Fibrohistiocytic tumors

Solitary lesions most common in middle-aged adults

Multiple lesions in patients with tuberous sclerosis can be present at birth, but usually develop during childhood and are seen in about 90% of adult patients

Equal sex distribution

Solitary small, skin-colored, dome-shaped papule, rarely pedunculated

Predilection for the nose and face

Size from 1 to 5 mm

Multiple lesions associated with tuberous sclerosis (referred to as adenoma sebaceum ) typically develop over the nose and cheeks in a “butterfly” pattern, with bilateral and symmetrical, periungual proliferations known as Koenen tumors

No treatment generally required

Simple excision curative

Well-circumscribed proliferation in the superficial dermis composed of

• Plump, spindle-shaped, stellate and/or multinucleated cell fibroblasts

• Vascular channels, frequently dilated

• Sparse inflammatory cell infiltrate, mainly composed of lymphocytes

Sclerotic dermal collagen in the background

Mitoses of spindle cells exceptional

Focal nuclear hyperchromatism of spindle cells can be seen

Additional features include

• Perivascular and periadnexal fibrosis

• Scattered vellus hairs

• Lentiginous proliferation of melanocytes above the dermal lesion

• Epidermis with hyperkeratosis, acanthosis, and flattened rete ridges pattern

Histological variants

• Clear cell

• Hypercellular

  • Marked proliferation of fibroblasts in comparison to classical fibrous papule

• Pigmented

  • Hyperplasia of melanocytes, can be prominent

  • Dermal melanophages

• Pleomorphic

  • Bizarre-shaped fibroblasts in the papillary dermis

• Granular cell

• Inflammatory

  • Predominance of inflammatory cells

  • Admixture of lymphocytes, plasma cells, and histiocytes

  • Eosinophilic and neutrophilic granulocytes rare

• Epithelioid

  • Large cells, forming sheets and nests

  • Medium-sized centrally or peripherally located nuclei with prominent nucleoli

  • Prominent pink cytoplasm

Factor XIIIa positive, may also be CD34 positive

Clear cell variant can be NKIC3 and CD68 positive

Epithelioid cell variant diffusely procollagen positive, scattered CD68 positivity (70%), factor XIIIa negative

Consistently negative for cytokeratins, EMA, and S100 protein

Melanocytic lesions (intradermal melanocytic nevus, Spitz nevus, lentigo maligna, balloon cell nevus)

Epithelioid cell fibrous histiocytoma

Pleomorphic fibroma

Granular cell tumor

Dermal nonneural granular cell tumor

Female predominance (F:M = 3 : 1)

Middle-aged adult patients

Slowly growing single or multiple firm, red-brown to violaceous papules

Multiple lesions usually distributed over the same area, occasionally bilateral

Surface is usually smooth, occasionally scaly

Size less than 1 cm in diameter

Most common over distal extremities, particularly dorsum of hands, wrists, thighs, and legs, with less frequent involvement of the face and trunk

Mucosal sites distinctly uncommon (oral cavity)

Usually asymptomatic, pruritic lesions rare

Clinical variants

• Linear

• Eruptive

• Plaque-like

• Disseminated/generalized

Spontaneous regression possible, but rare

Association with mycosis fungoides, diabetes mellitus, or vitiligo most likely coincidental

Vascular proliferation, composed predominantly of thin-walled capillaries and veins

• Lumina dilated or narrow

• Lined by a single layer of bland endothelial cells

• Each vessel surrounded by layer of pericytes

Scattered multinucleated cells

• Bizarre shaped

• Hyperchromatic nuclei

• Angulated cytoplasm

Fibroblast-like and histiocyte-like mononuclear cells

Thickened collagen bundles, frequently hyalinized

Occasional inflammatory cells, predominantly lymphocytes

Hemorrhage absent, no hemosiderin deposition

Decreased elastic fibers in the dermis can be observed

Overlying epidermis normal, but can also be hyperplastic

Proliferation restricted to upper and middermis

Multinucleated cells display variable CD68 positivity

Vascular markers delineate endothelial cells

Atrophic dermatofibroma

Microvenular hemangioma

Angiofibroma

Kaposi sarcoma

One of the most common benign soft tissue proliferations in the skin

Broad age distribution, most common in middle-aged adults

Slight female predominance

Virtually any site of skin can be affected

Most commonly on the limbs (about 70%), followed by the trunk

Slowly growing, firm solitary nodule, round to oval

Overlying skin often reddish-brown to darkly pigmented and scaly

Size of the lesion is usually less than 10 mm

Central dimple formation on lateral compression or squeezing is a common clinical sign

