Cutaneous Spindle Cell Lesions

INTRODUCTION

This chapter considers diagnosis of common spindle cell lesions predominantly occurring in dermis and superficial subcutis. They include reactive lesions and benign and malignant neoplasms, which can be cellular or accumulate variable amounts of myxoid or collagenous stroma. Many are fibroblastic or myofibroblastic but some melanocytic lesions also enter the differential diagnosis as well as tumors with smooth muscle differentiation (Chapter 6) or nerve sheath differentiation (Chapters 9 and 10). Vascular tumors are discussed in Chapter 17, and predominantly myxoid lesions are discussed in Chapter 20. The differential diagnosis is summarized in Table 4.1.

KELOID

Clinical Features

This is an aberrant reaction to injury, especially surgical incision, or infection, often some time before the development of the lesion. It is most common in young adults and more often seen in the upper part of the body, including anterior chest wall, head and neck, and upper limb and limb girdle. There is a familial component in some cases, an increased incidence in individuals with pigmented skin, and an association with scleroderma and other connective tissue diseases.¹ Mechanical factors such as stretching of the skin may also play a role in genesis of the lesions, which can enlarge during pregnancy. Keloid presents as a raised rounded or linear skin nodule, which is at first red and later paler. The lesions continue to grow, albeit slowly, and do not regress, but are prone to local recurrence following excision. Other available treatments include radiation therapy and intralesional and topical application of various agents, including corticosteroids, interferon, 5-fluorouracil, and imiquimod.² However, most therapeutic applications for keloid (and hypertrophic scar) offer little improvement.³

