Soft tissue neoplasms

Clinical features

Lipoma represents the most common mesenchymal soft tissue tumor of adults. Most commonly, lipomas are localized to the subcutaneous adipose tissue, presenting as a painless mass/swelling, although examples may arise in intramuscular locations and intrathoracic/intra-abdominal/retroperitoneal regions. If associated with peripheral nerves, there may be tenderness. Unlike ordinary lipomas, angiolipomas present as small and often painful subcutaneous masses, frequently in adolescence and young adults. Myolipomas (extrauterine lipoleiomyomas) are typically an incidental finding, originating in the abdominal cavity (usually retroperitoneum), but may also be found in the soft tissues of the trunk and extremities. Chondroid lipomas are generally deep-seated, painless lesions, most commonly occurring in the proximal extremities and limb girdles.

Pathologic features

Microscopic findings

Lipomas are benign tumors composed of mature adipocytes, with little to no variation in size and shape ( Fig. 8.1 ). Some have thin fibrous septa dissecting the tumor proper. There is no to minimal cytologic atypia, and mitotic activity is virtually non-existent. Because of their infiltrative nature, intramuscular lipomas commonly entrap skeletal muscle fibers ( Fig. 8.2 ). Variable amounts of fat necrosis may occur.

Angiolipomas ( Fig. 8.3 ) are well circumscribed and characterized by variable numbers and aggregates of small caliber, thin-walled capillary vessels, often containing microthrombi ( Fig. 8.3 B). These vessels are lined by bland endothelial cells and surrounded by a pericytic layer. Thick, muscular-walled blood vessels are not a feature of angiolipoma.

Myolipomas are mature adipocytic neoplasms that contain variable amounts of well-differentiated smooth muscle. There is no cytologic atypia or increased mitotic activity.

Chondroid lipomas ( Fig. 8.4 ) are lobulated, well-encapsulated masses with a characteristic histologic presentation of mature adipose tissue admixed with cords and nests of vacuolated cells (lipoblasts), embedded in a chondromyxoid to hyalinized matrix.

Ancillary studies

The adipocytes are positive for S100. The smooth muscle component in a myolipoma is diffusely positive for SMA, desmin, and caldesmon. In addition to S100 protein, keratins are rarely expressed in chondroid lipoma, but EMA is negative.

FISH analysis for MDM2 gene amplification is negative among all lipomas and variants. Angiolipomas usually have a normal karyotype.

Chondroid lipomas have a recurrent t(11;16)(q13;p130), associated with the C11orf95-MKL2 gene rearrangement.

Differential diagnosis

The most important differential diagnosis, especially among deeply-seated benign adipocytic neoplasms, is atypical lipomatous tumor/well-differentiated liposarcoma (ALT/WDL). The presence of large and atypical, often multinucleated hyperchromatic cells is diagnostic of the latter, most frequently seen in the non-lipogenic fibrous tissue. FISH analysis for MDM2 gene amplification may be necessary in difficult cases, deep-seated tumors, especially in the abdominal and retroperitoneal regions, and among small needle biopsy specimens, primarily composed of normal-appearing adipose tissue.

In angiolipomas with a dominating “angio” component, the differential may include hemangioma. The presence of circumscription and interspersed adipose tissue will help establish the diagnosis of angiolipoma.

The extrauterine location of a myolipoma supports the diagnosis of myolipoma over leiomyoma with increased intralesional adipose tissue.

The differential diagnosis of chondroid lipoma includes myxoid liposarcoma (ML). Circumscription and encapsulation and absence of ML vascular pattern, accompanied by the characteristic epithelioid cells, lipoblasts, and mature fat, helps establish the diagnosis of chondroid lipoma.

Prognosis and therapy

Overall, local recurrences are rare in lipomas (<5%) and mainly seen in incompletely excised deeply seated lesion. In the absence of more obvious diagnostic features, locally recurrent “lipomas” probably should be evaluated for MDM2 gene amplification, to fully exclude an under-sampled ALT/WDL. Like ordinary lipomas, chondroid lipomas rarely locally recur. Surgical excision is curative for angiolipomas and myolipomas.

Clinical features

Lipoblastoma/lipoblastomatosis is a benign neoplasm of embryonal white fat that may present as a lobulated and localized, well-circumscribed mass (lipoblastoma) or, alternatively, a diffuse and infiltrative lesion (lipoblastomatosis). Most examples present in infancy and early childhood, before 5 years of age. There appears to be a slightly male predilection. The extremities and the trunk are the most common anatomic sites.

Pathologic features

Microscopic findings

Lipoblastomas are characterized by nodules of adipocytes of variable maturation embedded in a lightly myxoid stroma and separated by variably thick fibrous septa ( Fig. 8.5 ). The adipocytic maturation may represent a somewhat zonal maturation, ranging from primitive mesenchymal cells, to univacuolated (signet-ring like) lipoblasts, multivacuolated lipoblasts to mature adipocytes. The background myxoid stroma often exhibits thin-walled plexiform vessels, mimicking ML ( Fig. 8.5 B). Occasionally, heterologous elements can be seen, such as chondroid metaplasia, extramedullary hematopoiesis, and chronic inflammation. There is no significant cytologic atypia or mitotic activity.

