Dermatofibrosarcoma protuberans

Dermatofibrosarcoma protuberans Microchapters
Overview
Classification
Pathophysiology
Epidemiology and Demographics
Risk Factors
Diagnosis
Treatment
Differential Diagnosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sara Mohsin, M.D.[2], Kiran Singh, M.D. [3], Faizan Sheraz, M.D. [4]

Synonyms and keywords: Darier-Ferrand tumor, Darier-Hoffmann tumor, Dermatofibrosarcoma, DFSP, Intermediate fibrous histiocytoma, Borderline fibrous histiocytoma

Overview

Dermatofibrosarcoma protuberans (DFSP) is a rare non-hereditary neoplasm of the dermis layer of the skin which is sometimes described as having the tentacles growing into the surrounding fat, muscle and even bone and is therefore, classified as a soft tissue sarcoma. In many respects, the disease behaves as a benign tumor, but in 2-5% of cases it can metastasize, so it should be considered to have a malignant potential. Over 95% of DFSP tumors have the chromosomal translocation t(17;22). The translocation fuses the collagen gene (COL1A1) with the platelet-derived growth factor gene. The fibroblast, the cell of origin of this tumor, expresses the fusion gene in the belief that it is collagen. However, the resulting fusion protein is processed into mature platelet-derived growth factor which is a potent growth factor. Fibroblasts contain the receptor for this growth factor. Thus, the cell "thinks" it is producing a structural protein, but in fact produces a self-stimulatory growth signal. The cell divides rapidly and a tumor forms. In dermatofibrosarcoma protuberans, the tumor has a tendency to return after being removed. However, it does not often metastasize to other parts of the body.

Classification

There are several variants of dermatofibrosarcoma protuberans in which different cell types are involved in the tumor.

Different variants of dermatofibrosarcoma protuberans

Variant subtype	Details
Pigmented dermatofibrosarcoma protuberans (Bednar tumor)	Contains dark-colored, pigmented cells known as melanin-containing dendritic cells Red or brown in color Comprises of 1%-5% of all DFSP cases
Myxoid dermatofibrosarcoma protuberans tumor	Contains an abnormal type of connective tissue known as myxoid stroma Uncommon and difficult to diagnose
Juvenile dermatofibrosarcoma protuberans (Giant cell fibroblastoma)	Called as juvenile because it typically affects children and adolescents Contains giant cells in the tumor
Fibrosarcomatous (FS) Dermatofibrosarcoma protuberans	Appears as regions looking familiar to fibrosarcoma in different types of DFSP More aggressive type of soft tissue sarcoma More likely to metastasize than other types of DFSP

Pathophysiology

Epigenetics

• Dermatofibrosarcoma protuberans is associated with the genetic rearrangement (i.e. translocation) between chromosomes 17 and 22
• t(17;22)(q21;q13.1) leads to fusion of a part of COL1A1 gene from chromosome 17 with a part of the PDGFB gene from chromosome 22
• The translocation is found on one or more extra chromosomes that can be either the normal linear or circular in shape
• Circular extra chromosomes are known as supernumerary ring chromosomes (which form after a chromosome breaks in two places and the ends of the chromosomal arms fuse together to form a circular structure)
• Other genes from chromosomes 17 and 22 can be found on the extra chromosomes, but the role of these genes in the development of this condition is unclear
• Translocation is acquired during a person's lifetime and the chromosomes containing the translocation are present only in the tumor cells, this type of genetic change is known as somatic mutation
• In normal cells, the COL1A1 gene provides instructions for making part of a large molecule called type I collagen, which strengthens and supports many tissues in the body
• The PDGFB gene provides instructions for making one version (isoform) of the platelet derived growth factor (PDGF) protein which by attaching to its receptor, becomes activated and stimulates many cellular processes, including cell growth and division (proliferation) and maturation (differentiation)
• The abnormally fused COL1A1-PDGFB gene provides instructions for making an abnormal combined (fusion) protein that ultimately functions like the PDGFB protein
• This gene fusion leads to the production of an excessive amount of protein that functions like the PDGFB protein
• In excess, this fusion protein stimulates cells to proliferate and differentiate abnormally, leading to the tumor formation as seen in dermatofibrosarcoma protuberans
• COL1A1-PDGFB fusion gene is found in more than 90% of the dermatofibrosarcoma protuberans cases
• In the remaining 10% of the cases, changes in some other unidentified genes may be associated with this condition such as complex t(5;8) involving the CSPG2 and PTK2B genes

Gross Pathology

Gross features of dermatofibrosarcoma protuberans include:

• Nodular, polypoid or plaque-like mass
• Centered in the dermis
• Can also occur in deep soft tissue
• Mean size is 5 cm
• Gray-white, or brown/black in color (if melanocytes are present)
• May appear to be circumscribed
• Rarely shows:
  • Hemorrhage
  • Necrosis

Histopathology

Microscopic features include:

