Cutaneous xanthomas are often a manifestation of underlying lipid abnormalities. There are many different types classified both by clinical and histopathologic criteria.
Epidemiology Disease Associations Pathogenesis Laboratory/Radiologic/
Other Diagnostic Testing
Gross Appearance and Clinical Variants Bone
Histopathological Features and Variants Papular
Differential Diagnosis Prognosis Treatment Commonly Used Terms Internet Links
PATHOGENESIS CHARACTERIZATION VASCULAR ENDOTHELIAL CELLS
- Vascular endothelial cell distribution and adhesion molecule expression in xanthoma.
Department of Dermatology, Kochi Medical School, Kochi, Japan.
- J Cutan Pathol. 2007 Oct;34(10):754-61. Abstract quote
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.
CHARACTERIZATION General VARIANTS ADULT ORBITAL XANTHOGRANULOMATOUS DISEASE
Adult orbital xanthogranulomatous disease: review of the literature.
Guo J, Wang J.
Department of Pathology and Laboratory Medicine, Loma Linda University Medical Center, Loma Linda, California 92354, USA.
Arch Pathol Lab Med. 2009 Dec;133(12):1994-7. Abstract quote
This article provides an overview of the pathologic features of adult orbital xanthogranulomatous disease, a rare heterogeneous group of disorders that includes 4 clinical syndromes: adult-onset xanthogranuloma, necrobiotic xanthogranuloma, adult-onset asthma and periocular xanthogranuloma, and Erdheim-Chester disease. The diagnosis is made by biopsy of the lesion, demonstrating tissue infiltration by the hallmarks of xanthoma cells and Touton giant cells. The differential diagnosis is broad, including syndromes within the adult xanthogranulomatous disease category as well as other entities involving the eyelid and the orbital tissues.
Because of its rarity and sometimes close similarity to other disease entities, it is often misdiagnosed initially. This article focuses on the morphology and immunohistochemical patterns in diagnosis of adult orbital xanthogranulomatous disease with emphasis on adult-onset asthma and periocular xanthogranuloma in particular, its clinical features and associated systemic manifestations in differential diagnosis, as well as the current management strategy.
Benign fibrohistiocytoma (xanthomatous variant) of the acromion. A case report and review of the literature.
Macdonald D, Fornasier V, Holtby R.
Department of Anatomical and Clinical Pathology, Sunnybrook & Women's College Health Sciences Centre, Toronto, Ontario, Canada.
Arch Pathol Lab Med 2002 May;126(5):599-601Abstract quote
A number of fibrous lesions involving bone display almost identical histologic appearances yet may represent either reactive or neoplastic conditions, resulting in a confusing nomenclature and possible diagnostic confusion.
We report the case of a young man with no significant previous medical history who presented with a painful lesion in the left shoulder, which consisted almost entirely of xanthomatous material. We discuss the possible differential diagnosis of this lesion and why benign fibrous histiocytoma is the preferred terminology for this lesion.
To our knowledge, this is the first reported case of a benign fibrous histiocytoma involving the acromion in an adult.
BREAST XANTHOMATOUS PSEUDOTUMOR
Tan KB, Thamboo TP, Raju GC.
Department of Pathology, National University Hospital, National University of Singapore, Singapore.
Arch Pathol Lab Med 2003 Jun;127(6):739-41 Abstract quote
Neoadjuvant chemotherapy has become an integral part of the treatment for locally advanced breast cancer. It facilitates tumor resectability and also provides an opportunity for the assessment of therapeutic response and prognosis.
We report a case in which a large primary breast carcinoma was significantly reduced in size clinically and replaced by a mass lesion that was composed almost entirely of foamy histiocytes.
This peculiar phenomenon is described in detail, together with a brief review of the other known postchemotherapy histologic features that include tumor necrosis, tumor cell cytoplasmic vacuolation and marked nuclear atypia, accompanying chronic inflammatory cellular infiltrate, fibrosis, and ductal-lobular atrophy.
Cerebrotendinous xanthomatosis: a rare disease with diverse manifestations.
Moghadasian MH, Salen G, Frohlich JJ, Scudamore CH.
Healthy Heart Program, St Paul's Hospital, Suite 180, 1081 Burrard St, Vancouver, British Columbia, Canada V6Z 1Y6
Arch Neurol 2002 Apr;59(4):527-9 Abstract quote
This mini-review deals with a new appraisal of cerebrotendinous xanthomatosis. In addition to neurologic symptoms, patients with cerebrotendinous xanthomatosis develop cataracts, diarrhea, Achilles tendon xanthoma, atherosclerotic vascular disease, and many other abnormalities.
Although the pathophysiology of the disease is not completely understood, excess production and consequent accumulation of cholestanol in tissues may play a crucial role. Chenodeoxycholic acid is the most effective therapy.
The causative role and detrimental effects (at a low plasma level) of cholestanol merit further investigation.
Susana Bel, MD, etal.
