Nevus lipomatosus, also known by the complicated term ‘nevus lipomatosus cutaneus superficialis (Hoffmann–Zurhelle)’,^{7. and 8.} is a rare type of connective tissue nevus characterized by the presence of mature adipose tissue in the dermis. It is found as plaques or solitary lesions, or in an extremely rare generalized form.

The plaque type has aggregations of flesh-colored or yellow papules and nodules which are present at birth, or which develop in the first two decades of life. ⁹ There is a predilection for the pelvic girdle, particularly the gluteal region. Other sites, such as the face and scalp, are rarely involved.^{10.11.12. and 13.} Lesions are usually unilateral, and sometimes in a linear or zosteriform arrangement. The surface of most lesions is smooth, although it may be verrucous or dimpled. ¹⁴ Surface comedones have been noted occasionally. Lesions usually develop insidiously, but later become reasonably stable. There is one report with an associated chromosomal abnormality, a deletion of 2p24. ¹⁵

The colocalization of nevus lipomatosus and lipedematous scalp (see below) has been reported. ¹³

The solitary form consists of isolated papules or nodules, anywhere on the body, but with a predilection for the trunk. ¹⁶ They may not appear until the fifth decade. They usually have a broader base than the common skin tag (acrochordon), but there are some who doubt the existence of the solitary form, preferring to regard them as skin tags or ‘pedunculated lipofibromas’.^{7. and 17.}

There are reports of more generalized body involvement with a markedly folded skin surface (‘Michelin man’ appearance).^{18.19. and 20.} The generalized form needs to be distinguished from the abnormal fat distribution, which occurs particularly in the buttock region, in congenital disorders of glycosylation (CDG). ²¹ Folds of fat hang down from the buttocks in CDG-1a (OMIM 212065). ²¹

In piezogenic pedal papules there are usually multiple small papulonodules on the heels^{31.32.33.34.35. and 36.} which have a tendency to disappear when pressure is relieved from the heels. ³⁶ Although most are painless and small, ³⁷ there are a few reports of a painful variant.^{32.33.34. and 38.} This entity has recently been reported in one-third of a group of patients with Ehlers–Danlos syndrome and in the Prader–Willi syndrome.^{35. and 39.}

Piezogenic pedal papules are thought to represent pressure-induced herniations of the subcutaneous fat through acquired or inherited defects in the connective tissue of the heel.^{35.40. and 41.}

Similar lesions (piezogenic wrist papules) have been reported on the wrist. ⁴² A case of piezogenic palmar papules has been reported. ⁴³ It was due to a subcutaneous lipoma that herniated into the dermis at several points. ⁴³

Infantile pedal papules, congenital adipose plantar nodules, ⁴⁴congenital fibrolipomatous hamartoma^{45.46.47. and 48.} all refer to the same entity (OMIM 609808), which differs slightly from piezogenic pedal papules. Infantile pedal papules present at birth or in infancy as painless, symmetric nodules on the medial aspect of the heel. ⁴⁹ Autosomal dominant inheritance was present in three family members from two generations. ⁵⁰ Most cases are sporadic. In a recent study, they were found in 5.9% of newborns and 39.4% of infants. ⁵¹ They were not biopsied.

Lipoblastoma is a rare, benign tumor of infants and young children, thought to be related to fetal white fat.^{54.55.56.57. and 58.} It may also occur in adolescents and young adults. ⁵⁹ Most lipoblastomas occur on the proximal extremities, trunk, and head and neck. ⁶⁰ Rare sites include the scrotum and vulva.^{60.61. and 62.} Some earlier reports of liposarcoma in infants probably included examples of this entity. ⁶³ Chung and Enzinger delineated a circumscribed, usually superficial type, and a less common diffuse form, often in the deeper soft tissues, analogous to diffuse lipomatosis. ⁵⁶ In one study of 14 cases, 6 were of the circumscribed type and 8 were diffuse and ill defined (lipoblastomatosis), ⁶⁴ while in another study of 25 cases, 11 were circumscribed (discrete) and 14 were diffuse. ⁶⁵ Lipoblastoma/lipoblastomatosis behaves in a benign fashion, although local recurrence sometimes occurs. ⁶⁵ No metastases have been reported.