History of previous trauma occasionally present

Clinical variants

• Giant variant, including plaquelike, measuring from 35 to 300 mm

• Eruptive variant, usually related to immunosuppression, HIV infection, and highly active antiretroviral therapy

Simple excision is curative

Recurrences after incomplete or marginal excision have been estimated to develop in less than 2% of cases

Lesions occurring on the face and certain morphological variants (cellular, aneurysmal, atypical) are associated with a higher recurrence rate (up to 26%)

Exceedingly rare metastases have been reported in particular variants of fibrous histiocytoma (cellular, aneurysmal, atypical); however, no histological features have been detected to predict metastatic potential

Epidermis above the lesion is usually hyperplastic

Elongation and broadening of rete ridges associated with hyperpigmentation of basal keratinocytes especially over the tips of rete ridges (so-called dirty fingers )

Proliferation of immature hair-follicle structures above the dermal proliferation is frequently seen and can mimic a basal cell carcinoma or an adnexal tumor

Papillary dermis is usually, but not always, spared (so-called grenz zone )

Defining histological features include

• Spindle cells growing in a haphazard, vague, storiform or short intersecting fascicular pattern

• Histiocytes in variable proportions, including multinucleated giant cells (Touton and foreign body type), siderophages, and foamy cells

• Inflammatory cells in variable proportions, usually lymphocytes

• Delicate collagenous or loosely myxoid stroma containing thin-walled blood vessels

Ill-defined nonencapsulated proliferation in the dermis/superficial subcutis

• Growth into subcutis usually in the form of short extensions

• Individual bundles of collagen surrounded by lesional cells, so-called collagen trapping, especially at the periphery of the lesion

Lesions restricted to subcutis or deeper structures rare

Several histological variants have been recognized, including cellular, epithelioid, aneurysmal, atypical (pseudosarcomatoid), lipidized (“ankle type”), clear cell, palisading, deep, signet ring cell, fibrous histiocytoma with osteoclast-like cells, cholesterolotic

Different variants can coexist within a single lesion

Although factor XIIIa is usually positive, it may just delineate a background population of dermal dendrocytes

See variants for additional immunohistochemical features

Gene fusions involving multiple protein kinase C–encoding genes ( PRKCA, PRKCB, or PRKCD ) with a variety of other genes have been documented

Prevalence and distribution of these fusions in the various subtypes of benign fibrous histiocytoma are not known, but they are only present in a subset

Nodular fasciitis

Dermatofibrosarcoma protuberans

Scar

Xanthoma

Xanthogranuloma

Melanocytic proliferations

Represents about 5% of benign fibrous histiocytomas

Approximately equal sex distribution, although slight male predominance observed in the initial publication

Wide age range, but most common in young to middle-aged adults (between 33 and 42 years)

Solitary asymptomatic nodule

Multifocal growth and familial occurrence in a single patient

Preoperative duration of the lesion variable (2 weeks to 2 years)

Upper limb/limb girdle followed by lower limb/limb girdle, head and neck, and trunk

Propensity for unusual sites, like face, ears, hands, and feet

Complete excision usually curative

Recurrence rate as high as 26% after incomplete/marginal excision

Locoregional (lymph nodes) and systemic metastases (lungs) in exceptional cases; no histological features have been detected to predict metastatic potential

Twο growth patterns recognized on low-power examination

• Nonexophytic and ill defined (more common)

• Exophytic and circumscribed

Defining features include

• Cellular proliferation of plump spindle cells with tapering nuclei containing small eosinophilic nucleoli and relatively abundant ill-defined, pale eosinophilic cytoplasm

• Short fascicular growth predominates over storiform growth pattern

• Foci of more epithelioid cells occasionally present and represent a minor component of the lesion

• Normal mitoses common (up to 10 mitoses per 10 high-power fields)