J Am Acad Dermatol 2001;45:292-5 Abstract quote
Cerebrotendinous xanthomatosis is a rare autosomal recessive lipid-storage disease caused by mutations in the sterol 27-hydroxylase gene. The accumulation of cholestanol in various tissues characterizes this disease. Diagnosis is based on determination of urinary bile alcohols. Therapy with chenodeoxycholic acid may arrest the progression of the disease.
A 55-year-old woman presented with a slowly progressive paraparesia and two firm subcutaneous tumors over the knees. Her medical history revealed difficulty in standing and walking since infancy, bilateral juvenile cataracts, and mental retardation. Histopathologic examination of one subcutaneous tumor was consistent with tendinous xanthoma. Substantial elevation of urinary bile alcohols confirmed the diagnosis. Treatment with oral chenodeoxycholic acid was started, with only mild improvement of spasticity.
Recognition of tendon xanthomas in a young patient with neurologic symptoms or cataracts (or both) is crucial to start early treatment and to avoid irreversible neurologic sequelae.
Treatment of cerebrotendinous xanthomatosis with chenodeoxycholic acid in three siblings.
Chang WN, Kuriyama M, Chee EC.
Department of Neurology, Chang Gung Memorial Hospital, Kaohsiung, Hsien, Taiwan, R.O.C.
J Formos Med Assoc 1994 Mar;93(3):256-9 Abstract quote
We investigated the therapeutic effect of chenodeoxycholic acid (750 mg/day) in three siblings with cerebrotendinous xanthomatosis. All three siblings had characteristic clinical manifestations, abnormal findings of magnetic resonance imaging and electroencephalogram, and high serum levels of cholestanol, cholesterol precursor (lathosterol), and plant sterols (campesterol, sitosterol). After treatment for one year, the serum levels of these sterols were decreased and some neurologic improvements in the pyramidal tract signs and cerebellar signs were noted.
The electroencephalographic findings were markedly changed and normalized. However, mental defects and sensorimotor polyneuropathy still remained. No changes of neuroradiologic features could be detected. A longer period of treatment is required to estimate the overall effects of chenodeoxycholic acid in patients with cerebrotendinous xanthomatosis.
Treatment of cerebrotendinous xanthomatosis with low-density lipoprotein (LDL)-apheresis.
Mimura Y, Kuriyama M, Tokimura Y, Fujiyama J, Osame M, Takesako K, Tanaka N.
Third Department of Internal Medicine Kagoshima University School of Medicine, Japan.
J Neurol Sci 1993 Feb;114(2):227-30 Abstract quote
We studied the effects of LDL-apheresis on the biochemical and clinical abnormalities of 5 patients with cerebrotendinous xanthomatosis (CTX). Levels of both cholestanol and cholesterol decreased to approximately 60% of those of pretreatment after one perfusion and gradually returned to their initial levels within 2 weeks.
Improvement of clinical manifestations and regression of Achilles tendon xanthomas were detected after several perfusions, though dramatic changes could not be recognized. EEG abnormalities were improved immediately after LDL-apheresis in one patient.
We conclude that LDL-apheresis may affect the serum cholestanol level and clinical manifestations in patients with CTX.
Treatment of cerebrotendinous xanthomatosis with chenodeoxycholic acid.
Pedley TA, Emerson RG, Warner CL, Rowland LP, Salen G.
Ann Neurol 1985 Oct;18(4):517-8 Abstract quote
We describe a patient with cerebrotendinous xanthomatosis who was treated for one year with chenodeoxycholic acid.
Modest clinical improvement was accompanied by marked improvement in visual and brainstem auditory evoked potentials. Improved central nervous system function coincided with return of plasma and cerebrospinal fluid cholestanol levels to normal.
J Am Acad Dermatol 1995;33:834-835
Crops of small, yellow papules with an erythematous halo around the base, usually occurring over pressure points on extensor surfaces and buttocks
May be associated with prior injury, scar, or Koebnerize
Associated with hyperlipoproteinemia with elevated triglycerides, VLDL, chylomicrons
Types I, IV, V
May lead to acute pancreatitis
TUBEROUS Dorsal aspects of joints
Usually associated with hyperlipidemic state
HISTOLOGICAL TYPES CHARACTERIZATION GENERAL
Lipid laden histiocytes arranged diffusely within the dermis
May be associated with extracellular lipid
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
VERRUCIFORM 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
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.
CHARACTERIZATION 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.
Soft tissue tumors
Basic Principles of Disease
Learn the basic disease classifications of cancers, infections, and inflammation
Commonly Used Terms
This is a glossary of terms often found in a pathology report.
Learn how a pathologist makes a diagnosis using a microscope
Surgical Pathology Report
Examine an actual biopsy report to understand what each section means
Understand the tools the pathologist utilizes to aid in the diagnosis
How Accurate is My Report?
Pathologists actively oversee every area of the laboratory to ensure your report is accurate
Recent teaching cases and lectures presented in conferences
Last Updated 12.09.2009
Send mail to The Doctor's Doctor with questions or comments about this web site.
Read the Medical Disclaimer.
Copyright © The Doctor's Doctor