Ancillary studies

As with ordinary adult lipomas, the adipocytes in lipoblastoma also are positive for S100. CD34 reactivity is seen in the more spindled cells in myxoid and fibrous regions, and desmin positivity is sometimes observed. Lipoblastomas typically contain structural alterations or gene fusions involving 8q12 ( PLAG1 ). One or more extra copies of chromosome 8 may occur with or without the associated gene fusion.

Differential diagnosis

The most important differential diagnosis is ML. However, the presence of lobulation and more mature non-myxoid areas, especially when associated with a child, helps establish the diagnosis of lipoblastoma.

Prognosis and therapy

Surgical resection of the localized form (lipoblastoma) generally results in complete cure. Local recurrences are more likely to be associated with the diffuse form (lipoblastomatosis), ranging up to 50% of cases, when incompletely excised. Dedifferentiation does not occur, and there is no risk of distant metastases.

Clinical features

Hibernomas are benign, slowly growing, painless neoplasms, most often arising in young to middle-aged adults, with a slight male predominance. The most common anatomic location is the thigh, followed by the trunk and upper extremity. Radiographically, many will display a signal intensity within the tumor proper described as intermediate between mature adipose tissue and skeletal muscle.

Pathologic features

Microscopic findings

Hibernomas display varying proportions of brown fat admixed with mature, white adipose tissue. At low power, a distinct lobulation is evident. Cytologically, the brown fat cells exhibit a centrally placed nucleus and a prominent nucleolus, surrounded by a cytoplasm ranging from granular and eosinophilic to uniformly multi-vacuolated ( Fig. 8.6 ). Rarely, myxoid change and spindled cell areas occur. Mitotic figures are absent, and significant nuclear atypia is not a feature.

Ancillary studies

S100 protein is strongly and diffusely positive within both brown and white fat cells. CD10 has recently been noted to be expressed and may be helpful in distinguishing hibernoma from potential fatty lesion mimics. Desmin and SMA are negative.

Cytogenetic analysis reveals structural rearrangements, including translocations and deletions, involving chromosome 11q13. MDM2 gene amplification is not present.

Differential diagnosis

The most important differential diagnosis is ALT/WDL. The enlarged atypical and often multi-nucleated cells and lipoblasts associated with it are not seen in hibernoma. When hibernomas are composed of a predominance of brown fat with eosinophilic cells, rhabdomyoma may also be considered within the differential diagnosis. Desmin positivity excludes hibernoma.

Prognosis and therapy

Surgical resection is curative.

Clinical features

Most common presentation for spindle cell/pleomorphic lipoma is the posterior neck, back, and shoulders of elderly males. In women, these lipomas are frequently found outside the shawl region, often at younger ages and with a wider anatomic distribution, such as the extremities and the face.

Pathologic features

Microscopic findings

Spindle cell lipomas and pleomorphic lipomas represent spectrums of a similar neoplasm, both being well circumscribed and often encapsulated, usually subcutaneous, less commonly dermal or intramuscular. “Spindle” cell lesions are composed of mature adipocytes and various amounts of intermingled fibrous to myxoid tissue ( Fig. 8.7 ), within which are bland spindle cells, admixed with scattered variably thick, eosinophilic collagen fibers (“ropy collagen”) and mast cells. At the opposite end, “pleomorphic” forms are further characterized by the additional presence of randomly distributed multinucleated, “floret-like” giant cells ( Fig. 8.8 ).

Occasionally, there may be little to no adipocytes, so-called “fat-poor” spindle cell/pleomorphic lipoma. Rare examples display branching and dilated vascular-like spaces that separate the tumor to form pseudopapillary projections, designated as the pseudoangiomatous subtype.

Ancillary studies

The spindled and pleomorphic cells are diffusely and strongly positive for CD34 ( Fig. 8.7 C) and usually have loss of nuclear RB1 protein expression. As expected, the adipocytes express S100 protein.

Differential diagnosis

The recently described atypical spindle cell/pleomorphic lipomatous tumor represents a benign adipocytic neoplasm, characterized by ill-defined tumor margins, mild to moderate nuclear atypia, enlarged and bizarre lipoblasts, and occasional presence of pleomorphic, multinucleated cells. Admittedly, some examples may be indistinguishable from spindle cell/pleomorphic lipoma. There is no MDM2 gene amplification, low tendency to locally recur (10%–15%) if incompletely excised, but no risk for dedifferentiation. CD34 positivity and RB1 loss can be shared by both atypical spindle cell/pleomorphic lipomatous tumor and spindle cell/pleomorphic lipoma.

ALT/WDL is only rarely seen in the superficial soft tissues of the head and neck and shoulder regions; more often arises in deeply seated extremities, abdominal cavity, or retroperitoneum; and is characterized by MDM2 gene amplification. The atypical and enlarged, multinucleated cells in the latter exhibit some morphologic overlap with the floret cells seen in spindle cell/pleomorphic lipoma.

Prognosis and therapy

Local recurrences are rare, even with incomplete resection.

Clinical features

ALT/WDL is a potentially locally aggressive mature adipocytic neoplasm characterized by variably thick fibrous septa and enlarged, atypical and often multinucleated cells, predominantly within fibrous tissue and occasionally mature adipocytes. Intersecting adipocytic proliferation. It most commonly is deeply seated, arising bellow the fascia of the extremities. The retroperitoneum and the paratesticular soft tissues are common areas where ALT/WDL arises. Less common anatomic sites include the mediastinum, distal extremities, and rarely the head and neck region.

