrosarcoma arising in scar tissue (cicatricial fibrosarcoma) or at the site of a former injury. Ivins et al. noted a history of preceding trauma in 19 of 78 cases of fibrosarcoma but concluded that “only in one was an etiologic significance remotely possible.” Evaluation of the significance of these cases is difficult. In some, trauma may be a contributing factor, whereas in others trauma may merely serve to alert the patient or the physician to the presence of the disease and may be an incidental finding rather than a tumor-provoking factor.

Factors other than trauma have also been implicated to induce or contribute to the development of fibrosarcoma. A significant percentage of adult-type fibrosarcomas arise in association with prior irradiation or in burn scars. ^, Others have arisen following the placement of a plastic Teflon-Dacron prosthetic vascular graft, and in the vicinity of a total knee joint prosthesis.

Generally, the excised tumor consists of a solitary, soft to firm, fleshy, rounded, or lobulated mass that is gray–white to tan-yellow and measures 3–8 cm in greatest dimension. Small tumors are usually circumscribed and are partly or completely encapsulated. Large tumors are less well-defined; they often extend with multiple processes into the surrounding tissues or grow in a diffusely invasive or destructive manner. The frequent circumscription of small adult-type fibrosarcomas can be misleading and may result in an erroneous diagnosis of a “benign tumor” and inadequate surgical therapy.

Although there are minor variations in the histologic picture, most adult-type fibrosarcomas have a uniform fasciculated growth pattern consisting of fusiform or spindle-shaped cells that vary little in size and shape, have scanty cytoplasm with indistinct cell borders, and are separated by interwoven collagen fibers arranged in parallel fashion. Mitotic activity varies, but caution should be exercised when diagnosing fibrosarcoma in the absence of mitotic figures. The FNCLCC grading system should be used for the grading of adult-type fibrosarcomas; in general, Grade 3 tumors containing multinucleated giant cells or giant cells of bizarre size and shape are better classified as “undifferentiated pleomorphic sarcoma” ( Chapter 12 ) ( Figs. 9.31–9.35 ).

Low-power view of adult-type fibrosarcoma exhibiting distinct fascicular (herringbone) pattern.

Adult-type fibrosarcoma consisting of uniform spindle cells showing little variation in size and shape and distinct fascicular pattern.

Adult-type fibrosarcoma showing arrangement of fibroblasts in distinct intersecting fascicles (herringbone pattern).

High-power view of adult-type fibrosarcoma showing uniformity of tumor cells and characteristic fascicular pattern.

( A and B ), Grade 2 adult-type fibrosarcoma characterized by closely packed, less well-oriented, rounded tumor cells with high-grade nuclear features.

Adult-type fibrosarcomas, by definition, do not exhibit any lineage-specific markers such as keratin or S100 protein. The lack of keratin immunoreactivity aids in distinction from monophasic fibrous synovial sarcoma. Negative immunostaining for S-100 protein and/or SOX10 distinguishes adult-type fibrosarcoma from spindle cell or desmoplastic malignant melanomas but not necessarily from MPNST, because only 50%–60% of the latter express these antigens (sometimes to a very limited extent). Unlike adult-type fibrosarcoma, many MPNSTs show loss of staining for H3K27me3. In some adult-type fibrosarcomas, scattered cells express SMA or MSA, reflecting focal myofibroblastic differentiation. The distinction of these tumors from myofibroblastic sarcomas is subjective and not of known clinical significance. Strong CD34 staining is typically only seen in a subset of fibrosarcomas arising in DFSP or from a solitary fibrous tumor.

Little is known about the cytogenetic and molecular genetic alterations in adult-type fibrosarcoma. In contrast to infantile fibrosarcoma, this tumor does not appear to have a characteristic cytogenetic abnormality, although multiple complex chromosomal rearrangements have been reported. ^, Limon et al. found a nonrandom chromosomal change involving t(2; 19) with involvement of 2q21-qter.

It is difficult to compare the results of published studies because many of the tumors included in older series probably represent entities other than adult-type fibrosarcoma. Few studies (until recently) have used IHC or molecular genetics to exclude other lesions in the differential diagnosis. As such, the rate of local recurrence varies significantly among studies. For example, Mackenzie noted a recurrence in 93 of 190 cases (49%), with 113 of 199 (57%) recurrences in the Pritchard study. In the Scott study, overall rate of recurrence was 42% at 5 years. Although neither tumor grade nor tumor stage was associated with an increased risk of local recurrence, the status of the surgical margins was strongly predictive; the 5-year cumulative probability of local recurrence was 79% in tumors with inadequate surgical margins and 18% in tumors treated by wide or radical excision.

