Neurofibroma differential diagnosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sara Mohsin, M.D.[2] Shanshan Cen, M.D. [3]

Overview

Neurofibroma must be differentiated from schwannoma, dermatofibrosarcoma protuberans (DFSP), ganglioneuroma, dermal neurotized melanocytic nevus, myxoid liposarcoma, solitary circumscribed neuroma, traumatic neuroma, superficial angiomyxoma, nerve sheath myxoma, malignant peripheral nerve sheath tumor, spindle cell lipoma, Leiomyoma, inflammatory myofibroblastic tumor, and fibroepithelial polyp.

Differential Diagnosis

Neurofibroma must be differentiated from:

• 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): has marked atypia and increased mitotic activity, may have necrosis
• Spindle cell lipoma
• Leiomyoma: has cigar-shaped nuclei, S100 negative, positive for smooth muscle actin and desmin
• Inflammatory myofibroblastic tumor: reactive spindle cells in inflammatory background
• 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 Non-encapsulated Random pattern, only rare palisading No well formed verocy bodies Cells separated by collagen bundles Hypocellular with abundant mucinous matrix No peripheral perineural capsule Frequent mast cells Contains neural fibroblasts and fibrillary collagen Random proliferation of Schwann cells and scattered admixed axons No nevoid cells No epithelial component Diffuse growth pattern Scant cytoplasm Wavy 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 Sox10 Neurofilament (and Bielshowsky) GFAP CD34 Factor XIIIa Calretinin (focal)	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
Schwannoma		Encapsulated Biphasic (majority entirely hypercellular Antoni A & hypocellular Antoni B) Palisading Verocay bodies Infrequent extracellular collagen	Positive for: S-100 Sox10 CD34 Neurofilament (and Bielshowsky) Factor XIIIa (focal) Calretinin GFAP	NF-2 associated			Nerve often identifiable Eccentric to nerve, axons generally absent within lesion Occasionally cystic
Palisaded encapsulated neuroma		Solitary Moderately cellular lesion Rare mast cells Predominantly composed of mast cells	Positive for: EMA Negative for: GFAP		90% lesions affect the face		No known familial association
Traumatic neuroma		Numerous well formed small nerve twigs Limited soft tissue infiltration Contains axons in haphazardly arranged nerves		History of trauma or surgery
Neurotized Melanocytic Nevus		Superficial classic nevoid melanocytes Congenital and nested growth patterns More abundant cytoplasm Tends to surround adnexa	Positive for: S-100 MelanA Negative for: Factor XIIIa
Cutaneous Myxoma (Superficial angiomyxoma)		Spindle to stellate cells with oval nuclei 1-5cm in diameter	Positive for: CD34 S-100 (rarely)	Associated with Carney complex
Nerve sheath myxoma		Markedly hypocellular with abundant mucopolysaccharides Lobulated architecture	Positive for: S-100
Malignant peripheral nerve sheath tumor		Generalized atypia Increased mitotic activity Diffuse hypercellularity	Positive for: S-100 (30%)
Dermatofibrosarcoma protuberans (DFSP)		More cellular Distinct storiform pattern Usually forms a mass	Strongly positive for: CD34 Negative for: S-100		Deep soft tissue of posterior neck
Spindle cell lipoma		Delicate encapsulation Mostly cases contain fat Floret cell formation No degenerative atypia	Positive for: CD34 (strongly) S-100(stains only fat cells)
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 stromalcells distributed across the tissue, associated with lipoblasts filled with multiple vacuoles, and collagenousbackground of fibrillary appearance) Adipocyticliposarcoma(adipocytes with different cell sizes, hyperchromasia, and nuclear atypia. Fibrous septacontaining hyperchromaticstromal cellssurrounding 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 solidcomponents) Round cellliposarcoma ( small, round, or spindle cells with sparse eosinophilic and granular cytoplasmand large nuclei,scattered lipoblasts and areasof necrosis) Pleiomorphicliposarcoma(pleiomorphic cellswith 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 liposarcomamay cause: Dysphagia Vomiting Cough Gastrointestinal bleeding Hoarseness Bowel liposarcoma may cause: Gastrointestinalbleeding Mediastinal liposarcomamay cause: Dyspnea Cough Chest pain Weight loss	_
Leiomyoma	Loss of normal chromosome 1q (hereditaryleiomyomatosis) Renal cell cancer(HLRCC) gene mutation	Prominent cellularatypia Nuclear atypia, including nuclearpleomorphism, hyperchromatism, irregularity in nuclearmembranes, high nuclear size, and prominent nucleoli Abundant mitoses, mitotic index higher than 10 or more per 10 high-power fields Areas of coagulative necrosis (tumor cellnecrosis), always accompanied by cytologic atypia and brisk mitotic activity	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 (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			Associated with: Diabetes Abnormal lipid profile Other components of metabolic syndrome Multiple lesions can be seen in Birt-Hogg-Dube syndrome May increase in number during pregnancy	Occurs usually in intertriginous areas (i.e. axilla, groin) Face Neck Eyelids		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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