Pathologic features

Microscopic findings

The adipocytes show heterogeneity in size and shape, usually separated in lobules by variably thick fibrous septa ( Fig. 8.9 ). The scattered atypical and often multinucleated stromal cells are significantly pleomorphic (even bizarre), characterized by nuclei with irregular nuclear membranes and dense hyperchromatic chromatin pattern, giving the impression of “smudged” cells ( Fig. 8.9 B). Most are seen within the fibrous tissue, less commonly mature adipocytes and muscular walls of blood vessels. Lipoblasts are less commonly observed ( Fig. 8.9 C). Fat necrosis rarely dominates.

When fibrous tissue predominates, some designate these as “sclerosing” WDL ( Fig. 8.9 D). Even more rare, abundant lymphocytes and plasma cells within the fibrous tissue may obscure the background atypical cells/lipoblasts; this form has been referred to as “inflammatory” WDL.

Mature heterologous features, usually in the form of osseous, cartilaginous, or myogenic differentiation, are rare but should not be confused with dedifferentiation.

Mitotic figures tend to be rare, but, in more cellular examples, should never exceed 4 mitoses/10 high-power fields (HPF).

Ancillary studies

Immunohistochemistry usually shows MDM2 nuclear expression, particularly with the larger atypical cells. More sensitive, especially in lipoma-like WDL, and more specific is confirmation of MDM2 (12q15) gene amplification via FISH analysis. On cytogenetic analysis, karyotyping of ALT/WDL is characterized by supernumerary ring chromosomes and/or giant marker chromosomes, involving chromosome 12.

Differential diagnosis

The differential diagnosis includes most commonly lipoma, hibernoma, and spindle cell/pleomorphic lipoma. The deeper location, especially when seen in the retroperitoneum, presence of enlarged, atypical and hyperchromatic cells, less commonly lipoblasts, and, when necessary, MDM2 gene amplification help establish the diagnosis.

Prognosis and therapy

Lesions that arise in the retroperitoneum, paratesticular soft tissue, mediastinum, and similar places where complete excision is challenging, the term WDL is better used given the higher potential for local recurrence and progression compared with lesions arising within the extremities for which the term atypical lipomatous neoplasm is better applied. ALT/WDL has no metastatic potential, unless it has undergone dedifferentiation.

The risk for dedifferentiation varies depending on location, exceeding 20% for retroperitoneal forms but less than 2% when arising in the extremities. Consequently, the risk of mortality and metastases is greater for retroperitoneal and paratesticular lesions than for those localized to the extremities.

Clinical features

Dedifferentiated liposarcoma (DL) is defined as a high-grade sarcoma arising concomitantly from an ALT/WDL (most common) or occurring in the same anatomic site as a previously resected ALT/WDL. In cases where the precursor ALT/WDL is not present, the diagnosis can be confirmed molecularly, namely amplification of MDM2 via FISH analysis. The vast majority are found in older adults, especially in the deep soft tissues of the proximal extremities, intra-abdominal, and retroperitoneal locations.

Pathologic features

Microscopic findings

Most commonly, the transition of the ALT/WDL and DL components is sharply demarcated ( Fig. 8.10 A), but a gradual transition from the well-differentiated component to the high-grade, non-lipogenic areas is rarely present. Usually, the hypercellular dedifferentiated component is composed of atypical and pleomorphic spindled cells, arranged in fascicles and whorls ( Fig. 8.10 B), resembling undifferentiated pleomorphic sarcoma (UPS), without further defining features. However, in about 5% to 10% of cases, the dedifferentiated component exhibits varying degrees of heterologous differentiation including osteosarcoma/chondrosarcoma, leiomyosarcoma, myxofibrosarcoma, and rhabdomyosarcoma. So-called “homologous” lipoblastic differentiation, mimicking pleomorphic liposarcoma (PLS), is characterized by the presence of isolated and/or groups of lipoblasts. By definition, the dedifferentiated component should have at least ≥5 mitoses/10 HPF to qualify as “dedifferentiated,” separating it morphologically and prognostically from cellular forms of ALT/WDL.

Ancillary studies

MDM2 immunohistochemistry may be helpful ( Fig. 8.10 D), especially in small biopsy specimen and in instances where the low-grade component is not obviously present. Confirmation of MDM2 gene amplification by FISH analysis represents the gold standard.

Differential diagnosis

UPS is a diagnosis of exclusion, does not have MDM2 gene amplification, or is evidence of a concomitant or pre-existing ALT/WDL.

Primary PLS, leiomyosarcoma, rhabdomyosarcoma, and extraskeletal osteosarcoma can be excluded if the low-grade ALT/WDL component is confirmed or in the presence of MDM2 immunoexpression and/or MDM2 gene amplification via FISH.

Prognosis and therapy

Prognosis is significantly related to anatomic site, with retroperitoneal/intra-abdominal and paratesticular origins correlated with a worse survival than those localized to the deep soft tissues of the extremities. Local recurrence rates range up to 40%, while distant metastasis occurs in approximately 15% to 20% of cases. Overall mortality is estimated at 28% to 30% at 5 years.

There appears to be no association between the extent of the dedifferentiated component and survival, although data is limited. However, the presence of myogenic differentiation is associated with a worse clinical outcome.