To gain more reliable information about the true clinical behavior of adult-type fibrosarcoma, one should focus on modern studies that use ancillary techniques to exclude potential mimics. In the most recent Mayo Clinic study, of 26 adult-type fibrosarcomas (after starting with 163 putative tumors diagnosed as fibrosarcoma over 48 years), 12 of 24 patients (50%) with follow-up died of locally aggressive and/or metastatic disease; only 6 patients were alive without disease, and 6 died of other causes. In the 2006 Hansen study, local recurrences were reported in 7 of 21 patients (33%) with follow-up, and 3 of 21 (14.3%) developed metastases and died of a tumor. Unfortunately, data were insufficient in both studies to determine prognostic parameters.

The lung is the principal metastatic site, followed by the skeleton, especially the vertebrae and skull. Most metastases are noted within the first 2 years after diagnosis, although some patients develop metastasis late in their course. Lymph node metastasis is rare.

It is often difficult to distinguish adult-type fibrosarcoma from other spindle cell tumors, and in many instances, only careful examination of multiple sections and ancillary studies permit a correct diagnosis, which is always a diagnosis of exclusion. Benign processes likely to be mistaken for fibrosarcoma range from nodular fasciitis to cellular benign fibrous histiocytoma and fibromatosis. Malignant neoplasms considered in the differential diagnosis are much more numerous and include MPNST, undifferentiated pleomorphic sarcoma, and monophasic fibrous synovial sarcoma. Other tumors that tend to simulate fibrosarcoma include sarcomatoid mesothelioma, clear cell sarcoma, epithelioid sarcoma, DFSP, desmoplastic leiomyosarcoma, spindle cell forms of rhabdomyosarcoma, malignant melanoma, and spindle cell carcinoma. Because the differential diagnosis of most of these tumors is discussed elsewhere, the following comments are limited to lesions most frequently confused with adult-type fibrosarcoma.

Nodular fasciitis differs from adult-type fibrosarcoma by its smaller size and microscopically by its more irregular growth pattern; characteristically, its cells are arranged in short bundles—never in long, sweeping fascicles or a herringbone pattern as in adult-type fibrosarcoma. The cells lack nuclear hyperchromasia, and there is usually a prominent myxoid matrix and scattered chronic inflammatory cells.

Cellular benign fibrous histiocytoma may be difficult to distinguish from adult-type fibrosarcoma because this lesion is characteristically cellular and often forms fascicles. However, the fascicles are usually not as regular or as long and sweeping as those seen in adult-type fibrosarcoma. Areas of more conventional benign fibrous histiocytoma are usually identified and are extremely useful in this distinction. In most cases, cellular benign fibrous histiocytoma is situated in the dermis or subcutis; unlike adult-type fibrosarcoma, it is rarely found in deep soft tissue structures. Mitotic figures are present in cellular benign fibrous histiocytoma, but the presence of atypical mitotic figures lends strong support to a diagnosis of malignancy.

Deep fibromatosis has a growth pattern similar to that of adult-type fibrosarcoma but is less cellular and contains more collagen. The cells are uniformly spindled, with delicate chromatin and one or 2 minute nucleoli. In general, the cells do not touch one another but rather are separated by collagen, whereas the cells of adult-type fibrosarcoma frequently overlap with closely spaced hyperchromatic nuclei. Low levels of mitotic activity may be present in fibromatosis, so considerable overlap in mitotic activity may be encountered. Because fibromatosis-like areas may be present in low-grade adult-type fibrosarcoma, careful sampling of the tumor is mandatory. Clinical considerations are of little help in distinguishing these tumors because they may occur at the same location and in patients of similar age. As mentioned earlier, deep fibromatoses typically show aberrant nuclear β-catenin and LEF1 immunoreactivity.

Undifferentiated pleomorphic sarcomas have been included in many of the earlier reports of poorly differentiated or pleomorphic fibrosarcomas. Clinically, these tumors principally arise in elderly persons, with a peak during the seventh decade; microscopically, they are characterized by a storiform to haphazard growth pattern and the presence of multinucleated bizarre giant cells. Siderophages and xanthoma cells are also common features that assist in the diagnosis. Admittedly, where one draws the line between a high-grade adult-type fibrosarcoma, and UPS is, at times, quite subjective.

