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Background
Cutaneous xanthomas are often a manifestation of underlying lipid abnormalities. There are many different types classified both by clinical and histopathologic criteria.
OUTLINE
Epidemiology Disease Associations Pathogenesis Laboratory/Radiologic/
Other Diagnostic TestingGross Appearance and Clinical Variants Bone
Breast
Cerebrotendinous
Eruptive
TuberousHistopathological Features and Variants Papular
Plexiform xanthomatous
Tuberous
VerruciformSpecial Stains/
Immunohistochemistry/
Electron MicroscopyDifferential Diagnosis Prognosis Treatment Commonly Used Terms Internet Links
PATHOGENESIS CHARACTERIZATION VASCULAR ENDOTHELIAL CELLS
Department of Dermatology, Kochi Medical School, Kochi, Japan.
Background: The migration of circulating monocytes into the dermis is considered to be essential for both the initiation and the progression of xanthoma. The contribution of vascular endothelial cells to the migration process is unclear. Methods: Twenty cases of xanthelasma and six cases of tuberous xanthoma lesions were analyzed using immunohistochemical staining.
Results: Xanthoma lesions contained up to 25-fold more von Willebrand factor-stained endothelial cells than normal skin. The prevalence of E-selectin-positive endothelial cells increased by up to threefold more in xanthoma lesions than in normal skin. In contrast, the prevalence of intercellular cell adhesion molecule-1 (ICAM-1) decreased up to 3.5-fold more in xanthoma lesions than in normal skin. In xanthoma lesions, almost all ICAM-1-positive endothelial cells co-expressed with E-selectin but many endothelial cells, which only expressed E-selectin, were also found in the lesions and the ratio of macrophages to endothelial cells was higher (10:1) than that in normal skin (5:1).
Conclusions: Endothelial cells proliferate and express E-selectin rather than ICAM-1 under a microenvironment in which macrophages predominate rather than endothelial cells, thereby promoting macrophage migration into xanthoma lesions.
HISTOLOGICAL TYPES CHARACTERIZATION GENERAL Lipid laden histiocytes arranged diffusely within the dermis
May be associated with extracellular lipid
VARIANTS PAPULAR
Papular xanthoma: a clinicopathological study of 10 cases.Breier F, Zelger B, Reiter H, Gschnait F, Zelger BW.
Department of Dermatology, Lainz Municipal Hospital, Vienna and the Departments of Pathology and Dermatology, University of Innsbruck, Austria.
J Cutan Pathol 2002 Apr;29(4):200-6 Abstract quote Background: Papular xanthoma (PX) is one of several clinicopathologic variants of normolipemic cutaneous non-Langerhans cell histiocytoses (n-LCH). PX represents a monomorphous reaction pattern of n-LCH characterized by the presence of predominantly xanthomatized macrophages.
Objective: The purpose of this study was to identify the clinical, histological and immunohistochemical characteristics of PX.
Methods: A series of 10 cases of PX was identified and the results compared with the other histologic subtypes, namely the polymorphous and the remaining other monomorphous reaction patterns in n-LCH.
Results: In this clinicopathologic study, papular xanthoma presented clinically mainly as solitary papule, with a male to female ratio of4 : 1, in an age range from 13 to 57 years and a biphasic occurrence: in the young adolescence and middle ages. It was predominantly located on the trunk, the extremities, and rarely on the head. Clinically, PX was described as xanthoma, 'cutaneous tumor', but also as atheroma, keloid, histiocytoma, Spitz's nevus or clear cell acanthoma. Histology showed moderately well circumscribed exoendophytic papules with a regular epidermis and a dense infiltration of xanthomatized macrophages interspersed by numerous Touton type giant cells. Immunohistochemically mono- and multinucleated macrophages were consistently positive with KiM1p; while only giant cells were labeled with KP1 (CD68), the reactivity with HAM 56 was much more variable. Up to 50% of the xanthomatized cells labeled positive for the lectin peanut agglutinin. In one case the xanthomatized cells stained positive for CD34. Staining for factor XIIIa and CD1a were negative.
Conclusions: This series confirms PX as a rare, but distinguished clinicopathologic entity in the spectrum of n-LCH of the skin.
PLEXIFORM XANTHOMATOUS TUMOR
Plexiform xanthomatous tumor: a report of 20 cases in 12 patients.Michal M, Fanburg-Smith JC.
Am J Surg Pathol 2002 Oct;26(10):1302-11 Abstract quote We present 12 patients with 20 plexiform xanthomatous tumors (PXTs). All patients were male. Patient ages ranged from 20 to 59 years (mean 45 years). Clinical information was available for 11 (92%) patients. Only one patient with markedly elevated cholesterol levels had a family history of hypercholesterolemia; none of the others had a family or personal history of diabetes mellitus, hypercholesterolemia, or hyperlipoproteinemia.