Clinical features

ML presents as a large soft tissue mass, usually involving the deep soft tissues of the extremities. The most common anatomic location is the posterior thigh. Retroperitoneal ML most often represents either metastasis or evidence of a DL.

Pathologic features

Microscopic findings

ML presents as a lobulated neoplasm, variably cellular, with often noticeable increased cellularity at the periphery of the nodules. The background stroma is abundant and myxoid accompanied by a delicate network of plexiform and arborizing vessels ( Fig. 8.11 ). Sometimes foci of extracellular mucinous matrix appear extremely paucicellular, giving a pulmonary edema appearance. The uniform neoplastic cells have small, bland round to oval nuclei with minimal amounts of eosinophilic cytoplasm. Signet ring cell univacuolated lipoblasts are often present, at least focally ( Fig. 8.11 B).

High-grade ML (also known as round cell liposarcoma) is defined as ML with more than 5% of round cell component ( Fig. 8.11 C). The histologic features of the round cell component are characterized by marked hypercellularity, diminished background myxoid stroma, and a population of larger, round cells with prominent nucleoli and increased mitotic activity. Pure high-grade ML (round cell liposarcoma), especially in small biopsy specimens, may lack an obvious myxoid stroma, making the diagnosis difficult to establish by routine microscopy alone ( Fig. 8.11 D).

Ancillary studies

Immunohistochemistry is not generally helpful. In difficult cases, demonstration of a DDIT3 gene rearrangement, most often combined with FUS , associated with the t(12;16)(q13;p11) translocation, and, less often with EWSR1 , t(12;22)(q13;q12), is helpful in establishing the diagnosis. Generally, the diagnosis of ML, especially when low grade, does not require further ancillary studies.

Differential diagnosis

Intramuscular myxoma may be confused with ML, but is typically less cellular, lacks the characteristic vascular network, and does not display signet ring cell lipoblasts.

Myxofibrosarcoma is a relatively common sarcoma, most commonly arising in the superficial soft tissues of the extremities in elderly patients. The tumors are highly infiltrative and show significant nuclear pleomorphism and cytologic atypia, background curvilinear blood vessels, and an absence of DDIT3 gene fusions.

Lipoblastoma, commonly seen in infants and children, may focally mimic ML but is usually easily distinguished if attention is paid to the age of the patient and the presence of extensive mature fat.

ML-like lesions arising in the retroperitoneum should be considered ALT/WDL or, if higher grade, DL until proven otherwise.

Prognosis and therapy

Local recurrence is commonly seen (up to 25% per some studies) as well as distal metastasis (up to 60%). Distant metastasis can be seen many years after the initial diagnosis. The most common location for the distant metastases is bone, followed by the lung. The presence of a round cell component (hypercellularity) >5% and/or tumor necrosis correlates with increased risk of metastases and poor survival. Mainstay of treatment is surgical excision, but the tumor is very radiosensitive, responding well to radiation therapy.

Clinical features

PLS presents as a rapidly growing, often painless mass, most commonly involving the deep soft tissues of the extremities, followed by the trunk, retroperitoneum, and spermatic cord. Up to 25% of cases arise in the subcutaneous tissues. By definition, there are no areas of concomitant ALT/WDL.

Pathologic features

Microscopic findings

Histologically, PLS is a high-grade sarcoma, predominantly pleomorphic undifferentiated-appearing spindle to epithelioid cells with variable numbers of diagnostic multivacuolated lipoblasts ( Fig. 8.12 ). There is usually significantly increased mitotic activity with many atypical mitotic forms. Necrosis and myxoid stromal change, sometimes mimicking myxofibrosarcoma, are commonly seen. The lipoblasts are frequently quite large with multiple, variably sized intracytoplasmic vacuoles, usually indenting the large, central to para-centrally placed nucleus. Dominating epithelioid features, resembling a carcinoma, are seen in a minority of cases. The presence of at least focal lipoblasts is absolutely necessary for establishing the diagnosis.

Ancillary studies

There are no immunohistochemical or molecular features pathognomonic for PLS. In the absence of an obvious ALT/WDL liposarcomatous component, evaluation for MDM2 gene amplification may be useful to fully exclude DL with a homologous PLS component, especially among intra-abdominal and retroperitoneal tumors.

Differential diagnosis

DL should have a concomitant, often juxtaposed low-grade component, ALT/WDL, and MDM2 gene amplification. PLS with epithelioid features may express keratins, potentially confounding the diagnosis with “carcinoma.” The presence of lipoblasts helps establish the diagnosis of PLS.

UPS is a diagnosis of exclusion, by definition lacking lipoblastic differentiation.

Prognosis and therapy

PLS are aggressive sarcomas, commonly exhibiting local recurrence and metastatic events; overall 5-year survival rates approach 60%. Distant metastases are mostly seen in the lungs and pleura.

Clinical features

Nodular fasciitis is a benign, rapidly growing, and often self-limiting, typically subcutaneous lesion in the upper extremities, trunk, and head and neck, almost never exceeding 5 cm. Most patients are between 20 and 40 years of age. Occasionally, it localizes to intramuscular areas, but intradermal lesions tend to be rare. Head and neck localization is often seen in children.

