‘Adenoma sebaceum’ is the misnomer (there is no adenomatous proliferation of sebaceous glands as the name implies) used for the angiofibromatous lesions found in most patients with tuberous sclerosis (OMIM 191100), an autosomal dominant neurocutaneous syndrome in which learning disability and epilepsy are often present.^{40. and 41.} Major reviews of the tuberous sclerosis complex have been published in recent years.^{42. and 43.} Other organ systems are often involved.^{42.44. and 45.} Other cutaneous angiofibromatous lesions may accompany adenoma sebaceum, and these include plaque-like lesions of the forehead and scalp and ungual fibromas (seeacral fibrokeratomas on p. 812).^{46.47. and 48.} ‘Shagreen patches’, with the histology of connective tissue nevi, are commonly found in tuberous sclerosis. ⁴⁹ They are usually present by puberty. ⁵⁰ Hypopigmented macules are a common finding. ⁵¹ Molluscum pendulum is less common. ⁵² Oral fibromas, mostly gingival in location, and dental pits are common findings in the mouth. ⁵³ Genetic linkage studies initially indicated that about half of all families with tuberous sclerosis showed linkage to chromosome 9q34 (TSC1), and the remainder to chromosome 16p13 (TSC2).^{54. and 55.} Subsequent studies have shown that TSC1 mutations account for only 10–30% of the families identified with tuberous sclerosis complex. In sporadic cases, there is an even greater excess of mutations in TSC2. This latter group is usually associated with more severe disease. ⁴² No identifiable mutations can be found in 15–20% of patients meeting the clinical criteria of tuberous sclerosis. ⁴² Hamartin is encoded by TSC1 and tuberin, a tumor suppressor, by TSC2. There is a wide spectrum of mutations. More than 200 TSC1 and nearly 700 TSC2 unique allelic variants have been reported. ⁴² Approximately two-thirds of all cases are sporadic and assumed to result from new mutations, many of which are in TSC2. ⁵⁶ Other cases are inherited as an autosomal dominant trait. Mutation screening in tuberous sclerosis is labor intensive and expensive. ⁵⁷ It is now available commercially. Prenatal or preimplantation genetic testing is becoming more widely available. ⁴²

Adenoma sebaceum consists of several or multiple papules and nodules, sometimes grouped, with a predilection for the butterfly area of the face, particularly the nasolabial groove.44. ^{and 46.} They appear in early childhood as pink-red to yellow-brown lesions and their growth is usually progressive until adult life. A giant angiofibromatous plaque and a cluster growth of large nodules⁵⁸ have been reported. Unilateral facial involvement is another clinical variant. ⁵⁹ It probably represents mosaicism.^{60.61.62.63. and 64.}

Facial angiofibromas in tuberous sclerosis have been treated with a scanning carbon dioxide laser. ⁶⁵ The benefits of therapy should be weighed against both early morbidity and the risks of long-term complications such as scarring and hypopigmentation. ⁶⁵ Erbium lasers have also been used. Clinical trials using sirolimus (rapamycin), an mTOR inhibitor have shown promise.^{43. and 66.} mTOR has a central role in the control of cell growth and proliferation.^{67. and 68.} Its activation is influenced by heterodimers of TSC1 and TSC2. ⁴² It has been suggested that long-term therapy with sirolimus may increase the risk of malignant tumors in these patients. ⁴² The finding of increased levels of certain matrix metalloproteinases (MMPs) in lesional skin raises the possibility of antiprotease treatments in the future, or the use of retinoids, which inhibit the production of MMPs. ⁶⁹

Facial angiofibromas, both unilateral and bilateral, have already been mentioned as an important manifestation of tuberous sclerosis (see above). They have also been described in a patient with neurofibromatosis 2 (NF-2 – OMIM 101000) as a cluster of small papules on the ear. ⁷⁸ Multiple facial angiofibromas are seen quite often in patients with multiple endocrine neoplasia (MEN) type 1 (OMIM 131100). ⁷⁹ They tend to present in adult life. ⁸⁰ Other cutaneous tumors in this syndrome include collagenomas and lipomas. ⁸¹ There may also be café-au-lait macules and confetti-like hypopigmented macules. ⁸² The tumors show allelic deletion of the MEN1 gene. It encodes a protein called menin, which is presumed to act as a tumor suppressor. Basic fibroblast growth factor (BFGF) is elevated in many patients and may be responsible for the formation of the cutaneous tumors. ⁸⁰

Angiofibromas (often reported as perifollicular fibromas) have been reported in the Hornstein–Knickenberg syndrome, which appears to be a slightly different phenotypic expression of the Birt–Hogg–Dubé syndrome (see p. 771). Multiple facial angiofibromas have also been reported in the Birt–Hogg–Dubé syndrome (OMIM 135150). ⁸³

Multiple eruptive angiofibromas of the trunk have been reported in the absence of any underlying disease state. ⁸⁴ Unilateral facial angiofibromas were present in a teenage male, with no signs of a systemic syndrome. ⁸⁵

Fibrous papules of the face are usually solitary, dome-shaped papules, measuring 3–5 mm in diameter, found particularly on the nose of middle-aged adults.^{32.86. and 87.} They are flesh colored and usually asymptomatic, although some may bleed after minor trauma. They were originally regarded as fibrosed dermal nevi,^{86.87. and 88.} a proposition which has been disproved by electron microscopy^{89. and 90.} and immunohistochemistry.^{91.92. and 93.} The presence of factor XIIIa in the spindle cells and in some stellate cells suggests that fibrous papule is a proliferative reactive process consisting mainly of dermal dendritic cells.92. ^{and 93.}

Pearly penile papules are persistent asymptomatic pearly-white papules, 1–3 mm in diameter, occurring in groups or rows on the coronal margin and sulcus of the penis.^{31.104.105.106. and 107.} Rarely they may be found on the penile shaft¹⁰⁸ or glans. ¹⁰⁹ They are found in 10–30% of young adult males, and are more common in black people, and in the uncircumcised.^{105. and 110.} They may be misdiagnosed as warts, ¹⁰⁶ but there is no causative role for HPV in their genesis. ¹¹¹

Treatment with cryotherapy has been effective in some studies, but not in all. ¹¹⁰ Carbon dioxide laser has also proved effective. ¹¹⁰

Included in the acral fibrokeratoma group¹¹² are lesions reported as acquired digital fibrokeratoma,^{113.114.115. and 116.} acquired periungual fibrokeratoma, ‘garlic clove fibroma’, ¹¹⁷ and the subungual and periungual fibromas of tuberous sclerosis. ⁴⁶ This unifying concept is an attempt to overcome the needless proliferation of terms, and it gives recognition not only to the common histopathological features, but also to the fact that occasional lesions have been reported in sites other than digits. ¹¹⁸

The lesions are usually solitary, dome-shaped or elongated thin horns, 1–3 mm in diameter and up to 15 mm in height. ⁴⁸ A giant variant measuring almost 4 cm in diameter has been reported. ¹¹⁹ There is sometimes a history of trauma. ¹¹⁴ The ungual fibromas of tuberous sclerosis are often multiple, sometimes in clusters, and develop at about puberty. ¹²⁰ They are found in about half the patients with tuberous sclerosis.^{41. and 46.}

Some fibrokeratomas originate from the dermal connective tissue, whereas others appear to originate from the proximal nail fold. ¹²¹ An invaginated variant has been reported in relation to the nail apparatus. ¹²² This difference in the site of origin may account for the heterogeneous features observed in this entity.

Multiple acral fibromas with a myxoid but poorly vascularized stroma have been reported in a patient with familial retinoblastoma, leading to the suggestion that multiple acral benign tumors with a fibrous component might be a cutaneous marker of tumor suppressor gene germline mutation. ¹²³ Lesions reported as familial multiple acral mucinous fibrokeratomas¹²⁴ and familial myxovascular fibroma (see below) are probably further examples of this hypothesis.

Three kindreds have been reported in which multiple verrucous papules developed on the fingers and hands.^{124.129. and 130.} On histological examination the papules showed a fibrovascular proliferation of the papillary dermis, with variable myxoid change and overlying epidermal acanthosis and hyperkeratosis. There is some overlap with the lesions included within the concept of cutaneous myxomas (see p. 844).

Skin tags (soft fibromas, acrochordons, fibrolipomas, fibroepithelial polyps) are common cutaneous lesions that have received little attention in the dermatological literature, because hitherto they have been regarded as being of little consequence. However, there have been several reports suggesting an association between the presence of skin tags and underlying diabetes,^{160.161.162.163. and 164.} abnormal lipid profile, ¹⁶⁵ colonic polyps,^{166.167.168. and 169.} or acromegaly. ¹⁷⁰ The association with colonic polyps is controversial, and several studies have failed to confirm its existence.^{171.172. and 173.} HPV types 6/11 were detected in a significant number of cases in one study. ¹⁷⁴ This finding remains to be confirmed.

