Soft Tissue
John D. Pfeifer
Louis P. Dehner
If the term “soft tissue” were restricted to only mesodermally derived structures, then nerves and neural tumors would not be considered in the discussion. Similarly, there are other examples of “soft tissue tumors (STTs)” which are present in organs but may not be derived from mesoderm. By convention, however, neural tumors, gastroin-testinal stromal tumor, melanoma of soft parts, perivascular epithelioid cell tumor, and so on are regarded as “soft tissue neoplasms” despite the absence of any evidence of a well-characterized progenitor cell or mesenchymal stem cell (MSC, characterized immunophenotypically by reactivity for CD73, CD90, and CD105) with the multipotentiality to differentiate into a variety of tissues such as muscle, blood vessels, and fat (Stem Cells. 2011;29:397; J Pediatr Hematol Oncol. 2008;30:301).
I. TISSUE PROCESSING
A. Biopsy specimens. Incisional or core biopsy of a suspected soft tissue neoplasm is performed to determine the appropriate management based on the pathologic type. The biopsy tissue should be placed immediately into 10% formalin or other appropriate fixative. The number of biopsy fragments should be recorded, as well as their aggregate dimension, and all the submitted tissue should be processed. Three H&E levels should initially be prepared for microscopic examination. For very small specimens, in order to avoid wasting tissue when refacing the block, it is strongly recommended that additional unstained slides be cut from the block during initial sectioning in the event additional studies such as immunohistochemistry are needed.
B. Resection specimens. Excisional specimens are often complex and varied, and the macroscopic examination should be guided by tumor location, extent, and type. The margin of all intact specimens should be inked, and the gross distance from the tumor to the closest margin documented. The maximum dimension of the tumor should be recorded, as well as the color and consistency of the cut surface, and presence of hemorrhage and necrosis. In general, it is recommended that one section per centimeter of tumor should be submitted for microscopic examination (scout sections can be used to evaluate whether such thorough sampling is required for definitive diagnosis). The closest surgical margin should be evaluated by either shave or radial sections depending on the nature of the specimen.
For those tumors in which a biopsy did not permit definitive diagnosis, tissue should be collected and processed for electron microscopy. Consideration should always be given to the need to send a sample of viable tumor for
cytogenetic analysis. A sample of viable tumor should also be snap frozen and stored in the event it is needed for subsequent molecular evaluation, which plays an ever-increasing role in diagnosis as more and more types of STTs are shown to harbor characteristic genetic aberrations (Table 46.1).
TABLE 46.1 Recurring Cytogenetic Abnormalities Characteristic of Various Soft Tissue Neoplasmsa
Tumor type
Cytogenetic aberration
Loci involved
Alveolar rhabdomyosarcoma
t(2;13)(q35;q14)
t(1;13)(p36;q14)
PAX 3-FOX01 fusion
PAX 7-FOX01 fusion
Alveolar soft part sarcoma
der(17)t(X;17)(p11.2;q25)
ASPL-TFE3 fusion
Angiomatoid fibrous histiocytoma
t(12;22)(q13;q12)
t(2;22)(q33;q12)
t(12;16)(q13;q11)
EWSR1-ATF1 fusion
EWRS1-CREB1
FUS-ATF1 fusion
Atypical lipomatous tumor/well-differentiated liposarcoma (ALT/WDLPS)
Supernumerary ring and/or marker chromosomes with amplification of 12q14-q15
Amplification of MDM2, CDK4, HMGA2 genes
Clear cell sarcoma (melanoma of soft parts)
t(12;22)(q13;q12)
t(2;22)(q32;q12)
EWSR1-ATF1 fusion
EWSR1-CREB1 fusion
Congenital infantile fibrosarcoma
t(12;15)(p13;q25)
ETV6-NTRK3 fusion
Dedifferentiated liposarcoma
Supernumerary ring and/or marker chromosomes with amplification of 12q14-q15
Amplification of MDM2, CDK4, HMGA2 genes
Dermatofibrosarcoma protuberans/giant cell fibroblastoma
t(17;22)(q22;q13) and derivative ring chromosomes
COL1A1-PDGFB fusion
Desmoid fibromatosis
Trisomy 8 or 20; loss of 5q
Somatic CTNNB1 or APC mutations (only in deep tumors)
Desmoplastic small round cell tumor
t(11;22)(p13;q12)
EWSR1-WT1 fusion
Elastofibroma
1q abnormalities
Unknown
Embryonal rhabdomyosarcoma
Loss of heterozygosity at 11p15; gains of 2, 7, 8, 11, 12, 20, 21, 13q21, 20; losses of 1p35-36.3, 7, 6, 9q22, 14q21-32, 17
Unknown
Epithelioid hemangioendothelioma
t(1;3)(p36;3q25)
WWTR1-CAMTA1 fusion
Epithelioid sarcoma, proximal type
Alterations of 22q11.2
Biallelic inactivation of hSNF5/INI1
Ewing sarcoma/primitive neuroectodermal tumor
t(11;22)(q24;q12)
t(21;22)(q22;q12)
EWSR1-FLI1 fusion
EWSR1-ERG fusion
Extrarenal malignant rhabdoid tumor
Alterations of 22q11.2
Biallelic inactivation of hSNF5/INI1
Extraskeletal myxoid chondrosarcoma
t(9;22)(q22;q12)
t(9;17)(q22;q11.2)
t(9;15)(q22;q21)
EWSR1-NR4A3 fusion
TAF2N-NR4A3 fusion
TCF12-NR4A3 fusion
Giant cell tumor of tendon sheath/diffuse-type giant cell tumors
Translocations involving 1p13, including t(1;2)(p13;q135)
CSF1 fusions, including CSF1-COL6A3
Inflammatory myofibroblastic tumor
Translocations involving 2p23
ALK fusions with a variety of other genes
Leiomyosarcoma
Structural alterations of 1, 7, 10, 13, 14
Unknown
Lipoblastoma
Rearrangements of 8q12
Rearrangement of PLAG1 gene
Lipoma
Rearrangements 12q14-q15 and 6p21-22; deletions of 13q12-14
HMGA2 and HMGA1 fusions; unknown
Low-grade fibromyxoid sarcoma
t(7;16)(q33;p11)
t(11;16)(p11;p11)
FUS-CREB3L2 fusion
FUS-CREB3L1 fusion
Malignant peripheral nerve sheath tumor
Unknown
Myxoid/round cell liposarcoma
t(12;16)(q13;p11)
t(12;22)(q13;q12)
FUS-DD1T3 fusion
EWSR1-DD1T3 fusion
Nasopharyngeal angiofibroma
Gains of 1p, 7q, 10q, 12q, 16p, 16q, 17q, 19p, 20q, 22q
Activating mutations in CTNNB1
Soft tissue myoepithelial tumor
Translocations involving 22q12
EWSR1 fusions with a variety of other genes
Synovial sarcoma
t(X;18)(p11;q11)
SSX18-SSX1, SSX18-SSX2, SSX18-SSX4 fusions
aOnly the most common abnormalities are indicated. For more details see Pfeifer JD. Molecular Genetic Testing in Surgical Pathology. Philadelphia, PA: Lippincott, Williams & Wilkins; 2006.