Pathologic features

Microscopic findings

Nodular fasciitis is a circumscribed, but non-encapsulated, neoplasm, composed of plump, uniform, and proliferating spindled cells, arranged loosely in short fascicles ( Fig. 8.13 ) and storiform patterns, creating a “tissue culture” appearance. The stroma is variably collagenous to myxoid with microcysts and frequent extravasated red blood cells and lymphocytes. The borders of nodular fasciitis can be infiltrative ( Fig. 8.13 C). Mitotic activity may be prominent; however, atypical mitotic figures are never seen.

Ancillary studies

Immunohistochemistry is generally not required for the diagnosis. The spindled cells display a myofibroblastic phenotype, virtually always diffuse smooth muscle actin positivity, variable to negative desmin expression, but negativity for S100, cytokeratin, EMA, and CD34. At the molecular level, most examples harbor a USP6 (17p13.2) gene rearrangement, most commonly t(17;22)(p13.2;q12.3) with the USP6-MYH9 gene fusion, supporting the concept of a neoplasm.

Differential diagnosis

Various spindle cell sarcomas, typically dermatofibrosarcoma protuberans (DFSP) and low-grade fibromyxoid sarcoma (LGFS), represent the most important differential diagnoses for nodular fasciitis. Nevertheless, the characteristic superficial location and circumscription, loose tissue culture-like growth pattern, uniformity of the tumor cells without significant atypia, and the presence of SMA but absence of CD34 expression is diagnostic of nodular fasciitis. MUC-4 positivity, characteristic of LGFS, is not seen in nodular fasciitis, and diffuse CD34 expression is characteristic of DFSP.

Intravascular fasciitis has virtually identical histologic features to nodular fasciitis but, as the name implies, involves blood vessels, typically intravascular and muscular walled veins.

Cranial fasciitis refers to a rapidly growing, nodular fasciitis-like lesion, involving the skull outer table of infants within the first year of life. It is commonly associated with myxoid stroma and foci of osseous metaplasia.

Prognosis and therapy

Self-limiting and spontaneous resolution, even following incomplete excision, is typical, leading to the designation of “transient neoplasia.” Local recurrence (or persistence) is very rare, less than 1%.

Clinical features

Ischemic fasciitis, also known as atypical decubital fibroplasia, is a reactive pseudosarcomatous fibroblastic/myofibroblastic proliferation commonly arising in areas of constant pressure and/or injury, frequently associated with immobilization (sacral region, limb girdles, greater trochanter). Most cases are elderly patients, over 60 years of age, and it tends to be more common in males.

Pathologic features

Microscopic findings

It is poorly circumscribed but there is a distinct zonal appearance. Central hypocellular areas are characterized by fibrinoid degeneration/necrosis and pseudocyst formation ( Fig. 8.14 ), transitioning to a granulation tissue-like vascular proliferation with large ganglion-like reactive fibroblasts ( Fig. 8.14 B), similar to that seen in proliferative fasciitis and myositis.

Ancillary studies

Sometimes SMA and less often desmin are observed in the lesional cells. S100 is negative.

Differential diagnosis

Proliferative fasciitis and myositis, although associated with similar ganglion-like fibroblasts, lack the distinct zoning appearance and are found exclusively in subcutaneous fat and skeletal muscle, respectively. Proliferative fasciitis, typically seen in the upper extremities of middle-aged to older adults, forms poorly circumscribed lesions in subcutaneous tissue, resembling nodular fasciitis but associated with ganglion-like fibroblasts. Proliferative myositis shows virtually identical morphologic features in the same age group but more frequently involves the trunk and shoulder girdles and is typically larger, and the ganglion-like fibroblasts are more prominent ( Fig. 8.15 ). Neither are associated with overlying ulceration of the skin. FOS/FOSB gene rearrangements have been documented in proliferative fasciitis and myositis.

Prognosis and therapy

Local excision is usually curative but may persist if underlying cause is not addressed.

Clinical features

Myositis ossificans (MO) is a benign, rapidly growing but self-limited neoplasm, usually occurring in areas susceptible to trauma. It may develop anytime from early childhood and until late adulthood, but most arise in active young adults. On radiology, the early phases are characterized by well-demarcated, soft tissue fullness and edema. Focal (flocculent) mineralization in the periphery of the neoplasm begins after 2–6 weeks, evolving into an eggshell-like mineralized layer of bone with a radiolucent center. In the latest stages, MO becomes circumscribed, entirely mineralized, and hard.

Fibro-osseous pseudotumor of digits (FOPD), also known in the literature as florid reactive periostitis, is related to MO but represents a benign neoplasm specifically of the subcutaneous tissues of the phalanges and metatarsals/metacarpals of the fingers and, less frequently, the toes. Formation of a peripheral eggshell-like bone does not generally occur. Radiologically, a characteristic fusiform swelling is associated with juxtacortical calcifications and a periosteal reaction. The mineralization tends to be randomly distributed.

Pathologic features

Microscopic findings

A typical zonal appearance is characteristic of in MO ( Fig. 8.16 ). The periphery is composed of at least a partial rim of osteoid to woven bone trabeculae, rimmed by osteoblasts, merging centrally with a densely cellular but uniform spindled to ganglion-like cell proliferation, often devoid of osteoid/bone, closely resembling nodular/proliferative fasciitis. These latter cells often are haphazardly arranged, have eosinophilic cytoplasm, plump to ovoid nuclei with open chromatin, and may be quite mitotically active. The background stroma is variably fibrous to edematous with increased vascularity. Extravasated erythrocytes, lymphocytes, and osteoclast-type giant cells are frequent. Rarely, MO undergoes central cystic degeneration, resembling an aneurysmal bone cyst. In FOPD, the bone does not usually form a peripheral outer layer, but instead, the bone and fibrous tissue are admixed and randomly distributed ( Fig. 8.17 ).

