Malignant peripheral nerve sheath tumor

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Marjan Khan M.B.B.S.[2]

Malignant peripheral nerve sheath tumor (MPNST) is a form of cancer of the connective tissue surrounding nerves. On gross pathology, a large firm mass with necrosis and hemorrhage is the characteristic finding of malignant peripheral nerve sheath tumor. On microscopic histopathological analysis, spindle cells, nuclear atypia, mitoses, and herring bone pattern are characteristic findings of malignant peripheral nerve sheath tumor.^[1] Neurofibromatosis type I (NF1) gene is involved in the pathogenesis of malignant peripheral nerve sheath tumor.^[2] Malignant peripheral nerve sheath tumor must be differentiated from neurofibroma and schwannoma.^[3] The incidence of malignant peripheral nerve sheath tumor is approximately 0.1 per 100,000 individuals worldwide.^[4] The incidence of malignant peripheral nerve sheath tumor increases with age.^[4] Malignant peripheral nerve sheath tumor affects men and women equally.^[3] Common risk factors in the development of malignant peripheral nerve sheath tumor are pre-existing plexiform neurofibromas, pre-existing perineuriomas, radiation therapy, and neurofibromatosis type 1.^[5][6][7] Symptoms of malignant peripheral nerve sheath tumor include peripheral edema, difficulty in moving the extremity, pain, and numbness.^[8] MRI may be diagnostic of malignant peripheral nerve sheath tumor. Findings on MRI suggestive of malignant peripheral nerve sheath tumor include isointense on T1 weighted image and low signal on T2 weighted image.^[3] The predominant therapy for malignant peripheral nerve sheath tumor is surgical resection. Adjunctive chemotherapy and radiation therapy may be required. Common complication of malignant peripheral nerve sheath tumor is metastasis. Prognosis is generally poor.^[9]

There is no classification system established for malignant peripheral nerve sheath tumor.

On gross pathology, a large firm mass with necrosis and hemorrhage is the characteristic finding of malignant peripheral nerve sheath tumor. On microscopic histopathological analysis, spindle cells, nuclear atypia, mitoses, and herring bone pattern are characteristic findings of malignant peripheral nerve sheath tumor.^[1] Neurofibromatosis type I (NF1) gene is involved in the pathogenesis of malignant peripheral nerve sheath tumor.^[2]

Malignant peripheral nerve sheath tumor may be caused by a mutation on neurofibromatosis type I gene.^[10][2]

Malignant peripheral nerve sheath tumor must be differentiated from neurofibroma and schwannoma.^[3]

Malignant peripheral nerve sheath tumors comprise ∼2% of all sarcomas whichare a small fraction of a group of cancers that affect 5 people per million per year. The incidence of malignant peripheral nerve sheath tumor is approximately 0.1 per 100,000 individuals worldwide. The incidence of malignant peripheral nerve sheath tumor increases with age. Malignant peripheral nerve sheath tumor affects men and women equally.

Common risk factors in the development of malignant peripheral nerve sheath tumor are pre-existing plexiform neurofibromas, pre-existing perineuriomas, radiation therapy, and neurofibromatosis type 1.^[5][6][7]

According to the the U.S. Preventive Service Task Force (USPSTF), there is insufficient evidence to recommend routine screening for Malignant peripheral nerve sheath tumor.^[11]

In general Malignant peripheral nerve sheath tumor is known to have high metastatic potential and poor prognosis.[1] long-term outcomes vary widely across multiple series, with 5-year survival ranging between 15% and 50%. Large tumor size at presentation (typically >5 cm) has been the most consistently determined adverse prognostic factor. Other reported factors include tumor grade, truncal location, surgical margin status, local recurrence, and heterologous rhabdomyoblastic differentiation. The true prognostic impact of NF1 syndrome in MPNST remains somewhat in flux. Several large series report significantly worse outcomes for MPNST arising in the setting of NF1 compared with sporadic disease, with inferior responses to cytotoxic chemotherapy and 5-year survivals that are up to 50% worse.

There is no established system for the staging of malignant peripheral nerve sheath tumor.