Skin tags have a predilection for the axilla, neck, groin, eyelids and beneath pendulous breasts. They are more common in obese females, and they may develop in pregnancy. ¹⁷⁵ In one autopsy study they were present in 64% of individuals over the age of 50, ¹⁷¹ whereas in a more recent study they were present in 46% of 750 individuals examined. ¹⁷⁶ There are three clinical types: ¹⁷¹ furrowed papules approximately 2 mm in width and height; filiform lesions, approximately 2 mm in width and 5 mm in height; and large bag-like protuberances, usually on the lower trunk.^{177. and 178.} These larger lesions are very occasionally multiple.^{160. and 179.} The term fibroepithelial polyp is sometimes used for this latter variant. Experimentally, these polyps show down-regulation or loss of tuberin and/or hamartin expression which may promote collagen formation, leading to their formation and growth. ¹⁸⁰

Vestibular papillae of the vulva are skin tag-like smooth projections of the vestibular mucosa that appear to be normal anatomical variants.^{181. and 182.} They are not related to human papillomavirus infection, as previously suggested.^{181. and 183.}

Fibroepithelial polyps of the anus are relatively common lesions, some of which are thought to arise from enlargement of anal papillae. ¹⁸⁴ They should be distinguished from the much smaller infantile perianal (perineal) pyramidal protrusion which occurs predominantly in young girls in the midline, anterior to the anus.^{185.186. and 187.} Sometimes they are posterior to the anus. ¹⁸⁸ Underlying constipation and anal fissures are often present. ¹⁸⁸ A variant associated with lichen sclerosus may also occur.^{188. and 189.} They are edematous, flesh-colored, sessile protrusions measuring 1–2 cm in length. They should not be mistaken for condylomas. ¹⁹⁰ One case has been successfully treated with topical steroid applications. ¹⁹¹

The lymphedematous fibroepithelial polyp of the penis is a rare polyp of the glans penis or prepuce associated with long-term condom catheter use. ¹⁹² On rare occasions it has been associated with chronic phimosis. ¹⁹³ The lesions are gray-white polyps measuring 2–7.5 cm in diameter. ¹⁹² The majority of lesions affect the ventral surface of the glans near the urethral meatus. It has been postulated that the lesions represent a reactive hyperplastic process involving the subepithelial stroma. ¹⁹³ A related lesion is the polyp of the glans penis that developed in a man who practiced genital hanging kung fu. ¹⁹⁴

Prepubertal vulval fibroma was the term used by Iwasa and Fletcher in 2004 for a hitherto unrecognized mesenchymal tumor of the vulva in 11 prepubertal girls. ²⁰⁴ They regarded them as tumors on the basis of recurrences in several cases after excision. The following year, Vargas and colleagues reported 14 cases, also from Boston, of a similar lesion that presented with enlargement of one, or occasionally both labia majora. On the basis of its occurrence at an age roughly coincident with the time of breast budding, its capacity for spontaneous regression, and its composition of elements native to the vulva, the authors concluded that the entity represented an asymmetric physiological enlargement in response to hormonal surges of pre- and early puberty. ²⁰⁵

The girls were aged 4 to 13 years. The lesions were ill-defined and consisted of fibro-fatty tissue ranging in size from 2 to 8 cm in greatest dimension.^{204. and 205.} As already mentioned, several cases recurred after initial excision.

Gardner fibroma is a benign lesion of the superficial and deep soft tissues with a predilection for childhood and adolescence and an association with familial adenomatous polyposis and desmoid fibromatosis.^{156. and 206.} Sporadic cases also occur. The majority of cases involve the back and paraspinal region, followed by the head and neck, and the extremities. Almost 20% of patients have concurrent or subsequent desmoid tumors. ²⁰⁶ There is a strong association with familial adenomatous polyposis or adenomatous polyposis coli, but the proportion of sporadic cases that have the APC mutation remains to be elucidated. ²⁰⁶

There are some overlap features with nuchal fibroma (see p. 320) but the predilection of nuchal fibroma for middle-aged males, its location on the posterior neck, and its association in some patients with diabetes mellitus, but not familial adenomatous polyposis, usually allows a distinction to be made.

Pleomorphic fibroma of the skin was described by Kamino et al in 1989. ²⁰⁷ It presents as a slow-growing lesion, clinically indistinguishable from a polypoid skin tag. ²⁰⁸ A subungual lesion has been reported.^{209. and 210.}

Sclerotic (‘plywood’) fibroma is an uncommon fibrocytic neoplasm that occurs sporadically as a solitary lesion, and in a multifocal form in patients with Cowden’s disease.^{215.216.217.218. and 219.} A solitary lesion may be the presenting feature of this syndrome. ²²⁰ The terms ‘hypocellular fibroma’ and ‘circumscribed, storiform collagenoma’²²¹ have also been used for this entity. The lesions are flesh-colored papules or nodules measuring 0.5–3 cm in diameter. Sporadic cases, unassociated with Cowden’s disease, have been reported in the oral mucosa.222.^{223. and 224.}

Although it was initially regarded as an involutional lesion, one study has demonstrated ongoing type I collagen synthesis and deposition, suggesting that the lesion is a proliferating neoplasm.^{217. and 225.} Local recurrence has been reported. ²²⁶

Collagenous fibroma, a recently described tumor, may arise in the subcutaneous tissue or muscle.^{242. and 243.} Dermal involvement is rare.^{244. and 245.} The tumors are firm and non-tender. Most measure 2–3 cm in diameter but larger lesions have been reported. ²⁴⁶ There is a predilection for adult males. ²⁴⁷ Any part of the body may be involved. ²⁴⁷

Few cases have been subject to cytogenetic analysis. It appears that a specific breakpoint of 11q12 occurs, combined in several cases with a reciprocal translocation. ²⁴⁸

Surgery is the treatment of choice with no reports of recurrence. ²⁴⁸

Knuckle pads (discrete keratodermas over the knuckle and finger articulations) are well-formed skin-colored nodules overlying the interphalangeal and metacarpophalangeal joints of the hands.^{250.251. and 252.} They are usually multiple. There are several clinical variants, including a familial group, an occupational or recreational-related group, and an acquired idiopathic group. They have followed the prolonged playing of video games. ²⁵³ An association with knuckle cracking and with pseudoxanthoma elasticum has been reported.^{254. and 255.} Of historical interest is the prominent knuckle pad on the right thumb of Michelangelo’s statue of David. ²⁵⁶

Inherited knuckle pads of the feet have been described in association with leukonychia and deafness, with and without keratosis palmoplantaris. They have also been associated with acrokeratoelastoidosis. ²⁵⁷ They are well-defined plaques on the dorsal aspect of the feet. Acquired lesions of the feet have been associated with repetitive friction from athletic gear. ²⁵⁷

Pachydermodactyly is characterized by fibrous thickening of the lateral aspects of the proximal interphalangeal joints of the fingers, usually in males.^{259.260.261.262.263. and 264.} The thumbs and fifth fingers are usually not involved. More extensive lesions have been reported.^{262.265. and 266.} It has been reported in two siblings. ²⁶⁷

Pachydermodactyly is regarded as a localized form of superficial fibromatosis. Trauma, such as finger rubbing, has been implicated in the etiology.^{268. and 269.} It has also been suggested that this entity might be related to knuckle pads (see above). ²⁷⁰

Nodular fasciitis is a reactive proliferation of myofibroblasts with a predilection for the subcutaneous tissues of the forearm, upper arm, and thigh of young and middle-aged adults.^{272. and 273.} Dermal and intravascular variants have been reported.^{274.275.276.277.278. and 279.} It usually grows quite quickly to reach a median diameter of 1.5 cm. Multiple lesions have been reported. ²⁸⁰ Recurrences are rare, even after incomplete surgical removal, and their occurrence should lead to a reappraisal of the original histological diagnosis.^{281. and 282.} The diagnosis can usually be made readily by fine needle aspiration. ²⁸³ Regression of the lesion has followed this procedure. ²⁷⁹ Regression may also occur after the use of intralesional corticosteroids. ²⁸⁴ Despite having high activity for proliferating cell nuclear antigen (PCNA), the cells do not express p53 or show aneuploidy.^{285. and 286.} It is polyclonal and a reactive process. ²⁸⁷

Cranial fasciitis of childhood is a distinct clinical variant arising in the deep soft tissues of the scalp, with involvement of the underlying cranium.^{288.289. and 290.} Conservative surgical excision is curative.^{291. and 292.} Intralesional corticosteroids were used in one case with a successful outcome. ²⁹³

Atypical decubital fibroplasia (ischemic fasciitis) is a pseudosarcomatous proliferation, found in immobilized or debilitated patients, which is different from decubitus ulcers. ³¹⁰ The affected area measures 1–9 cm in diameter. It involves the shoulders, ribs, sacrococcygeal region, and the tissues overlying the greater trochanter. There is involvement of the deep dermis, subcutis, and deep fascia with a zonal arrangement of fibrinoid necrosis, reactive fibrosis, neovascularization, fat necrosis, and ectatic vessels.^{310. and 311.} Atypical fibroblasts are usually present.

A recent study of 44 cases by Liegl and Fletcher found there was an inconsistent association with immobility or debilitation. ³¹¹

Postoperative spindle-cell nodule is a rare lesion that develops soon after a surgical procedure in genital skin or the genitourinary system. ³¹² Lesions have now been reported at other sites. ³¹³ It is composed of spindle-shaped cells in a pattern of interlacing fascicles. There are occasional mitotic cells. The cells express vimentin; desmin and muscle-specific actin have been present in some cases. ³¹² They do not express keratin. ³¹³

Solitary fibrous tumor is a rare mesenchymal tumor that most commonly involves the pleura. It has been reported in many other sites, including the skin.^{314.315.316.317. and 318.} It presents as a circumscribed nodule, often mistaken for a cyst. Most cases have been on the head and neck. ³¹⁹ Cases have also been reported in the vagina.^{320. and 321.} Although 10–20% of lesions in other organs have been malignant,^{322.323.324. and 325.} all cutaneous tumors reported so far have behaved in a benign fashion. ³¹⁴

The tumor cells are predominantly fibroblastic although focal myofibroblastic differentiation is often seen. ³¹⁴ This tumor was originally included with the hemangiopericytomas. ³²⁶ No consistent (cyto)genetic alterations have been documented to date. ³²⁴

Treatment of cutaneous cases is surgical excision of the lesion.

