Although previously grouped together in this textbook, superficial and deep fibromatoses are now discussed separately because of distinct differences in clinical behavior. The superficial fibromatoses are described with the benign fibroblastic/myofibroblastic proliferations (see Chapter 7 ). Deep fibromatoses are included in this chapter, which focuses on fibroblastic/myofibroblastic tumors of borderline and malignant behavior. This chapter also describes congenital/infantile fibrosarcoma and inflammatory myofibroblastic tumor (previously discussed with fibrous tumors of infancy and childhood; see Chapter 8 ), because these entities are better considered variants of fibrosarcoma with borderline clinical features.
Deep (Desmoid-Type) Fibromatoses
The deep fibromatoses, whether arising from the abdominal wall, mesentery, or other, extraabdominal locations, share overlapping clinical, morphologic, immunohistochemical (IHC), and molecular genetic features, although certain attributes are unique to each. This section discusses the features shared by the deep fibromatoses as well as features that distinguish these entities from one another.
Extraabdominal fibromatosis arises principally from the connective tissue of muscle and the overlying fascia or aponeurosis ( musculoaponeurotic fibromatosis ); it chiefly affects the muscles of the shoulder, pelvic girdle, and thigh of adolescents and young adults. Other terms used to describe this condition include extraabdominal desmoid, desmoid tumor, and aggressive fibromatosis .
Abdominal fibromatosis occurs 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. The relative frequency of abdominal and extraabdominal desmoid tumors varies among studies. In Reitamo’s study in Finland, abdominal fibromatoses (49%) outnumbered extraabdominal (43%) and mesenteric (8%) fibromatoses.
The intraabdominal fibromatoses are a group of closely related lesions (rather than a single entity) that pose similar problems for the histologic diagnosis but can be distinguished by the clinical setting and location. This category includes pelvic fibromatoses and mesenteric fibromatoses , including those associated with familial adenomatous polyposis (FAP)/Gardner syndrome .
Despite their relatively common occurrence, desmoid-type fibromatosis continue to present a problem in recognition and management, especially because of the striking discrepancy between their deceptively bland microscopic appearance and their propensity to recur locally and infiltrate neighboring soft tissues.
Extraabdominal Fibromatosis
Extraabdominal fibromatosis occurs in patients typically between puberty and 40 years of age, with peak incidence between 25 and 35 years. In the Mankin study of 234 patients, the mean age was 36.7 years, and 61% were female. Children are affected infrequently; only 5% of patients in the Mayo Clinic study 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, a stabbing or shooting pain, or motor weakness, may occur when the lesion compresses nearby nerves.
Radiographically, the lesion appears as a soft tissue mass that interrupts the adjacent intermuscular and soft tissue planes; it 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 the diagnosis and assessment of tumor extent before surgery. Pritchard et al. found a lower local recurrence rate after the introduction of these improved imaging techniques compared to before their routine use, presumably because of better surgical planning.
The principal site of extraabdominal fibromatosis is 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, whereas those in the region of the thigh affect the quadriceps muscle and muscles of the popliteal fossa.
The head and neck region is also a common location for these lesions. As many as 23% of all extraabdominal fibromatoses occur in this location. In children, more than one-third of extraabdominal fibromatoses are located in the head and neck. Clinically, fibromatoses arising in this location 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.
Fibromatosis of the breast may arise in the mammary gland or from extension of a lesion arising in the aponeurosis of the chest wall or shoulder girdle. Rare cases have been associated with breast implants.
Up to 5% of extraabdominal fibromatoses are multicentric, usually involving the same anatomic region. In most cases, the second growth develops proximal to the primary lesion. Coexistence of abdominal and extraabdominal fibromatoses has been observed in the same patient.
Grossly, the tumor is almost always confined to the musculature and the overlying aponeurosis or fascia ( Figs. 9.1 and Fig. 9.2 ). Large tumors may extend along the fascial plane or infiltrate the overlying subcutaneous tissue ( Fig. 9.3 ). The tumor may involve the periosteum and lead to bone erosion, thereby closely resembling desmoplastic fibroma of bone. Most tumors measure 5 to 10 cm in greatest dimension, although lesions as large as 20 cm have been reported.
Abdominal Fibromatosis
Although abdominal fibromatosis is indistinguishable grossly and microscopically from extraabdominal fibromatosis, it deserves separate consideration because of its characteristic location and its strong propensity to occur in women of childbearing age during or after pregnancy. The tumor arises from musculoaponeurotic structures of the abdominal wall, especially the rectus and internal oblique muscles and their fascial coverings.
Abdominal fibromatosis occurs 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. Most tumors measure 3 to 10 cm in greatest dimension and, when arising in the rectus muscle or its fascia, usually remain at the site of origin and do not cross the abdominal midline.
