Fibroblastic and myofibroblastic proliferations Flashcards
4 IHC profiles of myofibroblasts
V type (vimentin + only)
VA type (vimentin + SMA)
VD type (vimentin + desmin)
VAD type (vimentin + desmin + SMA)
Four categories of fibroblastic/myofibroblastic lesion
- Reactive lesions (eg, nodular fasciitis)
- Fibromatoses, locally recurring but non-metastasizing lesions
- Sarcomas with fibroblastic or myofibroblastic features that range from low-grade to high-grade behavior
- Fibroblastic/myofibroblastic proliferations of infancy and childhood
Nodular fasciitis
Always consider this as your major benign ddx for sarcomas! It is often called “pseudosarcomatous,” but is a benign, self-limiting process. It is, however, neoplastic, with virtually all cases bearing a translocation, most commonly MYH9::USP6.
Histologically, it resembles organizing granulation tissue. Fibrous or myxoid. Composed of plump, immature-appearing fibroblasts with a loose fascicular-to-storiform (“tissue culture”) or granulation tissue appearance. Mitoses are common, but none should be atypical. Focal myxoid cystic degeneration is a good hint. Scattered osteoclast-like giant cells may also be sparsely intermixed. Mostly well circumscribed, nonencapsulated lesions, 2 cm or less in largest dimension when excised. Intramuscular lesions tend to be larger.
Lesions are classified by location: Subcutaneous (extending upwards to dermis), intramuscular (ovoid mass, often larger), or fascial-type (stellate or ray-like growth).
In terms of IHC, most stain positive for SMA and negative for H-caldesmon and beta-catenin, which are seen in smooth muscle proliferations and fibromatoses, respectively.
Clinically, may present as a rapidly growing mass or nodule present for only 1-2 weeks. 50% of cases have tenderness or pain. May sometimes compress nerves locally. May occur at any age, most commonly ages 20-40. Most commonly subcutaneous, but may appear essentially anywhere.
Ossifying fasciitis
A neoplasm related to nodular fasciitis and myositis ossificans and which also has metaplastic bone, but is less well circumscribed than NF and lacks the zonal maturation of MO. When arising from the periosteum, parosteal fasciitis.
Effectively looks like NF with regions of immature woven bone composed of irregular osteoid.
Intravascular fasciitis
Rare form of nodular fasciitis with involvement of small or medium-sized veins or arteries.
Often presents as a slow growing, painless, solitary subcutaneous mass, usually 2 cm or smaller.
Closely resembles nodular fasciitis histologically, but has a conspicuous number of multinucleated giant cells.
Molecular features of nodular fasciitis
92% of cases involve rearrangements of USP6 (17p13) with MYH9 (22q13.1) being the most common translocation partner (MYH9::USP6).
This is the first known case of a self-limited process characterized by a recurrent gene fusion.
Desmoid fibromatosis
Intermediate grade tumor (locally aggressive, nonmetastasizing)
Histologically composed of long, sweeping fascicles with thin walled vessels and microhemorrhages; bland cells with mild to moderate cellularity and minimal atypia.
Deep-seated, poorly circumscribed, painless tumors. May arise in the abdominal wall in gravid or postpartum women. Multiple/systemic may be associated with FAP.
IHC: Nuclear beta catenin positive, SMA positive
Molecular: CTNNB1 mutations, often associated with FAP (germline APC mutations)
Palmoplantar fibromatosis
Superficial fibromatosis of the hands or feet.
Palmar fibromatosis: Most commonly affect the metacarpophalangeal joint, the proximal interphalangeal joint or both joints. Worse in White men with a strong family history, bilateral involvement, severe disease and ectopic manifestations.
Plantar fibromatosis: Most often affects al and central bands of plantar aponeurosis. Worse with bilateral involvement, multiple nodules and a positive family history.
Unlike desmoid fibromatosis, there are not defining molecular features. Some do have nuclear beta catenin, but there is no defining mutation.
Biopsy taken from the sternocleidomastoid an infant with torticollis
Fibromatosis colli, aka congenital torticollis
Fibromatosis that appears at birth, often bilateral, affecting lower 1/3 of sternocleidomastoid muscle, causing thickened muscle. May be due to birth injury (breech presentation, forceps).
Treatment:
If caught early, stretching / physiotherapy resolves in 70% of cases. Some cases require resection of the muscle, in which case recurrence is rare.
Inclusion body fibromatosis (Also called infantile digital fibromatosis, infantile digital fibroma)
Dermal fibroblastic and myofibroblastic lesion with cytoplasmic eosinophilic inclusions, usually in digits of infants. Usually exterior surface of distal phalanges of fingers and toes, but not thumb or great toe, also oral cavity and breast.
Nonencapsulated, dermal proliferation of hypocellular sheets or fascicles of fibroblasts and myofibroblasts with variable collagen. Some spindle cells have peculiar eosinophilic (hyaline) cytoplasmic inclusions the size of a lymphocyte nucleus. Usually mitotic figures are present to some degree. May infiltrate into adjacent tissue. There should be no atypia.