Symptoms of malignant peripheral nerve sheath tumor include peripheral edema, difficulty in moving the extremity, pain, and numbness.^[8]

Common physical examination findings of malignant peripheral nerve sheath tumor include edema, paresthesia, and weakness.

There are no laboratory findings associated with malignant peripheral nerve sheath tumor.

There are no X-ray findings associated with malignant peripheral nerve sheath tumor.

CT scan may be diagnostic of malignant peripheral nerve sheath tumor. Finding on CT scan suggestive of malignant peripheral nerve sheath tumor is a rapid growth mass with irrefular border.^[3]

MRI may be diagnostic of malignant peripheral nerve sheath tumor. Findings on MRI suggestive of malignant peripheral nerve sheath tumor include isointense on T1 weighted image and low signal on T2 weighted image.^[3]

There are no ultrasound findings associated with malignant peripheral nerve sheath tumor.

Scintigraphy may be diagnostic of malignant peripheral nerve sheath tumor. Finding on Gallium⁶⁷ scintigraphy suggestive of malignant peripheral nerve sheath tumor is higher uptake.^[3]

There are no other diagnostic study findings associated with malignant peripheral nerve sheath tumor.

Biopsy is helpful in the diagnosis of schwannoma.

In the setting of localized disease, as is the case with all soft tissue sarcomas, complete surgical extirpation with clear margins is the treatment of choice.The predominant therapy for malignant peripheral nerve sheath tumor is surgical resection.In the setting of advanced or metastatic MPNST, outcomes are generally poor. Doxorubicin and ifosfamide are the most active agents in unselected soft tissue sarcomas, with a Response Evaluation Criteria in Solid Tumors (RECIST) response rate of approximately 25% for the combination. Adjunctive chemotherapy and radiation therapy may be required.Multiple retrospective datasets have shown the negative prognostic impact of involved margins and local recurrence. As in the case with most large (>5 cm) high-grade limb sarcomas, adjuvant radiation is advocated to reduce local recurrence. The risk-benefit profile of adjuvant radiation in patients with NF1 must be carefully discussed with all patients in view of the heightened risk of radiation-induced sarcomas.

Surgery is the mainstay of treatment for malignant peripheral nerve sheath tumor. For patients suffering from neurofibrosarcomas in an extremity, if the tumor is vascularized and has many nerves going through it and/or around it, amputation of the extremity may be necessary. Some surgeons argue that amputation should be the procedure of choice when possible, due to the increased chance of a better quality of life. Otherwise, surgeons may opt for a limb-saving treatment, by removing less of the surrounding tissue or part of the bone, which is replaced by a metal rod or grafts.

There is no established method for prevention of malignant peripheral nerve sheath tumor.

There are no secondary preventive measures available for malignant peripheral nerve sheath tumor.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Marjan Khan M.B.B.S.[2]

NF1-like cutaneous tumor syndromes appeared in the literature in 1880s, when Friedrich von Recklinghausen published seminal observations detailing cutaneous tumors comprised of both neuronal and fibroblastic tissue finally termed as neurofibromas. In 2006, Yang et al demonstrated a critical neurofibroma microenvironment interaction that includes SCF-stimulated Nf1+/− mast cells potentiating Nf1+/− fibroblast functions.

• In 18th century, NF1-like cutaneous tumor syndromes appeared in the literature. ^[1]
• In 1880s, Friedrich von Recklinghausen published seminal observations detailing cutaneous tumors comprised of both neuronal and fibroblastic tissue finally termed as neurofibromas.
• In 2006, Yang et al demonstrated a critical neurofibroma microenvironment interaction that includes SCF-stimulated Nf1+/− mast cells potentiating Nf1+/− fibroblast functions. ^[2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Marjan Khan M.B.B.S.[2]

There is no classification system established for malignant peripheral nerve sheath tumor.

There is no classification system established for malignant peripheral nerve sheath tumor.