Pelvic Fibromatosis
Pelvic fibromatosis is a variant of intraabdominal fibromatosis, distinguished by its location in 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. As with fibromatosis of the abdominal wall, the tumor arises from the aponeurosis or muscle tissue and occurs chiefly in young women 20 to 35 years of age; in most cases it is unrelated to gestation or childbirth. Grossly and microscopically, the tumor is indistinguishable from other forms of extraabdominal or abdominal fibromatosis and requires similar modes of therapy.
Mesenteric Fibromatosis
Fibromatosis is 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 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. 9.4 ).
As with pelvic fibromatosis, 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.
Like many other neoplasms in the abdomen and retroperitoneum, most mesenteric fibromatoses are quite large at 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.
Mesenteric Fibromatosis in FAP/Gardner Syndrome
In 1951, Gardner reported the familial occurrence of intestinal polyposis, osteomas, fibromas, and epidermal or sebaceous cysts; the term Gardner syndrome was coined by Smith in 1958. This syndrome is inherited as an autosomal dominant trait that occurs in approximately half the children of afflicted parents. It is more common in women than in men and is usually diagnosed in adults 25 to 35 years of age. Approximately 10% to 15% of patients with FAP/Gardner syndrome develop intraabdominal fibromatoses, an estimated 800-fold increased risk of developing such lesions.
In this setting, mesenteric or retroperitoneal fibromatosis usually has its onset 1 to 2 years after excision of the diseased portion of the intestinal tract, and these lesions are the most common cause of death in polyposis patients after colectomy is performed. In the classic study by Gurbuz et al., almost 70% of FAP patients who developed these lesions had abdominal surgery before the discovery of the fibromatosis. Compared with sporadic lesions, FAP-associated mesenteric fibromatoses arise in slightly younger patients (36 vs. 42 years, according to a large study in the Netherlands). FAP-related tumors also tend to be larger, multicentric, and intraabdominally situated. In a meta-analysis of 10 published studies, a positive family history of a desmoid tumor was the only factor predictive of development of this lesion in patients with FAP/Gardner syndrome. Durno et al. found that early colectomy, especially in female patients, significantly increased the risk of developing mesenteric fibromatosis.
Clinically, the fibromatosis may be asymptomatic or may cause mild abdominal pain or intestinal obstruction as a result of infiltrative growth into the wall of the small or large bowel. Histologically, the fibromatosis is virtually indistinguishable from those at other sites, and one cannot distinguish polyposis-related cases from sporadic cases by morphology alone.
Mesenteric fibromatoses with or without associated FAP/Gardner syndrome frequently recur, an observation that is not surprising given the central location and difficulty of complete surgical extirpation. There is significant morbidity associated with attempted resection, including ischemia, fistula formation, obstruction, and additional small bowel resections, which can result in short bowel syndrome and necessitate small bowel transplantation.
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 distinguishing recurrent/residual fibromatosis from scar tissue. Mutations of this gene are not found in the spindle cell lesions likely to enter the diagnosis. CTNNB1 mutations result in the intranuclear accumulation of β-catenin protein, which can also be used as a diagnostic adjunct.
Pathologic Findings
The morphologic features of deep fibromatoses are essentially identical in all anatomic locations, although some minor variation may be seen. The tumor is firm, cuts with a gritty sensation, and on cross section reveals a glistening white, coarsely trabeculated surface resembling scar tissue (see Figs. 9.1 and 9.2 ). As such, surgeons may have difficulty distinguishing recurrent fibromatosis from scar tissue related to a prior excision.
Histologically, the lesion is poorly circumscribed and infiltrates the surrounding tissue ( Fig. 9.3A ), where it may evoke a focal lymphocytic response and cause striking atrophy of the skeletal muscle ( Fig. 9.3B and C ). Mesenteric fibromatosis typically shows microscopic infiltration into the surrounding soft tissues, including the bowel wall (see Fig. 9.4 ).
Architecturally, the tumor grows in long, sweeping fascicles or graceful arcs ( Fig. 9.5 and 9.6 ) composed of elongated, spindle-shaped cells arranged in parallel fashion, a pattern sometimes likened to a school of fish ( Figs. 9.7 ). The uniform cells are separated from one another by a collagenous stroma with little or no cell-to-cell contact. The nuclei are small and pale staining with one to three pinpoint nucleoli ( Fig. 9.8A ). Nuclear atypia is not seen, although the presence of multinucleated giant cells on rare occasions may simulate the appearance of nuclear atypia ( Fig. 9.7C ). In cross section of fascicles of fibromatosis, the cells appear as widely spaced nuclear profiles ( Fig. 9.9 ). Mitotic figures are occasionally seen but rarely are numerous. There is no “cutoff” that distinguishes fibromatosis from fibrosarcoma , and this distinction instead is made on architectural and cytologic grounds. 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.