Ancillary studies

Immunohistochemically, the spindled cells often express SMA but are generally negative for desmin and CD34. As in nodular fasciitis, USP6 gene (17p13) arrangements are characteristic, but most commonly associated with the COL1A1 (17q21) gene.

Differential diagnosis

Calcifying aponeurotic fibroma (CAF) may be mistaken for FOPD. CAF is a rare benign neoplasm, most commonly seen in children, between 5 and 15 years of age, arising in association with fibro-tendinous tissues on the distal extremities, palmar, and plantar surfaces. There is no involvement of underlying bone or periosteal reaction. It has high risk of local recurrence (50%) if incompletely excised. The tumors are variably cellular with infiltrative fibromatosis-like spindled cell areas admixed with less cellular zones, characterized by plump epithelioid fibroblasts admixed with zones of calcification, sometimes appearing hyalinized to chondroid ( Fig. 8.18 ). CAF is not associated with USP6 gene rearrangements.

Extraskeletal osteosarcomas form deeply seated masses, arising in older adults, lacking the characteristic zonal pattern of MO. Microscopically, they appear obviously malignant, with significant cytologic atypia and pleomorphism along with other signs of malignancy (increased mitotic activity, necrosis, infiltration) ( Fig. 8.19 ). There is no characteristic gene fusion associated with extraskeletal osteosarcoma.

Prognosis and therapy

Although clinical follow-up without further therapy is a reasonable decision, the preferred treatment for MO and FOPD is simple excision, and both entities have an excellent prognosis. Local recurrence rarely occurs in FOPD.

Clinical features

Elastofibroma presents as an ill-defined, slowly growing, and painless solid tissue proliferation, which on MRI has a signal intensity similar to skeletal muscle with interspersed adipose tissue, commonly seen in the deep connective tissues between the lower scapula and the thoracic wall. Females older than 50 years of age are more commonly afflicted than males. Extrascapular localization has been described but is considered exceedingly rare.

Pathologic features

Microscopic findings

Elastofibromas form bland, ill-defined masses composed of mixtures of adipose and fibromyxoid tissue, with the latter containing haphazardly arranged abnormal and dystrophic elastic fibers ( Fig. 8.20 ). The background fibroblasts lack cytologic atypia, and mitotic activity is essentially non-existent.

Ancillary studies

Elastin stains highlight the abnormal elastic fibers, described as coarse, deeply eosinophilic, and fragmented into linear beads of serrated discs. There is no characteristic gene fusion diagnostic of elastofibroma.

Differential diagnosis

The most important differential diagnosis is desmoid-type fibromatosis, which is significantly more cellular and composed of sweeping fascicles of uniform spindled cells infiltrating fat and skeletal muscle.

Prognosis and therapy

Elastofibroma is an entirely benign lesion. Local recurrence is exceptionally rare after simple excision.

Clinical features

Fibrous hamartoma of infancy (FHI) typically presents as a small, superficial and mobile, painless mass, arising in the anterior and posterior axillary folds of infants and young children (<2 years old). Other common locations include the upper arm, trunk, inguinal region, and external genitalia.

Pathologic features

Microscopic findings

FHI is characterized by a typical triphasic morphology with variable proportions of three distinct components: bland fibroblastic/myofibroblastic fascicles, primitive myxoid mesenchymal cells, and mature adipose tissue ( Fig. 8.21 ). The bland fibroblastic/myofibroblastic cell proliferation is composed of monomorphic spindled cells with dense eosinophilic collagenous background stroma. Hyalinization also may occur. The primitive mesenchymal component consists of primitive, rounded to stellate cells within myxoid stroma ( Fig. 8.21 B). Mitotic figures are rare.

Ancillary studies

SMA is variably positive in the fibroblastic areas and occasionally in the primitive mesenchymal zones, which also are positive for CD34. S100 is absent.

Differential diagnosis

Lipofibromatosis also is composed of mixtures of fat and cellular fascicles of fibromatosis-like tissue, arising in subcutaneous tissues of children ( Fig. 8.22 ). However, it has a predilection for the hands and feet and lacks the classic triphasic organoid appearance of FHI.

Prognosis and therapy

Simple excision with potential for local recurrence if incompletely excised is usual for FHI.

Clinical features

Desmoid fibromatosis presents as a deeply seated, painless but non-mobile mass typically arising in the extremities, trunk, retroperitoneum or abdominal cavity and, less commonly, in the head and neck, paraspinal and flank regions, of young to middle aged adults, especially females. It may be associated with prior trauma and/or surgery. A minority of patients with familial adenomatous polyposis (Gardner syndrome) develop intra-abdominal fibromatosis, usually multifocal, involving children and young adults.

Superficial fibromatoses represent a spectrum of similar nodular fibroblastic/myofibroblastic proliferations involving the hands (palmar fibromatosis, Dupuytren contracture.) and feet (plantar fibromatosis, Ledderhose disease). Palmar disease forms painless nodules and cords, causing contractures in the palms and fingers of older adults, usually males. The plantar form is more often seen in young to middle-aged adults, typically females. It is associated with painless swelling and no contractures.