Fibrous hamartoma of infancy is an uncommon fibroproliferative lesion of the subcutaneous tissue that is present at birth or develops in the first 2 years of life.^{333.334.335.336. and 337.} It most commonly occurs around the shoulder, axilla, and upper arms, but cases involving the scalp, ³³⁸ inguinal region, scrotum, ³³⁹ perianal area, ³⁴⁰ and lower extremities^{341. and 342.} have been reported. There is a male predominance of 3 : 1. ³³⁴ The clinical course is benign, despite its infiltrative appearance and tendency to local recurrence. ³³⁵ It has been reported in an infant with Williams’ syndrome (see p. 348). ³⁴³ A reciprocal translocation [t(2;3)(q31;q21)] was present in one case. ³⁴⁴

The subcutaneous tissue of excised lesions has a glistening gray-white appearance interspersed with fatty tissue. The involved area measures 2–8 cm in maximum diameter.

This tumor should be treated by complete excision; an aggressive approach should be avoided, as the overall prognosis is excellent. ³⁴⁵

Digital fibromatosis of childhood (infantile digital fibromatosis,^{353. and 354.} recurring digital fibrous tumor of childhood, ³⁵⁵ inclusion body fibromatosis³⁵⁶) is a rare benign tumor of myofibroblasts with characteristic cytoplasmic inclusion bodies. ³³⁶ It presents as a dome-shaped firm nodule, up to 1 cm in diameter, usually on the digits.^{357. and 358.} The thumbs and great toes are spared. ³⁵⁹ Lesions are usually solitary, but a second tumor is sometimes noted at the time of presentation, or develops subsequently. ³⁵⁷ The tumors may be present at birth, or appear in the first year of life.^{360. and 361.} Onset in late childhood or adult life is rare.^{356.362. and 363.} A history of preceding trauma has been reported. ³⁶⁴ There is a rare syndrome consisting of recurrent digital fibroma, focal dermal hypoplasia, and limb malformations. ³⁶⁵

A viral etiology was originally suspected because of the characteristic inclusion bodies, but all cultures have been negative, excluding this hypothesis.^{366.367. and 368.} The inclusions are now known to be filamentous aggregations composed largely of actin.^{369. and 370.}

The tumor often recurs after local excision; very occasionally it may regress spontaneously, but this may be accompanied by functional impairment.^{371.372. and 373.} Spontaneous regression increases after long-term follow-up, casting some doubt on the benefits of surgical excision with its high (up to 60%) recurrence rate. ³⁷⁴ Intralesional fluorouracil has also proven effective in the treatment of this entity. ³⁷³

Fewer than 10 cases of angiofibroblastoma have been described.^{381. and 382.} It presents as a solitary dermal nodule on the extremities. ³⁸² It consists of stellate and spindle-shaped cells, with the phenotype of fibroblasts, embedded in a fibromyxoid to dense fibrous stroma. Numerous capillary-sized vessels, often in small groups, are scattered throughout the stroma. Staining for HHF35 is focal and pale. A small population of dendritic cells within the tumor express factor XIIIa. All other spindle-cell markers are negative. ³⁸² It needs to be distinguished from other fibromyxoid tumors of the skin.

Surgical excision has been curative. ³⁸²

Angiomyofibroblastoma is a rare tumor of the vulva that may be confused with aggressive angiomyxoma of the pelvic soft tissues and vulval region, which appears to be a related tumor.^{383.384.385.386.387.388.389. and 390.} Angiomyxoma will not be considered further, although rare superficial tumors have been described. ³⁹¹

The morphologically similar lesion described in the male genital tract by Laskin et al as having features of both angiomyofibroblastoma and spindle-cell lipoma has now been reclassified as cellular angiofibroma (see below). Angiomyofibroblastoma is often misdiagnosed clinically as a Bartholin’s cyst. ³⁹² The tumors are well circumscribed, measuring 0.5–12 cm in diameter. They do not recur if completely excised. Sarcomatous transformation has been reported. ³⁹³

Cellular angiofibroma is a recently described benign mesenchymal tumor, usually of the genital region, with some histological resemblance to angiomyofibroblastoma and spindle-cell lipoma. ³⁹⁷ It has an equal sex incidence. It occurs predominantly in middle-aged and slightly older individuals. The majority occur in the vulvovaginal region,^{398. and 399.} and the inguinoscrotal region. ⁴⁰⁰ Most cases present as a painless mass that measures 0.5–25 cm in diameter. Lesions tend to be larger in males than in females. ³⁹⁷ Recurrences are rare even in cases excised with positive margins.

Two cases with deletions of the FOX1A1/13q14 region have been reported. ⁴⁰¹ A similar finding is seen in some spindle-cell lipomas and in (extra)mammary myofibroblastoma. ⁴⁰¹

Dermatomyofibroma is a benign tumor of fibroblasts and myofibroblasts first reported by Hügel in 1991. ⁴⁰⁴ It has a predilection for the shoulder girdle, axilla, and abdomen of young adults.^{405. and 406.} There is a female predominance. Cases in young males have a predilection for the posterior neck.^{407. and 408.} The lesions present as firm red-brown plaques or nodules, 1–2 cm in diameter; they may resemble a keloid. ⁴⁰⁹ A hemorrhagic form has been reported. ⁴¹⁰ Linear and giant annular variants occur.^{411. and 412.} A similar lesion has been reported under the term ‘myoid fibroma’.^{413. and 414.}

Conservative surgical excision is usually carried out. There is no tendency to local recurrence. ⁴¹⁵

The entity of infantile myofibromatosis, which is regarded as a proliferative disorder of myofibroblasts, was established by Chung and Enzinger in 1981, with their report of 61 cases. ⁴¹⁹ Previous reports had appeared under several designations including congenital fibrosarcoma, ⁴²⁰ congenital generalized fibromatosis,^{346.421. and 422.} and congenital mesenchymal hamartoma. ⁴²³ Fletcher and colleagues have suggested that the spindle-cell component shows true smooth muscle differentiation rather than being of a myofibroblastic nature. ⁴²⁴ Requena et al have suggested an origin from myopericytes. ⁴²⁵ More recently, Fletcher and colleagues have described a spectrum of tumors showing perivascular myoid differentiation, which included adult cases of myofibromatosis (myofibroma). ⁴²⁶

The lesions are solitary in approximately 70% of cases.^{419. and 427.} Almost half of these are situated in the deep soft tissues, and the remainder are located in the skin and/or subcutaneous tissue.^{336. and 428.} The head, neck, and trunk are the usual sites of involvement.^{419. and 427.} The finger is an uncommon site. ⁴²⁹ There is a male predominance. Most lesions are present at birth, ⁴³⁰ or appear in the first 2 years of life; onset in adult life has been recorded.^{431. and 432.} The term ‘cutaneous myofibroma’ would seem to be an appropriate designation for the solitary lesions occurring in adults.^{433.434.435. and 436.} Multiple acral myofibromas have been reported in a patient with generalized morphea. ⁴³⁷

In approximately 30% of cases the lesions are multicentric (congenital generalized fibromatosis, OMIM 228550) and involve the skin, soft tissues, bones and, uncommonly, the viscera.^{419.438. and 439.} They are usually present at birth, and there is a female predominance. Spontaneous regression of soft tissue and osseous lesions sometimes occurs,^{419.440.441.442. and 443.} but cases with visceral involvement are usually fatal.^{419.427. and 444.} Cases with systemic involvement and a favorable outcome have been reported. ⁴⁴⁵ The various clinical types of myofibromatosis are shown in Table 34.1. Recurrence after a long period of quiescence has been documented. ⁴⁴⁶ Central nervous system abnormalities were present in one case. ⁴⁴⁷ Both autosomal recessive⁴⁴⁸ and dominant inheritance with reduced penetrance have been proposed.^{446.449. and 450.}

Macroscopically, the tumors measure 0.5–7 cm or more in diameter. They are grayish-white in color, and fibrous in consistency.

The plaque-like myofibroblastic tumor of infancy is an exceedingly rare tumor that presents in the first few months of life. ⁴⁵¹ Histologically it resembles a dermatofibroma, the diagnosis given by the author to a similar case, seen some years ago.

The prognosis is excellent, with recurrence unlikely after excision; aggressive variants are rare. ⁴⁵² The complex regional pain syndrome has followed the surgical excision of a solitary adult myofibroma. ⁴⁵³ There is increasing evidence that adult myofibromas show overlapping features with the myopericytoma, a tumor derived from pericytes/perivascular myoid cells. This aspect is considered further below (see p. 823).

‘Perivascular myoma’ is the suggested designation by Granter, Badizadegan, and Fletcher for a histological continuum of three lesional groups of tumor – myofibromatosis in adults, glomangiopericytoma, and myopericytoma – showing perivascular myoid differentiation. ⁴²⁶ Hemangiopericytoma is another category of perivascular tumors, but its existence has been questioned as several other lesions may have a similar growth pattern. ³⁶² Perivascular myomas have been reported in patients of all ages, with a predilection for the subcutis and superficial soft tissues of the extremities. ⁴²⁶ Some lesions are multifocal. This group of perivascular tumors has been further expanded in recent years by the addition of three further entities:

It seems that these tumors are derived from a perivascular cell with different immunohistochemical and morphological features to the perivascular myoma and the glomus tumor. They will be considered next.