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 the cells are more widely spaced and more randomly arranged (Fig. 9.10B ). Hyalinization can be restricted to scattered dense keloidal bundles of collagen ( Fig. 9.10C ) or almost completely replace the tumor ( Fig. 9.10D and Fig. 9.11 ). In such cases, one should be alert to the presence of the characteristic ectatic vessels. In rare cases there is calcification or chondroid or osseous metaplasia, but this is never a prominent feature of the tumor. In assessing the morphologic features of fibromatoses of various sites, Zreik and Fritchie found the only significant difference to be that intraabdominal fibromatoses were more likely to have prominent keloidal collagen and a staghorn vascular pattern compared to extraabdominal and abdominal lesions. Gardner-associated fibromatoses tend to have a prominent myxoid matrix .
Ancillary Findings
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. Approximately 70% of fibromatoses show aberrant nuclear accumulation of β-catenin, although this finding is not perfectly specific for fibromatoses ( Fig. 9.8B ). In the Amary study, all deep fibromatoses stained for this antigen, but 72% of the lesions that can mimic fibromatosis also stained, indicating a lack of specificity. In our experience, this stain can be difficult to interpret because of background or nonspecific staining. More recently, lymphoid-enhancer factor 1 (LEF1) has been found to be consistently expressed in deep fibromatoses, but given its staining in scars, it has limited clinical utility.
Some studies have found consistent expression of CD117 (c-kit) in fibromatoses. For example, Yantiss et al. found that CD117 was expressed in 88% of gastrointestinal stromal tumors (as expected) but also in 75% of fibromatoses. Similarly, 6 of 10 mesenteric fibromatoses reported by Montgomery et al. expressed CD117. In our experience, mesenteric fibromatoses are consistently negative for CD117; reports to the contrary may be related to antibody choice or excessive epitope retrieval. DOG1 expression has not been reported in fibromatoses.
Because of the issues regarding the sensitivity and specificity of immunohistochemistry for the detection of β-catenin, there has been considerable interest in the development of other methods to test for this molecular alteration (see later).
Etiology
The etiology of deep fibromatosis is almost certainly multifactorial because genetic, endocrine, and physical factors seem to play an important role in its pathogenesis. Features suggesting an underlying genetic basis are the occasional case in siblings and the occurrence of extraabdominal fibromatosis in patients with FAP. Mutations of the adenomatous polyposis coli (APC)/β-catenin pathway are identified in the majority of sporadic and FAP-associated deep fibromatoses.
Although clearly implicated in the development of abdominal fibromatosis, endocrine factors may also play a role in the development and growth of extraabdominal fibromatoses. Physical factors such as trauma or irradiation likely serve as a trigger mechanism, since examples of extraabdominal fibromatosis have been reported in the chest wall following trauma and reconstructive mammoplasty. An antecedent history of trauma has been reported in up to 16% to 28% of cases. Trauma likely plays a contributory role in the development of abdominal fibromatoses, as some tumors arise in the scars of radical nephrectomy sites, the insertion site of peritoneal dialysis catheters, and other abdominal surgery sites ( cicatricial fibromatosis ). Because most patients with abdominal fibromatosis have no history of gross injury to this region, minor and undetected trauma, such as minute muscle tears, may conceivably serve as a contributing etiologic factor that triggers the fibrous growth in a hormonally or genetically predisposed individual.
Genetic, endocrine, and physical factors also seem to play an important role in the development of intraabdominal fibromatoses. Some arise in the setting of FAP, often at the site of previous abdominal surgery. Endocrine factors are clearly implicated by the frequent occurrence of this tumor during or after pregnancy, and there are 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.
Clinical Behavior
As a group, deep fibromatoses share the common feature of frequent local recurrence, although there are some differences between subtypes. Despite their bland microscopic appearance, extraabdominal fibromatoses frequently behave in a locally aggressive manner. Although incapable of metastasizing, there is a high rate of local recurrence. In 203 consecutive patients with extraabdominal fibromatoses treated with surgery over a 35-year period at a single referral center, Gronchi et al. reported a local recurrence rate of 76% at 10 years. Although tumor size was associated with risk of local recurrence, microscopically positive surgical margins did not predict recurrence rate. However, other studies have found the extent and adequacy of initial excision to be prognostically significant. Cates and Stricker found that a positive or close (<1 mm) resection margin was an independent prognostic factor for local recurrence in a multivariate Cox regression model accounting for patient age and anatomic site. They also found that the probability of documenting a positive margin increased with the number of tissue sections submitted for assessing margin status and recommended multiple targeted tissue sections for accurate assessment of surgical resection margins for these tumors.