Three patients had markedly elevated serum triglyceride levels. The tumors were solitary in seven patients and multiple in five patients: three patients had two tumors, one presented had three, and one had four. PXTs were located on the knee (n = 8), elbow (n = 5), foot or hand (n = 3), and one each on the Achilles tendon, buttock, toe, and back. PXT was white to yellow in color and ranged in size from 0.7 to 5 cm (mean 2.7 cm). The tumors were located in the dermis and subcutis, had a distinctive plexiform arrangement, and were composed of various admixtures of uniform epithelioid and xanthomatous cells. All tumors in patients with solitary or multiple lesions had a plexiform architecture.
Most of the nodules of the plexiform pattern of PXTs measured 0.5-2 mm. Rarely cholesterol clefts, necrosis, sparse inflammation, and multinucleated Touton giant cells were present. In two patients with multiple tumors, the PXT completely lacked the xanthoma cells and thus resembled an epithelioid lesion. Immunohistochemically, all lesions were KP1 (CD68) and vimentin positive and lysozyme, S-100 protein, HMB-45, epithelial membrane antigen, cytokeratins, factor VIIIrag, CD34, muscle-specific actin, alpha-smooth muscle actin, desmin (D33), desmin (Der-11), chromogranin, synaptophysin, neurofilament protein, and glial fibrillary acidic protein negative. Two patients with multiple lesions noted recurrences over 10 years. With the exception of one patient who died of an unknown cause, all 10 patients with follow-up were alive, some with residual disease, over a mean of 9 years (range 1-25 years).
Some PXTs may represent a morphologic variant of tuberous or tendinous xanthoma, yet its exclusive occurrence in men, absence of personal/familial hyperlipemia/hypercholesterolemia in some patients, and relative paucity of inflammation and cholesterol clefts may make this a distinctive entity.
TUBEROUS Loosely arranged lipid laden histiocytes arranged in multinodular pattern Am J Dermatopathol 1994;16:532-536
Plexiform variantVERRUCIFORM Am J Dermatopathol 2000;22:447-452
Association with Human Papilloma Virus type 6-only known case
J Cutan Pathol. 2006 May;33(5):373-7. Abstract quote
Verruciform xanthoma is xanthomatous dermal infiltrate in a proliferating epidermal lesion and is an uncommon phenomenon. It has been reported in various neoplastic or inflammatory conditions.
We report a 72-year-old man who had an asymptomatic 1-cm black nodule on his abdomen. Histopathology showed a typical acanthotic type of seborrheic keratosis characterized by basaloid keratinocyte proliferation and pseudohorn cysts. Many aggregated xanthomatized cells were seen in dermal papillae within the acanthotic epithelium. Papillomatosis, parakeratosis, and neutrophil infiltrates, the histologic features of typical verruciform xanthoma, were not seen. The foamy cells were positive for CD-68 and vimentin and negative for cytokeratin and S-100. No human papillomavirus DNA was found by nested polymerase chain reaction. The blood lipid profile was normal.
The presence of verruciform xanthomatous change in seborrheic keratosis provides further evidence that verruciform xanthoma may be a reactive phenomenon occurring in common skin disorders.
- A novel somatic mutation of the 3beta-hydroxysteroid dehydrogenase gene in sporadic cutaneous verruciform xanthoma.
Mehra S, Li L, Fan CY, Smoller B, Morgan M, Somach S.
Department of Pathology, MetroHealth Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio 44109, USA.
Arch Dermatol. 2005 Oct;141(10):1263-7. Abstract quote
OBJECTIVE: To analyze the 3beta-hydroxysteroid dehydrogenase (NSDHL) gene in verruciform xanthoma (VX) to elucidate its potential role in the histogenesis of this lesion.
DESIGN: DNA was extracted from paraffin-embedded tissue, followed by polymerase chain reaction amplification of exons 4 and 6 of the NSDHL gene. The polymerase chain reaction products were then directly sequenced and analyzed for the presence of somatic mutations.
PATIENTS: Nine lesions of VX from 8 patients and 3 unrelated normal controls were evaluated.
RESULTS: Two of 9 VXs (22%) demonstrated a novel somatic missense mutation in exon 6 of the NSDHL gene. The mutation was not present in the remaining 7 lesions of VX, nonlesional internal controls, and 3 unrelated normal controls. No mutation of exon 4 was found in any case. Mutations of exons 4 and 6 previously identified in CHILD syndrome were not seen in our cases.
