Miscellaneous Tumors of Uncertain Differentiation

Presents during adulthood and shows slight male predilection

Commonly affects the head and neck and trunk areas

Usually solitary

Size: 1 to 5 cm

Benign tumors, but frequently recur locally

No reports of metastasis

Dermal or subcutaneous lobules of plump, stellate or spindle-shaped, bland-looking cells embedded in basophilic, highly vascular, myxoid matrix

Aggregates of inflammatory cells, particularly neutrophils, are commom

May contain entrapped epithelial component that resembles keratinous cysts

Some consider this equivalent to cutaneous myoma

Neoplastic cells express vimentin and sometimes CD68, factor XIIIa, and CD34

The myxoid stroma can be highlighted with Alcian blue or mucicarmine stains

Aggressive angiomyxoma

Angiomyofibroblastoma

Low-grade myxofibrosarcoma

Nerve sheath myxoma

An exclusively intramuscular neoplasm

It usually involves the large skeletal muscles of extremities, particularly the thigh

Superficial cases involving head and neck and hypothenar area of the hand are extremely rare

Majority of patients are adults

Two-thirds of patients are females

Rare cases are associated with Mazabraud syndrome (single or multiple intramuscular myxomas and polyostotic fibrous dysplasia)

Most cases present as slowly growing, painless muscular masses

Angiographic studies demonstrate poorly vascularized neoplasms

Surgical excision is virtually always curative

Recurrence is unusual even after incomplete resection

Cellular variant has a higher tendency for recurrence

Classically described as “hypocellular” and “hypovascular” tumor

Commonly infiltrates adjacent muscle fibers

Abundant myxoid stroma with sparse, capillary-sized blood vessels

Uniform, cytologically bland, spindle-shaped cells with eosinophilic cytoplasm

A cellular variant has been described

Tumors typically lack cytological atypia, mitoses, and necrosis

Neoplastic cells express vimentin

Variable expression with CD34, desmin, and smooth muscle actin

S100 protein is not normally expressed

Recurrent point mutations involving the GNAS1 gene are common

Chondrosarcoma

Low-grade myxofibrosarcoma

Low-grade fibromyxoid sarcoma

Myxoid liposarcoma

Myxoid neurothekoma

Wide age range

The majority of affected individuals are males (more than 70%) in their third to fifth decades

The most common location is around the knee

Mainly involves the periarticular tendons, ligaments, joint capsule, muscles, and the adjacent subcutis

Most cases present as a mass, sometimes associated with pain

Benign tumors often cured by complete excision

Recurrence is common; can be multiple

Recurrence usually takes place within 18 months

Recurrence commonly involves subcutaneous adipose tissue

Histologically virtually identical to intramuscular myxoma

Unlike intramuscular myxoma, cystic changes are more common, and rare mitoses as well as atypical reactive cells can be seen

Alcian blue–positive matrix

Neoplastic cells express vimentin

Variable expression with CD34, desmin, and smooth muscle actin

S100 protein is not normally expressed

Recurrent point mutations involving the GNAS1 gene are not seen

Ganglion cyst

Chondrosarcoma

Low-grade myxofibrosarcoma

Low-grade fibromyxoid sarcoma

Myxoid liposarcoma

Myxoid neurothekoma

Majority of patients are adults

Striking male predominance

Slowly growing, small, lower neck mass

Generally benign lesion

Cured by complete resection

No reports of metastasis

Tumors consist of three haphazardly arranged components: epithelial cell, spindle cell, and adipose tissue

Spindle cell component usually predominates

The epithelial component consists of either solid or cystic squamous epithelium

Glandular structures are less common

The spindle cells exhibit bland-looking elongated nuclei

Myoid differentiation of spindle cells is sometimes seen

Myoepithelial differentiation is uncommon

Tumor cells are devoid of pleomorphism

Mitoses are usually absent

Scattered lymphocytes may be seen

Both epithelial and spindle cells express cytokeratins, particularly high-molecular-weight forms

CD34 is expressed by the spindle cells only

Androgen receptor is expressed by the spindle cells

Muscle actin and myoglobin can be expressed by spindle cells

Desmin and S100 protein are negative

Ectopic cervical thymoma

Thymolipoma

Teratoma

Biphasic synovial sarcoma

Malignant peripheral nerve sheath tumor with glandular differentiation

Benign mixed tumor/myoepithelioma of soft tissue

Affected individuals are usually adults

Predilection for females

Slowly growing, may be painful

Size is variable

History of trauma is obtained in up to 70% of cases

Treated by local excision

Local recurrence can occur

No reports of metastasis

Well-circumscribed lobules of mature adipocytes admixed with areas composed of spindle cells