Spontaneous regression has been observed in sporadic cases, particularly in menarchal and menopausal patients. Thus, some have advocated a more conservative watch-and-wait approach before initiating surgery. In the Burtenshaw study, of the 58 patients treated with observation only, 93% experienced either spontaneous regression or stable disease with median follow-up of 38 months.
Like their extraabdominal counterparts, abdominal lesions also have a propensity to recur locally, although the rate of local recurrence (15%–30%) is slightly lower than that of extraabdominal lesions (35%–65%). In most cases, the lesions recur within the first 2 years after the initial excision or in connection with subsequent gestations or deliveries. Multiple recurrences are not uncommon.
Intraabdominal lesions also have a propensity for local recurrence, although data on the recurrence rates differ greatly. In the Burke study, 23% of tumors recurred, although there was a striking difference in recurrence rates between patients with (90%) and without (12%) FAP/Gardner syndrome. In fact, none of the patients with sporadic mesenteric fibromatosis had more than one recurrence, and none of those patients died as a direct result of their tumor. In contrast, most of the patients with FAP/Gardner syndrome had more than one recurrence, and four patients died of their tumor.
Treatment
A number of different modalities have been used in the treatment of deep fibromatoses, including surgery, chemotherapy, radiation therapy, and even clinical observation. The optimum treatment for any given patient depends on a number of tumor and patient-related factors, including tumor size, tumor site, the patient’s medical status, and comorbidities. As previously mentioned, observation is an acceptable mode of therapy for asymptomatic tumors. However, for symptomatic tumors, some form of treatment is indicated, particularly if vital structures are at risk. Surgical excision with negative microscopic margins is one of the mainstays of therapy, but local recurrences still follow apparently complete surgical excision. The goal of surgery is complete removal while preserving function and minimizing morbidity.
In situations where a wide local excision cannot be performed, postoperative radiation therapy is often used. Gluck et al. found equivalent local control for patients treated with surgery, radiation, or both. In a meta-analysis assessing the influence of surgical margins and adjuvant radiotherapy on local recurrence of these tumors, Janssen et al. found that adjuvant radiotherapy after surgery with negative margins had no significant effect on the risk of local recurrence. However, adjuvant radiotherapy after incomplete surgical resection improved recurrence rates in patients with both primary and recurrent deep fibromatoses.
Imatinib mesylate (Gleevec) therapy has been attempted in the salvage setting in patients with deep fibromatoses. Other tyrosine kinase inhibitors such as sorafenib and nilotinib may be useful following treatment failure with imatinib. Cytotoxic and noncytotoxic drug therapy has also been attempted for the treatment of these tumors. Chemotherapeutic agents and nonsteroidal antiinflammatory prostaglandin-inhibiting drugs, such as sulindac and indomethacin, have been reported to cause stabilization or regression of both primary and recurrent tumors. The efficacy of antiestrogenic therapy, including tamoxifen, progesterone, or the luteinizing hormone–releasing hormone analogue goserelin acetate, is not fully established but appears to be promising.
Differential Diagnosis
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 useful for 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 are useful for highlighting 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 immunohistochemistry (IHC) may be of some value in this distinction, although it is not a perfect ancillary test.
Desmoplastic fibroma of bone is histologically indistinguishable from fibromatosis, especially when it presents as a soft tissue mass after breaking through the thinned or expanded cortex of the involved bone. This lesion predominates in the metaphyseal or diaphyseal portions of long bones (e.g., femur) or in the jaw, and radiographic studies are essential for distinguishing between these lesions. Interestingly, desmoplastic fibroma of bone lacks β-catenin mutations, and ancillary testing for this genetic event may be helpful in select cases.
Confusion with myxoma is possible, particularly if only a small biopsy is available for examination. Myxoma is usually paucicellular, with the cells separated by 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, 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. 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 can be useful because mesenteric fibromatosis consistently shows strong nuclear β-catenin staining, whereas sclerosing mesenteritis does not express this antigen ( Table 9.1 ). This immunostain may, however, be difficult to interpret.
| GIST | Sclerosing Mesenteritis | Mesenteric Fibromatosis | |
|---|---|---|---|
| CD117 | + | − | − |
| DOG1 | + | − | − |
| β-catenin | − | − | + |
| CD34 | + | − | − |
| SMA | ± | + | ± |
| Desmin | − | − | Rare |
| S-100 protein | − | − | − |
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 anaplastic lymphoma kinase (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 plaquelike, 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 a 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 ).
