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, and melanocytic nevus.

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
• Acrochorda (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		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)	NF-1 associated	Can occur anywhere		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
Myxoid liposarcoma
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
Acrochorda

References

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