Inclusions stain with trichrome (red), PTAH, and variable actins. Cells stain for vimentin, muscle actins (tram track pattern), calponin, CD117, desmin, and CD99.
After resection, 50% recur, but the lesion does not metastasize.
Lipofibromatosis
Rare childhood tumor (first surgery usually at age 1), 2/3 male, often of distal extremities. Associated with macrodactyly of the foot. Clinically resembles lymphatic malformation or lymphedema.
Histologically, lobules of mature adipose tissue with fibroblastic foci consisting of bland fibroblasts involving adipose septa with a preserved lobular architecture. Often have minute small univacuolated cells at interface between fibroblasts and adipose. No atypia, no/rare mitotic figures. Rarely pigmented cells are associated with fibroblastic element; resemble those in Bednar tumor, pigmented neurofibroma, nevi.
IHC: Spindle cells stain for CD34, CD99, and SMA
Angiofibroma of soft tissue
Benign fibroblastic neoplasm of uniform spindle cells. Variable myxoid and collagenous stroma with a network of thin walled, branching blood vessels. Typically arises in extremities, mainly the legs.
IHC: Nuclear NCOA2+, CYP1A1 positive, variable EMA/CD34/SMA positivity, sometimes desmin positive. STAT6 negative, keratins negative.
Almost all cases involve a translocation upregulating NCOA2, most commonly AHRR::NCOA2. It is believed that this upregulates downstream AHR-regulated genes.
Angiomyofibroblastoma
A rare, benign, well circumscribed mesenchymal tumor that usually presents in young to middle aged women, predominantly in vulvovaginal area.
Histologically, a well circumscribed tumor that has alternating areas of hypercellularity and hypocellularity with stromal edema, abundant blood vessels and spindle to epithelioid stromal cells.
IHC: Positive for desmin, estrogen receptor / progesterone receptor and occasionally for CD34.
Molecular: MTG1::CYP2E1 fusion often present.
Calcifying aponeurotic fibroma
Rare benign fibroblastic tumor primarily of children and adolescents (patients less than 15 years of age), that involves the distal extremities, in association with aponeuroses, tendons and fascia. Characterized by bland spindle cells and less cellular zones of calcifications that have epithelioid to plump fibroblasts.
Infiltrative lesion composed of bland spindle cells within a collagenous matrix. Calcified areas that contain uniform, plump, epithelioid fibroblasts or scattered osteoclast-like giant cells. The lesion infiltrates the surrounding soft tissue. No significant nuclear atypia or mitoses are seen.
IHC: SMA, MSA, and CD99 positive. Beta catenin negative.
Molecular: In cases lacking calcification, FN1::EGF may be detected.
Calcifying fibrous tumor
Most commonly found in adolescents/young adults. May be found basically anywhere, but usually somewhere on the trunk or neck, including deep tissues/peritoneum/pleura.
Benign fibrous lesion histologically characterized by abundant hyalinized collagen, paucicellular bland spindle cells, psammomatous or dystrophic calcifications and lymphoplasmacytic infiltration.
Some believe that calcifying fibrous tumor may represent a stage of IgG4-related disease.
IHC: Factor XIIIa, CD34, and vimentin positive.
Cellular angiofibroma
Benign, cellular and richly vascularized fibroblastic neoplasm of the genital tract. Thought to be related to long term use of estrogen therapy. In women, presents as a slow growing, painless mass, mostly mimicking Bartholin cyst. In men, often presents with hernia or hydrocoele.
Histologically characterized by a well circumscribed lesion arising in the superficial soft tissue of the genital region. Has bland spindle shaped cells arranged without any pattern in a stroma with wispy collagen, numerous medium sized thick walled vessels and a variable adipocytic component.
Complete excision is curative with extremely rare recurrence and even rarer sarcomatoid transformation.
IHC: RB1 is lost. Positive for CD34 (30-60% of cases), ER, PR, SMA (minority of cases), desmin (minority of cases). Negative for STAT6, EMA, and keratins.
Molecular: RB1 deletions the most common feature.
Dermatofibrosarcoma protuberans (DFSP)
A locally aggressive, superficial mesenchymal neoplasm with fibroblastic differentiation. Virtually all cases contain fusion genes; COL1A1::PDGFB is the most common fusion product, although others have recently been reported. Rare, but one of the most common sarcomas of the skin and subcutis.
Classically presents clinically as an exophytic, nodular cutaneous mass; however, often initially presents as a flat plaque. Initially may show persistent slow growth, often for many years, then sudden progression.
Tumors are morphologically distinctive and frequently amenable to classification based on H&E. Tumors are generally centered within the dermis or subcutis and characterized by spindle cells with a storiform to whorled pattern. Cytoplasm is generally abundant and eosinophilic; nuclei are monomorphic and ovoid to elongated with variable mitotic activity. Tumors infiltrate and expand fibrous septa; interdigitation among lobules of fat yields a honeycomb pattern. Adnexal structures are typically spared. Stroma may be collagenous, myxoid or microcystic.