| Feature | Mesenteric Fibromatosis | GIST |
|---|---|---|
| Cell shape | Wavy, spindled | Spindled and/or epithelioid |
| Atypia | None | Variable |
| Growth pattern | Uniform, fascicular | Organoid, fascicles (variable) |
| Cellularity | Low to moderate | Moderate to high |
| Blood vessels | Regular, dilated, and thin-walled | Hyalinized |
| Keloidal collagen | Frequent | Absent |
| Skeinoid fibers | Absent | May be present |
| Necrosis | Absent | May be present |
| Margins | Infiltrative | Often pushing |
| CD117 | − | + |
| DOG1 | − | + |
| CD34 | − | + |
| β-Catenin | + (nuclear) | − |
Congenital/Infantile Fibrosarcoma
Fibrosarcoma in newborns, infants, and small children bears some resemblance to adult-type fibrosarcoma but is considered a separate entity because of its markedly different clinical behavior as well as its distinctive molecular features.
Congenital/infantile fibrosarcoma is relatively rare. The first detailed clinicopathologic study of this entity was reported by Stout in 1962, who reviewed 31 cases from the literature and added 23 new cases of juvenile fibrosarcoma, 11 of which developed during the first 5 years of life and 4 of which were present at birth. Even in this early description, he suggested that fibrosarcomas arising in this group of patients were more indolent than their adult counterparts. Although several subsequent smaller series of congenital/infantile fibrosarcoma were reported, the Chung and Enzinger series of 53 cases in 1976 provided conclusive evidence supporting this tumor as a distinct entity. Similar conclusions were reached by Soule and Pritchard in 110 cases, including 70 previously published cases and 40 new cases from the Mayo Clinic.
Clinical Findings
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.
Pathologic Findings
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 circumscribed, 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.
Histologically, most examples closely resemble their adult counterparts and 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 to 9.16 ). Bizarre cells and multinucleated giant cells are rare. Scattered chronic inflammatory cells, particularly lymphocytes, are another common, sometimes striking feature that distinguishes infantile from adult fibrosarcoma. A hemangiopericytoma-like vascular pattern may be prominent ( Fig. 9.17 ).
Immunohistochemical Findings
On IHC the spindle cells of congenital/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 a Pan-Trk antibody was recently found to correlate well with the presence of NTRK3 fusions, suggesting a clinical role for this IHC marker.
Cytogenic and Molecular Genetic Findings
Numerous studies have noted a nonrandom gain of chromosomes 11, 20, 17, and 8 (in descending order of frequency). 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. In contrast, alterations of these chromosomes were not found in four fibrosarcomas in patients age 6 to 17 years. Interestingly, one of three cases of “cellular fibromatosis” also showed these cytogenetic abnormalities, suggesting that “these two entities constitute a spectrum and that their distinction may not be clear-cut.”
Most congenital/infantile fibrosarcomas and cellular mesoblastic nephroma 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 cytogenetic findings in congenital/infantile fibrosarcoma and cellular mesoblastic nephroma, these two lesions may be histogenetically related entities arising in soft tissue and renal locations, respectively. 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 congenital/infantile fibrosarcoma with an EML4-NTRK3 fusion or an LMNA-NTRK1 fusion have also been reported. Recently, Kao et al. identified several spindle cell sarcomas with histologic features overlapping congenital/infantile fibrosarcoma with BRAF mutations, but the exact nature of these tumors and their relationship to congenital/infantile fibrosarcoma is somewhat unclear.
Differential Diagnosis
The microscopic picture may be confused with that of other pediatric mesenchymal neoplasms, but in most cases the uniformity of the spindle-shaped tumor cells, the solid growth pattern, the fascicular arrangement, and the lack of any other form of cellular differentiation permit a reliable diagnosis.
Spindle cell rhabdomyosarcoma may be difficult to distinguish from congenital/infantile fibrosarcoma. This tumor is most often encountered in the paratesticular region and the head and neck, but it may also be present at other sites, including the extremities. Histologically, it is composed of uniform spindled cells often with eosinophilic fibrillar cytoplasm and elongated hyperchromatic nuclei separated by abundant, partly hyalinized collagen. On IHC, this tumor characteristically expresses desmin and myogenin, which are absent in congenital/infantile fibrosarcoma.
In 1993, Lundgren et al. described three cases of infantile rhabdomyofibrosarcoma , each of which was initially diagnosed as congenital/infantile fibrosarcoma. This tumor, which was observed in children age 3 months to 3 years, has features that overlap spindle cell rhabdomyosarcoma and desmoplastic portions of congenital/infantile fibrosarcoma. On IHC the cells express SMA and desmin; focal MyoD1 expression is also present as well. Two of the three cases reported by Lundgren et al. showed monosomy of chromosome 19 and 22, among other abnormalities; a case reported by Miki et al. showed der(2) t(2;11)(q37;q13). Two of the patients from the original report developed metastases and died within 2 years of the primary operation; the third patient was alive with a local recurrence. The exact nature of this tumor is still not clear. It may represent an intermediate form between a congenital/infantile fibrosarcoma and a spindle cell rhabdomyosarcoma. Also, some tumors reported as congenital/infantile fibrosarcoma that have metastasized and followed a fatal course may actually be examples of this rare entity.