• Non-circumscribed
• Highly cellular with cells having following characteristics:
  • Monomorphic
  • Thin
  • Spindly
  • Scant eosinophilic cytoplasm
  • Hyperchromatic nuclei (resembling neurofibroma)
• Tight storiform pattern (cells radiating in spokes at right angles around a central point that often contains a vessel) infiltrating deeply into subcutaneous tissue and entraping fat cells to form a characteristic honeycomb pattern
• Areas of fascicular growth (seen in some cases)
• The early plaque stage may lack the particular storiform pattern
• Many non-atypical mitotic figures may be present
• Non-polarized, thin collagen
• Mild pleomorphism (not significant)
• Focal atypia
• May coexist with giant cell fibroblastoma
• Absent or rare histiocytes
• Following cell types are absent:
  • Histiocyte-like cells
  • Foam cells
  • Giant cells
  • Other inflammatory cells
• Different variants include:
  • Atrophic (depressed lesion)
  • Collagenous (with central thick collagen bundles)
  • Granular cell (S100 negative)
  • Myxoid
  • Palisading
  • Pigmented
  • Sclerosing

Histopathological image of dermatofibrosarcoma protuberans. Local recurrence long after the first excision. At higher magnification. H&E stain Source: Wikimedia Commons

Histopathological image of dermatofibrosarcoma protuberans. Local recurrence long after the first excision. H&E stain.Source: Wikimedia Commons

Histopathological image of dermatofibrosarcoma protuberans. Local recurrence long after the first excision. H&E stain.Source: Wikimedia Commons

Dermatofibrosarcoma protuberans (DFSP )Source: Wikimedia Commons

Cytology

Cytology of dermatofibrosarcoma has following characteristics:

• Homogeneous
• Isolated spindle cells
• Tissue fragments often present with storiform pattern
• Fibrillary stromal fragments
• Naked nuclei
• Slight to moderate atypia (occasionally)

Electron microscopy

• Stellate or spindle cells are present which have long, slender, ramified cell processes which are joined by primitive junctions, often with subplasmalemmal densities
• Multivesicular buds are also present commonly

Immunohistochemistry

• Immunhistochemical staining of dermatofibrosarcoma protuberans shows:
  • Positive staining for:
    • CD34 (strong in 95%)
    • Vimentin
    • Focal actin
    • ApoD
    • Bcl2
    • NKI-C3
    • CD99
    • CD99
    • Nestin
    • Tenascin
    • CD163
    • Factor XIIIa
    • CD10
  • Negative staining for:
    • Factor XIIIa (usually)
    • Keratin
    • EMA
    • S100
    • HMB45
    • Desmin
    • CD117

Epidemiology and Demographics

• Dermatofibrosarcoma protuberans is estimated to occur in 1 in 100,000 to 1-5 in 1 million people per year
• It usually occurs in adults of 20 - 40 years of age
• It affects twice more commonly the blacks than whites in US
• It can also occur in infants and children
• It has a stable incidence which is highest among women
• Worse survival is associated with:
  • Increased age
  • Male sex
  • Black race
  • Anatomic location of the limbs and head

Risk Factors

• Common risk factors for the development of dermatofibrosarcoma include:
  • A scar developing after surgery or a burn
  • Female sex
  • Age of 30-50 years
  • African-American race (Bendar or pigmented variant)
  • Pregnancy

Diagnosis

History and symptoms

• Symptoms include:
  • Flat or a slightly raised skin patch (first sign)
  • 1 to 5 centimeters in diameter
  • Rubbery (hard to touch)
  • Gives the appearance of a scar or a wrinkled skin patch
  • Skin-colored, violet or reddish-brown
  • Soft, depressed skin area (rarely, makes it difficult to diagnose)
  • Grows very slowly over the period of years

Common sites of involvement

• Tumors commonly involve the following body parts:
  • Torso/trunk (most common)
  • Arms
  • Legs
  • Head
  • Neck

Physical examination

• On physical examination, it can be felt as a small, purplish, reddish, or flesh-colored, flat or raised skin patch or nodule almost 1-5 centimeters in diameter

Skin

Extremities

Dermatofibrosarcoma protuberans.Source: Dermatology Atlas

Dermatofibrosarcoma protuberans.Source: Dermatology Atlas

Dermatofibrosarcoma protuberans.Source: Dermatology Atlas

Trunk

Dermatofibrosarcoma protuberans.Source: Dermatology Atlas

Dermatofibrosarcoma protuberans.Source: Dermatology Atlas

Dermatofibrosarcoma protuberans.Source: Dermatology Atlas

Dermatofibrosarcoma protuberans.Source: Dermatology Atlas

Diagnostic studies

• These include:
  • FNAC
  • Biopsy
  • Immunohistochemistry
    • CD34 staining

Histopathological image of dermatofibrosarcoma protuberans. Local recurrence long after the first excision. CD34 immunostain.Source: Wikimedia Commons

• • MRI
  • CT scan

CT image demonstrating a dermatofibrosarcoma protuberans Source: Wikimedia Commons

CT image demonstrating a dermatofibrosarcoma protuberans in the right groin

Treatment

• Treatment includes:

Treatment options for dermatofibrosarcoma protuberans

Treatment option	Details
Surgery	Mohs micrographic surgery Excisional surgery includes: Removal of subcutaneous fat (i.e. wide local excision with 2 - 3 cm margins) 3-dimensional histological evaluation of margins (necessarily recommended in order to prevent the tumor recurrence)
Targeted therapy	Imatinib-STI571 (tyrosine kinase inhibitor) therapy (may be effective in CD117- tumors) is the gold standard treatment of recurrent or inoperable tumor As imatinib inhibits PDGFB, may be effective for tumors positive for the t(17;22) translocation
Chemotherapy	Less beneficial than targeted therapy
Radiotherapy	May be required sometimes