Fibrosarcomatous transformation is associated with metastatic potential
IHC: Most tumors are diffusely CD34+.
Molecular: ALWAYS some sort of fusion, most often COL1A1::PDGFB.
Desmoplastic fibroblastoma
Rare benign lesion of adult men (70% between ages 40 and 70 years). Fibroblastic lesion centered in subcutaneous tissue with reactive fibroblasts, low cellularity and abundant collagen.
Histologically, a paucicellular, bland spindled (stellate) and reactive appearing fibroblasts and myofibroblasts separated by abundant collagen with variable myxoid stroma. Fibroblasts have amphophilic cytoplasm, vesicular nuclei and distinct nucleoli. 70% of cases involve subcutis, 25% extend into skeletal muscle.
IHC: Vimentin positive, desmin negative, CD34 negative.
Elastofibroma
Benign, ill defined proliferation of fibroelastic tissue with excessive abnormal degenerated elastic fibers. Lesion usually presents as a slow growing, asymptomatic mass or rarely causes stiffness, pain, scapular snapping and impingement. Most cases are asymptomatic masses in the infrascapular region incidentally found on radiological examination for other causes
Histologically characterized by bland appearing fibrofatty tumor with abnormal elastic fibers with infiltrating borders which may entrap skeletal muscle fibers at the periphery or invade periosteum. Stroma is collagenized with variable hypocellular myxoid to edematous areas and admixed entrapped mature adipocytes. Scattered abnormal elastic fibers appear as densely eosinophilic, round to irregular, variably sized globules, elongated structures with irregular fuzzy outlines or beaded cords. Scattered spindle to stellate, bland looking fibroblasts are seen. No atypia or foci of necrosis.
Elastotic degeneration of collagen or abnormal elastotic fibrogenesis may underlie the pathogenesis of elastofibroma and active neovascularization or endothelial mesenchymal transition plays a potential pathogenetic role. Most recently, chromosomal abnormalities have been described in a few cases, including those for chromosome 1, suggesting a neoplastic nature for this tumor. Traditionally, it was more thought to be related to microtrauma, as it is reported more commonly in laborers
Surgical excision is curative, required mostly in symptomatic cases, with very rare local recurrence
EWSR1::SMAD3 positive fibroblastic tumor
The name says it all.
Extremely rare, fusion defined, locally aggressive soft tissue tumor. So far described only on the extremities, with a strong predilection for acral parts. Wide age range (1 - 68 years).
Presents as a small, painless, infiltratively growing tumor located in the dermis / subcutis. Frequently recurs due to infiltrative growth. May recur many years after initial excision.
Histologically, has 2 main components: hypercellular spindled fibroblasts merging with acellular hyalinized areas. Has a nodular or less frequently vaguely lobulated / plexiform low power growth pattern. Usually infiltrative growth, sometimes leading to engulfment of the surrounding subcutaneous adipose tissue. Spindled cells form hypercellular, well organized fascicles that frequently intersect with each other. Spindled cells have relatively uniform, elongated, focally wavy nuclei that are round when observed on a cross section, with moderate eosinophilic cytoplasm. There are no pleomorphism, atypia, or mitoses.
IHC: All cases show diffuse strong nuclear expression of ERG, which seems to be very specific in the pertinent differential diagnosis.
Molecular: Go figure, it has an EWSR1::SMAD3 translocation.
Fibroma of tendon sheath
A benign fibroblastic / myofibroblastic nodular proliferation usually attached to a tendon / tendon sheath. Presents as a slow growing, painless and firm mass.
Histologically, a well circumscribed tumor of variable cellularity, with higher cellularity at the tumor edges. Composed of bland spindle cells in a collagenous background and characteristic thin walled slit-like vessels. Degenerative changes and bizarre pleomorphic cells may be present, but there should be no significant mitotic activity or necrosis.
IHC: May be focally CD34, SMA, and vimentin positive. Rare cells may show calponin.
Fibrous hamartoma of infancy
A benign soft tissue neoplasm of infants and young children. Presents as a solitary, painless and freely movable mass of subcutis or dermis. May be well or poorly cirucmscribed. Rarely associated with tuberous sclerosis and William syndrome.
Primarily based on histological findings of characteristic triphasic morphology with bland fibroblastic / myofibroblastic cell bundles, primitive mesenchyme nodules and mature adipose tissue. Shows organoid, triphasic morphology with bundles of bland fibroblastic / myofibroblastic cells, nodules of primitive, rounded or stellate cells with myxoid stroma and mature adipose tissue.
Cured with local excision.
IHC: SMA+ (fibrotic areas), CD34+ in primitive mesenchymal cells, BCL2+ in primitive mesenchymal cells, S100+ in adipocytic areas. Desmin negative, beta catenin negative.