II. TERMINOLOGY REGARDING THE BIOLOGIC POTENTIAL OF SOFT TISSUE NEOPLASMS.
A. The current WHO classification of STTs (Table 46.2) assigns each neoplasm to one of four categories, benign, intermediate (locally aggressive), intermediate (rarely metastasizing), and malignant. The four categories provide a standard nomenclature to indicate the biologic potential of the various STTs. It is important to emphasize that the intermediate categories are not defined on the basis of histologic grade, but rather biologic potential. Some of the latter tumors may have rather bland microscopic features as in the case of a desmoid fibromatosis, or hypercellular and mitotically active as in the case of some fibrohistiocytic tumors.
1. Benign. Most tumors in this category do not locally recur. If recurrence does occur, it is typically nondestructive. Complete local excision is curative. The common lipoma is an example of this category.
2. Intermediate (locally aggressive). Tumors in this category have a locally destructive and infiltrative growth pattern, and often locally recur. Wide excision is required for local control, but that is not necessarily an indemnification against a local recurrence. These tumors do not metastasize. An example of this tumor type is desmoid fibromatosis.
3. Intermediate (rarely metastasizing). Tumors in this category also have a locally destructive and infiltrative growth pattern. However, they also can give rise to distant metastases in a small subset of cases (typically <2%),
although the risk for metastasis of an individual tumor cannot be reliably predicted on the basis of morphologic features. Examples of this category include congenital infantile fibrosarcoma, dermatofibrosarcoma protuberans, and angiomatoid fibrous histiocytoma (AFH).
TABLE 46.2 WHO Classification of Soft Tissue Tumors
Adipocytic Tumors
Benign
Lipoma
Lipomatosis
Lipomatosis of nerve
Lipoblastoma/lipoblastomatosis
Angiolipoma
Myolipoma
Chondroid lipoma
Extra-renal angiomyolipoma
Extra-adrenal myelolipoma
Spindle cell/pleomorphic lipoma
Hibernoma
Intermediate (locally aggressive)
Atypical lipomatous tumor/well-differentiated liposarcoma
Malignant
Dedifferentiated liposarcoma
Myxoid liposarcoma/round cell liposarcoma
Pleomorphic liposarcoma
Mixed-type liposarcoma
Liposarcoma, not otherwise specified
Fibroblastic/myofibroblastic tumors
Benign
Nodular fasciitis
Proliferative fasciitis
Proliferative myositis
Myositis ossificans
Fibro-osseous pseudotumor of digits
Ischemic fasciitis
Elastofibroma
Fibrous hamartoma of infancy
Myofibroma/myofibromatosis
Fibromatosis colli
Juvenile hyaline fibromatosis
Inclusion body fibromatosis
Fibroma of tendon sheath
Desmoplastic fibroblastoma
Mammary-type myofibroblastoma
Calcifying aponeurotic fibroma
Angiomyofibroblastoma
Cellular angiofibroma
Nuchal-type fibroma
Gardner fibroma
Calcifying fibrous tumor
Giant cell angiofibroma
Intermediate (locally aggressive)
Superficial fibromatosis (palmar/plantar)
Desmoid-type fibromatoses
Lipofibromatosis
Intermediate (rarely metastasizing)
Solitary fibrous tumor and hemangiopericytoma
Inflammatory myofibroblastic tumor
Low-grade myofibroblastic sarcoma
Myxoinflammatory fibroblastic sarcoma
Infantile fibrosarcoma
Malignant
Adult fibrosarcoma
Myxofibrosarcoma
Low-grade fibromyxoid sarcoma/hyalinizing spindle cell tumor
Sclerosing epithelioid fibrosarcoma
So-called fibrohistiocytic tumors
Benign
Giant cell tumor of tendon sheath
Diffuse-type giant cell tumor
Deep benign fibrous histiocytoma
Intermediate (rarely metastasizing)
Plexiform fibrohistiocytic tumor
Giant cell tumor of soft tissues
Malignant
Pleomorphic MFH/undifferentiated pleomorphic sarcoma
Giant cell MFH/undifferentiated pleomorphic sarcoma with giant cells
Inflammatory MFH/undifferentiated pleomorphic sarcoma with prominent inflammation
Smooth muscle tumors
Angioleiomyoma
Deep leiomyoma
Genital leiomyoma
Leiomyosarcoma
Pericytic (perivascular tumors)
Glomus tumor
Malignant glomus tumor
Myopericytoma
Skeletal muscle tumors
Benign
Rhabdomyoma (adult type, fetal type, genital type)
Malignant
Embryonal rhabdomyosarcoma (including spindle cell, botryoid, anaplastic)
Alveolar rhabdomyosarcoma
Pleomorphic rhabdomyosarcoma
Vascular tumors
Benign
Hemangiomas of subcutaneous/deep soft tissue
Capillary
Cavernous
Arteriovenous
Venous
Intramuscular
Synovial
Epithelioid hemangioma
Angiomatosis
Lymphangioma