Differential Diagnosis

Dermatofibrosarcoma protuberans must be differentiated must be differentiated from the following:

• Neurofibroma
• Schwannoma
• Ganglioneuroma
• Dermal neurotized melanocytic nevus
• Myxoid liposarcoma
• Solitary circumscribed neuroma/palisaded encapsulated neuroma
• Traumatic neuroma
• Superficial angiomyxoma
• Nerve sheath myxoma
• Malignant peripheral nerve sheath tumor (MPNST)/malignant schwannoma
• Spindle cell lipoma
• Leiomyoma
• Inflammatory myofibroblastic tumor
• Fibroepithelial polyp/acrochordon (aka skin tag or soft fibroma)

Differentiating neurofibroma from other diseases

Disease entity	Etiology (Genetic or others)	Histopathological findings	Immunohistochemical staining	Risk factors	Common site of involvement	Clinical manifestations	Other associated features
Neurofibroma	Can be sporadic or as a part of Neurofibromatosis 1 and 2 NF1 gene located at chromosomal region 17q11.2, codes forneurofibromin Functional part of neurofibromin GAP (or GTPase-activating protein) accelerates the conversion of the active GTP-bound RAS to its inactive GDP-bound form Loss of RAS controlleads to increased activity of other signaling pathwaysincluding RAF, ERK1/2, PI3K, PAK, MAPK, SCF/c-kit and mTOR-S6 kinase	Uniphasic, low to moderate cellularity No peripheral perineural capsule Random pattern, only rare palisading No well formed verocy bodies Hypocellular with abundant mucinous/myxoid matrix without hypercellular areas Frequent mast cells Contains neural fibroblasts and fibrillary or shredded carrot collagen Random proliferation of Schwann cells and scattered admixed axons No nevoid cells No epithelial component Diffuse growth pattern Scant cytoplasm Wavy spindle cells with buckled nuclei Pseudomeissnerian bodies representing specific differentiation may be present Lacks storiform pattern Neurofibroma with degenerative atypia ("ancient change") has following microscopic features: Localized cells with large pleomorphic nuclei, cytoplasmic nuclear inclusions, smudgy chromatin, and inconspicuous nuclei Absent or very low mitotic activity Low to moderate cellularity	Positive for: S100 (weaker) SOX10 Neurofilament (and Bielshowsky) GFAP CD34 (stronger) Factor XIIIa Calretinin (focal) MBP (myelin-basic protein) Negative for: EMA (except in plexiform neurofibromas)	Neurofibromatosis 1 Neurofibromatosis 2(multiple neurofibromas, meningiomas of the brainor spinal cord, and ependymomas of the spinal cord)	Can occur anywhere Diffuse neurofibromas commonly involve scalp	Soft masses/bumps on or under skin (internal or superficial) Transient itching (mast cells release histamine) Transient pain Numbness and tingling in the affected area Severe bleeding (sign of tumor growth) Physical disfiguration Cognitive disability Stinging Neurological deficits Changes in movement (clumsiness in hands, trouble walking) Bowel incontinence Scoliosis (an abnormal curvature of the spine, if the tumor creates muscular imbalance or erodes bones of the spine) Following symptoms may occur with genitourinary tract involvement (rarely): Urinary tract infection (most common clinical manifestation) Urinary retention Urinary frequency Urgency Hematuria Pelvic mass Hydronephrosis Urinary incontinence (decreased bladder capacity or compliance) Appears as a focal mass or diffuse bladder wall thickening in case of a plexiform neurofibroma	Nerve often not identified, incorporates nerve, axons often present in lesion Seldom cystic Frequently multiple Widespread soft tissue infiltration Tends to displace adnexa <2cm in diameter Lacks distinct lobulation Lacks fat Affects individuals between 20-40 years of age Men and women are equally affected Plexiform neurofibroma are thought to be congenital and occur earlier in life
Schwannoma	Loss of function of the tumor suppressor gene merlin (schwannomin) Direct genetic change involving the NF2 gene on chromosome 22 Can occur spontaneously Mutations and biallelic inactivation of SMARCB1 (spinal schwannomas)	Encapsulated Aggregates of spindled cells with indistinct cytoplasm and elongated nuclei with blunt pointed ends Ancient changes may show nuclear pleomorphism and occasionally nuclear inclusions as well Infrequent extracellular collagen Biphasic: majority entirely, and compactly hypercellular Antoni A & myxoid hypocellular Antoni B areas (may be absent in small tumors) Nuclear palisading evident around fibrillary process (Verocay bodies) in cellular areas Large, irregularly spaced vessels prominent in Antoni B areas Narrow, elongated and wavy cells with tapered ends, interspersed with collagen fibers Tumor cells with ill defined cytoplasm, dense chromatin Often displays degenerative nuclear atypia (ancient change) Rare mitotic figures Blood vessels may show gaping tortuous lumina having thickened hyalinized walls; may have thrombi Dilated vessels surrounded/invested by hemorrhage Foamy macrophages Lymphoid aggregates Amianthoid fibers or