• Abnormal mitoses not present

• Focal necrosis (in up to 12%), generally not associated with surface ulceration

• Surface ulceration uncommon

Most frequently arise in superficial dermis and subsequently infiltrate the deep dermis, but mid dermal and deep dermal origin not uncommon

Extension into the subcutis present in roughly one-third of the cases

• Fascicular growth along the septa (perpendicular to the epidermis)

• Lacelike growth between the fat cells

Infiltration beyond subcutis into the underlying skeletal muscle rare, usually in the head and neck area, most likely due to the more superficial localization of skeletal muscles at this particular site

Areas of a classical benign fibrous histiocytoma consistently identified at least focally, usually at the periphery of the cellular proliferation

Smooth muscle actin–positivity in over 90%

Cytoplasmic desmin positivity in 32%

• Consistent with myofibroblastic differentiation

Genuine CD34 positivity in 6%

• Usually seen at the periphery of the lesion or in a patchy pattern

• Diffuse CD34 staining is an exception

Consistently negative for cytokeratins, S100 protein, and EMA

Factor XIIIa reveals nonneoplastic cells in the background

Atypical dermal smooth muscle tumor

Dermatofibrosarcoma protuberans

Represents less than 2% of fibrous histiocytomas

Develops most frequently in the fourth decade of life (mean age 37 years)

Shows female predominance, with male-to-female ratio of 1 : 1.5

Broad anatomical distribution with predilection for the lower limbs/limb girdle (55%), followed by upper limbs/limb girdle (17%), trunk (12%), and head and neck (4%)

Solitary papule of variegated color from dark brown to red or blue

Diameter of the lesion from 5 to 40 mm

Multiple lesions develop exceptionally

Rapid growth due to hemorrhage within the preexistent long-standing lesion is a common presenting symptom

Simple excision is usually curative

Recurrences after incomplete/marginal excision are common (up to 20%)

Metastatic disease exceptional; no histological features have been detected to predict metastatic potential

Epidermis overlying the lesion demonstrates variable degrees of acanthosis

Generally located in the dermis; extension into the subcutis not uncommon, but infiltration into the underlying skeletal muscle rare

The lesion can be ill defined

Defining features include blood-filled spaces ranging from slitlike to large cavities, similar to cavernous hemangioma

Blood-filled spaces

• Lack of endothelial lining

• Are lined by the lesional cells, including histiocytes, fibroblasts, and giant cells

• Are most frequently located within the most cellular parts of the lesion, usually central, which are devoid of collagen and elastic fibers

• Can represent the predominant component of the lesion

Surrounding stroma contains numerous small capillaries, prominent interstitial hemorrhage, and hemosiderin deposition

Classical histological features of benign fibrous histiocytoma can usually be recognized at the periphery of the lesion

Lesional cells can stain focally for smooth muscle actin

Factor XIIIa–positive and CD34-positive cells may represent reactive cells within the lesion

Lesional cells are consistently negative for desmin, CD34, CD31, CD68, and factor XIIIa

Angiomatoid fibrous histiocytoma

Spindle cell hemangioma

Nodular Kaposi sarcoma

Angiosarcoma

Most frequent in the fifth decade of life

Slight male predominance with M:F ratio of 1.4 : 1

Solitary lesion, multicentric growth exceptional

Slightly raised or polypoid, symmetrical

Reddish papule/nodule of 5 to 20 mm in diameter

Most frequent sites of origin are lower extremities (60%), followed by upper extremities (20%), trunk (10%), and head and neck (less than 10%)

Simple excision is curative

Nondestructive recurrences after incomplete excision are rare

Two patterns at low-power magnification

• Well-demarcated exophytic proliferation in the papillary and superficial reticular dermis (more common)

• Less circumscribed and frequently more cellular proliferation extending into deep dermis but also into the superficial fatty tissue

Epidermal collarette frequently surrounds the lesion and can extend along its base

Epidermis above the lesion hyperplastic, atrophic, or both

Tumor-free zone between the epidermis and dermis, typical of common fibrous histiocytoma, is generally lacking

Rounded or polygonal epithelioid cells with abundant eosinophilic cytoplasm containing round-to-oval vesicular nuclei with small eosinophilic nucleoli should represent at least 50% of the lesional cells