Cytogenetic studies have shown that the majority of lipoblastomas have rearrangements of 8q11–13, with similar numbers showing polysomy of chromosome 8.^{59. and 66.} Many other abnormalities have been reported, including cases with a complex or even normal karyotype.^{60. and 67.} The altered gene is PLAG1, an oncogene which encodes a zinc-finger protein involved in transcriptional regulation.^{60. and 67.} The oncogenic capability of PLAG1 is mediated, in part, by the IGF-II mitogenic signaling pathway. ⁶⁸ This gene also plays a role in other human tumors, such as hepatoblastoma and acute myeloid leukemia. ⁶⁸

Lipoblastomas are light yellow to tan-yellow tumors, averaging 5 cm in greatest diameter, with focal gelatinous areas on the cut surface. Larger variants have been reported. ⁶⁰ They are usually thinly encapsulated.

The treatment of choice for the localized variant is complete yet conservative surgical excision, ⁵⁸ while for the diffuse variant complete excision may not be possible. Local recurrence has been reported in up to 22% of patients, especially with incompletely excised lesions of the lipoblastomatosis (diffuse) subtype. ⁶⁹

Lipofibromatosis is a rare pediatric neoplasm, with a propensity for the hands and feet, which occurs in the subcutis and deep soft tissues. ⁷³ It may be present at birth. Similar cases have been diagnosed in the past as infantile fibromatosis, fibrous hamartoma of infancy, and fibrosing lipoblastoma. Regrowth or persistence of the tumor is common following incomplete excision. ⁷³

This tumor, reported by Browne and Fletcher in 2006 (with English spelling of two of the words in the title), ⁷⁴ is the same entity as a hemosiderotic fibrohistiocytic lipomatous lesion reported a few years earlier. ⁷⁵ Although originally regarded as reactive in nature (sometimes to trauma), it is now thought to be neoplastic because of its infiltrative border and local recurrence in some cases. No metastasis has been reported. ⁷⁴

Most cases have been reported in the ankle/foot region, but unlike lipofibromatosis, there is a predilection for middle-aged and elderly individuals. ⁷⁴ Lesions range in size from 1 to 13 cm. They are situated in the superficial soft tissues/subcutis. Grossly the lesions are fatty/gelatinous or lipoma-like.

Although Folpe and Weiss have regarded this lesion as a precursor of pleomorphic hyalinizing angiectatic tumor, ⁷⁶ this concept is not supported by Browne and Fletcher. ⁷⁴

The term ‘pseudolipomatosis cutis’ was coined by Trotter and Crawford for the incidental finding of grouped and coalescent spaces in the dermis resembling fatty infiltration. ⁷⁸ Similar changes have been reported in acrodermatitis chronica atrophicans (see p. 580) and in a case of psoriasis (see p. 79). ⁷⁹ Although Trotter and Crawford regarded these spaces as artifactual, subsequent correspondence refuted this suggestion in favor of a prelymphatic origin. ⁷⁹

Lipomas are relatively common, usually asymptomatic, subcutaneous tumors with a predilection for the upper trunk, upper extremities, thighs, and neck of individuals in the fifth and sixth decades. ⁸⁰ Lesions on the finger are very rare.^{81.82. and 83.} A deep variant arising on the forehead has been described. ⁸⁴ Intramuscular lipomas may occur at other sites. ⁸⁵ Lipomas account for 90% or more of tumors of fat seen in most laboratories. They are soft, often mobile, encapsulated tumors of varying size, but averaging 3–5 cm in diameter. ‘Giant’ variants have been recorded. ⁸⁶ Blunt trauma has been suggested as an etiological factor in some cases, but pseudo-lipomas from prolapse of fat may be difficult to distinguish from true lipomas in these circumstances.^{87. and 88.} Multiple lipomas have developed after total body electron beam therapy. ⁸⁹ Ectopic axillary breast tissue may mimic a lipoma. ⁹⁰