collagenous spherules: large nodular masses of collagen with radiating edges No axons except where nerve is attached Malignant transformation may have malignant epithelioid cells and rarely shows divergent differentiation as angiosarcoma-like areas	Positive for: S-100 SOX10 CD56 Podoplanin CD34 (weak) Neurofilament (and Bielshowsky) Factor XIIIa (focal) Calretinin GFAP EMA (capsule) highlights the perineural fibroblasts Laminin Type IV collagen Vimentin CD68 Negative for: Cytokeratin Desmin SMA	NF-2 associated Schwannomatosis Carney complex	Upper limbs Head and neck area (oral cavity, orbit and salivary glands) Deeply seated tumors are mainly in: Posterior mediastinum Retroperitoneum Posterior spinal roots Bone Gastrointestinal tract Pancreas Liver Thyroid Adrenal glands Lymph nodes Penis (rarely) Vulva (rarely)	Symptoms of schwannoma depend on the location of the tumor: Intracranial schwannoma: Acoustic neuroma (most common): Sensorineural hearing loss Vertigo Tinnitus Facial weakness Facial numbness and tingling Headaches Dizziness Difficulty swallowing and hoarseness Taste changes Confusion Trigeminal schwannoma: Trigeminal nerve dysfunction Facial nerve schwannoma: Facial nerve dysfunction Jugular foramen schwannoma: Hearing loss Tinnitus Dysphagia Ataxia Hoarseness Hypoglossal schwannomas: Hypoglossal nerve dysfunction Spinal schwannoma: Back pain Urinary incontinence Urinary retention Clumsiness Weakness Paresthesias Intercostal nerve schwannoma: Usually asymptomatic Intramuscular schwannoma: Painless mass	Nerve often identifiable Eccentric to nerve, axons generally absent within lesion Occasionally cystic Can cause other neoplasms including: Meningioma Mesothelioma Glioma multiforme Breast cancer Colorectal cancer Kidney (clear cell type) carcinoma Hepatocellular carcinoma Prostatic cancer Dermal cancer Affects individuals between 20-50 years of age Men and women are equally affected
Palisaded encapsulated neuroma (PEN) /solitary circumscribed neuroma	Spontaneous development RET proto-oncogene genetic mutations (inherited PEN)	Solitary dermal or subcutaneous tumor Encapsulated by perineurium Club-like extension in the subcutaneous tissue Moderately cellular lesion with proliferation of schwann cells and axons Nuclear palisading may be present Rare mast cells Silver stains show the axons traversing the Schwann cells	Positive for: EMA S100 (schwann cells) Neurofilament (axons) Collagen type IV EMA (perineurium) Neuron-specific Enolase CD57 (Leu-7) Myelin basic proteins Negative for: GFAP	Positive family history of tumor occurrence Multiple mucosal neuroma syndrome Multiple endocrine neoplasia syndrome (MEN 2B)	90% lesions affect the face involving: Eyelid Nose Oral mucosa Remaining 10% can occur anywhere in body involving: Shoulder Arm Hand Foot Glans of penis	Small, solitary, raised, dome-shaped, firm, flesh-colored painless nodule on skin Cosmetic issues due to facial involvement Scar after surgery	Benign tumor of the nerve fibers Affects middle aged people (40-60 years) No known familial association Affects females more frequently than males
Traumatic neuroma	Tangle of neural fibers and connective tissue that develops following a peripheral nerve injury Interruption in continuity of nerve causing wallerian degeneration (loss of axons in proximal stump and retraction of axons in distal segment), followed by exuberant regeneration of nerve and formation of mass of Schwann cells, axons and fibrous cells	Numerous well formed small nerve twigs Limited soft tissue infiltration Contains axons in haphazardly arranged nerves within mature collagenous scar with entrapped smooth muscle	Positive for: S100	History of trauma to a nerve (especially during a surgery) Cone biopsy (rare complication) 55% of hysterectomy patients have microneuromas, associated with childbirth	Most common oral locations are: Tongue Near mental foramen of mouth Rarely involves: Head Neck	Firm, oval, whitish, slowly growing, palpable nodule on skin (no discoloration of skin on the top of nodule) </=2cm in size Traumatic neuropathic pain with the presence of a typical trigger point in the area of a neuroma (especially with the pressure application) causing the patient to feel burning, stabbing, raw, gnawing or sickening sensations Paresthesia over the injured area Dysesthesia (painful hypersensitivity to normal light tactile stimuli) Functional impairment Psychological distress (severely decreasing the quality of life)	Also known as: Amputation neuroma Pseudoneuroma