Template:WikiDoc Sources

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Marjan Khan M.B.B.S.[2]

On gross pathology, a large firm mass with necrosis and hemorrhage is the characteristic finding of malignant peripheral nerve sheath tumor. On microscopic histopathological analysis, spindle cells, nuclear atypia, mitoses, and a herring bone pattern are characteristic findings of malignant peripheral nerve sheath tumor.^[1] The neurofibromatosis type I (NF1) gene is involved in the pathogenesis of malignant peripheral nerve sheath tumor.^[2]

• Malignant peripheral nerve sheath tumors are a rare type of cancer that arise from the soft tissue that surrounds nerves. They are a type of sarcoma. Most malignant peripheral nerve sheath tumors arise from the nerve plexuses that distribute nerves into the limbs—the brachial and lumbar plexuses—or from nerves as they arise from the trunk.^[3]

• The genotypic hallmark of NF1 involves mutations to or other loss of the 350 kilobase gene NF1 on the long arm of chromosome 17, which encodes the tumor suppressor protein neurofibromin.
• NF1 inactivation leads to ras hyperactivity and consequent activation of multiple downstream survival and proliferative pathways, including the mitogen-activated protein kinase (MAPK), mammalian target of rapamycin (mTOR), and AKT (Mouse breed AK thymoma, also termed protein kinase B, or PKB) pathways.
• Molecular pathways from neurofibroma to MPNST in NF1 syndrome remains uncertain, although NF1 deficiency in and of itself is clearly insufficient, given that only approximately 10% of all NF1 patients eventually develop MPNST.

• About half of the cases of malignant peripheral nerve sheath tumor (MPNST) occur along with NF1. The lifetime risk of having both of these conditions is at 8–13% while those with only MPNST have a 0.001% in the general population.^[4]

• A recent study in a genetically engineered mouse model showed that EGFR overexpression was sufficient to transform neurofibroma into MPNST via Janus kinase 2/signal transducer and activator of transcription 3 (STAT3) activation.

• Recent studies have demonstrated that there is an overall downregulation of genes in MPNST as compared with neurofibromas

• The NF1 gene locus is on chromosome 17q11.2 and the gene product is neurofibromin, acts as a tumour suppressor; inactivation of the gene thus predisposes to tumour development.Closing </ref> missing for <ref> tag
• Necrosis
• Hemorrhage

• Histologic features of MPNST are rather nonspecific.
• tumors are composed of monotonous spindle cells arranged in intersecting fascicles.
• Hypercellular and hypocellular areas may be present often with hypercellular areas localized in close proximity to blood vessels.
• Malignant peripheral nerve sheath tumors demonstrate a marked increase in tumor cellularity, pleomorphism, and mitotic activity and show a more organized cellular growth pattern, with less extracellular matrix material when compared with benign neurofibromas.
• Malignant peripheral nerve sheath tumors demonstrating skeletal muscle differentiation are particularly aggressive and associated with poor prognosis.
• There is no pathognomonic molecular or immunohistochemical study for malignant peripheral nerve sheath tumors.
• S100 protein is weakly and patchily present in <50% of cases.
• The most reliable method of diagnosis remains electron microscopy, which can identify ultrastructural features of Schwann cells.

• 
  Malignant peripheral nerve sheath tumor^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Marjan Khan M.B.B.S.[2]

Malignant peripheral nerve sheath tumor may be caused by a mutation in the neurofibromatosis type I gene.^[1][2]

• Malignant peripheral nerve sheath tumor may be caused by a mutation in the neurofibromatosis type I gene.^[1][2]

• About half of the cases of malignant peripheral nerve sheath tumor (MPNST) occur along with NF1. The lifetime risk of having both of these conditions is at 8–13% while those with only MPNST have a 0.001% in the general population.^[2]

• The NF1 gene locus is on chromosome 17q11.2 and the gene product is neurofibromin, which acts as a tumor suppressor. Inactivation of the gene predisposes to tumor development.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Marjan Khan M.B.B.S.[2]

Malignant peripheral nerve sheath tumor must be differentiated from neurofibroma and schwannoma.