Inflammatory myofibroblastic tumor, also known as inflammatory fibrosarcoma, occurs predominantly in the lungs and mesentery, although the soft tissues of the head and neck, or the extremities, may be involved.^{480.481. and 482.} The mean age at presentation is 13 years. ⁴⁸¹ Systemic symptoms are often present. It appears to represent a spectrum of myofibroblastic proliferations, some of which have been included in the past as inflammatory pseudotumor, a heterogeneous ‘entity’.^{24.483.484. and 485.} Helmut Kerl and colleagues believe that inflammatory pseudotumor includes tumors with detectable myofibroblasts that represent inflammatory myofibroblastic tumor and a group best called plasma cell granuloma, that represents a reaction pattern found in disorders, such as spirochete-induced fibroid nodules and localized chronic fibrosing vasculitis.^{484.486. and 487.} HHV-8 specific DNA has been detected in one cutaneous case. ⁴⁸⁸

This tumor has a potential for recurrence and persistent local growth. ⁴⁸⁹ Metastases have been recorded but no reliable morphological parameters have been identified that predict prognosis.^{480. and 490.} A recent report of 59 cases by Coffin, Hornick, and Fletcher noted that metastases were confined to ALK-negative cases. ⁴⁸¹ Approximately 50% of cases recurred locally. ⁴⁸¹ It has been suggested that inflammatory myofibroblastic tumor and inflammatory fibrosarcoma are synonymous or closely related entities. ⁴⁹¹ They have been regarded as synonymous here. Recently it has been suggested that this tumor is derived from fibroblastic reticulum cells (myoid cells), and not from myofibroblasts. ⁴⁹²

The neoplastic nature of this lesion has been confirmed by the finding of recurrent clonal aberrations involving chromosome 2p23 similar to the ones found in anaplastic large cell lymphoma. ³⁹⁶ The fusion genes found are ALK-TPM4 and TPM3-ALK. ¹⁵⁹ Approximately 50–70% of all tumors harbor ALK gene rearrangements. ⁴⁸¹

Surgery remains the preferred treatment option for this tumor. Re-excision can be effective in managing recurrences. ⁴⁸¹ Adjunctive therapy such as radiation and chemotherapy have been used, but there have been insufficient cases for meaningful analysis. ⁴⁸¹ Steroids and NSAIDS have also been used. The use of imatinib has been reported to be effective. The development of kinase inhibitors of ALK is awaited.

There has been one report of a benign fibroblastic tumor, with a myxoid matrix, that does not fit into one of the recognized entities. ⁴⁹⁶ The well-circumscribed tumor was confined to the dermis and composed of stellate and spindle-shaped cells arranged loosely in a fascicular pattern resembling ‘tissue cultures of fibroblasts’. There was abundant stromal mucin. The cells expressed vimentin only and had the ultrastructural characteristics of fibroblasts. ⁴⁹⁶ A further case has since been reported. ⁴⁹⁷ It was on the nose of a 27-year-old woman. ⁴⁹⁷

Low-grade fibromyxoid sarcoma is a rare tumor characterized by bland histological features and a paradoxically aggressive clinical course.^{498.499.500.501. and 502.} The hyalinizing spindle-cell tumor with giant rosettes (low-grade fibrosarcoma with palisaded granuloma-like bodies) is a variant of low-grade fibromyxoid sarcoma.^{502.503. and 504.} They share the same cytogenetic abnormality (see below). ⁵⁰⁵ Low-grade fibromyxoid sarcoma has a tendency to develop in the deep soft tissues of young adults, whereas the myxofibrosarcoma occurs in older patients. ⁵⁰⁶ A variant of low-grade fibromyxoid sarcoma occurring in the superficial soft tissues has been described. It appears to affect children at a higher rate than the usual deep variant; its prognosis is also better than the deep tumors. ⁵⁰⁷ Local recurrence is common; distant metastasis, particularly to the lungs, occurs in up to 50% of cases.

The majority of low-grade fibromyxoid sarcomas bear either the t(7,16)(q32–34;p11) or t(11,16)(p11;p11) translocations, resulting in FUS-CREB3L2 or FUS-CREB3L1 fusions, respectively. ⁵⁰⁴ The former translocation is the more common. ⁵⁰⁴

The immunophenotype and ultrastructure suggest a fibroblastic tumor possibly with focal myofibroblastic differentiation. A recent study suggested a relationship to sclerosing epithelioid fibrosarcoma. ⁵⁰⁴

Formerly regarded as a myxoid variant of malignant fibrous histiocytoma (MFH), myxofibrosarcoma is now considered to be a distinct entity on the basis of its reproducible cytoarchitecture and consistent clinicopathological characteristics.^{509.510.511. and 512.} Myxofibrosarcoma is one of the most common fibroblastic sarcomas of older individuals.^{513.514.515. and 516.} It is often located in the subcutaneous tissue of the limbs. Dermal involvement has also been reported but in such cases the bulk of the tumor is usually in the subcutis in the form of ill-defined nodules.^{517. and 518.}

Myxofibrosarcoma is believed to be derived from fibroblasts. A large number of immature dendritic cells are present in the stroma. ⁵¹⁹ The tumor is characterized by complex chromosomal aberrations, none of which is specific for this entity. ⁵¹¹

Treatment is wide surgical excision, with at least a 2 cm clearance. Radiotherapy has also been used for cases with infiltrative morphology, although there is no evidence that this is of any value. ⁵¹⁷ Superficial tumors less than 5 cm in diameter have an excellent prognosis while disease-specific mortality rates are significantly related to tumor necrosis, large size (>5 cm in diameter), and decreased myxoid areas. ⁵²⁰

The myxoinflammatory fibroblastic sarcoma is a rare, low-grade sarcoma of the hands and feet.^{510.525. and 526.} It has been described at other sites.^{527. and 528.} It is thought to be of fibroblastic origin, but a synovial origin has not been excluded. Its low-grade nature has been questioned, as metastases have been recorded. ⁵²⁹

Chromosomal abnormalities (translocations and supernumerary ring chromosomes) have been reported. ⁵³⁰

Enzinger and Weiss have defined a fibrosarcoma as a malignant tumor of fibroblasts that shows no evidence of other cellular differentiation. ⁵³² There has been a marked decline in the diagnosis of fibrosarcoma in the last 20–25 years as a result of the delineation of the fibromatoses as a diagnostic entity and the recognition of low-grade fibromyxoid sarcoma and its variants hyalinizing spindle-cell tumor with giant (collagen) rosettes, and sclerosing epithelioid fibrosarcoma (see below). Furthermore, other spindle-cell tumors, which in the past were sometimes misdiagnosed as fibrosarcoma, such as spindle-cell melanoma and spindle-cell squamous carcinoma, as well as malignant peripheral nerve sheath tumors, can now be more confidently diagnosed with the assistance of various monoclonal antibodies and immunoperoxidase techniques. Malignant fibrous histiocytoma, while extant, also included cases that had previously been diagnosed as fibrosarcoma.

Very little has been written on fibrosarcoma in recent years. ⁵³³ However, as it is primarily a tumor of the deep soft tissues which only rarely develops in the skin and superficial subcutis, only brief mention will be made of it. Cutaneous fibrosarcomas may follow thermal burns and radiation therapy, or result from extension of a tumor arising in deeper tissues. The tumor affects predominantly middle-aged adults, although there is an uncommon clinical subset involving neonates and young children (congenital-infantile fibrosarcoma).^{534.535.536. and 537.}

Congenital-infantile fibrosarcoma is much less aggressive than adult-type fibrosarcoma despite a similar histological appearance. It accounts for 20–50% of malignant soft tissue tumors in infants and neonates. Up to one-half may be present at birth, with the remainder appearing in the first 2 years of life. ⁵³⁸ Approximately 70% develop on the extremities, with the remaining 30% occurring on the head and neck. Axial lesions are uncommon. The lesions may be highly vascular and masquerade clinically as a hemangioma. ⁵³⁹ Recently, a novel chromosomal translocation t(12;15)(p13;q25) has been identified in the congenital-infantile group. ⁵⁴⁰ This translocation gives rise to an ETV6–NTRK3 gene fusion.^{159. and 540.} It can be detected in paraffin-embedded tissue. ⁵⁴¹

The term ‘fibrosarcoma, low-grade fibroblastic type’ has been used as a diagnosis of exclusion, for tumors not encompassed by the entities of low-grade fibromyxoid sarcoma and its histological variants. ⁵⁴² It remains to be seen whether this represents a distinct fibrosarcoma type. ⁵⁴² The cases reported as fibroblastic/myofibroblastic sarcoma of the skin are difficult to categorize. ¹⁴⁸ There was a quantitative predominance of fibroblasts over myofibroblasts. All five cases were free of recurrence although the follow-up period for some cases was short. ⁵⁴³

Malignant tumors composed of myofibroblasts are increasingly being recognized, although their existence remains controversial. ²⁷ They have a spectrum of histological grades, and this has led to a proliferation of terminology. Furthermore, some tumors contain a mixture of cells that mark for fibroblasts and myofibroblasts. In a review of myofibroblastic malignancies in 2004, Fisher classified myofibroblastic sarcomas as follows: ²⁷

Most cases of myofibrosarcoma occur in the oral cavity, deep soft tissues, and bone, but about 10% or more involve the subcutaneous tissue. Low-grade lesions are usually indolent and often cured by complete excision, whereas some intermediate-grade myofibrosarcomas may recur and even metastasize. Pleomorphic myofibrosarcomas are usually regarded as being the same as pleomorphic malignant fibrous histiocytomas (see p. 838). ²⁷

Low-grade myofibrosarcomas (myofibroblastic sarcomas, low grade) are distinctive spindle-cell tumors showing myofibroblastic differentiation. ⁵⁴⁷ Of the 18 cases reported by Mentzel et al in 1998, only two involved the subcutis. ⁵⁴⁷ Recurrences and metastases were recorded for some of the cases, but there was no follow-up for the subcutaneous cases. ⁵⁴⁷ Fisher has subsequently suggested that at least one of these cases is likely to have been of intermediate-grade malignancy. Other series have been reported that have included low-grade and intermediate-grade tumors. ⁵⁴⁸ Unlike inflammatory myofibroblastic tumor, low-grade myofibrosarcoma (myofibroblastic sarcoma) is not a member of the family of ALK-positive tumors. ⁵⁴⁹

The large number of terms that have been used for dermatofibroma (histiocytoma,^{552. and 553.} fibrous histiocytoma,^{554.555. and 556.} sclerosing hemangioma, ⁵⁵⁷ nodular subepidermal fibrosis^{558. and 559.}) reflects the remarkable variation in its histological features, and continuing controversy regarding its histogenesis. ⁵⁶⁰ However, the presence of transitional patterns and different morphological components in the same lesion is strong evidence in favor of its basically common nature and histogenesis. ⁵⁵⁴ There has been a tendency to use the term ‘dermatofibroma’ for the usual fibrocollagenous and storiform variant and ‘fibrous histiocytoma’ for some of the unusual variants.