Neurotized melanocytic nevus	Melan-A (Mart-1) gene Defect in embryologic development causing fast proliferation rate of melanocytes (during first twelve weeks of pregnancy)	Neurotized Nevus is a type of mole in which melanocytes are in the dermis with accompanying fibrosis Biphasic consisting of malignant melanoma and mature appearing neural component Superficial classic nevoid melanocytes (i.e. melanocytes appear like spindle cells resembling a nerve; and hence, called a neurotized nevus) Congenital and nested growth patterns More abundant cytoplasm Tends to surround adnexa Scattered nests of type A or B nevus cells, surrounded by basement membrane, present in the papillary dermis of lesions (otherwise indistinguishable from neurofibromas)	Positive for: S-100 MelanA (MART-1) Negative for: Factor XIIIa Leu-7 GFAP MBP	Sun exposure (ultraviolet light) Hormonal changes during: Pregnancy Diabetes Fair-skinned individuals (Caucasians of America and Europe) Positive family history of mole	Can occur anywhere in body, mostly involving following areas: Head Neck	Slowly growing, benign, oval or round, well-circumscribed macule, papule or nodule Color varies from skin color to light brown to black Cosmetic concerns	_
Cutaneous myxoma (Superficial angiomyxoma)	Sporadic Associated with: Carney's syndrome (autosomal dominant condition associated with abnormalities in chromosomes 2p and 17q, especially mutation in the PRKAR1α gene on the chromosome 17q22–q24 locus) NAME syndrome LAMB syndrome	Predominantly involves dermis and subcutis Multilobulated, poorly circumscribed Alcian blue positive, and hyaluronidase sensitive myxoid stroma/acellular mucin pools forming cleft-like spaces Scattered bland stellate to spindled cells with multiple oval nuclei Rarely, pleomorphism, and mitotic figures seen Occasional intranuclear pseudoinclusions Many thin-walled small blood vessels Frequent neutrophils Entrapped epithelial component in 20-30% of cases: Keratinous cyst Thin strands of squamous epithelium Basaloid buds	Positive for: CD34 Smooth muscle actin (90%) Muscle specific actin (67%) Factor XIIIa (60%) Vimentin S-100 (rarely, 40%) Factor VIIIa (variable) Negative for: Cytokeratin Desmin GFAP ER PR	Associated with Carney's complex/syndrome which includes following: Myxomas: Cutaneous External ear Heart Breast myxoid fibroadenoma Cutaneous melanocytic lesions: Lentigines Blue nevus Endocrine hyperplasia and neoplasia: Pituitary Thyroid Adrenal cortex Testis large cell calcifying Sertoli cell tumor Psammomatous melanotic schwannoma May be associated with NAME or LAMB syndrome	Trunk Limbs Head/face (eyelids and external ear canal in Carney's syndrome) Neck Perineal Nipples Buttocks	Solitary or multiple flesh-colored nodules 1-5cm in diameter	Sometimes, may be the earliest manifestation of Carney complex Affects men more frequently than women Involves mostly middle-aged population
Nerve sheath myxoma	Unknown etiology	Tumors involve the dermis and/or subcutis Distinct multinodular/multilobular masses Markedly hypocellular with abundant myxoid stroma Peripheral fibrous border made up of collagen IV Schwann cells may show the following different features: Cytoplasmic-nuclear invaginations Small epithelioid Schwann cells in corded, nested, and/or syncytial-like aggregates Schwann cells with a ring-like appearance Scattered spindled and stellate-shaped Schwann cells	Positive for: S-100 Glial fibrillary acidic protein Neuron specific enolase CD57 Epithelial membrane antigen CD34	_	Can occur anywhere in body: Most commonly involves extremities especially: Fingers Knees Rarely involves: Scalp/head Trunk	Painless skin mass or nodule Occasionally painful to touch Skin over the nodule is pink, soft, and usually intact (no ulceration) 0.5-2 cm in size Cosmetic issue (when present in head and neck region)	First described by Harkin and Reed in 1969 Peak incidence in the fourth decade of life Strong predilection for the extremities Also known as: Classical Nerve Sheath Myxoma Cutaneous Lobular Neuro Myxoma Myxomatous Perineuroma
Malignant peripheral nerve sheath tumor (MPNST)/malignant schwannoma	50% arise denovo 50% associated with neurofibromatosis (loss of heterozygosity of p53 on 17p chromosome)	Generalized atypia Increased mitotic activity Diffuse hypercellularity Infiltrative growth Pleomorphic nuclei Areas of geographic necrosis may show divergent differentiation, with tumor palisading at edges, resembling glioblastoma multiforme Monomorphic serpentine cells, large gaping vascular spaces, perivascular plump tumor cells May have bizarre cells 15% have metaplastic cartilage, bone, and muscle May have glandular differentiation, if so, presume malignant May have melanin in tumor cells, particularly if arise from spinal nerve roots (overlaps with primary melanoma of nerves) Some have no discernable Schwannian features at any level Electron microscopy shows: Cell membrane infoldings with lamellar configuration, discontinuous basal lamina, conspicuous intercellular junctions, and occasional dense-core granules	Positive for: CD99/O13 (86%) S-100 (patchy in 62% cases) CD57 (55%) Collagen IV p53 Leu7/CD57 (in neurofibroma-like areas) Protein gene product 9.5 (more sensitive than S100 but not specific) In case of glandular differentiation (malignant), positive for: Keratin EMA CEA Chromogranin Negative for: CD19	Associated with: NF1 May be associated with: Radiations Ganglioneuroma (rarely)	Bulky deep-seated tumor usually arising from major nerves in: Neck Forearm Lower leg Buttock	Painless swelling in extremities (arms or legs, aka peripheral edema) Difficulty moving the extremity with tumor (limping) Localized soreness in tumor area Neurological symptoms Pain or discomfort: numbness, burning, or tingling (pins and needles) Dizziness Loss of balance	Most common frequent soft tissue sarcoma in the pediatrics population