Intermediate (locally aggressive)
Kaposiform hemangioendothelioma
Intermediate (rarely metastasizing)
Retiform hemangioendothelioma
Papillary intralymphatic angioendothelioma
Composite hemangioendothelioma
Kaposi sarcoma
Malignant
Epithelioid hemangioendothelioma
Angiosarcoma of soft tissue
Chondro-osseous tumors
Soft tissue chondroma
Mesenchymal chondrosarcoma
Tumors of uncertain differentiation
Benign
Intramuscular myxoma
Juxtaarticular myxoma
Deep (aggressive) angiomyxoma
Pleomorphic hyalinizing angiectatic tumor
Ectopic hamartomatous thymoma
Intermediate (rarely metastasizing)
Angiomatoid fibrous histiocytoma
Ossifying fibromyxoid tumor
Mixed tumor/myoepithelioma/parachordoma
Malignant
Synovial sarcoma
Epithelioid sarcoma
Alveolar soft part sarcoma
Clear cell sarcoma of soft tissue
Extraskeletal myxoid chondrosarcoma
PNET/extraskeletal Ewing tumor
Desmoplastic small round cell tumor
Extra-renal rhabdoid tumor
Malignant mesenchymoma
Neoplasms with perivascular epithelioid cell differentiation (PEComa)
Clear cell myomelanocytic tumor
Intimal sarcoma
From: Fletcher CDM, Unni K, Mertens K, eds. World Health Organization Classification of Tumours. Pathology and Genetics. Tumours of Soft Tissue and Bone. Lyon: IARC Press; 2002. Used with permission.
4. Malignant. Tumors in this category also have a locally destructive and infiltrative growth pattern. However, they metastasize in high percentage of cases; low-grade sarcomas have a metastatic rate of 2% to 10%, and high-grade sarcomas metastasize in 20% to 100% of cases.
B. Histologic grading of soft tissue sarcomas (STS). Although several grading systems of STSs have been proposed over the past 30 to 40 years, the two systems in widespread use are from the National Cancer Institute (NCI) and the French
Federation Nationale des Centres de Lutte Contre le Cancer (FNCLCC) (Arch Pathol Lab Med. 2006;130:2006; Histopathology. 2006;48:42) (Table 46.3). Three histologic features are the basis of the grading systems: tumor differentiation, necrosis, and mitotic count. However, many sarcomas have a specified histology-specific tumor differentiation score (J Clin Oncol. 1997;15:350), and some STSs in children have their own grading system (Cancer. 2010;116:2266). In general, the mitotic index and extent of necrosis are predictive of metastatic behavior and survival in adults whereas the mitotic index (less than or greater than 10 mitoses per 10 high-power fields (HPFs)) is the most significant prognostic variable in the case of non-rhabdomyosarcoma (RMS) STS in children.
TABLE 46.3 Grading of Soft Tissue Sarcomaa
FNCLCC Grading. The FNCLCC grade is determined by three parameters: differentiation (histology specific), mitotic activity, and extent of necrosis. Each parameter is scored: differentiation (1-3), mitotic activity (1-3), and necrosis (0-2). The scores are summed to designate grade.
Grade X Grade cannot be assessed
Grade 1 2 or 3
Grade 2 4 or 5
Grade 3 6—8
Differentiation. Tumor differentiation is histology specific and is generally scored as followsb:
Score 1 Sarcomas closely resembling normal, mature mesenchymal tissue
Score 2 Sarcoma of definite histologic type
Score 3 Synovial sarcomas, embryonal sarcomas, undifferentiated sarcomas, and sarcomas of unknown/doubtful type
Mitotic count. In the most mitotically active area of the sarcoma, ten successive high-power fields (HPFs) are assessed using a 40X objective.
Score 1 0-9 mitoses/10 HPFs
Score 2 10-19 mitoses/10 HPFs
Score 3 20 or more mitoses/10 HPFs
Tumor necrosis. Evaluated on gross examination and validated with histologic sections.
Score 0 No tumor necrosis
Score 1 ≤50% tumor necrosis
Score 2 >50% tumor necrosis
aModified from J Clin Oncol. 1997;15:350; some soft tissue sarcomas in children have their own grading system as outlined in Cancer. 2010;116:2266.
b Many sarcomas have a histology-specific tumor differentiation score as outlined in J Clin Oncol. 1997;15:350.
It must be emphasized that it can be difficult to accurately assess a STS for grading purposes when it is resected after adjuvant chemotherapy.
III. ADIPOCYTIC TUMORS. This morphologic category of STTs includes some of the most commonly occurring neoplasms in adults which arise in the superficial and deep soft tissues. Generally, the deeper and larger the fatty tumor in adults, the greater the likelihood of a liposarcoma (LPS) (ANZ J Surg. 2007;77:524).