Pathologic features

Microscopic findings

Both desmoid and superficial fibromatosis have overlapping morphologic features, characterized by long sweeping fascicles of elongated and uniform spindled cells. Cytologically, the cells have eosinophilic cytoplasm and elongated nuclei with open chromatin, without significant pleomorphism. The cellular proliferation in superficial fibromatoses, particularly the palmar form, often are confined to the fibro-tendinous and fascial tissues. Desmoid fibromatosis exhibits widespread infiltration, entrapping fat and skeletal muscle ( Fig. 8.23 A). At the periphery of the lesion, lymphoid aggregates often are seen ( Fig. 8.23 B). The background is commonly uniformly collagenous but rarely may exhibit keloid-like areas and myxoid changes, more common in intra-abdominal and mesenteric forms. The scattered background blood vessels have thin walls with characteristic perivascular edema ( Fig. 8.23 C). Mitotic figures tend to be uncommon, and tumor necrosis is not present.

Ancillary studies

Immunohistochemical stains are not necessary for diagnosis. SMA is usually expressed by the lesional cells, but desmin positivity is variable. CD117 expression represents a potential diagnostic pitfall in intra-abdominal lesions, but cytokeratin, CD34, DOG1, and S100 are negative. Nuclear β-catenin positivity ( Fig. 8.23 D) is considered characteristic, but, in our experience, interpretation can be challenging. Somatic CTNNB1 mutations (β-catenin gene) and, in patients with Gardner syndrome, germline APC gene mutation are seen.

Differential diagnosis

Superficial fibromatoses, despite morphologic overlap, have characteristic and distinct locations and presentations. Both plantar and palmar forms are commonly negative for β-catenin ( Fig. 8.24 ).

When involving viscera, sarcomatoid carcinoma should be considered; however, it is keratin positive and typically exhibits more significant cytologic atypia and pleomorphism.

DL may have fibromatosis-like areas, but the presence of a low-grade lipomatous component and, when necessary, confirmation of MDM2 gene amplification, helps to confirm this diagnosis.

Prognosis and therapy

The prognosis is variable, depending on the location, size, involvement of viscera, and resectability. Desmoid fibromatosis is an aggressive tumor, so wide surgical resection with negative margins is required. However, up to one third of the patients develop local recurrences, but distant metastases do not occur. The most important prognostic factor is adequacy of surgical excision. The goal of achieving negative margins should be balanced with a desire to preserve function.

Clinical features

Fibroma of tendon sheath presents as a slowly growing nodule, usually <3 cm and associated with tendon sheaths of fingers, involving patients, between the ages of 20 and 50 years.

Pathologic features

Microscopic findings

Well circumscribed and nodular, bland spindle cell proliferation ( Fig. 8.25 ), arranged in short fascicles within dense collagenous stroma, accompanied by thin-walled blood vessels with slit-like appearance ( Fig. 8.25 B). Cytologically the cells do not exhibit significant cytologic atypia and pleomorphism.

Ancillary studies

Immunohistochemically, most express SMA but are negative for S100 and desmin. A subset of more cellular examples, possibly representing a spectrum with nodular fasciitis, display USP6 gene rearrangements.

Differential diagnosis

Nodular fasciitis is typically significantly more cellular, displaying a loose tissue culture appearance, variably collagenous stroma, extravasated red blood cells and lymphocytes, and predominantly occurs in the subcutis. More cellular forms of fibroma of tendon sheath, especially those with USP6 gene rearrangements, likely represent rare examples of tenosynovial nodular fasciitis.

Tenosynovial giant cell tumor (TGCT; localized type) may exhibit a virtually identical clinical presentation. However, TGCTs are not spindled cell lesions, being instead composed of mostly uniform epithelioid to histiocytoid mononuclear cells, scattered multinucleated osteoclast-type giant cells, and hemosiderin pigment.

Prognosis and therapy

Fibroma of tendon sheath is a benign tumor but may locally recur in up to 25% of cases. Surgical resection should be undertaken with the aim to preserve function.

Clinical features

Myofibroblastoma is a benign neoplasm, originally described as arising in the mammary regions, within the superficial soft tissues of mostly males. However, mammary-type myofibroblastomas appear more common in extramammary sites, primarily the inguinal and groin areas, including the vulva/vaginal region and scrotum. Less common anatomic sites are extremities, viscera, and retroperitoneum. Most present as painless masses of older patients, although the age range is wide.

Pathologic features

Microscopic findings

Myofibroblastoma is a well-circumscribed but unencapsulated spindled cell neoplasm composed of short and stubby spindled cells with indistinct cell borders and eosinophilic cytoplasm. The cells are usually arranged in short fascicles and sheets ( Fig. 8.26 ). Their nuclei are oval with even chromatin and occasional pinpoint nucleoli. The background stroma is myxoid with scattered ropy to thick collagenous bundles and randomly distributed mast cells.

Ancillary studies

Immunohistochemically, the spindled cells are diffusely and strongly positive for ER ( Fig. 8.26 C), CD34 ( Fig. 8.26 D), and desmin, but usually negative for SMA. Loss of RB1 also is present. At the molecular level, myofibroblastomas have loss of 13q14 ( RB1 gene), a shared genetic abnormality with spindle cell/pleomorphic lipoma and cellular angiofibroma.

Differential diagnosis

Spindle cell lipomas typically arise in the neck, shoulder, and upper back subcutis of elderly adults. Desmin always is negative.