Malignant peripheral nerve sheath tumor Neurofibroma must be differentiated from:^[1][2][3]

• Schwannoma
• Dermatofibrosarcoma protuberans (DFSP)
• 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[4][5][6][7][8][9][10][7][11][12][13][14]	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[15][16][17][18][19]	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[20]	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[21][22][23][24]	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[25][26][27][28]	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)[29][30][31][32]	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[33][34][35][36][37][38]	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[39][40][41][42][43][44]	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[45][46]	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[47][48][49][50][51][52][53][54][55][56]	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[57][58][59][60][61][62][63][64][58][61][65]	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)[57][58][59][60][61][62][63][64][58][61][65]	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[66][67][68][69][70][71][72][73][74][75][76][77][78][79][80][81][82][83][84][85]	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

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Marjan Khan M.B.B.S.[2]

Malignant peripheral nerve sheath tumors comprise ∼2% of all sarcomas whichare a small fraction of a group of cancers that affect 5 people per million per year. The incidence of malignant peripheral nerve sheath tumor is approximately 0.1 per 100,000 individuals worldwide.^[1] The incidence of malignant peripheral nerve sheath tumor increases with age.^[1] Malignant peripheral nerve sheath tumor affects men and women equally.^[2]

• Malignant peripheral nerve sheath tumors comprise ∼2% of all sarcomas whichare a small fraction of a group of cancers that affect 5 people per million per year.
• The incidence of malignant peripheral nerve sheath tumor is approximately 0.1 per 100,000 individuals worldwide.^[1]
• Malignant peripheral nerve sheath tumor may arise at any age with no gender predilection.
• Half of MPNSTs are associated with neurofibromatosis type 1 (NF1), the autosomal dominant condition that, affecting 1 in 3000 live births, represents the most common human cancer genetic predisposition syndrome.

• Malignant peripheral nerve sheath tumor may arise at any age with no gender predilection and affects men and women equally .^[1]

• Malignant peripheral nerve sheath tumor may arise at any age with no gender predilection and affects men and women equally.^[2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Marjan Khan M.B.B.S.[2]

Common risk factors in the development of malignant peripheral nerve sheath tumor are pre-existing plexiform neurofibromas, pre-existing perineuriomas, radiation therapy, and neurofibromatosis type 1.^[1][2][3]

Common risk factors in the development of malignant peripheral nerve sheath tumor include:^[1][2][3]

• Pre-existing plexiform neurofibromas
• Pre-existing perineuriomas
• Radiation therapy
• Neurofibromatosis type 1

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Marjan Khan M.B.B.S.[2]

According to the the U.S. Preventive Service Task Force (USPSTF), there is insufficient evidence to recommend routine screening for malignant peripheral nerve sheath tumor.

According to the the U.S. Preventive Service Task Force (USPSTF), there is insufficient evidence to recommend routine screening for malignant peripheral nerve sheath tumor.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Marjan Khan M.B.B.S.[2]

In general Malignant peripheral nerve sheath tumor is known to have high metastatic potential and poor prognosis.^[1] long-term outcomes vary widely across multiple series, with 5-year survival ranging between 15% and 50%. Large tumor size at presentation (typically >5 cm) has been the most consistently determined adverse prognostic factor. Other reported factors include tumor grade, truncal location, surgical margin status, local recurrence, and heterologous rhabdomyoblastic differentiation. The true prognostic impact of NF1 syndrome in MPNST remains somewhat in flux. Several large series report significantly worse outcomes for MPNST arising in the setting of NF1 compared with sporadic disease, with inferior responses to cytotoxic chemotherapy and 5-year survivals that are up to 50% worse.

• A common complication of malignant peripheral nerve sheath tumor is metastasis.
• Metastasis occurs in about 39% of patients, most commonly to the lung.^[2]

• In general Malignant peripheral nerve sheath tumor is known to have high metastatic potential and poor prognosis.[1]
• long-term outcomes vary widely across multiple series, with 5-year survival ranging between 15% and 50%.
• Large tumor size at presentation (typically >5 cm) has been the most consistently determined adverse prognostic factor.
• Other reported factors include tumor grade, truncal location, surgical margin status, local recurrence, and heterologous rhabdomyoblastic differentiation.
• The true prognostic impact of NF1 syndrome in MPNST remains somewhat in flux.
• Several large series report significantly worse outcomes for MPNST arising in the setting of NF1 compared with sporadic disease, with inferior responses to cytotoxic chemotherapy and 5-year survivals that are up to 50% worse.

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