There are several distinct clinical syndromes in which disfiguring masses of mature adipose tissue develop in the subcutaneous tissues. They are discussed in some detail by Allen. ⁹¹ In benign symmetric lipomatosis (multiple symmetric lipomatosis/Madelung’s disease/Launois–Bensaude syndrome – OMIM 151800), the tumors develop on the neck, back, and upper trunk, with a predilection for middle-aged men.^{92.93.94.95.96.97. and 98.} Variants involving the hands, ⁹⁹ the thighs, ¹⁰⁰ or the feet¹⁰¹ have been reported. The distinction between obesity and localized (zonal) variants of the buttocks and thighs is often problematic in females. ¹⁰² Familial cases have also been recorded, but no pattern of inheritance has been delineated. Some cases have been associated with the mitochondrial DNA syndromes. ¹⁰³ Various metabolic abnormalities may occur in this condition,^{104. and 105.} and there is sometimes alcohol-related liver disease, suggesting that alcoholism may be a trigger.^{102.106.107.108. and 109.} A case with lipoatrophy of the face, mimicking HAART-related lipodystrophy (see below), has been reported. ¹¹⁰ In familial multiple lipomatosis,^{106.111.112. and 113.} multiple discrete, usually asymptomatic, lipomas develop on the forearms, trunk, and thighs in the third decade. Non-symmetrical lesions may be present. ¹¹⁴ An autosomal dominant inheritance has been proposed, despite the predominance in males. The gene map locus is 12q14.3. Reciprocal translocations have been reported in the lipomas that develop in familial multiple lipomatosis (OMIM 151900). The masses are encapsulated and vary from a few millimeters to 5 cm or more in diameter. In adiposis dolorosa (Dercum’s disease – OMIM 103200) there are painful, circumscribed or diffuse fatty deposits with a predilection for the lower legs, abdomen, and buttocks.^{115. and 116.} There may be obesity, weakness, and mental disturbances. Familial cases related to an autosomal dominant gene with variable expressivity have been reported.^{117. and 118.} Juxta-articular fatty deposits, resembling those seen in adiposis dolorosa, have been reported in a patient receiving long-term treatment with high doses of corticosteroids. ¹¹⁹Diffuse lipomatosis^{63.120.121. and 122.} consists of infiltrating masses of mature adipose tissue, extensively involving part of a limb or the trunk, with onset before 2 years of age. It has been associated with tuberous sclerosis. ¹²⁰ In encephalocraniocutaneous lipomatosis^{123.124.125. and 126.} there are subcutaneous lipomas on the scalp with overlying alopecia, as well as cranial and ocular abnormalities. The cutaneous component has been called ‘nevus psiloliparus’.^{127.128. and 129.} Infiltrating lipoma of the face¹³⁰ is another variant of this hamartomatous condition. The term has also been used for intermuscular and intramuscular lipomas. ¹³¹ Other variants of infiltrating lipoma occur. ¹³²Lipedematous scalp refers to a thickening of the subcutaneous fat of the scalp, leading to a clinically thickened and soft scalp.^{133. and 134.} It may present as an alopecia (see p. 431).

The use of protease inhibitors in the treatment of human immunodeficiency virus type 1 (HIV-1) may be associated with several abnormalities of fat including subcutaneous lipomas, ¹³⁵ angiolipomas, ¹³⁶ peripheral lipodystrophy (see p. 471), and benign symmetrical lipomatosis. ¹³⁵ Multiple lipomas have developed in a patient undergoing highly active anti-retroviral therapy (HAART) that did not include a protease inhibitor. ¹³⁷

Nearly a half of all lipomas have an abnormal karyotype, characterized by rearrangements of three different chromosome regions: 12q14–q15, 6p21, and 13q12–q14. Translocations involving the long arm of chromosome 12 and chromosome 3 (band q27–28) are a common finding, but other chromosome bands may be involved in the translocation. ¹³⁸ At the molecular level, 12q14–q15 rearrangements affect the high-mobility-group (HMG) protein gene HMGIC. Other mesenchymal tumors share abnormalities of this or related genes. ¹³⁸

Although surgical extirpation is the usual method of treatment, liposuction and the injections of phosphatidylcholine have also been used.^{139.140. and 141.} Dramatic reduction in the size of a lipoma has occurred in a patient commenced on statin therapy. ¹⁴² In adiposis dolorosa (Dercum’s disease) intravenous lidocaine, and low-dose, daily prednisolone have helped in some cases. Improvement has been reported with the combined use of infliximab and methotrexate. ¹⁴³ Surgical debulking has produced an acceptable cosmetic result in a patient with lipedematous alopecia. ¹⁴⁴

Angiolipomas are subcutaneous tumors of the extremities and trunk; they comprise approximately 10% of tumors of fat.^{153.154. and 155.} They are often multiple, with the first tumors appearing just after puberty.^{153. and 156.} A family history is found in about 10% of cases (OMIM 206550), but no pattern of inheritance has been proposed. A history of previous trauma to the site or the therapeutic use of protease inhibitors is rarely elicited.^{136. and 157.} Numerous angiolipomas appeared in a young adult male with familial angiolipomatosis upon starting anabolic steroids. ¹⁵⁸ Mild pain or discomfort is often noted when pressure is applied or the lesions are moved; ¹⁵⁹ the pain appears to be related to the vascularity of the lesions.