The spindle cell areas show striking hemosiderin deposition

No or mild atypia

No or rare mitoses

Sometimes associated with venous stasis and can be histologically virtually identical to early pleomorphic, hyalinizing angiectatic tumor (but is not pathogenically related to this tumor)

Hybrid lesions with myxoinflammatory fibroblastic sarcoma can be encountered (the two tumors do appear to be pathogenically related in at least a subset of cases)

The spindle cells express vimentin, CD34, and calponin

Distinctive translocation t(1;10)(p22;q24) involving the TGFBR3 and MGEA5 genes in the great majority of cases, frequently also associated with amplifications of chromosome 3p11~12, resulting in formation of ring chromosomes (also designated marker chromosomes ) with increased expression of VGLL3 and CHMP2B genes

Myxoinflammatory fibroblastic sarcoma can harbor this fusion in a subset of cases

TGFBR3-MGEA5 fusions are more commonly encountered in hybrid hemosiderotic fibrolipomatous tumor/myxoinflammatory fibroblastic sarcoma lesions than in classical “pure” myxoinflammatory fibroblastic sarcomas

These features suggest a pathogenical relationship between at least a subset of these two tumor types

Spindle cell lipoma

Atypical lipomatous tumor

Affected patients are almost exclusively females 40 to 60 years of age

Much less common in women older than 60 years and does not affect children

Tumors are usually deeply located in pelvic, perineal, anorectal, or retroperitoneal regions

Commonly present as asymptomatic, slowly growing mass

Patients may present with feeling of pressure, discomfort, or pain

Size is variable but often large (>10 cm)

Locally aggressive tumors (intermediate)

Recurrence is common, which can be late, but usually not more than once

No metastases have been reported

Usually managed by surgical excision

May respond to hormonal therapy using gonadotropin-releasing hormone agonist

Sparsely to moderately cellular neoplasms composed of bland stellate and spindled cells embedded in a loosely collagenized, myxoid matrix with scattered vessels of varied caliber

Higher cellularity may be observed at perivascular and peripheral areas

Some neoplastic cells show relatively abundant eosinophilic cytoplasm and exhibit fibroblastic and myofibroblastic features and appear to be hormonally influenced

Well-developed myoid differentiation best evident around medium-size blood vessels and nerve trunks

Mitoses are rare or absent

Neoplastic cells focally express desmin, smooth muscle actin, muscle specific actin, vimentin, CD34, and estrogen and progesterone receptors

S100 protein is negative and Ki-67 index is very low (<1%)

The myxoid stroma can often be highlighted with Alcian blue or mucicarmine stains

Superficial angiomyxoma

Angiomyofibroblastoma

Low-grade myxofibrosarcoma

Nerve sheath myxoma

Adult patients, most commonly in the eighth decade of life (mean age 77 years)

Male predominance (M:F = 9 : 1)

Ultraviolet (UV) irradiation a key factor implicated in pathogenesis

Sun-exposed and sun-damaged skin

Most frequently on the scalp, followed by forehead, ear, nose, and face

Rapidly growing polypoid or nodular lesion, frequently ulcerated on the surface

Complete excision usually curative

Invariably benign when strict criteria applied

Virtually always benign when confined to the dermis

Locally aggressive behavior and even metastasis can be seen with significant subcuticular involvement (see Pleomorphic dermal sarcoma later)

Admixture of (in variable proportions)

• Pleomorphic, fibroblast-like spindle cells

• Histiocyte-like epithelioid cells

• Multinucleated giant cells

Lesional cells growing in sheets and fascicles

No connection with the epidermis

Numerous mitoses, including atypical ones

Tumor necrosis absent

Lymphovascular invasion absent

Perineural invasion absent

Generally well-demarcated proliferation in the dermis

Focal, limited extension into superficial subcutis not uncommon and allowed by some authorities

• Expansile

• Limited lacelike

Surface ulceration in about 50% of cases

Epidermal collarette at the periphery of the lesion in 20%, possible extension at variable length along the base of the lesion

