Fibroblastic and Myofibroblastic Tumors

Clinical Features

Nodular fasciitis occurs mostly in young and middle-aged adults (20–50 years of age), with no sex predilection. Patients describe a small (<2 to 3 cm), sometimes painful mass that develops rapidly (often <1 month). However, these lesions may be present for some time before receiving clinical attention. Tumors may arise anywhere in the body, but are most common in the upper extremities (50% of cases), especially in the subcutaneous tissue of the forearm.

Pathologic Features

Gross Findings

Nodular fasciitis presents as a solitary, well-circumscribed, but non-encapsulated nodule usually less than 3 cm in diameter ( Fig. 3.1A ). This nodule is often found within the fibrous septa of the deep subcutis, although the deep soft tissues can be involved; intramuscular tumors tend to be larger than subcutaneous tumors. In section, recently developed lesions have a myxoid appearance, whereas older, resolving lesions are firm and more fibrous.

Nodular Fasciitis — Fact Sheet

Definition

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  A self-limiting neoplasm composed of fibroblasts and myofibroblasts

Incidence and Location

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  Common, mostly subcutaneous, soft tissue lesion

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  Upper extremities, trunk, head, and neck most frequently affected

Sex, Race, and Age Distribution

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  More common in young adults

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  No race or sex predilection

Clinical Features

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  Rapidly growing (1 to 2 months), sometimes painful nodule

Radiologic Features

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  Nonspecific, well-circumscribed soft tissue mass

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  Calcifications in a soft tissue mass may be possible

Genetics

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  Recurrent gene fusions involving USP6 ; most common partner is MYH9

Prognosis and Treatment

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  Benign

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  Local recurrences <2%

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  Simple excision is curative

Nodular Fasciitis — Pathologic Features

Gross Findings

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  2- to 3-cm, solitary, well-circumscribed nodule

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  Myxoid appearance of early/active lesions; old lesions are more fibrous

Microscopic Findings

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  Variably cellular, fascicular proliferation of fibroblasts and myofibroblasts

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  Microcystic change

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  Myxoid (early lesions) to collagenized (long-standing lesions) extracellular matrix

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  Mitoses often numerous, especially in young lesions; abnormal mitoses absent

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  Inflammation prominent around the lesion

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  Osteoclast-like multinucleated giant cells in 10% of cases

Diagnostically Helpful Immunohistochemistry

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  “Tram-track” pattern of actin/calponin expression

Differential Diagnosis

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  Myxoma, myxofibrosarcoma, fibrous histiocytoma, fibromatosis, adult fibrosarcoma, leiomyosarcoma

Differential Diagnosis

Because nodular fasciitis is highly proliferative and has an infiltrative growth pattern, it is commonly mistaken for sarcoma. Predominantly myxoid lesions are likely to be confused with myxofibrosarcoma, while more cellular lesions may be mistaken for inflammatory myofibroblastic tumors (IMTs). Long-standing, collagenized lesions may mimic fibromatosis, fibromas of the tendon sheath, or desmoplastic fibroblastomas (collagenous fibromas), particularly in small biopsy specimens. Intradermal tumors may be confused with fibrous histiocytomas. The presence of osteoclast-type giant cells may prompt misinterpretation as a tenosynovial giant cell tumor. The important clues to the diagnosis of nodular fasciitis include short, randomly arranged fascicles, the absence of a well-developed thick-walled vasculature, the absence of nuclear pleomorphism or hyperchromatism, and the presence of microcystic changes. Attention to the areas typical of nodular fasciitis should allow for the resolution of the differential diagnoses in most cases without great difficulty. In challenging cases, the demonstration of USP6 rearrangement may be helpful in confirming the diagnosis.

Prognosis and Treatment

Nodular fasciitis is a benign, self-limiting process. A simple excision is the treatment of choice. Local recurrences are exceptional (less than 2% of cases).