Dermatofibrosarcoma protuberans (DFSP)	t(17,22)(q21;q13) (collagen type 1 alpha 1(COL1A1) gene and platelet derived growth factor (PDGF) beta chain gene), resulting fusion protein is processed into mature platelet-derived growth factor which is a potent growth factor Supernumerary ring chromosomes derived from t(17;22)	Usually forms a mass Non circumscribed, highly cellular, tight storiform pattern (cells radiating in spokes at right angles around a central point that often contains a vessel) deeply infiltrating into subcutaneous tissue and entraping fat cells leading to characteristic honeycomb pattern Areas of fascicular growth (some tumors) Distinct storiform pattern may be absent in early plaque stage Monomorphic, thin and spindly cells with scant eosinophilic cytoplasm and hyperchromatic nuclei (resembling neurofibroma) Numerous mitotic figures (not atypical ones) Non-polarizable and thin collagen Only mild pleomorphism and focal atypia May coexist with giant cell fibroblastoma Usually no significant pleomorphism, no / rare histiocytes, no histiocyte-like cells, no foam cells, no giant cells or other inflammatory cells Variants: Atrophic (depressed lesion), collagenous (with central thick collagen bundles), granular cell, myxoid, palisading, pigmented, and sclerosing	Positive for: CD34 (strong in 95%) Vimentin Actin (focal) ApoD Bcl2 NKI-C3 CD99 Negative for: S-100 Factor XIIIa (usually) Keratin EMA S100 HMB45 Desmin CD117	_	Head Deep soft tissue of (posterior) neck Trunk Arms Legs Doesn't involve hands and feet	Begins as a minor firm area of skin 1 to 5 cm in diameter Resembles a bruise, birthmark, or pimple Can become a raised nodule after growth May cause redness, open up or bleed	Also called intermediate (borderline) fibrous histiocytoma More common in blacks in US Involves adults of 20 - 40 years of age
Spindle cell lipoma	16q abnormalities (usually)	Delicate encapsulation Floret cell formation No degenerative atypia Mixture of mature adipocytes and mildly pleomorphic bland spindle cells (pale eosinophilic cytoplasm with uniform wavy nuclei similar to neurofibroma) in mucinous / myxoid or fibrous background with thick collagen bundles Spindle cells arranged in short fascicles with occasional nuclear palisading Hemangiopericytic or angiomatous vascular pattern may be seen Minimal or no fat Variable mast cells and lymphocytes No storiform pattern, no lipoblasts, no/rare mitotic activity	Positive for: CD34 (strongly, spindle cells) Androgen receptors in men and usually women (spindle cells) S-100(stains only adipocytes) Spindle cells are negative for: S100 Desmin	_	Neck Posterior upper back Shoulder	Multiple well-circumscribed painless nodules involving several body parts	_
Ganglioneuroma	Genes involved in the pathogenesis of ganglioneuroma include: MYCN oncogene Chromosome 1p36 Activating RET protooncogene mutation (adrenal ganglioneuromas)	Derived from the primordial neural crest cells (undifferentiated cells of the sympathetic nervous system) Admixture of ganglion cells, schwann cells, and fibrous tissue Doesn't contain neuroblasts, intermediate cells, or mitotic figures Characterized by spindle-shaped cells with cell borders in a fibrillar matrix containing ganglion cells with large round nuclei, prominent nucleoli, and abundant eosinophilic cytoplasm No significant atypia, necrosis or mitotic activity is present Well differentiated neuronal tumors that do not contain immature elements Ganglion cells are mature to mildly dysmorphic: Mature: compact, eosinophilic cytoplasm with distinct cell borders, single eccentric nucleus, prominent nucleolus Dysmorphic: single or multiple pyknotic nuclei Vary in distribution and number, may be quite sparse May contain finely granular, gold to brown pigment (lipofuscin or neuromelanin) Schwann cells: Ensheath neuritic processes Arranged in small intersecting fascicles, separated by loose myxoid stroma Two histologic subtypes: Mature = every ganglion cell is mature Maturing = minor component of scattered collections of differentiating neuroblasts or maturing ganglion cells (unlike intermixed subtype of ganglioneuroblastoma, these immature foci do not form distinct microscopic nests) Background may include lobules of mature adipose tissue (especially at periphery of lesion), mast cells, chronic inflammation, dense collagenized stroma Mild variation in cellularity may be present Masculinizing ganglioneuroma is an