Dermatofibromas are common, accounting for almost 3% of specimens received by one dermatopathology laboratory. ⁵⁶¹ There is a predilection for the extremities, particularly the lower, of young adults.^{552. and 561.} There is a female preponderance. ⁵⁶¹ Rare sites of involvement have included the fingers,^{558. and 562.} palms and soles, ⁵⁶³ the scalp, ⁵⁵⁸ the face, ⁵⁶⁴ a vaccination scar, ⁵⁶⁵ and within a tattoo. ⁵⁶⁶

Dermatofibromas are round or ovoid, firm dermal nodules, usually less than 1 cm in diameter. A ‘giant’ variant has been recorded.^{567.568.569. and 570.} It preferentially develops on the lower limbs.^{571. and 572.} Satellitosis is a rare finding at the edge of a giant dermatofibroma. ⁵⁷³ Polypoid, flat, atrophic, and depressed configurations also occur.^{574. and 575.} Both the Meyerson phenomenon and a halo of asteatotic eczema have been reported around a dermatofibroma. ⁵⁷⁶ Lesions with a preponderance of histiocytes are often larger, and the aneurysmal (angiomatoid) variants may measure up to 10 cm in diameter.^{577. and 578.} Dermatofibromas are usually a dusky brown in color but aneurysmal variants may be red, and tumors with abundant lipid can be cream/yellow, particularly on the cut surface of the excised lesion. They often show a characteristic central white, scar-like patch on dermatoscopic examination,^{579. and 580.} and a delicate pigment network at the periphery. Other findings have been recorded,^{581.582. and 583.} including homogeneous blue pigmentation simulating a blue nevus. ⁵⁸⁴ Dermatofibromas are most often solitary, but 2–5 lesions are present in 10% or so of individuals. ⁵⁵² Multiple lesions have been reported,^{585.586.587. and 588.} usually as a rare complication of immunosuppressive therapy^{563.589.590. and 591.} or the acquired immunodeficiency syndrome.^{592.593.594.595.596. and 597.} Eruptive lesions have appeared after the commencement of highly active anti-retroviral therapy (HAART), ⁵⁹⁸ and in other clinical circumstances.^{599.600.601.602.603.604.605.606. and 607.} Familial eruptive dermatofibromas have also been reported. ⁶⁰⁵ There are only a few reports of patients with large numbers of tumors;^{556.608.609.610.611.612. and 613.} one such case was reported as ‘disseminated dermal dendrocytomas’. This case may have been a different entity – progressive nodular histiocytosis (see p. 955). Clinical variants include the aneurysmal type, already referred to, ⁵⁷⁷ and the rare annular hemosiderotic histiocytoma in which multiple brown papules in annular configurations were present on the buttocks. ⁶¹⁴ Some authors regard the hemosiderotic dermatofibroma as an early stage in the development of the aneurysmal variant. ⁶¹⁵ Some aneurysmal lesions may recur. ⁶¹⁶ Spreading satellitosis has been reported in one case. ⁶¹⁷

Although regarded as a benign tumor or reactive inflammatory process that may uncommonly recur locally (see below), several cases of metastasizing cellular dermatofibroma have been recorded.^{618.619.620. and 621.} Clonality has since been found in some cases of dermatofibroma but no consistent karyotypic aberration has been found.^{622. and 623.} Mentzel and colleagues have drawn attention to the aggressive nature of dermatofibromas arising on the face. ⁶²⁴ They often involve deeper structures, and have an increased rate of local recurrence. They need to be excised with wider margins than the classic type. ⁶²⁴

The deep fibrous histiocytoma, initially reported by Fletcher in 1990, occurs in the subcutaneous or deep tissues. ⁶²⁵ A larger series of 69 cases from Fletcher’s consultation files was reported in 2008. ⁶²⁶ The series included 41 males and 28 females, ranging in age from 6 to 84 years. More than half were located on the extremities, but about 10% occurred in the deep soft tissues of the peritoneum, mediastinum, or pelvis. ⁶²⁶ The non-visceral lesions were subcutaneous in location. They were well-circumscribed tumors that ranged in size from 0.5 to 25 cm (median, 3.0 cm). Of those cases with available follow-up, 8 (22%) had a local recurrence, but in all 8 cases, the tumor had been marginally or incompletely excised. ⁶²⁶ Metastases occurred in two patients; both ultimately died of the disease. Apart from their large size, the metastasizing tumors were otherwise identical to the other tumors. ⁶²⁶ A case associated with a melanoma has been reported. ⁶²⁷

The atypical fibrous histiocytoma (dermatofibroma with monster cells) ⁶²⁸ is another uncommon variant with a low recurrence rate and the rare development of distant metastases. ⁶²⁹

Fibroblasts, non-lysozyme containing histiocytes, ⁵⁵⁹ and endothelial cells have all been regarded at some time as the cell of origin. ⁵⁵² Dermatofibromas have been regarded by some authors as a benign tumor, and by others as a fibrosing inflammatory or reactive process.^{628.630. and 631.} In support of the latter concept is the history of trauma, blunt or piercing, recorded in up to 20% of cases. ⁵⁵⁸ An insect bite has preceded the development of a dermatofibroma. ⁵⁵² HHV-8 has not been detected. ⁶³² On the basis of the immunoreactivity of 30–70% of the constituent cells with factor XIIIa, an origin from the ‘dermal dendrocyte’ has been proposed.^{633.634. and 635.} The dendritic cells appear to be derived from blood monocytes or a stem cell common to both. ⁶³⁶ Recent studies have found HSP47-positive fibroblasts in dermatofibromas.^{305. and 637.} They were the major constituent cells in the fibrocollagenous type. The authors postulated two cell lineages – fibroblastic, and bone-marrow derived monocyte/macrophages (dermal dendrocytes). ⁶³⁷ A recent study concluded that a dermatofibroma is composed predominantly of cells of macrophage phenotype with a variable amount of myofibroblastic elements. ⁶³⁸ It has been suggested that fibroblastic tumor cell-derived stem cell factor is responsible for the epidermal hyperpigmentation that overlies dermatofibromas. ⁶³⁹

Surgical excision (including shave excision) is the usual method of treatment. Recurrence is uncommon, even in cases with positive margins. Two exceptions to this statement exist. The cellular variant, which often extends into the subcutis, and dermatofibromas of the face need to be excised with wider margins than the classic type to prevent recurrence. ⁶²⁴

Epithelioid cell histiocytoma is regarded as a variant of fibrous histiocytoma (dermatofibroma). ⁶⁹³ It is considered separately from dermatofibroma because of its distinctive histological appearance, which resembles to some extent the intradermal variant of Spitz nevus. ⁷²⁷ The lesion usually presents as an elevated nodule on the extremities of adults, although other sites have been recorded. ⁷²⁸ In one patient a lesion on the arm was followed a month later by another lesion on the nostril. ⁷²⁹ Although a dendrocyte origin is usually favored, an endothelial cell origin has also been proposed on the basis of the ultrastructural findings in one case. ⁷³⁰ On the basis of immunohistochemistry, an origin from microvascular fibroblasts and dendritic cells has been proposed (see below). ⁷³¹ The term ‘solitary epithelioid histiocytoma’ has recently been proposed as a group term for tumors previously called reticulohistiocytoma and multicentric reticulohistiocytosis (see p. 956). ⁷³² This is bound to lead to confusion.

Plexiform fibrohistiocytic tumor is a rare tumor that involves predominantly the upper limb of infants and children.^{741. and 742.} It presents as a slow-growing, painless mass. Over 100 cases have now been reported. ⁷⁴² It has an immunophenotype suggestive of myofibroblastic differentiation.^{743. and 744.} Grossly, the tumor involves the superficial soft tissue, often arising at the dermal–subcutaneous junction. ⁷⁴⁵ Dermal variants have been described. ⁷⁴⁶ The lesion is poorly demarcated, lobulated or micronodular. It is white-gray in color, and averages 1–3 cm in size. ⁷⁴⁷

Local recurrence is common, usually because of incomplete removal. Metastasis has been recorded, ⁷⁴⁸ but not in infants. ⁷⁴⁷ It is included here with the fibrohistiocytic lesions, rather than the myofibroblastic tumors, because of the dual cell population.