Clinical Features

Inflammatory myofibroblastic tumor (IMT) (previously called inflammatory pseudotumor, plasma cell granuloma, or inflammatory fibrosarcoma) is primarily a tumor in children and young adults (median age, 9 years), with a slight female predilection. The lungs, omentum, mesentery, and soft tissues are predominantly affected, although they may be found virtually anywhere in the body. Approximately 40% to 45% of extrapulmonary IMTs occur in the omentum and mesentery. The lesions in these two sites mostly affect children and adolescents, whereas pulmonary lesions predominate in adults.

The symptoms depend on the site of the lesion: patients with pulmonary IMT may describe dyspnea, chest pain, or both; abdominal tumors may cause discomfort or gastrointestinal tract obstruction. A significant proportion of IMTs (up to 30%) are associated with systemic symptoms (e.g., weight loss, fever, or night sweats) and/or laboratory abnormalities (e.g., anemia, thrombocytosis, hyperglobulinemia, or increased erythrocyte sedimentation rate) that disappear when the tumor is removed but may reappear if it recurs.

Pathologic Features

Microscopic findings

Three basic histological patterns have been identified. In the first pattern, plump myofibroblasts are loosely dispersed in an abundant edematous/myxoid extracellular matrix, together with numerous dilated vessels (granulation tissue–like capillaries), extravasated erythrocytes, lymphocytes, plasma cells, and eosinophils ( Fig. 3.4A and B ). Mitoses can be numerous, but not atypical. The second growth pattern consists of a denser, storiform, or fascicular spindle cell proliferation, with a prominent inflammatory infiltrate comprising predominantly lymphocytes and plasma cells ( Fig. 3.4C ). Lymphoid follicles with germinal centers are observed. Ganglion-like myofibroblasts with vesicular nuclei, prominent nucleoli, and abundant eosinophilic/amphophilic cytoplasm are frequently observed in these two patterns. In the third pattern, the lesion is less cellular and more collagenized, resembling a scar or desmoid fibromatosis with marked inflammation. Calcifications and/or foci of the metaplastic bone are observed.

Epithelioid inflammatory myofibroblastic sarcoma is an aggressive and rare variant characterized by clusters of polygonal, ganglion-like, or epithelioid atypical cells with vesicular nuclei and prominent nucleoli, and numerous, often atypical mitoses set in a prominent myxoid stroma.

Inflammatory Myofibroblastic Tumor — Fact Sheet

Definition

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  A distinctive lesion composed of myofibroblasts, lymphocytes, plasma cells, and eosinophils

Incidence and Location

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  Rare

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  Predominant in the lungs, soft tissues, and abdominal viscera (mesentery, omentum, genitourinary tract)

Sex, Race, and Age Distribution

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  Children and young adults; pulmonary form more common in middle age

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  Slight female predominance

Clinical Features

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  Pulmonary inflammatory myofibroblastic tumor (IMT): chest pain and dyspnea

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  Abdominal IMT: pain, discomfort, gastrointestinal obstruction

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  Mass, fever, and/or weight loss frequent

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  Anomalous laboratory findings (anemia, hyperglobulinemia, increased erythrocyte sedimentation rate) occasional

Genetics

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  IMT occurring in young adults shows ALK1 rearrangements in most cases; ROS1, NTRK3, and RET rearrangements are less common

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  Translocations are rare in IMT arising in older adults, and their genetics are not well described

Prognosis and Treatment

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  Local recurrence rate of 30% to 40% for extrapulmonary and extravesicular IMT (5% to 10% for pulmonary lesions; 25% for lesions from the urinary bladder)

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  Metastasis in less than 5% of cases

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  Treatment: wide excision whenever possible

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  ALK inhibitors are effective in treating ALK1 -rearranged IMT

Inflammatory Myofibroblastic Tumor — Pathologic Features

Gross Findings

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  Circumscribed multinodular mass

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  Whitish to myxoid

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  Mean diameter: 6 cm (range, 1 to 17 cm)

Microscopic Findings

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  Three patterns:

  • 1.