TABLE 4.1 Differential Diagnosis of Cutaneous Spindle Cell Neoplasms

Tumor Type	Pattern	Morphology	Ancillary Investigations
Keloid	Randomly oriented thick collagen fibers in dermis, can extend beyond site of wound Low cellularity	Eosinophilic thick collagen bundles, sparse bland fibroblastic spindle cells	Nil specific
Cellular (hypertrophic) scar	Variously oriented fibroblasts More cellular than keloid and restricted to site of wound	Bland tapered spindle cells, no nuclear atypia	SMA+, low MIB proliferation index
Cellular fibrous histiocytoma	Epidermal hyperplasia Cellular fascicles in dermis, extensions into fat, short and pointed, radial to surface Peripheral collagen bundles	Uniform tapered cells with ovoid nuclei and scanty cytoplasm, Touton giant cells Hemorrhage and siderophages if aneurysmal component Focal cellular pleomorphism in atypical variant	SMA+, FXIIIa+
Dermatofibrosarcoma	Diffusely storiform, infiltrates parallel to skin surface with extensive honeycombing of fat Pattern changes to fascicular in fibrosarcomatous transformation.	Long cells, scanty cytoplasm, uniform tapered, slightly wavy nuclei Focal or diffuse myxoid change Mitotic activity increases in fibrosarcomatous variant	CD34+, bcl-2+. S100 protein + in pigmented cells of Bednar variant t(17;22)(q22;q13) with fusion gene COL1A1-PDGFRB Fibrosarcomatous variant similar but can be CD34−
Giant cell fibroblastoma	Poorly circumscribed in skin and subcutis, variably cellular without distinct pattern except where coexistent dermatofibrosarcoma Irregular pseudovascular spaces lined by lesional cells	Spindle and apparently multinucleated cells (in reality, each has a single highly convoluted nucleus) in fibrous and myxoid stroma	CD34+, bcl-2+, t(17;22) (q22;q13) with fusion gene COL1A1-PDGFRB
Dermal nerve sheath myxoma	Circumscribed multilobulated myxoid lesion, low cellularity	Spindle cells can show focal pleomorphism	S100 protein+ in myxoid areas, EMA+ at periphery of nodules
Superficial angiomyxoma	Noncircumscribed, multinodular, infiltrative in dermis and subcutis Random pattern, not storiform or fascicular	Bland short to medium-length spindle or stellate fibroblasts in myxoid stroma, variable vascularity, scattered neutrophils	CD34+ (focally), S100 protein−
Neurofibroma, typical	Nonencapsulated, ill-defined fascicles but not widely infiltrative except diffuse type	Mixture of wavy cells, axons, collagen fibers, mast cells	S100 protein+ (not all cells), EMA+ very rarely focally, CD34+ focally. NF+ in axons
Neurofibroma, diffuse	Subcutaneous infiltrative plaque Some associated with plexiform neurofibroma—extends outside nerve bundles into soft tissue	Sheets of short spindle cells in loose fibrous stroma, infiltrating between normal structures Wagner-Meissner bodies in various stages	S100 protein+ diffusely in nuclei
Atypical fibroxanthoma	Dome-shaped with overlying epidermal thinning or ulceration Dermal infiltrate is storiform, fascicular, or patternless	Pleomorphic spindle and polygonal cells throughout, abnormal mitoses Clear cell, spindle cell, and giant cell variants	SMA+ focally, CD10+
Kaposi sarcoma	Cellular, curved fascicles, sievelike areas in cross-section, hemorrhage	Mildly pleomorphic cells, mitoses, hyaline globules, red cell extravasation	HHV8+, CD31+, CD34+, podoplanin (D2-40)+ S100 protein−
Angiosarcoma	Variable vascular channel formation and cellular areas, with hemorrhage	Spaces lined by atypical endothelial cells Solid areas can have spindled or epithelioid cells	CD34+, CD31+, ERG, FVIIIRAg+, FLI-1+, CK±, S100 protein− protein−, desmin−
Leiomyoma	Nodular or diffuse, fascicles intersecting at right angles	Spindle cells with eosinophilic cytoplasm, nontapering nuclei No pleomorphism, mitotic activity, or necrosis	SMA+, desmin+, h-caldesmon+, S100 protein−
Leiomyosarcoma (and atypical intradermal smooth muscle tumor)	Fascicles of varying size, intersecting at right angles	Spindle cells with eosinophilic cytoplasm, nontapering nuclei Variable pleomorphism, mitotic activity, or necrosis according to grade	SMA+, desmin+, h-caldesmon+, S100 protein−
Spindle cell carcinoma	Sheets, nests, and storiform whorls Areas of epithelial morphology Overlying epithelial dysplasia or carcinoma	Pleomorphic spindle or epithelioid tumor cells Sheet-like epithelial areas, transitions to sarcomatous morphology Nested reticulin pattern	CK+, EMA+, INI1+, CD34 negative, SMA+, P63+ in some, desmin−, h-caldesmon−, S100 protein−
Myofibroma	Bundles or whorls of myofibroblastic spindle cells with foci of smaller darker cells, focal pericytomatous pattern Can be focally necrotic or calcified	Spindle cells have ovoid nuclei, small nucleoli, tapering eosinophilic cytoplasm Mitoses in some but no atypia	SMA+, calponin+, desmin−, h-caldesmon−
Dermatomyofibroma	Cellular fascicles run parallel (tangential) to skin surface Mild adjacent epidermal hyperplasia	Bland myofibroblastic spindle cells, ovoid nucleoli, small nucleoli, tapering cytoplasm	SMA+, calponin+, desmin−, h-caldesmon−
Nodular fasciitis	Variably myxoid, cellular, and collagenous areas Mitoses but no nuclear atypia or necrosis	Spindle cells have ovoid nuclei, small nucleoli, tapering cytoplasm Mitoses in some but no atypia	SMA+, desmin±, h-caldesmon−
Spindle cell lipoma	Circumscribed, fatty component, collagen fibrils, mast cells Myxoid variant	Short spindle cells, very occasional lipoblasts acceptable	CD34+, rarely S100 protein+, MDM2 and CDK4 usually−
Perineurioma	Circumscribed, variably cellular fascicles, with myxoid or fibrous stroma	Elongated bipolar or tripolar cells with very long terminal processes	EMA+, claudin-1+, GLUT-1+, CD34+,
Low-grade fibromyxoid sarcoma	Ill-defined Fibrous and myxoid areas with swirling pattern collagen cracking Occasional hyaline rosettes	Bland cells with uniformly staining nuclei, sometimes rectangular, indiscernible cytoplasm	MUC4+, occasional EMA+, claudin-1+. Rarely SMA+ or CD34+ t(7;16)(q34;p11) with fusion gene FUS-CREB3L2 or CREB3L1, rarely t(16;22) (p11;q12) with fusion gene EWSR1-CREB3L1
Malignant melanoma, desmoplastic	Junctional activity present or absent Spindle cells singly or in separated bundles infiltrating dermis and subcutis Neurotropism	Spindle or focally epithelioid cells with nuclear pleomorphism, scanty cytoplasm, mitoses	S100 protein+ diffusely, HMB45 or melan-A+ rarely
Malignant peripheral nerve sheath tumor	No junctional activity Bundles and sheaves of spindle cells Occasional neurotropism	Elongated spindle cells, wavy or buckled nuclei Epithelioid areas	S100 protein+ focally
Clear cell sarcoma	Extremities especially lower limb, young adults	Round or spindled cells in nests, round nuclei with central nucleolus, clear or granular cytoplasm, multinucleated cells, melanin pigment	S100 protein+, HMB45+ and melan A+ (other markers negative, t(12;22)(q13;q12), EWSR1-ATF1 in soft tissue cases
PEComa	Can rarely arise in skin	Nests of ovoid or spindled cells with abundant clear or rarely granular cytoplasm, delicate fibrous septa	SMA+, HMB45+, melan-A+, desmin+ in some, TFE3+ in some, CD117+ in some, S100 protein+ rarely
Anaplastic large cell lymphoma	Cutaneous involvement can occur with or without nodal disease	Sheets of cells with prominent nucleoli, multinucleated forms Can be spindled	CD30+, ALK+, CD43+, CD45+, CD3+, TIA1+, t(2;5)(p23;q35), TMP3-ALK fusion
Mycobacterial spindle cell pseudotumor	Sheets of spindle cells with storiform pattern and plump epithelioid macrophages	Cells have abundant eosinophilic cytoplasm Foamy and multinucleated cells sometime seen	Ziehl-Neelsen stain reveals numerous acid-fast bacilli