admixture of ganglioneuroma and Leydig cells with crystalloids of Reinke or strands/clusters of cells resembling adrenal cortical cells Electron microscopy: Mixture of neural bundles and normal appearing ganglion cells with eccentric nuclei and large numbers of cytoplasmic organelles	Positive for: Schwann cells/stroma: S100 Synaptophysin Neurofilament (NF) protein Ganglion cells: S100 Synaptophysin Chromogranin A NF protein Glial fibrillary acidic protein (GFAP) PGP 9.5 Type IV collagen Vasoactive intestinal peptide (VIP) Negative for: EMA Cytokeratin HMB45 WT1 CD99 CD45 Desmin Myogenic markers (myogenin, MyoD1)	Ganglioneuromas may be associated with: Multiple endocrine neoplasia type IIb (mucosal ganglioneuromas) Turner syndrome Neurofibromatosis type 1	Located along distribution of sympathetic nervous system: Posterior paraspinal mediastinum (most common) Adrenal gland (~20-30% of cases) Paraspinal retroperitoneum (especially presacral space) Cervical and parapharyngeal area in neck Urinary bladder Prostate Bone Pancreas Skin Orbit Paratesticular area Appendix Gastrointestinal tract	Symptoms of ganglioneuroma vary depending on the location of tumor, and include the following: Mediastinum: Dyspnea Chest pain Trachea compression Retroperitoneum: Abdominal pain Bloating Spinal cord: Paresis Pain and numbness/loss of sensation in limbs Patients with ganglioneuroma may also have paraneoplastic syndrome, which may manifest with: Diarrhea Diaphoresis Hirsutism Enlarged clitoris (in females) High blood pressure Sweating	Ganglioneuromas are included in the neuroblastic tumors group, which includes: Ganglioneuroma (benign) Ganglioneuroblastoma (intermediate) Neuroblastoma (aggressive)
Myxoid liposarcoma	Atypical lipomatous tumor/well differentiated liposarcoma and dedifferentiated liposarcoma are associated with: Presence of a large/giant markerchromosome and/or ring chromosomes at 12q13-15 region Amplification of this chromosome region rich in protooncogenes, including CHOP, CDK4, MDM2, HMGI-C, GLI, SAS, OS1, HMGA2 andOS9 Myxoid liposarcoma is associated with: t(12:16)(q13;p11) - CHOP(DDIT3) / FUSor t(12;22)(q13;q22) - CHOP(DDIT3) / EWS Pleomorphicliposarcoma is associated with: Complex karyotypicaberrations	Well-differentiated liposarcoma: Sclerosing liposarcoma (distinctive stromal cells distributed across the tissue, associated with lipoblasts filled with multiple vacuoles, and collagenous background of fibrillary appearance) Adipocyticliposarcoma (adipocytes with different cell sizes, hyperchromasia, and nuclear atypia. Fibrous septacontaining hyperchromatic stromal cells surrounding adipocytes) Inflammatoryliposarcoma (heavy chronic inflammatoryinfiltrate composed of different lympho-plasmacytic aggregates) Spindle cellliposarcoma(proliferation of neural-like spindle cells organized in a fibrous structurecontaining lipoblasts) De-differentiated liposarcoma: Myxoid liposarcoma ( non-homogenous appearance with cystic and solid components) Round cellliposarcoma (small, round, or spindle cells with sparse eosinophilic and granular cytoplasmand large nuclei,scattered lipoblasts and areas of necrosis) Pleomorphicliposarcoma (pleomorphic cells with enlarged round to bizarre nuclei)	Atypical lipomatous tumor/well differentiated liposarcoma is positive for: MDM2 CDK4 p16 S100 (stainsadipocytes and lipoblasts)	Chemical carcinogens Phenoxyacetic herbicides Chlorophenols Dioxincontaminations Arsenic Thorium dioxide (Thorotrast) Radiation (dose of 50 GY) Immunodeficiency(regional acquiredimmunodeficiency) Genetic susceptibility Li-Fraumeni syndrome Neurofibromatosis(NF1; von Recklinghausen disease) Gardner syndrome (Familial adenomatous polyposis) Retinoblastoma Werner syndrome Nevoid basal cell carcinoma (Gorlin syndrome) Viral infections	Retroperitoneum Esophagus Bowel Mediastinum	Retroperitonealliposarcoma maybe asymptomatic or causes: Weight loss Abdominal pain Oliguria renal failure (due to ureters or kidneys' compression) Palpable abdominalmass Abdominal tenderness Abdominal distention Esophageal liposarcoma may cause: Dysphagia Vomiting Cough Gastrointestinal bleeding Hoarseness Bowel liposarcoma may cause: Gastrointestinalbleeding Mediastinal liposarcoma may cause: Dyspnea Cough Chest pain Weight loss	_