    Fairly dispersed spindled fibroblasts/myofibroblasts; some ganglion-like myofibroblasts

    • Prominent inflammation (lymphocytes, plasma cells, eosinophils)

    • Edematous/myxoid background with numerous vessels

  • 2.

    Dense, fascicular myofibroblastic proliferation

    • Prominent inflammatory infiltrate/plasma cell aggregates/lymphoid nodules

    • Variably myxoid to collagenized background

    • Ganglion-like myofibroblasts

  • 3.

    Moderate to hypocellular myofibroblastic proliferation

Well-developed collagenized extracellular matrix

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  Epithelioid inflammatory myofibroblastic sarcoma characterized by:

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    Atypical, polygonal, ganglion-like, epithelioid cells with vesicular nuclei and prominent nucleoli

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    Numerous/atypical mitoses

Diagnostically Helpful Immunohistochemistry

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  Cytoplasmic ALK or ROS expression correlates with underlying gene rearrangement

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  Pan-TRK antibodies positive in rare cases with NTRK3 rearrangement

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  Focal or diffuse reactivity for smooth muscle actin, calponin, and desmin

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  Keratin reactivity in approximately 30% of cases (especially in lesions from the urinary bladder)

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  Negative for myogenin, h-caldesmon, S-100 protein, and CD117

Differential Diagnosis

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  Granulation tissue/reactive processes

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  Nodular fasciitis

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  Fibrous histiocytoma

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  GIST

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  Spindle cell carcinoma

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  Dendritic cell neoplasms

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  Desmoid-type fibromatosis

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  Well-differentiated sclerosing/inflammatory liposarcoma

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  Hodgkin Lymphoma

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  Autoimmune-associated fibrosing processes (Ormond disease, sclerosing mediastinitis)

Differential Diagnosis

The differential diagnosis depends on the histologic appearance of the lesion. When the tumor is predominantly myxoid and mitotically active, it resembles a pseudosarcomatous lesion such as granulation tissue, nodular fasciitis, or proliferative fasciitis (if ganglion-like cells are numerous). When IMTs are markedly cellular, smooth muscle neoplasms, fibrous histiocytoma, inflammatory cell–rich gastrointestinal stromal tumors, and dendritic cell neoplasms must be considered. In the liver and spleen, most lesions resembling IMT correspond to dendritic cell tumors. Immunoreactivity for CD21 and CD35, signs of Epstein–Barr virus infection in inflammatory EBV+ follicular dendritic cell sarcoma, and S-100 and CD1a positivity in interdigitating dendritic cell tumors are useful features in this setting. Benign histiocytic spindle cell lesions associated with infections, especially mycobacterial infections, should also be distinguished from IMT. Special stains (methenamine silver and Ziehl stains) should always be performed, especially if the patient is immunodeficient or treated with corticosteroids. When IMTs are relatively sclerotic and less cellular, desmoid-type fibromatosis, scarring, and calcifying fibrous pseudotumors are potential mimics. Contrary to the former belief, it is now thought that IMT and calcifying fibrous pseudotumors are unrelated. In the retroperitoneum, mesentery, and mediastinum, sclerosing IMT should be distinguished from well-differentiated sclerosing/inflammatory liposarcoma, sclerosing carcinoma, Hodgkin lymphoma, and all fibrosclerosing inflammatory processes, including IgG4-related diseases. The epithelioid inflammatory myofibroblastic sarcoma variant should be differentiated from undifferentiated pleomorphic sarcoma, epithelioid leiomyosarcoma, rhabdomyosarcoma, and spindle cell carcinoma. Clinical presentation (children), tumor site (intra-abdominal lesion), and immunohistochemical profile (positivity for ALK) assist in making the distinction.

Prognosis and Treatment

Most IMTs are locally aggressive, with a low risk (<5%) of distant metastasis. In children and young adults, the overall 5-year recurrence rate is 15%–20%, reflecting more frequent recurrence in extrapulmonary tumors (30%–40%) compared to pulmonary IMT (5%). ALK/ROS-negative IMTs arising in older adults tend to be more aggressive, with higher rates of local recurrence and metastasis.