Pathologic Features

The characteristic feature is the presence of thick, eosinophilic collagen fibers arranged randomly in the dermis (Fig. 4.1, e-Figs. 4.1 to 4.3). There are scattered bland spindle cells, and in older, more hyalinized lesions, there can be calcification or ossification. The overlying epidermis is thinned, and adnexa are separated by lesional tissue at the deep aspect. The lack of cellularity helps to exclude the rare dermatofibroma with focal keloidal change.⁴

Ancillary Investigations

The lesional spindle cells are fibroblastic and lack lineage markers including SMA, which can help in diagnosis from other dermal myofibroblastic proliferations. Ki67 demonstrates proliferative activity, notwithstanding the sparse cellularity. Gene profiling has shown altered expression in multiple fibrosis-related pathways and differences in expression of caspase genes between normal skin of keloid-prone individuals and normal skin of keloid-resistant patients, which might contribute to susceptibility to develop keloids.⁵

Cellular scars are intradermal fibroblastic myofibroblastic lesions characterized by nodules of spindle cells orientated in various directions, without nuclear atypia or pleomorphism (e-Figs. 4.2 and 4.3). There is usually a recent history of trauma or surgery, and there is a predilection for flexor surfaces near joints and the abdominal wall. They can be distinguished from keloid by their lack of infiltration beyond the original wound site, prominent blood vessels, absence of thick collagen fibers, SMA positivity, lower proliferation index with Ki67, and tendency to regress; from dermatomyofibroma by the lack of tangential orientation; and from
fibromatosis by the hypocellularity, lack of alignment, and regular spacing of the lesional cells (e-Figs. 4.4 and 4.5).

FIGURE 4.1 Keloid. Thick eosinophilic collagen fibers are disposed in a cellular fibroblastic stroma.

SCLEROTIC FIBROMA (CIRCUMSCRIBEDSTORIFORM COLLAGENOMA)

Clinical Features

This is a solitary dermal nodule arising mainly on face, limbs, and trunk, and presenting as a small, pale, well-demarcated papule. It is histologically identical to the multiple skin nodules that arise in Cowden syndrome.⁶ The lesion is benign but an occasional example has recurred.

Pathologic Features

The lesions are rounded, sharply demarcated dermal nodules formed of whorled or laminated, thickened, collagen bundles containing scanty bland spindle cells and separated by clefts containing stromal mucin (Fig. 4.2, e-Figs. 4.6 to 4.9). The overlying epidermis is thinned. A pleomorphic variant, with a component resembling pleomorphic fibroma, has been described.⁷ Similar features can be seen focally in the rare sclerotic fibroma-like dermatofibroma⁸ and in a variety of other neoplastic and inflammatory skin lesions.

Ancillary Investigations

Some sclerotic fibromas display immunoreactivity for CD34 and CD99. SMA positivity and the presence of FXIIIa-positive dermal dendrocytic cells have also been described.⁹

FIGURE 4.2 Sclerotic fibroma. Interwoven laminae formed by collagen fibers form the lesion within the dermis. Bland fibroblasts are seen between the laminae. Note that the overlying epidermis is thinned.

PLEOMORPHIC FIBROMA

Clinical Features

Pleomorphic fibroma is a rare dome-shaped or polypoid skin lesion occurring in adults of either sex on extremities, trunk, or face. Reported cases have been benign, with occurrence only of an incompletely excised example. A relationship with sclerotic fibroma has been postulated.¹⁰

Pathologic Features

This is a circumscribed lesion with sparse spindle cells in a collagenous stroma with scattered cells with enlarged irregularly shaped degeneratelooking nuclei, or multinucleated cells, and rarely mitoses (Fig. 4.3, e-Figs. 4.10 and 4.11). The stroma contains mast cells and occasionally foamy macrophages, and a myxoid variant has been described.¹¹

Ancillary Investigations

The lesional cells in some cases are positive for CD34 and CD99.

DERMATOMYOFIBROMA

Clinical Features

This is a dermal lesion that occurs mostly in young adult females and is mostly seen in the shoulder and axilla, with occasional lesions on the neck or trunk.¹² It forms a slowly growing ovoid erythematous plaque that can reach several centimeters in diameter or length. Multiple lesions have been described. The lesion is benign and does not usually recur after surgical excision.

FIGURE 4.3 Pleomorphic fibroma. Spindle cells with hyperchromatic enlarged nuclei are scattered between coarse collagen fibers. Occasional cells are multinucleated.