A. Benign
1. Lipomas are composed of mature adipocytes and are the most common soft tissue neoplasms in adults. Superficial lipomas arise in the subcutis; deep lipomas arise within the deep soft tissue; parosteal lipomas arise on the surface of bone; intramuscular and intermuscular lipomas arise within and between skeletal muscle; and lipoma arborescens arises in synovial membranes. Superficial tumors are generally <5 cm in maximum dimension, while deep tumors are often >5 cm. Lipomas are well circumscribed and have an oily light yellow cut surface, except in children whose tumors are pale white. Regardless of the anatomic site, the tumor is composed of mature
adipocytes separated into complete and incomplete lobules. Numerous histologic subtypes have been described but none has prognostic significance, including the following (Adv Anat Pathol. 2006;13:279).
a. Angiolipoma typically occurs in the subcutaneous tissue and consists of mature adipocytes with a variably prominent capillary network with scattered microthrombi. These vessels are typically found at the periphery of the lobules (e-Fig. 46.1).* These tumors may be multiple in the subcutis, and also occur in and around the spinal cord (Childs Nerv Syst. 2002;18:725).
b. Myolipoma (intramuscular lipoma) is found in the deep soft tissues of the abdominal cavity, inguinal region, and retroperitoneum. Mature adipose tissue is intermixed with mature smooth muscle or skeletal muscle.
c. Chondroid lipoma occurs in the limb girdle and proximal extremities. Cords and nests of lipoblasts as well as mature adipocytes are present in a myxoid to hyalinized chondroid matrix in the absence of true hyaline cartilage. Despite the presence of immature fat cells, surgical excision is curative. This tumor is distinct from chondrolipoma, which is characterized by hyaline cartilage within a lipoma.
d. Spindle cell lipoma/pleomorphic lipoma occurs predominantly on the posterior neck and shoulder area in middle aged and elderly men (only 10% of cases occur in women). The tumor presents as a mobile dermal or subcutaneous nodule that often has been present for many years. The microscopic features are variable: at one end of the spectrum are tumors composed of bland spindle cells with associated dense collagen bundles between mature adipocytes; at the other end are tumors with small hyperchromatic cells admixed with multinucleated giant cells between mature adipocytes. The spindle cells are immunopositive for CD34, and in some cases also for S-100 protein. This neoplasm is one of several cutaneous and STTs, which express CD34 (J Cutan Pathol. 2009;36:89). In the presence of atypical lipoblasts, spindle cell LPS must be considered since the latter tumor also rises in the subcutis (Mod Pathol. 2010;23:729).
2. Lipomatosis occurs in several different clinicopathologic settings, all of which are characterized by a diffuse overgrowth of mature adipose tissue. Regardless of the clinical subtype, the neoplastic cells are indistinguishable from those found in lipomas, which emphasizes the role of clinical history in arriving at the correct diagnosis.
a. Diffuse lipomatosis preferentially occurs in children <2 years old, and involves a substantial part of an extremity as well as the trunk, head and neck, pelvis, abdomen, or intestinal tract. In this setting, the phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome as expressed in the Proteus syndrome, encephalocraniocutaneous lipomatosis, Bannayan-Ruvalcaba-Riley syndrome, and Cowden disease should be considered (Genet Med. 2009;11:687).
b. Symmetric lipomatosis occurs predominantly in middle aged men of Mediterranean ancestry, and is characterized by symmetric deposition of fat in the upper body.
c. Pelvic lipomatosis, which affects black males over a wide age range, usually manifests as an overgrowth of fat in perirectal and perivesical areas.
d. Steroid lipomatosis occurs in the setting of adrenocortical hormonal therapy or with endogenous endocrine abnormalities, and characteristically involves accumulation of fat in the face, sternal region, or middle of the upper back (the so-called buffalo hump).
e. HIV-lipodystrophy in patients with AIDS occurs in those undergoing treatment with protease inhibitors or other forms of antiviral therapy, and is characterized by the accumulation of visceral fat with fat wasting in the face and limbs.
f. Nevus lipomatosus is a developmental anomaly presenting as a yellowish polypoid lesion of skin, typically in the lower abdominal-sacral-pelvic region (J Dermatol. 2000;27:16). It is characterized by mature adipose tissue in the papillary and reticular dermis. Soft fibroma and acrochordon have some overlapping features, but adipose tissue is not found in the papillary dermis in these latter two lesions.
3. Lipomatosis of nerve (neural fibrolipoma, fibrolipomatous hamartoma) is noted at birth or in early childhood, but is seen through the fourth decade. The median nerve and ulnar nerves are the usual sites of involvement, and a subset of cases is associated with macrodactyly. Perineurial and epineurial infiltration by a mixture of mature adipocytes and fibrous tissue typically separates individual nerve bundles. Another congenital fatty lesion related to peripheral nerves is lumbosacral lipoma in infants, which is characterized by a tethered filum terminale or conus medullaris (Childs Nerv Syst. 1997;13:298).
4. Lipoblastoma occurs in children (90% of cases occur in children under the age of 10 years) with a predilection for the lower extremity, but can also involve the trunk, mediastinum, abdomen-retroperitoneum, and head and neck (Am J Surg Pathol. 2009;33:1705). It is either a localized, well-circumscribed tumor (lipoblastoma) or has a diffuse infiltrating pattern (lipoblastomatosis). Like other fatty tumors, it has a lobulated architecture and is composed of a mixture of cell types including mature and immature adipocytes, a variable number of lipoblasts, multinucleated cells, signetring lipocytes, and stellate mesenchymal cells (e-Fig. 46.2). Grayish myxoid areas noted grossly have a resemblance to myxoid LPS, which can be problematic. Despite the presence of immature fat cells, this tumor is benign and does not metastasize, although approximately 20% to 25% of cases recur (most are examples of lipoblastomatosis). These tumors have the potential for maturation, and some cases have predominantly lipomatous features with residual immature myxoid areas at the periphery of the lobules. These tumors express for S-100 and CD34.