Wide local excision is the recommended treatment. ⁷⁴⁷

Giant cell fibroblastoma is a rare soft tissue tumor occurring predominantly in childhood. ⁷⁵³ The back, thigh, and chest are the favored sites. The vulva is a rare site of involvement. ⁷⁵⁴ There is a male predominance. Macroscopically, the tumor appears gray-pink with a partly gelatinous consistency. ⁷⁵⁵ Cases recurring as, or transforming to, dermatofibrosarcoma protuberans (DFSP) have been reported.^{756.757.758. and 759.} Foci resembling giant cell fibroblastoma have also been seen within a DFSP (hybrid lesions),^{760. and 761.} as has the phenomenon of a DFSP recurring as a giant cell fibroblastoma.^{762. and 763.} Furthermore, both possess a similar cytogenetic abnormality (see below).^{761. and 764.} These findings have led to the suggestion that giant cell fibroblastoma is a juvenile variant of DFSP. Giant cell fibroblastoma has been misdiagnosed as dermatofibroma. ⁷⁶⁵

Wide local excision is the recommended treatment. ⁷⁶¹ Local recurrence is common, following incomplete surgical removal. ⁷⁶⁶

Dermatofibrosarcoma protuberans (DFSP) is a slow-growing, locally aggressive tumor of intermediate malignancy, and of disputed histogenesis, with a marked tendency to local recurrence, but which rarely metastasizes.^{777.778.779. and 780.} Its annual incidence in the United States is 4.2 per million; ⁷⁸¹ it is slightly less in one area of France. ⁷⁸² It occurs in all races.^{783. and 784.} It has a predilection for the trunk and proximal extremities of young and middle-aged adults,^{785.786. and 787.} but other sites are rarely involved.^{775.788.789.790. and 791.} Congenital and familial cases, and onset in childhood are all rare.^{792.793.794.795.796.797.798.799.800.801. and 802.} Congenital cases may be misdiagnosed as benign lesions because of their deceptive appearance;^{803.804. and 805.} they may be mistaken for a vascular birthmark. ⁸⁰⁶ In the United States, DFSP is more common in blacks than in whites, and there is a higher incidence in women than men. ⁷⁸¹ The lesions are solitary or multiple polypoid nodules, often arising in an indurated plaque of tumor.^{807.808.809. and 810.} Approximately 40% of cases are initially non-protuberant. ⁸¹¹ Atrophic variants are uncommon; they may be difficult to diagnose clinically.^{792.799.812.813.814. and 815.} The involved area of skin measures from 0.5 to 10 cm or more in greatest diameter. A violaceous or red color is sometimes present, but at other times the nodules are flesh colored. ⁸⁰⁸ A history of previous trauma at the site is sometimes given.^{788. and 816.} Accelerated growth has been reported during pregnancy; ⁸¹⁷ metastases followed pregnancy in one case. ⁸¹⁸ Previous arsenic exposure was present in one case. ⁸¹⁹ It has also been reported in a patient with X-linked agammaglobulinemia, ⁸²⁰ in a renal transplant recipient, ⁸²¹ and at the site of prior leishmanization, and in a smallpox vaccination scar.^{822. and 823.} DFSP has also been reported in association with a nuchal-type fibroma, ⁸²⁴ and with multiple spindle-cell lipomas. ⁸²⁵ Rarely, DFSP may masquerade as a skin tag, ⁸²⁶ a cyst, ⁸²⁷ or as a primary breast lesion when located in the skin of the breast. ⁸²⁸

Local recurrence occurs in up to one-third of all cases.^{808. and 829.} Lower recurrence rates have been reported using Mohs micrographic surgery.^{830. and 831.} Hematogenous metastases, although rare, ⁸³² are more common than those to regional lymph nodes.^{833.834.835. and 836.} In a recent study, the relative 5-year survival was estimated to be 99.2%. ⁷⁸¹ Progression of a recurrent DFSP to a malignant fibrous histiocytoma, ⁸³⁷ and the development of fibrosarcomatous, neurofibrosarcoma, and myxofibrosarcomatous areas in DFSPs is well documented, occurring in 10–15% of cases.^{838.839.840.841. and 842.} This progression to fibrosarcoma is associated with microsatellite instability and p53 mutations.^{843. and 844.} The fibrosarcomatous variant of DFSP is said to be a much more aggressive lesion with metastatic potential;^{845. and 846.} however, a study of 17 cases showed that only four cases recurred and none developed metastasis within the 5-year follow-up period. ⁸⁴⁷ The lesions were treated initially with wide local excision with negative margins. ⁸⁴⁷ In a recent study from the Mayo Clinic on the prognostic significance of fibrosarcomatous transformation, four patients (10%) had metastases and two patients died of disease. ⁸⁴⁴ Giant cell fibroblastoma has a close relationship with DFSP; either tumor may recur with features of the other (see above).

The pigmented storiform neurofibroma of Bednar (Bednar tumor) is now regarded as a pigmented variant of DFSP.^{848.849.850.851.852.853.854. and 855.} It is an exceedingly rare tumor which accounts for only 1–5% of all cases of DFSP. ⁸⁵³ It occurs in a similar clinical setting to DFSP but, as yet, no metastases have been recorded. It is thought to represent the colonization of a DFSP by melanocytes. ⁸⁵⁶ Dermal melanocytosis has been reported in one case raising the possibility of neuroectodermal multidirectional differentiation for both this and the DFSP components. ⁸⁵⁷ A case has been reported that arose at the site of a previous immunization. ⁸⁵⁸ A congenital variant has also been reported. ⁸⁵⁹

The myxoid DFSP is uncommon. In a review of 23 cases from his consultation files, Fletcher found that the majority of cases were found on the extremities, and the head and neck. Three cases were from the anogenital region. ⁸⁶⁰ Clinical follow-up in eight cases revealed local recurrence in two, but there was no evidence of metastasis. ⁸⁶⁰

Although DFSP is traditionally regarded as a fibrohistiocytic tumor, several ultrastructural and immunohistochemical studies have questioned this viewpoint; ⁸⁶¹ a neuroectodermal origin has also been suggested, but the immunophenotype (see below) does not support this concept. Fletcher and colleagues have commented that ‘the most pragmatic solution at this time may be to regard these tumors as a heterogeneous group, in line with the pluripotentiality of mesenchyme’. ⁸⁶² A fibroblastic origin seems most likely on the basis of the immunophenotype and ultrastructure of the cells. ⁸⁶³ Platelet-derived growth factor has been identified in DFSP and other fibrohistiocytic lesions. ⁸⁶⁴

Cytogenetically, DFSP is characterized by a reciprocal translocation, t(17;22)(q22;q13), and a supernumerary ring chromosome derived from the translocation r(17;22).^{791. and 865.} Other rare abnormalities have been found. Cloning studies reveal that the translocations result in the fusion of two genes, COL1A1 and PDGFB, related respectively to the formation of type I collagen and platelet-derived growth factor.^{865.866.867. and 868.} A recent study has shown that COL1A1–PDGFB fusion can be identified in virtually all cases of DFSP when investigated by newly developed multiplex reverse transcription polymerase chain reaction and fluorescence in-situ hybridization assays. ⁸⁶⁹ Cases without a detected cytogenetic abnormality are in the literature from earlier days. ⁸⁷⁰ This fusion product has also been demonstrated in the granular cell and myxoid variants, in the Bednar tumor, and in giant cell fibroblastoma.^{761.871. and 872.} A recent study has suggested that genomic gains of COL1A1–PDGFP are associated with the histological evolution of giant cell fibroblastoma into DFSP. ⁸⁷³

Macroscopically, the cut surface of the tumor nodules appears firm, and gray-white in color. Recurrent lesions with abundant mucin may have a more glistening appearance. The pigmented variant may appear slate gray or black if sufficient melanin is present within the tumor. ⁸⁵³

‘Atypical fibroxanthoma’ (AFX) is the term coined by Helwig for a cutaneous tumor with marked cellular pleomorphism, yet with a course that is usually benign. ⁹²⁹ As such it has been regarded as one of the so-called ‘pseudomalignancies’ of the skin. ⁹³⁰ This view must be modified somewhat in the light of rare reports of metastasis (see below). Similar cases were reported about the same time as those of Helwig, under several different names.^{931. and 932.} The tumors usually occur as a solitary, gray to pink or red nodule, often dome-shaped, on the head or neck of the elderly.^{933. and 934.} There is a rare plaque form. ⁹³⁵ In some series there has been a predominance in males.^{935. and 936.} They may develop quickly, but they are usually less than 2 cm in diameter. Another clinical variant occurs in younger patients, and these lesions may be larger, more slowly growing, and with a predilection for the trunk and extremities.^{934.937. and 938.} AFX has been reported in children with xeroderma pigmentosum^{939. and 940.} and, rarely, in children without this condition. ⁹⁴¹ In both groups, the lesions may be ulcerated and bleed. It has also arisen in an area of syringocystadenoma papilliferum associated with nevus sebaceus (organoid nevus). ⁹⁴²

The nature of AFX is speculative. It has been regarded as a proliferative mesenchymal, possibly fibrohistiocytic, response to a variety of cutaneous injuries. ⁹⁴³ The diversity of immunoperoxidase markers raises the possibility of heterogeneous, bimodal ‘fibrohistiocytic’ and ‘myofibroblastic’ phenotypes. ⁹⁴⁴ In older patients there is often a history of prolonged actinic exposure, but lesions may also develop at sites of irradiation and even trauma. ⁹⁴⁵ This tumor may also develop in renal transplant recipients.^{946.947. and 948.} It has been suggested that there is a close relationship to malignant fibrous histiocytoma (MFH), and that it is merely the small size and dermal location of most cases of atypical fibroxanthoma that lead to its benign behavior.^{949. and 950.} A more likely explanation for these differences in behavior is the absence of ras-oncogene mutations in AFX, whereas MFH has both H- and K-ras gene mutations.^{951. and 952.} Although the large atypical cells in AFX are aneuploid, as they are in MFH, the smaller spindle-shaped cells in AFX are diploid.953. ^{and 954.} These theories will need reconsideration in the light of the ‘break-up’ of MFH as an entity.