Mild nuclear pleomorphism

Variable proportions of binucleated or trinucleated cells scattered among epithelioid cells; multinucleated giant cells, however, are rare

Occasional regular mitoses (average 1 per 10 high-power fields)

Numerous small blood vessels dispersed among epithelioid cells are a constant feature. They can form a predominant component of the proliferation, thus mimicking a vascular lesion

Delicate collagenous stroma, hyalinized in older lesions

Myxoid change can be prominent and can even predominate

Adnexal structures usually not seen within the lesion

Typical histological features of benign fibrous histiocytoma are usually seen at least focally

Admixture of factor XIIIa–positive dendritic histiocytes and CD34-positive dermal fibroblasts

EMA positivity can be present in roughly two-thirds of cases and D2-40 positivity in about 50%

Consistently negative for low- and high-molecular-weight cytokeratins, S100 protein, smooth muscle actin, desmin, and CD31

ALK expression (usually cytoplasmic) reported in most cases

ALK rearrangements are present in most cases

PRKCA, PRKCB, and PRCKD rearrangements are seen in a subset of other benign fibrous histiocytoma subtypes

Clonality detected in a limited number of cases

Spitz nevus

Reticulohistiocytoma

Juvenile xanthogranuloma

Epithelioid perineurioma

Most frequently occurs in young to middle-aged adults in the fourth to fifth decade of life (mean age about 40 years)

Roughly equal gender distribution

Solitary non-painful nodule most common, polypoid lesion or a slightly raised plaque much rarer

Size of 4 to 80 mm in largest diameter (median 1.5 cm)

Lower limb/girdle (44%), followed by upper limb/girdle (32%), and trunk (11%), few cases in the head and neck area and genital region

Complete excision usually curative

Incomplete/marginal excision associated with recurrences in up to 14%

Two patients from the largest series developed distant metastases, one of whom died due to metastatic disease

No histological features have been detected to predict metastatic potential

Pleomorphic cells represent the hallmark of the lesion

• Spindle (fibroblast-like) and polygonal/epithelioid (histiocyte-like) pleomorphic cells in variable proportions, admixed with multinucleated giant cells

• Nuclei are irregular, large, hyperchromatic; bizarre-shaped forms not uncommon

• Nucleoli prominent

• Cytoplasm abundant, eosinophilic with indistinct borders, occasionally contains hemosiderin

• Frequent regular mitoses (1–15 per 10 high-power fields [HPF], mean 3.4 per 10 HPF), atypical forms can also be observed

• Pleomorphism varies from mild to moderate to severe and can be focal or diffuse

Geographical necrosis, usually found in lesions with moderate/marked degree of pleomorphism

Large areas of central collagen degeneration, surrounded by lesional cells, reminiscent of necrobiotic granuloma

Mainly localized in the dermis, but focal and superficial extension in the subcutis present in about one-third of the cases

Background proliferation

• Ordinary fibrous histiocytoma in 100% of the cases

  • Proliferation of spindle cells and histiocyte-like cells in a vague storiform pattern with collagen trapping

  • Usually found at the periphery of pleomorphic component

  • Represents an important clue for correct recognition of the proliferation

• Aneurysmal fibrous histiocytoma in roughly 25% of the cases

Epidermis can be hyperplastic with elongated rete ridges pattern

Focal positivity for smooth muscle actin and CD34 in limited number of cases

Consistently negative for S100 protein, low- and high-molecular-weight cytokeratins, desmin, CD68, and EMA

Pleomorphic fibroma

Dermatofibrosarcoma protuberans

Atypical fibroxanthoma

Spindle cell squamous cell carcinoma

Melanoma

Atypical intradermal smooth muscle neoplasm

Leiomyosarcoma

Similar age distribution as a common benign fibrous histiocytoma (median age about 50 years)

Male predominance (M:F = 2.7 : 1)

Solitary polypoid, yellow papule or nodule

Initial study demonstrated predilection for lower extremities, particularly around the ankle, hence connotation “ankle-type”; however, subsequent study demonstrated similar site distribution to classical fibrous histiocytoma

Larger size than classical fibrous histiocytoma (median size 2.5 cm)

Not associated with elevated serum lipid levels