Molecular: EGFR exon 20 insertion / duplication mutations
From the deep soft tissue of the left arm.
Gardner-type fibroma
Effectively the same histology as nuchal fibroma, just different locations and more frequently associated with FAP.
Benign soft tissue lesion with thick, haphazard collagen and bland fibroblasts that entrap adjacent tissue. 90% associated with FAP / Gardner’s syndrome / APC germline mutation. 45% also develop desmoid-type fibromatosis.
May occur at superficial or deep soft tissue sites.
Histologically characterized by thick, haphazardly arranged collagen bundles, hypocellular bland fibroblasts, small blood vessels, plaque-like growth pattern with infiltration of adjacent structures.
IHC: CD34+, cyclin D1+, vimentin +, nuclear beta catenin positive (64% of cases).
From the neck.
Nuchal-type fibroma
Bundles of thick collagen fibers in posterior neck.
Rare benign lesion of dermis and subcutis in posterior neck (70%), upper back or other regions. More common in men, mean age 40 years, but can happen at any age. Associated with diabetes mellitus in 44% of cases.
Histologically, characterized by hypocellular, thick collagen fibers with delicate elastic fibers with no capsule. Entrapped adipose tissue and entrapped nerves (may resemble traumatic neuroma). May infiltrate into skeletal muscle and adipose tissue, may have scattered lymphocytes.
IHC: CD99+, vimentin +, C34+. S100 highlights any entrapped nerves. SMA and demsin are negative.
Giant cell fibroblastoma
Rare childhood fibroblastic tumor of intermediate malignant potential. Usually children less than 10 years old, 2/3 male. Presents as a painless nodule of subcutis, usually in trunk, extremities, head and neck. 50% recur but recurrences are controllable, no metastases.
Low power appearance of floret-like giant cells and ectatic pseudovascular spaces lined by stromal cells and giant cells.
Dermis and subcutis contains hyperchromatic spindle or stellate shaped cells in a collagenous or myxoid matrix with scattered hyperchromatic, multinucleated, floret-like giant cells with prominent nucleoli, similar to those in pleomorphic lipomas. Ectatic pseudovascular spaces are lined by a discontinuous row of floret-like cells and tumor cells. Cells have a honeycomb or parallel pattern of infiltration. Features also include hyalinized areas, perivascular lymphocytes in onionskin pattern, intralesional hemorrhage. Foci of DFSP may be seen. Should have no histiocyte-like cells, no mitotic figures.
Appears to evolve into DFSP by genomic gains of COL1A1-PDGFB. Considered the juvenile form of DFSP, as both have the same translocation.
IHC: Vimentin +, CD34+, CD99 + in 40%, variable actin staining. S100 neg, CD31 neg, Factor VIII neg, keratin neg, desmin neg
Inflammatory myofibroblastic tumor
Myofibroblastic spindle cell neoplasm of borderline malignancy (rarely metastasizing). May present with constitutional symptoms.
Histologically characterized by a myofibroblastic spindle cell proliferation in short fascicles with mixed inflammation (lymphocytes, plasma cells and eosinophils). Number of mitotic figures varies, atypical figures can be seen, however significant pleomorphism should be viewed with concern, may not fit with diagnosis of IMT. Some tumors may show ganglion-like cells (shown).
Variety of histologic patterns sometimes seen, including
1. loosely arranged myxoid or hyaline stroma, spindle to stellate cells and admixed inflammatory cells (nodular fasciitis-like)
2. Storiform or fascicular growing elongated spindle cells without overt hyperchromasia or cytologic atypia, associated with prominent lymphoplasmacytic infiltrate
3. Hypocellular, scar-like pattern with occasional metaplastic bone or associated calcifications
4. Epithelioid variant predominantly composed of plump round to epithelioid cells with vesicular chromatin, large, prominent nucleoli and amphiphilic to eosinophilic cytoplasm; a prominent neutrophilic component and abundant myxoid stroma are common
Epithelioid inflammatory myofibroblastic sarcoma is a distinct, highly aggressive variant that is predominantly intra-abdominal and is associated with a worse outcome.
IHC: Up to 60% ALK+ by IHC, 40-70% can be keratin positive. Negative for S100, myogenin, CD117, EMA.
Molecular: Up to 60% of cases show ALK rearrangement. Fusion partners are varied, including EML4, TPM3, TPM4, CARS, RANBP2, IGFBP5, and others. ALK negative IMTs may show ROS1 and PDGFRB alterations. ETV6-NTRK3 fusion found in a subset.
Myofibroblastoma
Bland, spindled cells composed of fibroblasts and myofibroblasts that are arranged in short, haphazardly intersecting fascicles.
Interspersed thick collagen bundles are often present. Minimal mitoses and atypia.
Presents as a slow-growing, painless mass that is well-circumscribed and unencapsulated.
IHC: Loss of RB1, spindle cells are positive for desmin, BCL-2, CD34, ER, PR, and AR.