5. Hibernoma is a neoplasm composed of brown fat (adipocytes with multivacuolated granular cytoplasm) admixed with conventional adipose tissue. It occurs in young adults and is found in the neck, axilla, thigh, retroperitoneum, head and neck, trunk, and upper extremities (Am J Dermatopathol. 2009;31:685). The cut surface has a yellowish to brownish appearance, is usually oily and spongy; may be lobulated but is well demarcated; and can measure over 20 cm. Microscopically, lobules of brown fat are separated from conventional adipose tissue (e-Fig. 46.3).
B. Intermediate (locally aggressive)
1. Atypical lipomatous tumor/well-differentiated LPS (ALT/WDLPS) (50% to 55% of cases) occurs in adults in the fifth through eighth decade of life (Cytogenet Genome Res. 2007;118:138). The deep soft tissues of the lower extremity and retroperitoneum are usual primary sites; the paratesticular region and mediastinum are less common sites. Tumors arising in the retroperitoneum may attain sizes in excess of 20 cm and weigh 500 to 1000 g. The tumor has a lobulated, yellow to white, soft to firm cut surface that varies on the basis of lipomatous, fibrous, and myxoid components, and discrete margins are often difficult to discern from gross examination. Microscopically, the tumor is composed of cells with lipomalike features except for the presence of scattered hyperchromatic, often
multinucleated and vacuolated cells with features of atypical lipoblasts. Four histologic subtypes are designated, namely adipocytic (lipoma-like), sclerosing, inflammatory, and spindle cell types, but more than one pattern may be present in the same neoplasm. Sclerosing foci are helpful in diagnosis because the areas of collagen contain atypical stromal cells (e-Fig. 46.4). Fluorescence in situ hybridization (FISH) for MDM2 amplification characteristic of ALT/WDLPS is a sensitive and specific tool for distinguishing ALT/WDLPS from benign lipomatous neoplasms (Mod Pathol. 2008;21:943; Adv Anat Pathol. 2009;16:383).
Prognosis is largely determined by anatomic site and size. Smaller, more superficial tumors can be locally resected with negative margins, but those in the retroperitoneum are likely to recur because of positive surgical margins. Recurrent tumors may show evidence of so-called dedifferentiation (see below) which clearly demonstrates the overt malignant potential of ALT/WDLPS. Multifocal ALT/WDLPS is an uncommon but well-documented presentation.
C. Malignant
1. Dedifferentiated LPS shows a transition from ALT/WDLPS to a pleomorphic and/or high-grade spindle cell sarcoma (e-Fig. 46.5), either in the primary tumor (85% to 90% of cases) or in a recurrence (10% to 15% of cases) (Virchows Arch. 2010;456:167). The transition in pattern from ALT/WDLPS to high-grade sarcoma is usually abrupt. By convention, the focus of dedifferentiation should be at least several millimeters in greatest dimension. Because the area of dedifferentiation may be limited, thorough sampling and careful microscopic examination of all ALT/WDLPS is required in order to exclude the presence of dedifferentiation.
2. Myxoid LPS/round cell LPS peaks in incidence at the age of 30 to 40 years, occurs predominantly in the deep soft tissues of the extremities (more than two-thirds of cases arise in the musculature of the thigh), and is the most common type of LPS in the first two decades of life (Ann Diagn Pathol. 2000;4:252; Am J Surg Pathol. 2009;33:645). If this tumor is discovered in the retroperitoneum, it likely represents metastatic disease rather than a primary tumor (Mod Pathol. 2009;22:223).
The cut surface of myxoid LPS is tan, glistening, and gelatinous; the round cell morphology is associated with a fleshy, white cut surface. Myxoid tumors are composed of uniform, round to oval, primitive nonlipogenic mesenchymal cells and small lipoblasts embedded in a myxoid stroma with a delicate arborizing capillary network (e-Fig. 46.6). In contrast, areas composed of sheets of high-grade primitive round cells are not accompanied by a myxoid stroma. It is not uncommon to identify a subset of round cells in myxoid LPS, usually in a perivascular distribution, but by convention round cell LPS has a composition of 80% or more of round cells. Immunohistochemically, the round cells are often S-100 protein positive. A poorer outcome is associated with round cell LPS, unlike the more favorable prognosis of pure myxoid LPS. Although the same two translocations are characteristic of both tumor types (Table 46.1), they do not correlate with prognosis (Cytogenet Genome Res. 2007;118:138).
3. Pleomorphic LPS, as the name implies, is by definition a high-grade sarcoma with a variable number of convincing pleomorphic lipoblasts. This tumor has a preference for the extremities, usually measures in excess of 10 cm, and primarily occurs in individuals over 40 years old. The tumor is either a well-circumscribed or an infiltrative mass with a variable appearance on cut surface ranging from solid to cystic, to necrotic, to hemorrhagic, to myxoid. Pleomorphic lipoblasts with enlarged hyperchromatic nuclei that are scalloped by cytoplasmic lipid vacuoles are not always numerous in the
background of highly atypical, even anaplastic round cells, spindle cells, and multinucleated tumor giant cells (e-Fig. 46.7). These tumors may have a prominent inflammatory infiltrate. Atypical, even bizarre mitotic figures are often present. Well-differentiated LPS can dedifferentiate to pleomorphic LPS (Am J Surg Pathol. 2010;34:1122; Am J Surg Pathol. 2010;34:837). In the absence of identifiable lipoblasts, these neoplasms are otherwise diagnosed as pleomorphic undifferentiated sarcomas but there is marked morphologic overlap between these tumors (Am J Surg Pathol. 2009;33:1594).