Subcutaneous angiolipomas have a normal karyotype, setting them apart from most other tumors of fat, including lipomas. ¹⁶⁰ For this reason, they have been regarded as a hamartoma of blood vessels and fat, rather than a true tumor of fat. ⁶

Subcutaneous angiolipomas must be distinguished from the infiltrating angiolipoma, which is a solitary lesion of the deep soft tissues.161. ^{and 162.} It will not be discussed further.

This rare microscopic variant of lipoma, characterized by mature fat admixed with eccrine glands, was first reported in 1993. ¹⁷² It is probably an analogue of adenolipomas reported in other organs. ¹⁷³ The cutaneous variant occurs in the dermis or subcutis with a predilection for the thigh. ¹⁷³ The lip was involved in one case. ¹⁷⁴

On gross examination, they have a soft, yellow, lobulated appearance, often surrounded by a thin capsule. ¹⁷³

The chondroid variant of lipogenic tumor was described by Meis and Enzinger in 1993. ¹⁷⁶ The lesion is usually deep seated, although subcutaneous variants occur. It has a predilection for females. The lower extremity is the most common location. Its histogenesis is disputed. One view is that the lesion is composed only of white adipocytes, but the other view suggests that the cells have features of embryonal fat and, to a lesser extent, embryonal cartilage. ¹⁷⁷ A cytogenetic study has shown a three-way translocation between chromosomes 1, 2, and 5 together with an 11;16 translocation with a breakpoint in 11q13. ¹⁷⁸

Chondroid lipomas are firm yellow tumors averaging 3–5 cm in diameter.

Ossification is another change that can be seen in lipomas. Only 25 cases of this rare phenomenon had been reported by late 2007. ¹⁸⁰ They arise in the subcutaneous and deeper fat of the trunk, the extremities or the head and neck region. ¹⁸⁰ No recurrences have been recorded. Ossification may be secondary to the long duration of the underlying lipoma.

Sclerotic lipoma, first described by Zelger and colleagues in 1997, is a further rare variant of lipoma. ¹⁸¹ It shows prominent stromal sclerosis. It is more common in males. There is a predilection for the distal extremities, particularly the fingers.^{181. and 182.} The scalp has also been involved. ¹⁸³ Excision is usually curative. ¹⁸²

Spindle-cell lipoma is a slow-growing benign tumor of the subcutis. It primarily affects the shoulders, upper back, and back of the neck of men in the fifth to seventh decades.^{185. and 186.} Fewer than 10% of cases occur in women. ¹⁸⁷ Uncommonly, the tumors arise on the extremities, ¹⁸⁵ lower trunk, ¹⁸⁸ oral cavity, ¹⁸⁷ and the head.^{189. and 190.} They are generally painless. Multiple lesions are rare; the clinical presentation of such cases may mimic symmetrical lipomatosis (see above). ¹⁹¹ Some cases are familial. ¹⁹¹ Cytogenetic studies generally show monosomy 16 or partial loss of 16q, a finding distinct from liposarcoma. ⁶ Anomalies of chromosome 13 have also been reported. ¹⁹² There is a view that spindle-cell lipoma and pleomorphic lipoma form a spectrum of adipose tumors, which is supported by the finding of similar cytogenetic abnormalities.^{193. and 194.}

Macroscopically, the tumors are soft, oval, lobular masses with an average diameter of 5 cm. They are yellow or gray-yellow in color, and sometimes have a glistening or mucoid appearance on the cut surface.

Pleomorphic (giant-cell) lipoma is a benign tumor of adipose tissue with atypical histological features that may lead to a misdiagnosis of liposarcoma.^{205. and 206.} It presents as a soft subcutaneous mass, averaging 5 cm in diameter. A case confined to the dermis has been reported. ²⁰⁷ Pleomorphic lipoma has a predilection for the shoulders, back of the neck, back^{205. and 208.} and, less frequently, the face and thighs²⁰⁹ of middle-aged to elderly males. ²⁰⁵ Pleomorphic lipomas resemble spindle-cell lipomas cytogenetically with a consistent loss of chromosome 16q material. ⁶ For this reason, these two entities are often regarded as forming a spectrum of related adipose tumors. ¹⁹⁴ Macroscopically, the tumor resembles a lipoma, although gelatinous gray areas may be present on the cut surface. Some of the reported cases of atypical lipoma are examples of this entity.^{210. and 211.}