Molecular: RB1 loss, 13q14 deletions (detect by FISH)
Cured by simple local excision.
Myositis ossificans (fibro-osseous pseudotumor, soft tissue aneurysmal bone cyst)
Myositis ossificans and fibro-osseous pseudotumor of digits are self limited, benign neoplasms composed of spindle cells and osteoblasts. Myositis ossificans, fibro-osseous psedotumor and soft tissue aneurysmal bone cyst belong to the same neoplastic spectrum.
Benign, reactive, ossifying soft tissue mass lesion, associated with trauma (often repetitive microtrauma) and characterized by zonal pattern. Usually physically active young males (second and third decade) with rapid growth of mass. 60 - 75% have history of trauma in prior 4 - 6 weeks. May also occur after elective surgery, severe burns, neurological injury. Usually occurs in anterior muscle groups of thigh and arm (more prone to injury); e.g., brachialis, adductors and quadriceps.
Histologically, zonal pattern is characteristic with different degrees of cellular differentiation (inner zone, intermediate zone and peripheral zone).
* Inner zone: Composed of fibroblastic / myofibroblastic proliferation, which is richly vascular, rich in inflammatory cells and resembles nodular fasciitis; sometimes with multinucleated giant cells. Cells show mild degree of pleomorphism and brisk mitosis.
* Intermediate zone: There is a mixture of fibroblasts and osteoblasts along with erratic osteoid separated by small sized vessels. Scattered chondrocytes.
* Peripheral zone: Osteoid undergoes calcification and leads to lamellar bone formation. Mature cartilage islands may be present. Extreme periphery / margin shows mature bone with osteoblastic rimming and little to no pleomorphism. The lesion is separated from the normal tissue (muscle) by a zone of loose, myxoid fibrous tissue
Thought to develop from differentiation of fibroblast to osteoblast secondary to inflammatory cytokine activity, particularly bone morphogenetic protein 1 (BMP1), BMP2 and transforming growth factor (TGF). These cytokines promote differentiation of perivascular mesenchymal cells into osteoblasts and chondroblasts, which then undergo endochondral ossification.
Does not recur if completely excised.
Nodular fasciitis
A boards favorite.
A benign, self-limited translocation tumor. Predominates in young adults but can occur at virtually any age. Tumors arise throughout the body; common locations include the extremities, head and neck and trunk. Most commonly originates in subcutis but may also arise in the dermis, fascia, skeletal muscle.
Tumors are morphologically distinctive and typically amenable to classification on the basis of H&E. Histologically, characterized by variable cellularity, an extracellular matrix ranging from myxoid to collagenous, and areas of cystic degeneration. Composed of spindle stellate cells with a loose fascicular to storiform pattern (so called tissue culture-like and feathery growth). Nuclei are bland and ovoid, but may be conspicuously mitotically active. There should be no atypical mitoses. Scattered lymphocytes, histiocytes and osteoclast type giant cells often present.
Younger tumors are more myxoid, older tumors are more collagenous.
Special cases:
Under the scalp/cranium: Cranial fasciitis
Involving small or medium-sized vessels: Intravascular fsaciitis
Simple excision is generally curative. May even spontaneously regress after biopsy. Rarely recurs after incomplete excision.
IHC: There is a limited role for immunohistochemistry as tumors show a myofibroblastic immunophenotype.
Molecular: Basically all are fusion associated. MYH9::USP6 is the most common fusion product, although other USP6 partners have been identified
Proliferative fasciitis
Proliferative fasciitis is a pseudosarcomatous proliferation of myofibroblastic / fibroblastic cells with large ganglion-like cells involving subcutaneous tissue. Morphology and clinical course are similar to nodular fasciitis.
Presents as a small, firm, mobile subcutaneous mass. Often demonstrates rapid growth and is usually tender or painful.
Morphologically, has similar features to nodular fasciitis, with plump myofibroblastic / fibroblastic spindle cells and varying densities of large ganglion-like cells with round nuclei, prominent nucleoli and abundant amphophilic cytoplasm. Mitotic figures are found in both spindle and ganglion-like cells and may be numerous, but no atypical mitoses are present. Has a loose tissue culture appearance with myxoid to collagenous stroma (maturing over time). Extravasated red blood cells and stromal lymphocytes are common.
IHC: Epithelioid cells show strong staining for cFOS, a small subset has diffuse staining for FOSB. Negative for keratin, desmin, myogenin, MyoD1, ERG, SATB2.
Molecular: Subset of cases has a recurrent FOS gene rearrangement
Proliferative myositis
Infiltrative poorly demarcated intramuscular mass resembling nodular fasciitis but with large basophilic cells resembling ganglion cells; histologically almost identical to proliferative fasciitis except located in muscle.
On low power, splays out muscle fibers (shown).
Mean age 50 years, rare in children.
Conservative surgery is curative, may have spontaneous resolution. Recurrence suggests a diagnostic error.