Wide excision is the treatment of choice. Chemotherapy has been used for relapsed disease with some success, and ALK inhibitors show efficacy in ALK -rearranged IMT.

Clinical Features

Elastofibroma is a fibroelastic soft tissue pseudotumor of middle-aged adults (average age, 55 years) with a marked female predominance. The tumors develop in the connective tissues between the lower scapula and chest wall and can be bilateral with either synchronous or metachronous presentation. Repetitive trauma is thought to be causative, with many patients reporting a history of intensive manual work. The tumors present as slow-growing, generally painless, soft tissue masses. Rarely, elastofibromas are present in other anatomic locations.

Pathologic Features

Gross Findings

Elastofibromas measure 5–10 cm in maximal diameter and are unencapsulated. On sectioning, the lesion is composed of mature adipose tissue intermixed with whitish firm fibrous tissue ( Fig. 3.5A ).

Ancillary Studies

Elastin stains may help in identifying the fragmented elastic fibers ( Fig. 3.5C ).

Differential Diagnosis

Fibroma and desmoplastic fibroblastoma may be confused with elastofibroma, although neither contains the fragmented elastic fibers that are diagnostic of the lesion. The location beneath the lower scapula is also highly suggestive of elastofibroma.

Prognosis and Treatment

Elastofibroma is a benign, nonrecurring lesion. Simple excision is curative.

Clinical Features

Collagenous fibroma, also known as desmoplastic fibroblastoma, most commonly affects adults with a median age of 50 years, and is more common in men. The tumors most commonly arise in the subcutaneous tissue of the limbs, trunk, and limb girdles.

Pathologic features

Gross findings

The tumor size is usually <10 cm, although larger examples have been reported; tumors are well-circumscribed and firm, with a white-grey appearance on cut section ( Fig. 3.6A ).

Differential diagnosis

The differential diagnosis can include benign lesions such as fibroma of the tendon sheath (see Chapter 13), involuted nodular fasciitis, fibromatosis, or low-grade fibromyxoid sarcoma. Most tumors in the differential show higher cellularity and a more prominent vasculature than does a fibroma of the tendon sheath. Deep fibromatosis will express nuclear β-catenin in a majority of cases (negative in collagenous fibroma), and low-grade fibromyxoid sarcoma will diffusely express MUC4 .

Prognosis and Treatment

Complete excision is curative; tumors are benign and do not recur.

Clinical Features

Superficial palmar fibromatosis is the most common type of fibromatosis, mainly affecting adult patients, with a strong male predilection and an increasing incidence with advancing age; almost 20% of the general population is affected by the age of 65. For unknown reasons, palmar fibromatosis occurs most commonly in Northern Europeans and is rare in individuals of African descent. Patients present with slowly growing, small subcutaneous nodules, plaques, or cord-like indurations involving the dermis or underlying fascia of the palm. These nodules may lead to contractures that usually predominate on the ulnar side of the palm, affecting the fourth and fifth fingers. Dupuytren disease may be bilateral (50% of cases), and the soles of the feet may be affected simultaneously or metachronously. An association exists among Dupuytren disease and trauma, alcoholism, diabetes, epilepsy, and chronic lung disease. Coexistence with other superficial fibromatosis (penile fibromatosis and knuckle pads) has also been described, but not with deep fibromatoses. Plantar lesions are more common in children and adolescents, occurring within the plantar aponeurosis, usually in non-weight-bearing areas. They usually present as solitary or multiple firm nodules that hurt after long standing or walking. Plantar contractures are rare.

Pathologic Features

Microscopic findings

The lesions appear monotonous and variably collagenized, with fascicular proliferation of uniform, non-atypical fibroblasts ( Fig. 3.7A and B ). Some mitotic figures may be visible, especially in early cellular lesions. The lesion originates from, and blends into, the palmar or plantar aponeurosis, and extends into the overlying subcutaneous fat. Long-duration lesions are less cellular and more collagenized. Plantar lesions are often hypercellular and may be confused with spindle cell sarcoma.