IV. FIBROBLASTIC/MYOFIBROBLASTIC TUMORS
A. Benign
1. Nodular fasciitis occurs in all age groups but has a predilection for young adults. It usually involves the subcutaneous tissue of the head and neck (especially in children), trunk, or upper extremities (e-Fig. 46.8). Dermal involvement is uncommon, but deeper fascial or intramuscular tumors are other presentations. Similar lesions may involve small to medium sized veins or the soft tissue of the outer table of the scalp (infantile cranial fasciitis), as intravascular and cranial fasciitis (e-Fig. 46.9), respectively. Uncommonly, the tumor develops at intraneural and intra-articular sites.
These circumscribed, minimally infiltrative spindle cell proliferations have a fibrous to myxoid cut surface, and most are <2 cm in greatest dimension though some lesions can exceed 5 to 6 cm. Cystic degeneration is an uncommon gross feature, but one of the microscopic hallmarks is the presence of microcysts among the more cellular foci (Arch Pathol Lab Med. 2008;132:579). Collections of inflammatory cells, extravasated red cells, or osteoclast-like giant cells may be associated with the microcysts. Compactly cellular foci with storiform profiles or interlacing fascicles may reside adjacent to individual cells with a myxoid background with a tissue culture-like appearance (e-Fig. 46.8 and e-Fig. 46.9). More collagenized foci resemble a keloid. Mitotic figures, but not atypical ones, are expected in variable numbers. The spindle cells are strongly reactive for smooth muscle actin (SMA); unlike desmoid tumor, the cells are nonreactive for β-catenin (Histopathology. 2007;51:509).
2. Proliferative fasciitis and proliferative myositis primarily occur in middle aged and elderly patients. The subcutis in the upper extremity is the most common site of proliferative fasciitis, but some cases involve the trunk or lower extremity. Proliferative myositis is intramuscular, and primarily involves the trunk, shoulder girdle, and upper arm. Both lesions grow rapidly, measure between 3 and 5 cm, and are composed of plump fibroblastic and myofibroblastic spindled cells as in nodular fasciitis. However, the hallmark of proliferative fasciitis and proliferative myositis is the presence of large ganglion-like cells with an uneven distribution within the lesion. The ganglion-like cells may be mitotically active but atypical mitotic figures are not present. In addition to SMA, CD68 may be expressed in the ganglion-like cells.
3. Ischemic fasciitis occurs over bony prominences, usually due to impaired circulation and prolonged pressure in immobilized, often elderly individuals. A zonal architecture consists of central areas of coagulative necrosis and myxoid change, with fibroblastic and vascular proliferation at the periphery (Am J Surg Pathol. 2008;32:1546). There is some resemblance to deep granuloma annulare.
4. Myositis ossificans and fibro-osseous pseudotumor of digits are related lesions that occur in a broad age range of patients, though young adults are most frequently affected. Myositis ossificans has a propensity for the extremities, trunk, and head and neck, while fibro-osseous pseudotumor primarily occurs, as its name indicates, in the subcutis of the proximal
phalanx of the finger and toe. Both lesions are thought to be caused by soft tissue injury with resulting repair, which initially consists of a cellular fibroblastic focus resembling nodular fasciitis, followed by development of an equally cellular osteoblastic proliferation and a peripheral rind of osseous metaplasia (e-Fig. 46.10). A similar type of proliferative and metaplastic process arises in the periosteum. Biopsies from the fibroblastic and/or osteoblastic foci can be quite worrisome, but the mitotic activity is generally low and the mitotic figures are not atypical. The nuclei are not disproportionately large or hyperchromatic.
5. Elastofibroma is found predominantly in individuals over 50 years of age in the connective tissues between the chest wall and the inferior region of the scapula, deep to the rhomboid major and latissimus dorsi muscles, usually with attachment to the periosteum of the ribs. However, rare examples have been described in the axilla, ischial tuberosity, and greater trochanter (Sarcoma 2008;756565). The tumor can be unilateral or bilateral and has a gray-white, rubbery to fibrous cut surface with ill-defined margins. Microscopically, a paucicellular collagenized stroma (e-Fig. 46.11) contains elastic fibers with large, coarse, eosinophilic linear globules arranged in a so-called beads on a string pattern that is highlighted by a Weigert’s elastic or pentachrome stain.
6. Fibrous hamartoma of infancy (FHI) is one of the “fibrous tumors of childhood” and is generally seen before 2 years of age (J Am Acad Dermatol. 2011;64:579). The anterior or posterior axillary fold, arm and shoulder, back, thigh, and groin are the preferred sites. The tumor forms an illdefined mass in the subcutis and has a white fibrocollagenous gross appearance with interspersed fat. Microscopically, intersecting fibrous bands of variable thickness radiate through the subcutis and are associated with discrete nodules of immature mesenchyme or so-called neuroid nodules (e-Fig. 46.12). Without the latter nodules, there is a resemblance to another fibrous tumor of childhood, lipofibromatosis or infantile subcutaneous fibromatosis. When there is overgrowth of the subcutaneous fat by the fibrous component, the tumor acquires the features of fibromatosis or dermatofibrosarcoma protuberans. FHI has a low rate of recurrence (only 10% to 15%). Like most other fibrous tumors in infants and young children, FHI does not express β-catenin (Pediatr Dev Pathol. 2009;12:292).