Malignant peripheral nerve sheath tumor may display areas that are virtually indistinguishable from adult-type fibrosarcoma. However, by definition, some evidence of nerve sheath differentiation must be present to support the diagnosis of MPNST. For example, cells showing neural differentiation often have a wavy or buckled appearance rather than the finely tapered fibroblasts of adult-type fibrosarcoma. Although the cells can be arranged into an irregular fascicular growth pattern, the long, sweeping fascicles characteristic of adult-type fibrosarcoma are usually not present. Moreover, the cells of MPNST tend to show perivascular cuffing and may be arranged in distinct whorls or palisades. At low magnification, MPNST often shows a marbled appearance with alternating myxoid and cellular zones. In addition, MPNST may show transitions between malignant and benign neurofibroma-like areas. The finding of S-100 protein in scattered tumor cells supports a diagnosis of MPNST, although up to 50% of cases do not stain for this antigen, and S-100 protein staining is not specific for MPNST. SOX10 expression is also commonly found in MPNST, as is the loss of H3K27me3 (see Chapter 27 ).

Monophasic fibrous synovial sarcoma may also closely simulate an adult-type fibrosarcoma, although it is generally composed of more ovoid-appearing cells arranged in an irregular fascicular growth pattern. Moreover, many of these sarcomas have areas in which the cells contain more eosinophilic cytoplasm with a suggestion of cellular cohesion, even if well-formed glands are not present. On IHC, almost all cases of synovial sarcoma express at least one epithelial marker, a feature not found in adult-type fibrosarcoma. The identification of t(X; 18) by molecular genetic methods is a highly sensitive and specific method for identifying a tumor as a synovial sarcoma, in addition to SS18-SSX fusion-specific antibodies (see Chapter XX).

Low-grade fibromyxoid sarcoma (LGFMS) was first recognized by Evans in 1987, when he reported two bland fibromyxoid neoplasms arising in the deep soft tissue of two young women. Although initially diagnosed as benign, both tumors eventually metastasized; subsequent reports verified the metastatic potential of this histologically deceptive neoplasm. Despite great skepticism as to whether this tumor was a specific entity, subsequent clinicopathologic, cytogenetic, and molecular genetic studies have confirmed this lesion as a distinct variant of fibrosarcoma. This sarcoma is probably more common than the literature would suggest because some have undoubtedly been diagnosed as myxofibrosarcoma, low-grade myxoid sarcoma, “not otherwise specified” (NOS), or a variety of other benign or malignant fibrous or myxoid neoplasms. Lane et al. first described “hyalinizing spindle cell tumor with giant rosettes” in 1997 in 19 cases. Since its initial description, it is now clear that this simply represents an LGFMS with distinctive collagen rosettes.

Gross and Microscopic Findings.

Most examples of LGFMS arise in the skeletal muscle, although some appear to be centered in the subcutaneous tissue, with minimal or no muscle involvement. Occasionally, these tumors can be more superficially located and involve the dermis. Although typically grossly circumscribed, there is often extensive microscopic infiltration into the surrounding soft tissues. On cut section, the tumor often has a yellow-white appearance with focal areas having a glistening appearance secondary to the accumulation of myxoid ground substance; some exhibit cystic degeneration.

Histologically, LGFMS is of low or moderate cellularity and is composed of bland spindle-shaped cells with small hyperchromatic oval nuclei, finely clumped chromatin, and one to several small nucleoli. The cells have indistinct pale eosinophilic cytoplasm and show only mild nuclear pleomorphism with little mitotic activity. The cells are deposited in a fibrous and myxoid stroma that tends to vary in different areas of the tumor ( Figs. 9.36–9.44 ). In general, the lesions appear more fibrous than myxoid. The myxoid zones may abut abruptly with the fibrous zones, or there may be a gradual transition between these areas. Cells with a stellate configuration are often present in the myxoid zones and generally are arranged in a whorled or random manner. There is often a prominent network of curvilinear and branching capillary-sized blood vessels in the myxoid zones, somewhat reminiscent (although thicker walled) of that seen in myxoid liposarcoma ( Figs. 9.38 and 9.40C ), sometimes with perivascular hypercellularity. Epithelioid cells may also be present focally ( Fig. 9.41A ), and there are areas of higher cellularity in about 15%–20% of cases ( Fig. 9.45 ). As discussed later, some cases have foci that are indistinguishable from sclerosing epithelioid fibrosarcoma.

Low-grade fibromyxoid sarcoma showing alternating myxoid and cellular areas.

Low-grade fibromyxoid sarcoma with broad areas of hyalinization.

Myxoid foci within low-grade fibromyxoid sarcoma ( A ) showing prominent vessels with condensation of tumor cells along walls ( B ).

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1. Approach to the Diagnosis of Soft Tissue Tumors
2. General Considerations
3. Fibrous Tumors of Infancy and Childhood
4. Radiologic Evaluation of Soft Tissue Tumors

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