Primitive myxoid mesenchymal tumor of infancy is another rare tumor composed of primitive cells deposited in an abundant myxoid stroma that in some cases can resemble congenital/infantile fibrosarcoma. Recently, this tumor has been found to be characterized by recurrent BCOR internal tandem duplications; expression of BCOR and BCL6 allows for its separation from congenital/infantile fibrosarcoma.
Fat-poor, cellular forms of lipofibromatosis may also mimic infantile fibrosarcoma ( Table 9.3 ). Some authors have reported cases in which the primary tumor had the appearance and growth pattern of lipofibromatosis, whereas the recurrent tumor showed greater cellularity and was virtually indistinguishable from fibrosarcoma. On the other hand, tumors with a fibrosarcoma-like appearance in the primary neoplasm and a lipofibromatosis-like appearance in the recurrence have also been observed. Further, a congenital/infantile fibrosarcoma with a surrounding lipofibromatosis-like component has also been reported. Detection of the ETV6-NTRK3 fusion allows for distinction between these lesions.
| Feature | Lipofibromatosis | Congenital/Infantile Fibrosarcoma |
|---|---|---|
| Cellularity | Variable | Moderate to high |
| Herringbone pattern | Absent | Usually present |
| Fat | Focally present | Absent |
| Mitotic figures | Rare | Few to many |
| Hemorrhage | Absent | Often present |
| Necrosis | Absent | Often present |
| t(12;15)(p13;q25) | Absent | Present |
Discussion
Compared with adult-type fibrosarcoma, the clinical course of congenital/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 in regard to tumor site, age at onset, or size of the tumor. 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 congenital/infantile fibrosarcomas are cured by wide local excision. A number of reports have indicated that preoperative chemotherapy is useful for decreasing tumor bulk, enabling a more conservative surgical approach. There are also reports of success with postoperative chemotherapy and with chemotherapy alone as a mode of treatment for inoperable tumors. In view of the generally favorable clinical course, it appears that adjuvant radiotherapy and chemotherapy should be reserved for congenital/infantile fibrosarcomas that are unresectable or have recurred or metastasized.
Inflammatory Myofibroblastic Tumor
Inflammatory myofibroblastic tumor (IMT) is a histologically distinctive lesion that occurs primarily in the viscera and soft tissue of children and young adults. It is considered a tumor of borderline malignancy because of its tendency to recur locally (at least at certain sites) and its ability rarely to metastasize. Although original descriptions of this lesion focused on its occurrence in the lung, inflammatory myofibroblastic tumor has been described in virtually every anatomic location and under many appellations, including plasma cell granuloma, plasma cell pseudotumor, inflammatory myofibrohistiocytic proliferation, omental-mesenteric myxoid hamartoma, inflammatory fibrosarcoma, and most commonly, “inflammatory pseudotumor.” The term inflammatory myofibroblastic tumor is preferred because inflammatory pseudotumor has been applied to diverse entities, including pseudosarcomatous myofibroblastic proliferations of the lower genitourinary tract, infectious lesions (including those secondary to Mycobacterium avium-intracellulare complex), Epstein-Barr virus–associated follicular dendritic cell tumors usually found in the liver or spleen, and reactive inflammatory pseudotumors of lymph nodes ( Fig. 9.18 ). This discussion focuses on extrapulmonary IMTs.
Clinical Findings
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 sites attached to various parts of the gastrointestinal (GI) 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 GI 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.
Pathologic Findings
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 to 10 cm.
A variety of 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 to 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 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.
In some lesions, there is pronounced cytologic atypia, with cells containing large nuclei and distinct nucleoli ( Figs. 9.25 to 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.
Immunohistochemical Findings
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 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 a CLTC fusion.
Cytogenetic and Molecular Genetic Findings
Approximately 50% to 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, 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, which would be 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 congenital/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 congenital/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.