Superficial CD34+ fibroblastic tumor (aka PRDM10 rearranged soft tissue tumor)
Superficial CD34+ fibroblastic tumor is a distinctive low grade neoplasm of the skin and subcutis (superficial), characterized by a fascicular proliferation of spindled cells with abundant, eosinophilic, granular to glassy cytoplasm, marked nuclear pleomorphism (including interspersed pleomorphic giant cells) and low mitotic count.
Histologically, composed of spindle cells with eosinophilic granular to glassy cytoplasm. May have nuclear pleomorphism, but has an extremely low mitotic rate. Intranuclear cytoplasmic pseudoinclusions are often present. Necrosis is uncommon, but has been reported. An arborizing capillary sized vasculature is frequently present, as is a mixed inflammatory infiltrate.
IHC: Invariably express CD34 and are focally immunoreactive for keratin in close to 70% of cases. Nuclear PRDM10 is often positive.
Molecular: PRDM10 rearrangements in 3 of 7 tumors.
Superficial acral myxofibroma
Benign neoplasm of fibroblastic origin, with tendency for affecting periungual regions of the digits on acral sites. Slow growing, single and often painful tumors. Erosive or lytic lesion of underlying bone may be seen on imaging.
Histologically characterized by a poorly circumscribed lesion in dermis composed of spindle to stellate shaped fibroblastic cells arranged in a loose storiform / fascicular pattern with alternating myxoid and collagenous stroma. Microvasculature is prominent. Multinucleated stromal cells may be present and mast cells are frequent. Bland nuclei lacking significant mitoses or necrosis; occasionally degenerative atypia may be encountered. Infiltration in adipose tissue can occur. Cartilaginous and osseous metaplasia may be observed.
Prone to local recurrence. Surgical excision with adequate margins is treatment of choice.
IHC: CD34 diffuse and strong, CD99 diffuse and strong, focally EMA positive, focally SMA positive. RB1 loss is common.
Molecular: RB1 deletion is common, but not required for diagnosis.
Fibrosarcoma (adult type)
Malignant tumor of fibroblasts with herringbone architecture and variable collagen. Usually deep soft tissue of lower extremities or trunk, only rarely in retroperitoneum or mediastinum.
Histologically, characterized by a highly cellular fibroblastic proliferation in herringbone pattern (cells in columns of short parallel lines with all the lines in one column sloping one way and lines in adjacent columns sloping the other way). Cells have scant cytoplasm, tapering elongated dark nuclei with increased granular chromatin, variable nucleoli. Mitotic activity present, often with abnormal forms. There should be no pleomorphism - any pleomorphism suggests malignant fibrous histiocytoma.
Patterns: Keloid-like (thick hyalinized collagen fibers), loose fascicular, focally myxoid
IHC: Positive for vimentin, type 1 collagen, p53 (mutant pattern), high Ki67. May arise from a precursor SFT or DFSP, in which case CD34 will be positive. Negative for keratins.
Reticulin stain shows fibers surrounding each cell.
Phosphotungstic acid-hematoxylin demonstrates abundant cytoplasmic fibrils.
Prognostically, 50% recur, 25% metastasize (lung, bone). The more cellular and higher the mitotic index, the more likely to metastasize. Treated with radial excision.
Fibrosarcoma (infantile type)
Usually presents before age 2 years in axial regions or extremities with vary rapid growth. Related to congenital mesoblastic nephroma, the two share a characteristic ETV6-NTRK3 translocation. The same translocation may be seen in secretory breast carcinoma.
Morphologically resembles adult fibrosarcoma, but has a much better prognosis. 40 - 50% recur but only rarely metastasizes.
Histologically, a poorly circumscribed, lobulated mass of small to large spindled cells in fascicles or herringbone pattern with high cellularity, nuclear atypia and pleomorphism. Increased mitotic figures, hemorrhage and necrosis. May have prominent hemangiopericytoma-like areas, dystrophic calcification, extramedullary hematopoiesis. Infiltrates adjacent soft tissue with irregular margins.
IHC: Vimentin positive. Variably SMA, desmin, S100, and CD34 positive.
Molecular: 70% with a ETV6-NTRK3 translocation, t(12;15)(p13;q26). Trisomy 8, 11, 17, 20
Low grade fibromyxoid sarcoma
Morphologically bland sarcoma that can metastasize after years to decades. Usually occurs in young to middle aged adults (median age 34 years, range 3 - 78 years). Slow growing, painless.
Low to moderately cellular, bland fusiform or spindled cells with focal to diffuse whirling in heavily collagenized stroma with abrupt transition to myxoid areas. 45% have epithelioid areas, 40% contain poorly formed but large collagen rosettes (shown). Often infiltrates adjacent skeletal muscle. Occasionally has areas of increased cellularity, atypia, necrosis or mitotic activity characteristic of intermediate to high grade sarcoma.