Leiomyoma	Loss of normal chromosome 1q (hereditaryleiomyomatosis) Renal cell cancer(HLRCC) gene mutation	Prominent cellular atypia Nuclear atypia, including nuclear pleomorphism, hyperchromatism, irregularity in nuclear membranes, high nuclear size, and prominent nucleoli Cigar-shaped nuclei Abundant mitoses, mitotic index higher than 10 or more per 10 high-power fields Areas of coagulative necrosis (tumor cellnecrosis) Palisading and extensive degenerative changes in the form of hyalinization, calcification, and myxoid changes Elongated cells with eosinophilic or occasional fibrillar cytoplasm with distinct cell membranes	Positive for: HHF35 (90%) Alpha-smooth muscle actin (90%) Vimentin Desmin (75%) H-caldesmon PTAH (stainsmyofibrils) Keratin (30%) ER (usually in uterine and femaleretroperitonealtumors) S100 (occasionally weak staining) EMA (may be focal) CD34 Negative for: CD117	Immundeficiency (HIV) Digoxin exposure Human herpes virus type-8 (HHV-8) Epstein barr virus Long term tamoxifen use History of pelvicradiations Hereditary breast carcinoma with BRCA1mutation Hereditary nonpolyposis colorectal carcinoma with MSH2 mutation Li-Fraumeni syndrome Malignant melanoma Retinoblastoma	Uterus Abdomen Esophagus Rectum Skin / subcutis Retroperitoneum Extremities Large vessels (inferior vena cava, saphenous vein, femoral vein, pulmonary artery, femoral artery) Superficial or deep soft tissues Bone Breast Colon Epididymis Mediastinum Lungs	Asymptomatic (uterine leiomyosarcomamay be associated with: Irregular vaginal bleeding(intermenstrual or postmenopausal) New lump or a massprotruding into vaginaor growing mass in abdomen or pelvis Abdominal pain Abdominal distension Pelvic pain Urinary symptoms Esophagealleiomyosarcoma may cause: Dysphagia Hematemesis rectal leiomyosarcomamay cause: Black, tarry stools Rectal bleeding	_
Inflammatory myofibroblastic tumor(IMT)	Unknown underlying etiology, may be due to inflammatory reaction to: Infection Underlying low grade malignancy Mutations such as: ALK (anaplastic lymphoma kinase)gene mutations in the tyrosine kinaselocus at band 2p23	Spindle to stellate-shaped cells Spindle cellsarranged in short fascicles with a focal storiform (whorled or cartwheel-like) architecture Spindle cells show features of fibroblastsand myofibroblasts Variably dense, chronic, mixed polymorphic infiltrateof mononuclearinflammatory cells (plasma cells and lymphocytes, histiocytes, neutrophils, and occasional eosinophils) Histiocytes have multinucleated forms with finely vacuolated cytoplasmic lipiddroplets Plasma cells with cytoplasmic Russell bodies (globularcytoplasmicinclusions of immunoglobulin) and polyclonal pattern of light chain expression Absent hyperchromasia and atypical mitoses	Positive for: IG+ (plasma cells) IL-1 IL-6 Smooth muscle actin Desmin Calponin Activin-like kinase 1 Negative for: Beta-catenin	Multiorgan disease in association with chronicpersistent Eikenella corrodens infection Epstein Barr virusinfection Human herpes virus-8(HHV-8) infection(Kaposi's sarcoma, multicentric Castleman's disease)	Lungs Gastrointestinal system Pelvic region Bladder Uterus Retroperitoneum Skin Bone (femur, temporal bone, jawbone) CNS Soft tissues Larynx Heart (right ventricleis most commonly involved) Pancreas (rarely)	Asymptomatic (70%) Painless asymptomaticmass/lump/swelling Pulmonary IMT presents as: Chest pain Cough Dyspnea Hemoptysis (recurrent) Fever Fatigue Weight loss Appetite loss Bone IMT presents with: Mild bone pain Easy fractures Headache Dizziness Numbness at tumorsite Bone marrowinvolvement in some cases Heart IMT presents with: Chest pain Difficulty breathing Palpitations Fainting Obstruction of blood flow in the heart (large tumors) Bladder IMT presents with: Painless hematuria Chronic pelvic pain Difficulty in urinating Presence of burning sensation CNS IMT presents with: Presence of solitary or multiple tumors at various locations in the brain Recurrent headaches Headache Nausea and vomiting Blurred vision Double vision Drooping of the eyelid Dizziness Back pain (if spineinvolved) Seizures	Also known as: Pseudo-inflammatorytumors Inflammatory pseudotumor Plasma cell granuloma Inflammatory pseudotumor Fibrous histiocytoma Fibroxanthoma Xanthogranuloma Inflammatorypseudosarcoma Atypical fibromyxoid tumor Atypical myfibroblastic tumor
Fibroepithelial polyp/Acrochordon	Associated with: HPV 6 (low risk) HPV 11	Fibrovascular cores covered by squamous epithelium Larger lesions may have a flattened epidermis Smaller lesions can have epidermal hyperplasia or seborrheic keratosis-like changes Central core composed of loose collagen with increased blood vessels In larger lesion, may have a central core of adipose tissue Pagetoid dyskeratosis is sometimes present as an incidental finding May have ischemic necrosis due to torsion	Positive for: Desmin Vimentin ER PR Negative for: Actin	Associated with: Diabetes (elevated blood sugar and insulin) Abnormal lipid profile Other components of metabolic syndrome Birt-Hogg-Dube syndrome Acromegaly Polycystic ovary syndrome May increase in number during pregnancy	Occurs usually in intertriginous areas (i.e. axilla, groin) Face Neck Eyelids Vulva Tonsils Ureter Bowel Urinary bladder Bronchi	Soft papilloma, flesh colored to dark brown, sessile to pedunculated A few millimeters to multiple centimeters in size Larger lesions often attach to skin by slender stalks	Benign skin lesions in adults, excised for cosmetic reasons Also known as: Skin tag Soft fibroma Cutaneous papilloma Cutaneous tag Fibroma pendulum Fibroma molluscum

External links

• Thesis on DFSP