Differential Diagnosis
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 spindle cells with eosinophilic cytoplasm arranged in a focal fascicular growth pattern, differentiation from inflammatory leiomyosarcoma may pose a problem. However, the nuclei in leiomyosarcoma are cigar shaped and arranged in a more regular fascicular growth pattern. Rare IMTs have a conspicuous population of large, multinucleated tumor cells with prominent nucleoli resembling the Reed-Sternberg cells of Hodgkin lymphoma . The IHC reactivity of the spindle and ganglion-like cells for actins and ALK and negativity for CD15 and CD30 assist in distinguishing these two entities. IMT can occasionally arise in the GI tract and can be confused with an inflammatory fibroid polyp . The latter is a benign lesion that most often occurs 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 GISTs consistently express CD117 and DOG1 and are ALK negative. 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 virtue of their distinct clinicopathologic setting.
Discussion
Controversial issues over the years have included whether IMTs are a homogeneous entity, whether they are neoplastic, and if neoplastic, their level of malignancy. 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. In addition, as previously mentioned, some (but not all) tumors show aberrations of the ALK gene, supporting evidence of a neoplastic process.
Based on the two largest studies of abdominal and retroperitoneal lesions, it is clear that tumors in this location have a propensity for more aggressive behavior than their extraabdominal counterparts, with recurrence rates of 23% to 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 certainly an imperfect correlation between 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.
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 (e.g., crizotinib, alectinib) 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.
Adult-Type Fibrosarcoma
Definitionally, the cells of 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. More recently, Bahrami and Folpe revised this number to less than 1% of all adult soft tissue sarcomas, reflecting a fascinating evolution of diagnostic criteria.
On closer scrutiny, three major factors are probably responsible for the apparent decline in the incidence of adult-type 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 tumor (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.
Adult-type fibrosarcoma has largely become a diagnosis of exclusion. It presupposes that 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 myxoid fibrosarcoma (myxofibrosarcoma), low-grade fibromyxoid sarcoma , and sclerosing epithelioid fibrosarcoma ( Box 9.1 ). This discussion 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.
Adult-type fibrosarcoma
Myxofibrosarcoma (myofibroblastic sarcoma)
Low-grade fibromyxoid sarcoma (with and without collagen rosettes)
Sclerosing epithelioid fibrosarcoma
Juvenile/infantile fibrosarcoma
Clinical Findings
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. It is 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 56.3 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.
Fibrosarcoma predominantly involves deep structures, where it tends 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 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 (described later). In the recent Mayo Clinic study, only 5 of 26 tumors arose in a suprafascial location.
Pathologic Findings
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 to 8 cm in greatest dimension. Small tumors are usually well 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 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. Tumors containing multinucleated giant cells or giant cells of bizarre size and shape are better classified as undifferentiated pleomorphic sarcomas.
Histologic grading of adult-type fibrosarcomas is based on the cellularity and differentiation, mitotic activity, and necrosis. Low-grade fibrosarcomas are characterized by a uniform, orderly appearance of the spindle cells associated with abundant collagen ( Figs. 9.31 to 9.34 ). In some cases, the cells are oriented in curving or interlacing fascicles, forming a classic herringbone pattern. In others, the cells are separated by thick, wirelike collagen fibers. Secondary features may be seen, including focal chondroosseous differentiation. Some tumors have areas that are less cellular or extensively myxoid and closely mimic portions of fibromatosis, making distinction of these two lesions difficult in some cases, particularly when only a small sample is available for evaluation.
High-grade fibrosarcomas are characterized by closely packed, less well-oriented tumor cells that are small, ovoid or rounded, and associated with less collagen ( Fig. 9.35 ). The fascicular or herringbone growth pattern is less distinct; the nuclei are more pleomorphic; mitotic figures are more numerous; and there are areas of necrosis and hemorrhage. In general, such tumors are best classified as undifferentiated pleomorphic sarcoma (UPS).
Immunohistochemical Findings
Fibrosarcomas, by definition, do not exhibit any lineage-specific markers such as keratin or S-100 protein. The lack of keratin immunoreactivity aids in distinction from monophasic fibrous synovial sarcoma. Negative immunostaining for S-100 protein and/or SOX10 distinguishes fibrosarcoma from spindle cell or desmoplastic malignant melanomas but not necessarily from MPNST because only 50% to 60% of the latter stain focally for these antigens. In some fibrosarcomas, scattered cells express SMA or MSA, reflecting focal myofibroblastic differentiation. Strong CD34 staining is typically only seen in a subset of fibrosarcomas arising in DFSP or from a solitary fibrous tumor.
Cytogenetic and Molecular Genetic Findings
Little is known about the cytogenetic and molecular genetic alterations in adult-type fibrosarcoma. In contrast to congenital/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.
Differential Diagnosis
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 fibrosarcoma.