Recurrences develop in approximately 5% of cases, but in most instances this is due to incomplete removal. Extension into subcutaneous fat is another marker for local recurrence. ⁹⁵⁵ Lesions may even regress spontaneously or after incomplete removal. The diagnosis of AFX has been questioned in those cases that have behaved aggressively. ⁹⁵⁶ There is no doubt that AFX, as reported in the past, was a heterogeneous entity that included cases of malignant melanoma and the spindle-cell variant of squamous cell carcinoma.^{957. and 958.} The advent of immunoperoxidase markers, and the wider use of electron microscopy, should allow more accurate assessment and diagnosis of these tumors in the future. More than 20 cases of AFX with metastases have now been reported, and several of these have been studied with immunoperoxidase or electron microscopy to exclude melanoma and squamous cell carcinoma.^{943.959.960. and 961.} The cases reported have tended to metastasize to regional lymph nodes, ⁹⁴³ but more widespread systemic spread has been reported. ⁹⁶²

The author’s personal (anecdotal) experience with over 300 cases may be of interest. The tumor is usually histologically distinctive with its bizarre cells, numerous mitoses, level 4 extension (except for the rare plaque form), frequent ‘collarette’, and usual occurrence on the ear, forehead, or bald scalp. Experience has shown that it is prudent to perform immunohistochemistry for S100 protein and keratin, as melanoma and squamous cell carcinoma can produce morphological simulants. The author is not aware of any metastasis in these cases but at least 10 have recurred. In our published series of 89 cases of AFX, no recurrences or metastases were found on follow-up, despite encountering recurrences in earlier cases. ⁹³⁵ All these recurrent lesions were excised with positive or narrow margins and there was usually subcutaneous extension. It should be noted that most lesions were completely excised, as shave excisions have not been used widely in Australia until recently.

It has been suggested that atypical fibroxanthoma is a ‘myth’, and yet another variant of squamous cell carcinoma. ⁹⁶³ This statement has been strongly refuted by others.^{935. and 964.} The majority of cases do not have adjacent actinic keratosis change, which might be expected if AFX were truly a variant of squamous cell carcinoma. ⁹³⁵ Most authors with experience of numerous cases of AFX believe it is a distinct clinicopathological entity with established clinical, histological, and immunohistochemical features. ⁹⁵⁵

Atypical fibroxanthomas should be treated by wide local excision, even though several cases in our published series did not recur, despite the presence of positive margins in the original excision specimen. Mohs technique may be of benefit in cases on the head and neck.

Angiomatoid fibrous histiocytoma (AFH) is a rare soft tissue neoplasm first described by Enzinger in 1979. ¹⁰¹¹ It occurs predominantly on the extremities of children and young adults. ¹⁰¹² It was included for many years as a variant of malignant fibrous histiocytoma despite its more superficial location, the younger age of the patients, and its favorable prognosis.^{1013.1014. and 1015.} It is now recognized as a distinct entity.

The lesions are generally small, measuring 2–4 cm in largest diameter. Most cases behave in a relatively indolent manner although rare metastases have been recorded. ¹⁰¹⁶ It is regarded as a tumor of intermediate biologic behavior. ¹⁰¹³

Two specific translocations have been demonstrated – t(12:16)(q13:p11) and t(12:22)(q13:q12). The first mentioned involves fusion of the FUS and ATF-1 genes and the second the fusion of the EWSR1 gene with ATF-1.^{1013. and 1017.} Sometimes the fusion transcript is not identified. ¹⁰¹⁸ The first mentioned translocation is also seen in myxoid liposarcoma although it involves the FUS and DDIT3 (CHOP) genes. ¹⁰¹³ The EWSR1/ATF-1 fusion product is also seen in clear cell sarcoma.^{1019.1020.1021. and 1022.} The histogenesis of this tumor is uncertain. An origin from fibroblastic reticulum cells has been suggested. ¹⁰¹³

Malignant fibrous histiocytoma (MFH), formerly the most common soft tissue sarcoma of late adult life, is a controversial entity that is currently undergoing a systematic break-up into several entities, leaving behind the pleomorphic variant as a wastebasket of undifferentiated sarcomas.^{1027. and 1028.} In the 40 years that the author has been practicing pathology, there have been rotating wastebaskets into which the diagnostic dilemmas of soft tissue tumors have been placed for a decade or more. This is not a criticism of those pathologists working in the area, who have kept us well informed, but rather an acknowledgement of the complex histogenesis of many of these tumors, which have remained an enigma despite advances in electron microscopy, and then in immunohistochemistry. Some of these tumors are becoming transparent at last, under the surveillance of cytogenetics.

The angiomatoid variant of MFH is now classified as angiomatoid fibrous histiocytoma (see above) on the basis of its better prognosis, its more superficial location, and its occurrence in younger individuals than those with pleomorphic MFH.

The myxoid variant of MFH has been reclassified as myxofibrosarcoma (see p. 825) on the basis of its distinctive and consistent clinicopathological features, most notably the presence of prominent myxoid foci comprising nearly 50% of the tumor.^{509.511. and 514.}

The giant cell variant, which was not consistently included as a variant of MFH, is now regarded as a distinct entity – the giant cell tumor of soft tissues (see p. 839). It is exceedingly rare and has morphological similarities to the bone tumor of the same name.

The inflammatory variant remains, for the present, in the category of MFH. Some cases probably represent undifferentiated liposarcomas. Cytogenetic studies will undoubtedly lead to a reclassification of some of the tumors in this group.

The pleomorphic MFH, also called pleomorphic undifferentiated sarcoma, remains largely ‘unscathed’. It is a surprisingly large group, if the findings of the Scandinavian Sarcoma Pathology Review Group are in any way representative of the situation in other countries. ¹⁰²⁹ Fletcher, on the other hand, believes this entity will eventually be dropped. ¹⁰²⁷ The account which follows refers to the pleomorphic variant, although some of the references given include cases now reclassified into other groups.

Pleomorphic MFH usually involves the deep soft tissues and striated muscles of the proximal part of the extremities, particularly the lower. ¹⁰³⁰ The retroperitoneum is another favored site.^{861. and 1031.} Up to 20% of cases may arise in the subcutaneous tissues, although less than 10% are confined to the subcutis without underlying fascial involvement.^{1031.1032.1033. and 1034.} Cutaneous tumors are even rarer.^{1035. and 1036.} They usually extend into subcutis and deeper structures.^{1037. and 1038.} Adults between the ages of 50 and 70 years are most often affected. There are usually no predisposing factors but, rarely, cases have followed radiotherapy,^{1032. and 1039.} or developed at the site of a chronic ulcer, ¹⁰⁴⁰ osteomyelitis, ¹⁰⁴¹ vaccination scar, ¹⁰⁴² or burn scar. ¹⁰⁴³ MFH has also developed in HIV-positive patients, ¹⁰⁴⁴ and in a renal transplant recipient. ¹⁰³⁸

The tumors are multilobulated, often circumscribed, gray-white fleshy masses. ¹⁰³² The majority are 5 cm or more in diameter. Focal areas of hemorrhage and necrosis are quite common. The inflammatory variant may be yellow in color.

The prognosis is generally poor, with 5-year survivals ranging from 15% to 30%; ¹⁰⁴⁵ recent studies have recorded much-improved survival rates. ¹⁰⁴⁶ Tumors that are small and superficially located have a better prognosis than large, deep ones.^{1031.1047. and 1048.} Tumor size, local tumor recurrence, and necrosis are associated with a greater risk of metastasis. ¹⁰²⁹ Proliferative activity (MIB-1 index) is not an independent prognostic parameter, despite being so in other soft tissue sarcomas. ¹⁰⁴⁹ Tumor vascular endothelial growth factor (VEGF) expression correlates with stage, grade, and prognosis in soft tissue sarcomas in general. ¹⁰⁵⁰ Proximal deep tumors and those in the retroperitoneum have a poor prognosis. Local recurrence and metastases are common, with the lungs and regional lymph nodes most often affected. ¹⁰³¹

The histogenesis of this tumor has been controversial. The tumor cells show partial fibroblastic and histiocytic differentiation, as reflected by collagen production and the presence of cells which may be immunoreactive for the histiocytic markers, as well as showing occasional phagocytosis. ¹⁰⁵¹ Others believe that there are no histiocytic features. It may be derived from a poorly defined mesenchymal cell, which may differentiate along histiocytic and fibroblastic lines.^{1052.1053. and 1054.}

Multiple structural and numerical aberrations in many chromosomes have been found in this tumor. ¹⁰⁵⁵ It appears that genes involved in the RB1- and TP53-associated cell-cycle regulatory pathways may play a prominent role in the development of malignant fibrous histiocytoma. ¹⁰⁵⁶

Wide surgical resection is usually recommended for this tumor.^{1037. and 1046.} Radiotherapy and chemotherapy have generally been used as adjunctive or palliative measures but chemotherapy appears to have marginal efficacy. ¹⁰⁵⁷ There is increasing use of preoperative neoadjuvant treatments such as chemotherapy, radiotherapy, hyperthermia, or a combination of these methods for high-grade soft tissue sarcomas. While some tumors show a good response to these combined-modality treatments, the prognosis is still poor. ¹⁰⁵⁸

Primary giant cell tumor (osteoclastoma) of soft tissues is a rare tumor that may arise in both the superficial and deep soft tissues.^{1027.1074.1075.1076. and 1077.} It is found predominantly on the thighs, trunk, and upper extremities. It occurs in a broad age range. ¹⁰⁷⁸ There is no sex predilection. Morphologically, it has some resemblance to giant cell tumor of bone. Cases involving the dermis, but extending into the subcutaneous fat also, have been reported.^{1075. and 1079.} Although no recurrences had occurred at the time of publication of these cases, the follow-up period was brief. Metastases have been rare in cases having a deeper location. ¹⁰⁷⁸

Chung and Enzinger formally documented fibroma of tendon sheath in 1979, with a report of 138 cases. ¹⁰⁸¹ It is a solitary, slow-growing subcutaneous tumor with a predilection for the fingers, hands, and wrists of middle-aged adults, particularly males.^{1082. and 1083.} Recurrences occur in approximately 20% of cases.