Treatment: Complete excision with wide margins
IHC: MUC4 positive (highly sensitive and specific), CD99+ (90%), BCL2+ (90%), EMA positive, vimentin positive. CD34 negative, MDM2 negative, nuclear beta catenin negative, DOG1 negative.
Molecular: Has a characteristic t(7;16)(q32-34;p11) FUS-CREB3L2 fusion
Low grade myofibroblastic sarcoma (sometimes called myofibrosarcoma)
Deep intramuscular tumor of head and neck (tongue and oral cavity) and extremities (1.5 - 17 cm), rarely abdominopelvic. Can present at any age but predominantly patients in their 30s or 40s.
Circumscribed to diffusely infiltrative with fascicles or storiform growth of spindled tumor cells. Cells have ill defined pale eosinophilic cytoplasm, fusiform nuclei that are elongated or wavy with evenly distributed chromatin or round and vesicular with indentations and small nucleoli. At least focal moderate nuclear atypia with hyperchromasia and irregular nuclear membranes.
Collagenous matrix with prominent hyalinization. May have numerous thin walled capillaries. 1 - 6 mitoses/10 high power fields. No histiocytic giant cells or prominent inflammation.
IHC: At least one positive myogenic marker (demsin+, calponin+, or tram track SMA+). Negative for S100, EMA, h-caldesmon, ALK, CD34.
Molecular: Gains at 1p11, 12p12.2
Prognostically, commonly recurs, only rarely metastasizes; recurrences may be higher grade.
No uniformly accepted criteria for diagnosis; some authors suggest electron microscopy appearance is the gold standard.
Myxofibrosarcoma
Myxofibrosarcoma includes a range of malignant fibroblastic tumors with myxoid stroma, variable pleomorphism and characteristic curvilinear vasculature.
Most common sarcoma of elderly patients. Painless, superficial, subcutaneous mass of limbs. Multinodular, gelatinous, lobulated tumor with infiltrative margins.
Lobulated tumor with multinodular growth and incomplete fibrous septae. Cells are spindle to stellate in a myxoid stroma with curvilinear vessels and pleomorphic cells. Hypercellularity and severe pleomorphism are seen in high grade tumors. Rare epithelioid variant is characterized by nests and sheets of epithelioid cells with focal conventional areas.
Pseudolipoblasts (vacuolated fibroblasts) may be seen (shown).
3 tier grading system / FNCLCC grading system used.
IHC: Vimentin +, focal SMA+, focal MSA+, focal CD34+. Keratins negative, S100 negative, desmin negative.
Molecular: Complex karyotype with intratumoral heterogeneity and aneuploidy. Nondistinct numerical and structural chromosomal abnormalities. Higher grade and recurrent tumors show more complex cytogenetic aberrations.
Myxoinflammatory fibroblastic sarcoma
Rare, low grade sarcoma. Approximately 75% of tumors arise in the distal upper and lower extremities.
Histologically displays a multinodular lesion with prominent myxoid stroma, fibrous/hyalinized areas, mixed inflammation, virocyte-like cells, pseudolipoblasts and emperipolesis. Infiltrative growth pattern usually confined to subcutaneous tissue.
The tumor cell population composed of epithelioid to spindled tumor cells, some with bizarre nuclei and prominent nucleoli, some resembling Reed Sternberg cells. Low mitotic rate despite increased atypia; may display some areas of necrosis.
High grade variant: increased cellularity, increased mitotic activity and necrosis, retains characteristic virocyte / Reed-Sternberg-like cells, pseudolipoblastic cells.
IHC: (nonspecific) BCL1+, CD10+, and factor XIIIa+
Molecular: Most common molecular alteration is VGLL3 amplification; some cases show t(1;10) translocation or BRAF rearrangements
Diagnosis is primarily based on microscopic appearance and clinical characteristics.
Sclerosing epithelioid fibrosarcoma
Rare, aggressive, fusion-driven sarcoma. Mean age 45 years. Distinct sarcoma that behaves more aggressively than low grade fibromyxoid sarcoma with a shorter survival, higher metastatic rate and greater propensity to involve deep soft tissue and bone.
Histologically, a fibroblastic neoplasm composed of cords, nests or sheets of uniform epithelioid cells embedded in a dense collagenous stroma.
Cells are uniform, small, round to ovoid epithelioid cells with sparse, often clear cytoplasm and round to oval nuclei with inconspicuous nucleoli, arranged in nests, sheets, or cords, less commonly pseudoalveolar. There is prominent hyalinized sclerotic collagenous stroma, sometimes reminiscent of osteoid or cartilage. Occasional myxoid zones may be seen. Necrosis is uncommon.
May have low grade fibromyxoid sarcoma-like areas and conventional fibrosarcoma-like areas.
Variant cytology: plasmacytoid.
IHC: Muc4 +, vimentin +, BCL2+, CD99+ (50% of cases). If the EWSR1 fusion is present, FLI1+, CD45+, ERG+. Keratin negative, CD34 negative, desmin negative.