Cellular angiofibroma is a benign, hypercellular, and vascular neoplasm, located commonly in the superficial soft tissues of the scrotal and vulvar region, characterized by circumscription and uniform, short, spindled cells within an edematous stroma with admixed collagen bundles and medium-sized blood vessels with irregular branching lumina ( Fig. 8.27 ). Variable expression of SMA, desmin, as well as ER and PR, are described. CD34 may be positive in up to 30% of cases, but nuclear RB1 is lost.

Angiofibroma of soft tissue also is a benign, slowly growing, and painless neoplasm, most commonly arising in the extremities (legs) of middle-aged males. Histologically, they form well-demarcated lesions composed of uniform spindled cells, abundant myxoid to fibromyxoid stroma, and a prominent network of innumerable branching, thin-walled blood vessels ( Fig. 8.28 ). These tumors have near-diploid karyotypes with a recurrent t(5;8) (p15;q13) and AHRR-NCOA2 gene fusion.

Prognosis and therapy

Myofibroblastomas are benign neoplasms with exceptionally rare recurrence potential, even after marginal excision.

Clinical features

Angiomyofibroblastomas present as well-circumscribed and painless masses, arising in the subcutis of pelvic region, most commonly seen in the vulva and vagina of middle-aged females, typically premenopausal. A subset occurs in males, in the paratesticular region and scrotum.

Pathologic features

Microscopic findings

Histologically, angiomyofibroblastomas are well-circumscribed lesions, composed of spindled to epithelioid cells, often concentrated around blood vessels, within an edematous to lightly myxoid stroma with prominent vascularity ( Fig. 8.29 ). A minority display an adipocytic component. The epithelioid cells are frequently multi-nucleated and plasmacytoid. The background can be loose and edematous with scattered small vessels that can have hyalinized walls.

Ancillary studies

Immunohistochemically, strong and diffuse desmin and ER co-expression is typical, often accompanied by CD34 positivity. SMA may be focally positive.

Differential diagnosis

Deep angiomyxoma is the most important differential diagnosis. Although benign, deep angiomyxomas are “aggressive” infiltrative neoplasms, arising within the deep soft tissues of the pelvis/perineum of young to middle-aged females. Histologically they are relatively hypocellular spindled cell neoplasms with abundant edematous to myxoid stroma, accompanied by medium to large muscular-walled blood vessels ( Fig. 8.30 ). The cells are most often randomly distributed, uniform, and may be associated with entrapment of fat. Diffuse co-expression of desmin and ER is typical, with positivity for CD34 and SMA less consistent. HMGA2 (12q14) gene rearrangements have been confirmed by FISH analysis.

Prognosis and therapy

Marginal excision is rarely associated with local recurrence.

Clinical features

Nuchal-type fibroma is a benign, ill-defined neoplasm, usually occurring in the subcutaneous tissues of the posterior neck of middle aged to older males, often with diabetes mellitus. Extra-nuchal sites include the upper back and extremities.

Pathologic features

Microscopic findings

Nuchal-type fibromas are paucicellular and poorly circumscribed lesions, composed of monomorphic spindled cells, within a densely collagenous background stroma, entrapping fat and peripheral nerve bundles ( Fig. 8.31 ).

Ancillary studies

The spindled fibroblasts are positive for CD34 negative, variably positive for SMA, but negative for desmin and β-catenin.

Differential diagnosis

Gardner fibroma, histologically indistinguishable from nuchal type fibroma, but is associated with familial adenomatous polyposis and germline APC mutations. They are most commonly seen in children < 10 years of age. The spindled cells are positive for CD34 but typically negative for SMA.

Desmoplastic fibroblastoma (collagenous fibroma) is a relatively circumscribed, benign, hypocellular neoplasm with an abundantly collagenous to lightly myxoid stroma, composed of bland stellate to spindled fibroblasts ( Fig. 8.32 ). Most arise in the subcutaneous tissues of the extremities of adults. SMA is variably expressed, but S100, EMA, and CD34 are usually negative. Simple excision is curative.

Prognosis and therapy

Nuchal-type fibroma is a benign tumor with potential for local recurrence.

Clinical features

DFSP is a locally aggressive and rarely metastasizing neoplasm, arising as a solitary to multinodular, painless, and superficial mass of the trunk and proximal extremities/limb girdle, in young to middle-aged adults. It is rarely seen involving the head and neck, acral distal extremities, or genital area.

Pathologic features

Microscopic findings

DFSP is characteristically hypercellular and diffusely infiltrates the dermis and subcutis ( Fig. 8.33 ), often associated with trails of adipocytes even up into the superficial dermis. The spindled neoplastic cells are remarkably monotonous, arranged in tight storiform patterns and short fascicles. Infiltration within the subcutaneous tissue often creates a characteristic honeycomb-like appearance ( Fig. 8.33 C). Mitotic activity tends to be low, not exceeding 5 mitoses/10 HPF. Admixed inflammatory cells are not a feature of DFPS. Myxoid stromal changes rarely occurs.

In fibrosarcomatous transformation, the cells exhibit a morphologic progression toward greater cytologic atypia, forming intersecting fascicles, often with a herringbone appearance ( Fig. 8.33 D). Mitotic activity inherently becomes more prominent, frequently exceeding 10 mitoses/10 HPF.