Nodular fasciitis , a pseudosarcomatous benign myofibroblastic proliferation that grows rapidly and is marked by its cellularity and immature cellular appearance, differs from 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 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 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 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 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 fibrosarcoma but is less cellular and contains more collagen. The cells are uniformly spindled, with delicate chromatin and one or two minute nucleoli. In general, the cells do not touch one another but rather are separated by collagen, whereas the cells of fibrosarcoma frequently overlap with closely spaced hyperchromatic nuclei. Low levels of mitotic activity may be present in fibromatosis, so considerable overlap in mitotic activity between fibromatosis and fibrosarcoma may be encountered ( Table 9.4 ). Therefore, mitotic activity is not a reliable discriminant between fibromatosis and fibrosarcoma when dealing with low levels of mitotic activity but might become useful when higher levels of mitotic activity are present. Because fibromatosis-like areas may be present in low-grade fibrosarcoma, careful sampling of the tumor is mandatory. Clinical considerations are of little help for 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 immunoreactivity.
| Parameter | Low-Grade Fibrosarcoma | Fibromatosis |
|---|---|---|
| Cellularity | Low to moderate | Low to moderate |
| Nuclear overlap | Present | Usually absent |
| Nuclear hyperchromasia | Present | Absent |
| Nucleoli | More prominent | Inconspicuous |
| Mitotic figures | 1+ to 3+ | 1+ |
| Necrosis | Rare | Absent |
| Vessel wall infiltration | Rare | Absent |
Undifferentiated pleomorphic sarcoma (UPS, formerly known as malignant fibrous histiocytoma ) has 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. Transitions between fibrosarcoma and UPS do occur, suggesting a form of tumor progression, at least in some cases. Admittedly, where one draws the line between a high-grade fibrosarcoma and UPS is at times quite subjective.
Malignant peripheral nerve sheath tumor may display areas that are virtually indistinguishable from 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 fibrosarcoma. Although the cells can be arranged into an irregular fascicular growth pattern, the long, sweeping fascicles characteristic of 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 loss of H3K27me3 (see Chapter 27 ).
Monophasic fibrous synovial sarcoma may also closely simulate a 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 fibrosarcoma. In addition, TLE1 is a reliable marker of synovial sarcoma, although there have been only rare opportunities to stain adult-type fibrosarcomas for this antigen. The identification of t(X;18) by FISH or RT-PCR is a highly sensitive and specific method for identifying a tumor as a synovial sarcoma (see Chapter 33 ).
Discussion
It is difficult to compare the results of published studies because many of the tumors included in older series probably represent entities other than 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 tumors mimicking fibrosarcoma. 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, particularly those with low-grade fibrosarcomas, develop metastasis late in their course. Lymph node metastasis is rare; as such, regional lymph node excision is not a necessary part of the initial therapeutic regimen.
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 an etiologic significance was 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. There are reports of this tumor arising at the site of a burn scar, following the placement of a plastic Teflon-Dacron prosthetic vascular graft, and in the vicinity of a total knee joint prosthesis. Finally, it is clear that fibrosarcomas can arise following radiation therapy; 2 of 26 cases in the Mayo Clinic study arose in this setting.
As mentioned earlier in the chapter, the evolution of concepts and diagnostic criteria has resulted in this once commonly diagnosed sarcoma to become a relative rarity. This is well exemplified by the Mayo Clinic study that evaluated 163 cases diagnosed as fibrosarcoma over a 48-year period ( Table 9.5 ). In the end, after applying rigid diagnostic criteria and using both IHC and molecular techniques, only 26 cases (16%) met the modern diagnostic criteria of fibrosarcoma. Specifically, the authors required the tumor be composed of hyperchromatic spindled cells with mild or moderate nuclear pleomorphism with arrangement into a fascicular herringbone growth pattern and a variable degree of interstitial collagen. In addition, there had to be an absence of morphologic features of myxofibrosarcoma, low-grade fibromyxoid sarcoma (with or without rosettes), sclerosing epithelioid fibrosarcoma, or fibrosarcoma arising in DFSP. On IHC the cells could express only vimentin or focal SMA.
| Final Diagnosis | Number of Cases |
|---|---|
| True fibrosarcoma | 26 (16%) |
| Undifferentiated pleomorphic sarcoma | 32 (20%) |
| Synovial sarcoma | 21 (13%) |
| Solitary fibrous tumor | 14 (9%) |
| Myxofibrosarcoma | 11 (7%) |
| MPNST | 8 (5%) |
| Low-grade fibromyxoid sarcoma | 3 (2%) |
| Sclerosing epithelioid fibrosarcoma | 2 (1%) |
| Fibrosarcomatous DFSP | 4 (3%) |
| Myofibroblastic sarcoma | 3 (2%) |
| Miscellaneous/other mesenchymal tumors | 21 |
| Nonmesenchymal tumors | 7 |
| Sarcomatoid carcinoma | 3 (2%) |
| Spindle cell melanoma | 4 (3%) |
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