Solar elastosis, usually marked in the surrounding dermis

Diagnosis of exclusion

Morphological variants (represent either a focal phenomenon or predominant/exclusive component of the lesion)

• Spindle cell with more limited pleomorphism

  • Proliferation of monomorphic spindle cells

  • No pleomorphism of conventional atypical fibroxanthoma

  • Fascicular growth of spindle cells with eosinophilic cytoplasm

  • High mitotic activity

• Pseudoangiomatous or “pigmented” variant with hemosiderin deposition

  • Areas of hemorrhage, usually coupled with hemosiderin deposition

  • Pseudovascular spaces lined by lesional cells (pleomorphic spindle cells, epithelioid cells, multinucleated giant cells)

  • Pleomorphic lesional cells can protrude into the pseudolumina

  • Phagocytosis of hemosiderin and erythrocytes occasionally seen

• Keloidal

  • Bright eosinophilic, hypocellular/acellular, collagenous, keloidlike areas

  • Usually a focal phenomenon

  • Keloidal areas can be separated from the epidermis by a grenz zone

  • Occasionally in a perivascular distribution

• Regressing

  • Degree of fibrosis from 10% to 90% of the lesion

    • Thickened collagen bundles with sclerosis (early)

    • Lamellar arrangement of collagen fibers with hyalinization (late)

• Clear cell change

  • Numerous intracytoplasmic lipid vacuoles in lysosome-rich cells

  • Can also represent a degenerative phenomenon

  • Staining for glycogen uniformly negative

• Granular cell change

  • Bright eosinophilic granular cytoplasm

  • Likely a degenerative phenomenon related to the accumulation of intracytoplasmic lysosomes

• Myxoid degeneration

  • Accumulation of hyaluronic acid in the stroma

  • Can be highlighted by periodic acid–Schiff (PAS) or Alcian blue

• Osteoclast-like giant cells

  • Reactive, osteoclast-like giant cells dispersed among conventional atypical fibroxanthoma

  • True atypical osteoclast-like giant cells also described, likely developing from large, pleomorphic, multinucleated giant cells

Diagnosis of exclusion: must exclude other mimics by immunohistochemistry

By definition, consistently negative for low- and high-molecular-weight cytokeratins, desmin, and S100 protein

Reactive S100 protein–positive dendritic cells can on occasion be numerous and should not be mistaken for lesional cells

Smooth muscle actin positivity (45%), EMA positivity (24%), usually focal

CD99 and CD10 frequently positive, but very nonspecific

Cytoplasmic CD31 positivity in about 10%

• Staining is cytoplasmic and finely granular

• Not as prominent as in endothelial cells

• Lesional macrophages can also display cytoplasmic positivity

Granular cell variant

• NKIC3 positive

• PAS positive after diastase digestion

Squamous cell carcinoma

Metaplastic carcinoma

Melanoma

Angiosarcoma

Leiomyosarcoma

Undifferentiated (dermal) pleomorphic sarcoma

Affected patients are children or young adults

Tumors are usually located in the subcutaneous tissue of extremities or trunk

Deeply situated lesions are less commonly encountered

Superficial, slow growing

Size: few millimeters to 2 cm

May be associated with systemic symptoms (fever, anemia, malaise, and weight loss)

Good outcome achieved with simple surgical excision

Local recurrence is reported in 10%

Deep lesions elicit higher tendency for recurrence

Metastasis to local lymph nodes is seen in only 1% of cases

Pseudoencapsulated, multicystic, hemorrhagic lesions

Neoplastic elements are bland-looking, round or spindle cells admixed with chronic inflammatory cells

Inflammatory infiltrates can organize with germinal centers simulating lymph node metastasis

Tumor cells may exhibit mild to moderate pleomorphism and occasional mitoses

Neoplastic cells commonly express CD68, CD99, muscle actin, desmin, EMA, and calponin

No reactivity with factor VIII, CD34, CD31, S100 protein, or cytokeratin

t(12;16)(q13;p11) creating ATF1 - FUS fusion gene, t(12;22)(q13;q12) creating ATF1 - EWSR1 fusion gene, or t(2;22)(q33;q12) creating CREB1 - EWSR1 fusion gene—this latter being the most common

Cells show variable features, including fibroblastic, myofibroblastic, and histiocytic differentiation

Aneurysmal fibrous histiocytoma

Angiosarcoma