Molecular: EWSR1-CREB3L1 most common, some FUS-CREB3L2, FUS-CREM.
Cellular dermatofibroma
It’s a dermatofibroma, but it looks a bit dense, was clinically a bit too big, and has areas that look a bit fibrosarcomatous.
Cellular DFs are intermediate grade neoplasms of the rarely metastasizing type. Persist/recur more often than typical dermatofibromas. Recurrence is ~10%, margins usually not necessary.
Vessels may be staghorn, like an SFT/mesenchymal chondrosarc/myxoid liposarcoma.
Monster cells
Seen in dermatofibroma occasionally.
Completely benign.
It is ok to see these as long as they are not so frequent as to make you consider undifferentiated pleomorphic sarcoma.
Lipidized dermatofibroma
Most commonly occurs on the ankle – sometimes just called dermatofibroma, ankle type.
Foamy macrophages and rings/arcs of sclerotic collagen.
Plexiform fibrohistiocytic tumor
Small, slow-growing dermal or subcutaneous mass of the upper/lower extremities (rarely head/neck), usually found in children or young adults. 80% of cases are in females.
Intermediate grade neoplasm - rarely metastasizing, usually to lymph nodes or the lungs.
Histologically, a deep dermal or subcutaneous tumor with ray like extension into skeletal muscle or adipose tissue. Composed of a plexiform or multinodular proliferation of fibrohistiocytic cells with minimal atypia plus osteoclast-like giant cells and chronic inflammatory infiltrate. Prominent dilated vessels; more sclerotic than in “malignant fibrous histiocytoma.” Vascular invasion is present in 20% of cases.
IHC: CD68+ (in giant cells and mononuclear histiocyte-like cells), SMA+ (fibroblast-like cells). S100 negative, keratin negative, desmin negative, Factor VIII negative.
Tenosynovial giant cell tumor
“Tenosynovial giant cell tumor” encompasses a group of lesions that most often arise from the synovium of joints, bursae and tendon sheaths and show synovial differentiation. Malignant tenosynovial giant cell tumor is very uncommon and is defined by the coexistence of a benign tenosynovial giant cell tumor with overtly malignant areas or by recurrence of a typical giant cell tumor as a sarcoma.
This is the second most common tumor ofm the hand after ganglion cyst. It is well circumscribed, lobulated, and usually in close association with a tendon.
The tumor is composed of a mixed population of mononuclear cells, multinucleated giant cells, foamy macrophages, inflammatory cells and hemosiderin. The two principle types of cell which comprise the actual neoplastic tumor are small histiocyte-like cells with pale cytoplasm and round-to-reniform nuclei and large epithelioid cells with amphophilic cytoplasm, rounded, vesicular nuclei and a perihperal rim of hemosiderin granules.
Mitotic activity in neoplastic cells may be brisk, necrosis may be present. This does not necessarily imply malignancy.
Histologic subtypes:
* Localized-type: well-circumscribed, osteoclast-like giant cells readily apparent, xanthoma cells are frequent, hyalinized stroma.
* Diffuse-type: infiltrative borders, growth as expansile sheets, osteoclast-like giant cells are less frequent and may be absent, stromal hyalinization may mimic osteoid.
* Malignant-type: Composed of sheets and nodules of enlarged mononuclear cells, with significantly increased mitotic count, atypical mitoses, necrosis, enlarged nuclei with nucleoli, spindling of mononucleated cells, and myxoid changes. May contain areas resembling UPS or myxofibrosarcoma.
Molecular: Caused by a translocation of the CSF1 gene, however only a small subset of cells present actually harbor this translocation.
Fun fact: Since this is due to excess CSF1 signaling, malignant varieties respond to CSF1R inhibitors – and in fact much better to these than to conventional tyrosine kinase inhibitors.
Giant cell tumor of soft tissue
Soft tissue tumor with a wide age range (1-86 years). May be associated with Paget’s disease of bone. It is a tumor of low-grade malignant potential, cured by complete surgical resection. Arms, hand and thighs are most common sites.
Morphologically identical to giant cell tumor of bone.
Multinodular lesion diffusely infiltrating soft tissue. Tumor nodules consist of a mix of bland, round to oval mononuclear cells, spindle cells and multinucleated giant cells of osteoclast. Spindle cells may be arranged in a storiform or fascicular pattern. Tumors commonly have a peripheral rim of metaplastic bone that may extend to the center. Hemorrhage and cystic areas, consistent with secondary aneurysmal bone cyst-like changes, are commonly present.
Significant atypia excludes this diagnosis. However, mitotic activity is common, and may be brisk. Vascular invasion is seen in up to 50% of cases. Necrosis is uncommon.
IHC: Osteoclast-type giant cells are positive for TRAP, TRAIl, RANKL, and osteoprotegrin. Mononucl;ear cells are CD68, p63 positive.
Molecular: Unlike GCT of bone, there are no H3F3A mutations.