7. Myofibroma-myofibromatosis, another fibrous tumor of childhood, though seen in adults on occasion, is composed of contractile myoid cells that seemingly originates within small vessels and extends into the surrounding dermis, soft tissues, various organs, and bone. A solitary mass in the head and neck in a young child (aged 0 to 3 years) is the most common of the three clinical presentations (Table 46.4), although there are no excluded sites for origin as the tumor can also involve skin, soft tissues, visceral organs, and the central nervous system. Individual tumors range from <1 to over 7 cm in greatest dimension and have a cut surface that ranges from firm and fibrous, to cystic and hemorrhagic. Immature plump to spindled cells are arranged in whorls and fascicles within a fibromyxoid stroma; smaller nodules at the periphery of the mass may be associated with a vessel(s) to suggest an angiocentric origin (e-Fig. 46.13). Hypercellular spindle cell foci are present in some cases with a resemblance to congenital infantile fibrosarcoma, but the tumor cells lack the t(12;15) translocation characteristic of the latter tumor. Other findings include a hemangiopericytoma-like pattern centrally, often with ischemic or hemorrhagic regions, dystrophic calcifications, and hyalinization. The spindle cells express vimentin and SMA, whereas the hemangiopericytoma-like foci are variably CD34 positive. The differential diagnosis of myofibroma includes nodular fasciitis; the distinction can be problematic since the two lesions have some overlapping morphologic and immunophenotypic features (J Clin Pathol. 2009;62:236).
TABLE 46.4 The Three Clinical Presentations of Myofibroma-Myofibromatosis in Children
Solitary
Multicentric
Generalized
Sites
Skin, soft tissue, bone
Skin and soft tissue, and/or bone
Skin, soft tissue, bone plus organs (lung, heart, liver, intestinal tract, brain)
Percentage of total cases
90
3-6
1-3
Prognosis
Excellent
Excellent
Poor
8. Angiomyofibroblastoma, a rare tumor, occurs in women of reproductive age, where it arises in the rises in the pelviperineal region (vulva and vagina) as a painless, well-circumscribed, slowly enlarging mass (Int J Gynecol Pathol. 2005;24:26). In men, the neoplasm usually involves the paratesticular soft tissues or scrotum. Round to plump spindled myofibroblasts tend to cluster around blood vessels (e-Fig. 46.14); a subset of cases has a mature fatty component (Int J Gynecol Pathol. 2005;24:196). Binucleate and multinucleate cells are common in the absence of mitotic activity. These tumors are immunoreactive for desmin and estrogen and progesterone receptors. Some cases have an overlap with cellular angiofibroma and deep aggressive angiomyxoma (see below).
9. Cellular angiofibroma involves the superficial soft tissues of the vulva or inguinoscrotal region as well as the perineum, retroperitoneum, and subcutis of the chest (J Cutan Pathol. 2003;30:405). Grossly, the tumor is a well-circumscribed mass that usually measures <3 cm in diameter in women and <10 cm in men. The cut surface of the tumor has a yellow to tan-brown, soft to rubbery appearance. The tumor is composed of plump spindled cells with minimal eosinophilic cytoplasm, little cytologic atypia, and few mitotic figures; a background of delicate collagen fibers is present in tumors in females. The vascular component of the tumor is composed of small- to medium-sized vessels, with or without prominent hyaline walls, and is usually present throughout the entire lesion. Regressive/degenerative changes, including extravasated erythrocytes, hemosiderin deposition, cystic change, and intravascular thrombi are also present.
10. Giant cell angiofibroma, a slowly growing occasional painful tumor, has a predilection for the eyelids and orbital region of adults, although it has been identified in a number of other anatomic sites. The tumor is usually about 3 cm in greatest dimension, well-circumscribed, variably encapsulated, with cystic and/or hemorrhagic areas. Microscopically, cellular areas of round to spindled cytologically bland cells and multinucleated stromal cells (which often line pseudovascular spaces as is common in giant cell fibroblastoma) are set in a background of myxoid to collagenous stroma with small- to medium-sized blood vessels. Both the mononuclear and multinucleated cells are immunoreactive for CD34 and CD99, and occasionally also for BCL2.
11. Nuchal-type fibroma and Gardner-associated fibroma are virtually identical in terms of the microscopic features of dense, paucicellular collagenous bundles, which overgrow and occupy the dermis, subcutis, and deep soft tissues (Cancer. 1999;85:156). These tumors do not have the infiltrative
features of desmoid fibromatosis, however, a recurrence may be indistinguishable from a desmoid. As in desmoid tumors, there is nuclear immunopositivity for β-catenin. The possibility of Gardner syndrome should be raised in the presence of this tumor (Am J Surg Pathol. 2007;31:410). In the latter, multifocal lesions are seen.
B. Intermediate (locally aggressive)
1. Superficial fibromatoses. Palmar-plantar fibromatosis develops in males over 30 years of age (with a male to female ratio of 4:1) as an asymptomatic, isolated firm nodule, which evolves into cord-like bands between the nodules involving adjacent fingers. Plantar fibromatosis is seen more often in children and adolescents as painful subcutaneous nodules (Am J Surg Pathol. 2005;29:1095).
The microscopic features evolve over time. Greater cellularity is present early on, consisting of bland plump to spindle cells that have a low mitotic rate and are set in a background of collagen and elongated vessels (e-Fig. 46.15). Older lesions are much less cellular and have a stroma that consists of dense, often hyalinized collagen. The extent of surgical excision is the primary determinant of the rate of recurrence. These tumors may demonstrate focal rather than diffuse nuclear positivity for β-catenin (Mod Pathol. 2001;14:895).