Hibernoma is a rare benign tumor of the subcutaneous²¹⁴ and deeper soft tissues, ²¹⁵ generally considered to arise from brown fat. It is found in the scapular area, axilla, ²¹⁶ lower neck²¹⁴ and, less commonly, in the thigh,^{217. and 218.} abdominal wall, ²¹⁹ and retroperitoneum. ²²⁰ It grows slowly. There may be increased warmth over the area. ²²¹ Cytogenetic studies have shown rearrangements in the 11q13 region, frequently including deletions in the region between PLCB3 and PPP1A, leading to loss of the MEN1 gene.^{178. and 222.} In addition, abnormalities involving chromosome 10q22 have been reported. ⁶

Grossly, hibernomas are tan-brown lobulated tumors, averaging 10 cm in diameter. Several possible malignant variants have been reported, but these have been disputed by others.^{214. and 223.}

This category of fatty tumors is not a distinct entity, but the name given by Allen and colleagues to borderline lesions seen in a consultation practice. ²²⁶ The term ‘atypical lipomatous tumor’ is also used. ²²⁷ It comprises a histological spectrum ranging from atypical fibrolipomas, through various mixed spindle-cell and pleomorphic lipoma patterns, to tumors indistinguishable from dedifferentiated liposarcomas.^{226. and 228.} Of interest is the extremely good prognosis of atypical lesions confined to the subcutaneous fat, despite sometimes alarming histological features, including the presence of lipoblasts. ²²⁶ Local recurrence can occur.

The use of cytogenetics has allowed better, and often specific, characterization of tumors in this group. ²²⁹

Liposarcoma is the most common soft tissue tumor accounting for 16–18% of all malignant soft tissue sarcomas. ²³⁰ Only rarely do they arise in the subcutis or dermis, although they may eventually extend into it from below.^{231.232. and 233.} Accordingly, they will be considered only briefly. They have a predilection for the thighs and buttocks, but may sometimes involve the head and neck^{234. and 235.} or upper extremities. They arise in older adults, and are exceedingly rare in children.^{63. and 236.} Although a few cases have developed in patients with multiple lipomas, liposarcomas are not thought to arise from pre-existing lipomas.^{231. and 237.} They are often large and non-encapsulated, varying in color from yellow to gray, to gray-white. There may be some firmer areas and gelatinous foci in the generally soft tissue.

In 1998, primary liposarcoma of the skin (dermis) was described. ²³⁸ Four of the seven cases arose on the scalp. The median age of the patients was 72 years. Local recurrence occurred in two patients, but no metastases or disease-related deaths were recorded. ²³⁸ Since that time, a purely intradermal pleomorphic liposarcoma has been reported on the nose of an elderly female, ²³⁹ and Fletcher and colleagues have reviewed a series of 57 cases of pleomorphic liposarcoma 16 of which were superficial (dermal or subcutaneous). ²⁴⁰ Only two of these superficial lesions metastasized. ²⁴⁰

Cytogenetic studies have shown clonal karyotypic abnormalities, which often correlate with the histological subtype. ²⁴¹ For example, the myxoid liposarcoma often demonstrates a reciprocal translocation t(12;16)(q13;p11) that fuses the DDIT3 (CHOP) gene with FUS.^{241.242.243.244.245.246. and 247.} An EWSR1-DDIT3 fusion transcript has rarely been described in myxoid liposarcoma. ²⁴⁷ A similar chromosomal abnormality has been found in the round cell liposarcoma, suggesting that this variant is a poorly differentiated form of myxoid liposarcoma.^{248. and 249.} The well-differentiated liposarcoma (including sclerosing, inflammatory and dedifferentiated variants) is characterized by ring or long marker chromosomes derived from chromosome 12.^{246. and 250.} These long and/or ring chromosome markers are composed of 12q13–q15 amplicons with a constant amplification of the MDM2 gene and frequently CDK4.^{251.252.253. and 254.} Immunohistochemistry can be used to detect these markers, allowing differentiation from lipomas and in the case of the dedifferentiated variants from other pleomorphic sarcomas (see below).^{229.251. and 255.} The pleomorphic liposarcoma has complex karyotypes. ²⁵⁶