Differential Diagnosis

Diagnosing superficial fibromatoses in their conventional form is usually not a problem for pathologists. However, some cellular forms, especially of plantar fibromatosis, may be confused with sarcomas, especially fibrosarcoma, synovial sarcoma, or MPNST. The clinical presentation (large size and deep location for sarcomas), immunohistochemical profile (positivity for epithelial markers in synovial sarcoma, focal reactivity for S-100 protein in MPNST), and the presence of specific chromosomal abnormalities (for example, t(X;18)(p11;q11) for synovial sarcoma) are of great help in making the distinction. Desmoid-type fibromatoses, which may occur in the distal extremities, are typically less cellular than are superficial fibromatoses and are composed of longer fascicles of bland fibroblastic cells arrayed about a thin-walled, dilated vasculature. CTNNB1 gene mutations are observed in more than 90% of desmoid fibromatosis. Mitotic activity can be brisk in superficial fibromatoses, and such lesions should not be confused with fibrosarcoma.

Prognosis and Treatment

Superficial fibromatoses have a strong tendency for local recurrence. Fasciectomy/aponeurectomy followed by skin grafting is the recommended treatment whenever possible to prevent recurrence.

Clinical Features

Abdominal desmoid tumors, which develop from the musculoaponeurotic structures of the abdominal wall, tend to occur in young women during pregnancy or during the first year after childbirth, suggesting a hormonal role in their pathogenesis. Extra-abdominal desmoid tumors are mostly observed in the muscles and aponeuroses of the limb girdles (notably the shoulder and pelvic regions), chest wall, back, proximal limbs (thigh), and head and neck of young to middle-aged adults. Fibromatosis of the head and neck is more frequent in children, and tends to be more cellular and locally aggressive. Desmoids are rarely observed on the hands and feet. Abdominal and extra-abdominal desmoids usually present as painless, slow-growing, deep-seated, firm, and poorly circumscribed masses. Some tumors have received medical attention because of neurological compression symptoms or the limitation of motion. In 5% of cases, the disease is multicentric, with subsequent lesions often developing near the initial site. Rarely, extra-abdominal and abdominal desmoids may coexist in the same patient.

Intra-abdominal desmoid tumors develop in the mesentery, pelvis, and/or retroperitoneum of young to middle-aged adults (20–35 years). These tumors remain asymptomatic for a long time until they reach a large size (often ≥10 cm in maximal diameter). Pelvic desmoid that develop mainly in the iliac fossa are often misdiagnosed as ovarian neoplasms. These lesions may encroach on the urinary bladder, vagina, or rectum, or may compress the large vessels, resulting in a wide range of presenting symptoms, such as pain, gastrointestinal bleeding, or obstructive symptoms; retroperitoneal tumors are also often large and asymptomatic unless they compress adjacent structures such as ureters, causing hydronephrosis. Trauma is a potential cause of development; more than half of the patients had prior abdominal surgery. Mesenteric fibromatosis, the most common form of intra-abdominal fibromatosis, may be sporadic or associated with Gardner syndrome.

Pathologic Features

Gross Findings

Most desmoid tumors are solitary, firm, and grossly circumscribed masses with infiltrative borders. Their size is widely variable; most are larger than 2 cm. Sectioning reveals a fascicular, whitish surface resembling a leiomyoma or scar tissue ( Fig. 3.8A ). Myxoid or cystic changes, or both, are occasionally present and may be prominent, especially in intra-abdominal tumors ( Fig. 3.8B ). Necrosis is absent.