2. Desmoid-type fibromatosis (desmoid tumor, musculoaponeurotic fibromatosis) usually involves the head and neck region in children, and the proximal extremities and abdominal wall in adolescents and older females (Hematol Oncol Clin North Am. 2005;19:565). Both soft tissues and mesenteric desmoids may be associated with Gardner syndrome. A circumscribed mass measuring 5 to 10 cm with a firm white trabeculated surface is the typical gross appearance; the macroscopic circumscription may be deceptive since subtle and extensive infiltration into the interstitium between muscle bundles and along fascial planes is often present microscopically. Although desmoid tumor is classically a proliferation of fibroblasts, a number of patterns are seen, ranging from spindle cells forming bundles and fascicles in a dense collagenous background, to plump fibroblasts in a pale less fibrotic stroma (e-Fig. 46.16). Small blood vessels may be conspicuous, and when red blood cell extravasation is present, the lesion can resemble nodular fasciitis. Some mitotic figures may be present, and scattered small lymphoid nodules may be noted at the interface with surrounding normal tissues. If skeletal muscle is involved, it is usually infiltrated with remnants of muscle embedded in the fibrous proliferation (e-Fig. 46.17). SMA expression is common, and 46% to 50% of cases have nuclear reactivity for β-catenin (Am J Surg Pathol. 2007;31:1299).
3. Lipofibromatosis (infantile subcutaneous fibromatosis), another fibrous tumor of childhood, is a slowly growing, painless, ill-defined neoplasm occurring in a variety of sites including the distal extremities (Am J Surg Pathol. 2000;24:1491). Grossly, the tumor is an ill-defined white-tan to yellow mass that usually measures <5 cm in greatest dimension. Spindled fibroblastic cells form bands that surround and may separate lobules of fat; the growth pattern resembles fibrous hamartoma but without the nodules of immature mesenchyme. The tumor may express CD34, BCL2, S-100, actin, epithelial membrane antigen and CD99, an unusual phenotypic profile for a fibrous tumor.
4. Infantile digital fibroma-fibromatosis (inclusion body fibromatosis, recurring digital fibrous tumor of Reye) presents in the fingers and/or toes (10% to 30% of cases are multifocal), excluding the thumb and great toe, as a firm nodule or nodules. Rare examples of extradigital lesions have been reported (Am J Surg Pathol. 2009;33:1). The fibrous proliferation resembles
a desmoid tumor, with confluent infiltration and replacement of the dermis and deeper soft tissues including the skeletal muscle. Isolated adnexal structures are surrounded by the moderately cellular spindle cell proliferation. Paranuclear bodies consisting of actin microfilaments are one of the unique features of this tumor. These tumors are immunopositive for SMA, calponin, CD99, and CD117.
5. Juvenile nasopharyngeal fibroma occurs almost exclusively in adolescent males, often presenting with epistaxis. Extensive local growth occurs in the confined spaces of the nasopharynx and into the paranasal sinuses and pterygopalatine fossa (Int J Pediatr Otorhinolaryngol. 2011;75:1088). These tumors are firm and have a white-tan cut surface. A diffuse bland fibrous proliferation with a prominent component of small blood vessels is the typical microscopic appearance. This tumor is seen in the setting of familial adenomatous polyposis. The stromal cells express nuclear β-catenin.
C. Intermediate (rarely metastasizing)
1. Solitary fibrous tumor (SFT) and hemangiopericytoma (HPC) are grouped together as related (if not identical) neoplasms in the WHO classification (Histopathology 2006;48:36).
a. SFT is classically found on the pleura (Semin Diagn Pathol. 2006;23:44), but has been reported in many different locations (including the dura, intestinal tract, mesentery, liver, skin, thyroid, lung, and orbit) in a broad age group. The tumor is a well-circumscribed, nonencapsulated, firm, white mass measuring 8 cm or less, and may show hemorrhage and focal myxoid change. Bland plump to spindle-shaped cells with a patternless architecture surround branching blood vessels of the type associated with HPC (e-Fig. 46.18). The cellularity often varies within individual tumors, and the hypocellular background stroma can have a myxoid fibrous appearance, and can resemble a nerve sheath tumor or low-grade fibromyxoid sarcoma (LGFMS). The tumor cells are immunoreactive for CD34 and CD99, but a subset of tumors also shows reactivity for SMA, BCL2, EMA, and even focal positivity for desmin, cytokeratin, and/or S-100. D2-40 may be positive in a small subset of SFTs, but immunoreactivity is more common in mesotheliomas (Appl Immunohistochem Mol Morphol. 2010;18:411).
Malignant SFTs are usually 10 cm or greater in size and have increased mitotic activity (≥4 mitoses per 10 HPFs), focal necrosis, increased cellularity, marked cytologic atypia in a patchy distribution, infiltrative margins, and show p53 expression (Arch Pathol Lab Med. 2010;134:1645). However, the clinical behavior of an individual tumor is not always correlated with the histologic features. Some tumors have a solidly cellular fibrosarcoma-like pattern yet behave in a relatively innocuous fashion.
b. By the current WHO classification scheme, the diagnosis of HPC is limited to STTs that morphologically resemble the cellular areas of SFT (e-Fig. 46.19), and that are composed of cells that have the immunoprofile of SFT. By this definition most cases of HPC occur in the deep soft tissues, primarily in the retroperitoneum of the pelvis, but also in the limb girdle and proximal upper or lower extremity. Most tumors are <15 cm in greatest dimension. Microscopically, the tumor cells have a uniform ovoid to spindled appearance in a background of small clefted to branching vascular spaces which are highlighted by CD34 immunoreactivity. Variable immunostaining for SMA is present. Mature adipose tissue is found in the lipomatous variant of HPC. Other settings for HPC include dural-intracranial, sinonasal, or infantile presentations; the latter is regarded as a pattern of infantile myofibroma-myofibromatosis
(J Clin Neurosci. 2010;17:469; J Pediatr Hematol Oncol. 2011;33:356; Am J Surg Pathol. 2003;27:737). As a final note, an HPC-like pattern of growth is seen in synovial sarcoma, malignant peripheral nerve sheath tumor (MPNSTs), mesenchymal chondrosarcoma, infantile fibrosarcoma, thymoma (spindle cell), and endometrial stromal sarcoma, emphasizing the need for careful microscopic examination, immunohistochemistry, and molecular studies for correct diagnosis.
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