The fibromas are well-circumscribed, often lobulated, gray to white tumors that measure 1–2 cm in diameter. They are usually attached to a tendon sheath.

A (2;11) translocation has been found in some of the tumor cells in one case, suggesting that this lesion is neoplastic and not a reactive process. ¹⁰⁸⁴

Giant cell tumor of tendon sheath is a not uncommon benign tumor with a predilection for the dorsal surface of the fingers, in the vicinity of the distal interphalangeal joint.^{1091. and 1092.} Periungual lesions are rare. ¹⁰⁹³ It occurs particularly in young and middle-aged adults. It is a slow-growing, usually asymptomatic lesion, which may measure up to 3 cm in diameter at the time of removal. Multicentric lesions are rare. ¹⁰⁹⁴ Local recurrence, usually a result of incomplete removal, occurs in 15% of cases. ¹⁰⁹¹

Giant cell tumors are lobulated and gray-brown in color, with yellowish areas. They are usually attached to a tendon sheath or joint capsule, but cutaneous involvement can occur.^{1095. and 1096.} The histogenesis of giant cell tumors has been controversial. They have been regarded as a variant of fibrous histiocytoma, and as a tumor derived from mesenchymal cells. ¹⁰⁹⁷ One study concluded that the cells are of monocyte–macrophage lineage, closely resembling osteoclasts. ¹⁰⁹⁸ The immunophenotype (see below) is more suggestive of a synovial cell origin. ¹⁰⁸⁸ It appears to be a polyclonal proliferation. ¹⁰⁹⁹

This tumor must be distinguished from the giant cell tumor of soft tissue, a rare tumor resembling the lesion of bone (see p. 839).

Epithelioid sarcoma, first delineated by Enzinger, ¹¹⁰² is a rare aggressive tumor that usually involves the deep subcutis and underlying soft tissues. Infrequently, it arises in the dermis and superficial subcutis, where it may be confused both clinically¹¹⁰³ and histologically with various benign cutaneous diseases, including granuloma annulare.^{1104. and 1105.} It has a predilection for the extremities, particularly the hands, of young adult males.^{1106.1107. and 1108.} Childhood cases occur. ¹¹⁰⁹ Lesions of the face, ¹¹¹⁰ vulva, ¹¹¹¹ and penis¹¹¹² have also been described. A history of trauma is sometimes given. ¹¹⁰⁶ A case has been reported in a patient with neurofibromatosis type 2. ¹¹¹³

It presents as one or more slow-growing tan-white nodules with an indistinct infiltrating margin. Ulceration develops late, if at all. Local recurrence occurs in nearly 80% of cases, and metastases in 30–45%.^{1106.1114.1115. and 1116.} The regional lymph nodes and lungs are the most common initial sites of metastases. The skin of the scalp represents another common site of distant metastasis. ¹¹¹⁷ The tongue is one of several rare metastatic destinations. ¹¹¹⁸ Adverse prognostic features are older age, a proximal or axial location, tumor size greater than 5 cm, deep extension, necrosis, rhabdoid cytomorphology, vascular invasion, incomplete excision, metastases, and numerous mitotic figures.^{1106.1119. and 1120.}

Epithelioid sarcoma is of disputed histogenesis. A synovial origin, which was favored at one time,^{1121. and 1122.} now seems unlikely. ¹¹²⁰ A histiocytic, fibroblastic, ¹¹²³ myofibroblastic, ¹¹²⁴ perineurial, ¹¹²⁵ and mesenchymal reserve cell¹¹²⁶ origin have all been suggested. One tumor produced granulocyte colony-stimulating factor, but it is difficult to draw any histogenetic conclusions. ¹¹²⁷ An N-ras oncogene mutation has been demonstrated in the tumor cells in one study. ¹¹¹⁵ In another, allelic loss on chromosome 22q was present in 60% of cases. ¹¹²⁸ Subsequent studies have shown chromosomal gains at 22q and other sites, ¹¹²⁹ but there are no consistent or specific chromosomal rearrangements or changes. ¹¹³⁰

Fletcher and colleagues have drawn attention to an aggressive tumor with epithelioid and rhabdoid features, which they have called ‘proximal-type’ epithelioid sarcoma. ¹¹³¹ Most of the cases involved the deep soft tissues in axial proximal locations but several, in the region of the vulva, involved the subcutis. It usually occurs in middle-aged or older adults, ¹¹³⁰ but cases in children have been reported. ¹¹³² It recurs more frequently and metastasizes earlier than the classic type. ¹¹³³

Treatment of epithelioid sarcoma of both types consists of radical surgical excision of the tumor and, if indicated, therapeutic lymph node dissection. ¹¹³⁴ In patients who have large tumors, isolated limb perfusion with tumor necrosis factor and melphalan may be useful. ¹¹³⁴ The role of postoperative radiotherapy after wide surgical excision needs further research. Its use is usually confined to cases with positive surgical margins. ¹¹³⁵ Sentinel lymph node biopsy has also been suggested as a useful procedure. ¹¹³⁴

Only brief mention will be made of this soft tissue sarcoma, which has a predilection for the extremities of young and middle-aged adults. It exhibits a wide spectrum of biological behavior. The high-risk group includes older patients, ¹¹⁵¹ tumor size greater than 5 cm, and poor differentiation.^{1152. and 1153.}

Only one case of superficial synovial sarcoma involving the dermis has been reported. ¹¹⁵⁴ It involved the skin overlying the knee in a young woman. It recurred six times over a 24-year period. ¹¹⁵⁴

A study of 21 minute synovial sarcomas of the soft tissues of the hands and feet was reported from the AFIP in 2006. ¹¹⁵⁵ All lesions were less than 1 cm in diameter. The median age of the affected patients was 29 years (range, 8–60 years). ¹¹⁵⁵ SYT–SSX fusion transcripts were demonstrated in five cases. Minute tumors appear to have a favorable outcome if completely excised. ¹¹⁵⁵ Genomic deletion of p16^INK4A (CDKN2A) is a frequent genetic event in synovial sarcomas. ¹¹⁵⁶

The chromosomal translocation t(X;18) has been described in 90% of synovial sarcomas, and the presence of SYT–SSX fusion products is quite characteristic.^{1157. and 1158.} Usually the proximal portion of the SYT gene at chromosome 18q11 is fused to the distal portion of one of several duplicated SSX genes at chromosome Xp11. ¹¹⁵⁹SYT/SSX1 translocations are nearly three times more frequent than SYT/SSX2 translocations, and this latter pattern is usually associated with monophasic tumors. ¹¹⁵⁹

In general, aggressive treatment has been advocated for synovial sarcomas, and in earlier times, this often meant amputations. Postoperative radiation is usually used after conservative excisions, but its efficacy has been questioned. ¹¹⁵⁵ Chemotherapy is used for large, inoperable, and recurrent tumors, but it does not seem necessary for the minute variants. ¹¹⁵⁵ It is often used in children with synovial sarcoma. ¹¹⁶⁰ As some tumors express epidermal growth factor receptors and HER-2/neu protein, treatment with tyrosine kinase inhibitors has been suggested as a future alternative treatment modality. ¹¹⁵⁹

Fibro-osseous pseudotumor is a rare tumor of the subcutaneous and soft tissues of the digits, usually in young adults.^{1167. and 1168.} There is a close histological resemblance to myositis ossificans, with osteoid formation and a background stroma of fibroblasts, collagen and myxoid material.^{1167. and 1169.} Unlike myositis ossificans, the lesion usually involves the subcutis and has an irregular multinodular growth pattern. ¹¹⁶⁷

Ossifying fibromyxoid tumor is a rare tumor of soft tissues of intermediate malignant potential, that sometimes involves the subcutaneous tissue.^{1170.1171.1172. and 1173.} Dermal involvement is exceedingly rare. ¹¹⁷⁴ It occurs preferentially on the upper and lower extremities and, rarely, in the head and neck region. It has also presented as a scalp cyst. ¹¹⁷⁵ There is a male predominance. The tumors measure 1–14 cm in diameter (median 4 cm). ¹¹⁷⁶

Ossifying fibromyxoid tumor was initially thought to be of neural origin, but it seems more likely that it is derived from mesenchymal stem cells that also express neural differentiation, which is often weak, but occasionally quite prominent. ¹¹⁷⁴ Genomic analysis of malignant tumors has shown a clonal pattern, but no consistent chromosomal abnormality. ¹¹⁷⁵

In the vast majority of cases, complete surgical excision is curative, but local recurrences are common unless an adequate clearance is obtained. Mohs surgical technique has been used for this purpose. ¹¹⁷⁵ Metastases were recorded in 16% of patients in a series of consultation cases. ¹¹⁷⁶ There were no metastases in the series of 104 cases reported from the AFIP. ¹¹⁷⁷