Microscopic findings

Histologically, desmoids are poorly demarcated, uniform, monotonous, and fascicular proliferations of spindle-shaped fibroblasts and myofibroblasts ( Fig. 3.9A ). The fascicles seen in this tumor are quite long and frequently extend across an entire low-power microscopic field. A storiform growth pattern may also be present. The spindle-to-stellate tumor cells have a slightly fibrillary cytoplasm with ill-defined borders and bland nuclei with one to three small nucleoli ( Fig. 3.9B ). The amount of extracellular matrix observed between the cells varies from one lesion to another, but the individual nuclei do not appear to touch each other or overlap. Some lesions can be cellular, mimicking fibrosarcoma, whereas others are markedly collagenized, sometimes with a peculiar, keloid-like collagen, especially in mesenteric fibromatosis ( Fig. 3.9C ). Well-formed, sometimes gaping vessels with distinctive muscular walls and/or some degree of perivascular hyalinization are also characteristically observed in desmoids. Mitoses may be present in cellular lesions, and atypical mitoses and cellular pleomorphism are absent. Characteristically, desmoid tumors have infiltrative borders, encroaching on the surrounding skeletal muscle or adipose tissue ( Fig. 3.9D ). As a result, atrophic or regenerative skeletal muscle fibers entrapped by the lesion are commonly observed toward the edges, together with lymphoid aggregates. Areas of myxoid change resulting in a fasciitis-like morphology are quite common in early lesions, whereas calcifications, chondroid metaplastic foci, and/or osteoid metaplastic foci are occasionally observed in long-standing neoplasms.

Differential Diagnosis

Desmoid tumors displaying prominent myxoid changes may be confused with nodular fasciitis or reactive myofibroblastic proliferation. The distinction can be made by the large size of the lesion, deep location, and monotonous histologic appearance with low mitotic activity. Highly collagenized lesions should be differentiated from scar tissue. Sometimes, this distinction is almost impossible, notably in patients with previous operations at the same site for the same condition. Desmoplastic fibroblastoma, which is usually less cellular than is a desmoid tumor and lacks a fascicular growth pattern, and neurofibroma, which consists of bland S-100 protein–positive spindled cells with wavy nuclei admixed with bundles of eosinophilic collagen, also enter the differential diagnosis. The cellular variants of desmoid tumor may be confused with malignant lesions. However, desmoids lack the cellular atypia, numerous atypical mitoses, and tumor necrosis typical of fibrosarcoma or monophasic synovial sarcoma. Low-grade fibromyxoid sarcoma and low-grade MPNSTs should also be distinguished from desmoid tumor. Desmoid tumors are more fascicular and show neither the whorled or swirling pattern nor the alternating presence of fibrous and myxoid areas that typify low-grade fibromyxoid sarcomas. Desmoid tumors may display myxoid changes, particularly when intra-abdominal, but the cells have plump vesicular nuclei and are consistently and more diffusely positive for smooth muscle actin. In the mesentery and retroperitoneum, desmoid tumors should also be differentiated from rare fibrosclerosing idiopathic and IgG4-related diseases such as sclerosing mesenteritis and retroperitoneal fibrosis (Ormond disease). These lesions are heterogeneous in their histologic appearance, showing a varying admixture of cellular fibroblastic areas, fibrous (poorly cellular) zones, inflammatory areas containing numerous plasma cells and lymphocytes, and foci of fat necrosis with or without lymphocytic venulitis; in many cases, increased IgG4+ plasma cells are evident.

Prognosis and Treatment

Desmoid tumors do not metastasize, but they have a strong tendency for local recurrence and may ultimately invade structures such as the large vessels, large nerves, or viscera; some patients may also develop or present with multifocal disease. Meanwhile, a subset of tumors may spontaneously regress. Desmoid tumors rarely cause death, with a 5-year survival rate of >90%. Because complete surgical excision can be quite morbid, some experts now recommend watchful waiting in asymptomatic patients, with surgery reserved for those with symptomatic tumors. Local recurrence, even after complete surgical resection, is common and correlates with tumor location; extremity and intra-abdominal tumors show higher recurrence rates than do those arising in the abdominal wall.

Radiation therapy is mostly recommended for progressive disease, although it may be used in an adjuvant fashion for incompletely resected primary tumors. Antiestrogen agents (tamoxifen), chemotherapy, or both have been administered with variable success rates. Other strategies include chemotherapy with low doses of methotrexate or doxorubicin (adriamycin) to stabilize the lesion.