CONCLUSIONS: (1) A novel missense mutation (R199H) in exon 6 of the NSDHL gene was identified in a small subset of sporadic VXs. (2) Known CHILD syndrome mutations in exons 4 and 6 of the NSDHL gene do not contribute to the histogenesis of sporadic VXs.
APMIS. 2005 Sep;113(9):629-34. Abstract quote
Verruciform xanthoma is a rare condition that was first reported in the oral cavity in 1971. Its histopathology is distinctive on account of the presence of foamy histiocytes within elongated dermal papillae.
Three cases of oral mucosal verruciform xanthoma were studied. Immunohistochemical staining by streptavidin-peroxidase and in situ hybridization to detect human papillomavirus (HPV types 6, 11, 16, 18) DNA and matrix metalloproteinase (MMP-2, -9) RNA were performed to investigate the pathogenesis of verruciform xanthoma. This study showed that the foam cells were strongly positive for CD68 (KP1) and vimentin. Cytokeratin, PCNA and S-100 stained focally negative in foam cells. In situ hybridization failed to detect HPV (types 6, 11, 16, 18) in any of the three cases.
Based on our findings we conclude that verruciform xanthoma is most likely not a human papillomavirus-associated lesion; the foam cells, as a histological hallmark of the lesion, are most likely derived from the monocyte-macrophage lineage, and verruciform xanthoma is, at least partly, mediated by an immune mechanism. MMPs degrade basilar membrane that promotes the reciprocal induction between epithelium and mesenchyme. However, as yet unrecognized factors may play a role in the development of epithelium-mesenchyme reciprocal induction.
J Dermatol. 2005 Jun;32(6):464-8 Abstract quote.
A 52-year-old man presented to our department with a scrotal skin nodule, first noted as a papule two to three years previously. The nodule was red and pedunculated with a granular surface and a diameter of 10 mm. Three red papules were scattered around the nodule.
Histopathologic examination of the nodule showed epidermal papillary hyperplasia, collections of foam cells in the papillary dermis, and a dense infiltration of inflammatory cells into all dermal layers. In addition, granular degeneration was seen in the pedunculated lesion of the nodule free from the foam cells. Microscopic examination of the red papules also showed granular degeneration. The patient was diagnosed with verruciform xanthoma associated with isolated epidermolytic acanthoma.
This is the first report of these two lesions occurring at the same site on the scrotum.Verruciform xanthoma of the skin.
Barr RJ, Plank CJ.
J Cutan Pathol 1980 Dec;7(6):422-8 Abstract quote
Verruciform xanthoma is an unusual lesion characterized by verrucous epithelial proliferation accompanied by a prominent replacement of the dermal papillae with large numbers of foamy histiocytes.
Cases have been previously reported only as occurring in the oral cavity or, more rarely, on the vulva. A 16-year-old girl developed a verruciform xanthoma of the skin. The lesion appeared to arise within a large epithelia nevus involving the left inner thigh and inguinal area.
This association supports the concept that verruciform xanthoma is a rare inflammatory reaction pattern that may be seen in a variety of squamous epithelial lesions characterized by verrucous hyperplasia.
A giant verruciform xanthoma
Neera Agarwal-Antal
James Zimmermann
Theresa Scholz
R. Dirk Noyes
and Sancy A. Leachman
J Cutan Pathol 2002;29:119-124 Abstract quote
Background:Verruciform xanthoma (VX) is a rare, benign neoplasm arising predominantly in the oral cavity, but it has been reported to occur on the genital skin and mucosa as well. VX has also been described in association with epidermal nevi and squamous cell carcinoma. Because of the clinical and histologic similarities between VX and condyloma acuminata, and a recent report of HPV 6 in association with VX, we investigated the role of human papilloma virus (HPV) in the development of this entity.Methods:In situ hybridization and a nested PCR approach utilizing degenerate primers were utilized to establish whether HPV infection could be playing a role in the development of the VX.
Results:In situ hybridization failed to identify HPV DNA. The highly sensitive nested PCR approach also failed to detect HPV DNA.
Conclusions:The failure to detect HPV DNA, even by very sensitive methods, provides strong evidence that our case of VX is not an HPV-induced lesion. A review of other possible etiologies, including alternative infectious agents and genetic associations, are discussed.
SPECIAL STAINS/
IMMUNOPEROXIDASE/
OTHERCHARACTERIZATION Special stains Immunoperoxidase Positive for CD68, KP-1
PROGNOSIS AND TREATMENT CHARACTERIZATION Treatment Treatment of the underlying hyperlipidemic state Macpherson and Pincus. Clinical Diagnosis and Management by Laboratory Methods. Twentyfirst Edition. WB Saunders. 2006.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.
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