- Most areas are comprising of cellular wavy spindle cells without definite nuclear palisading however, vague palisading is appreciated
- Some areas show irregular fascicles of spindle cells without wavy nuclei, and cytoplasmic vacuolization (not easy to recognized as a Schwann cells)
- Occasional cells show intranuclear inclusion
- Focal giant cells formation and mild pleomorphism are also seen
- Some thick and hyalinized blood vessels of variable size with fibrinoid changes in lumen
- Occasional area show dilated irregular thin walled pointed blood vessels (stag-horn like vasculature)
- Perivascular whirling is present.
- Cystic changes with areas of hemorrhage are seen
- Epithelioid cells, Xanthoma cells, necrosis and mitotic activity are not seen
- The tumor cells are diffuse positive for S100 protein.
- SMA is negative in the area of interest.
- CD34 positivity is restricted in blood vessels only.
Practical Points of Pathoclinics:
- Schwannoma is an encapsulated benign peripheral nerve sheath tumour of schwann cells, arise in cranial, spinal, peripheral, or autonomic nerves. Multiple and bilateral vestibular schwannomas are common in Neurofibromatosis type 2, an autosomal dominant condition (inactivating germline mutation of NF2 gene on chromosome 22), along with association of meningioma, ependymoma, and glioma. Plexiform neurofibromas, but not plexiform schwannomas, are diagnostic of NF2. Neurofibromatosis type1 (NF1) is very rarely present with schwannomas.
- Soft tissue schwannomas are common in middle age and rare in children. Common presenting feature of schwannoma is an asymptomatic incidental mass or sometimes painful swelling, due to neural compression. Most schwannomas (approximately 90%) are sporadic, slowly growing, well-defined/well-circumscribed tumor, arising in superficial (more common) or deep locations. Schwannomas are common in head/neck region and the distal parts of the extremities, though they can occur in any body parts. Schwannomas in neck region easily mistaken for lymph nodes on clinical examination. Schwannomas in deep seated location like retroperitoneum and mediastinum are often large. Large tumour can show cystic and hemorrhagic changes, which can be mistaken for sarcomas on clinical and radiological ground.
- Grossly, schwannomas are commonly well circumscribed, nodular mass with fibrous capsule. Nerve attachment is commonly seen during surgical procedure, but uncommon in surgical resected specimen as surgeon try to spare the nerve. Size is usually smaller and most cases are restricted up to 5 cm. Mediastinal and retroperitoneal tumours are larger and can reach up to 10 cm or even more. Soft to firm myxoid/mucoid shiny grey-white or cystic areas with hemorrhage, or calcification can be seen.
- Characteristic histologic feature of schwannoma is areas of both cellular Antoni A and hypocellular Antoni B pattern. Antoni A is comprising of short wavy dark spindle cells with indistinct cytoplasmic borders. These cells are arranged in short or interconnecting fascicles or loose or sometimes cellular and tightly formed pattern. Nuclear palisading or whirling patterns are common in Antoni A areas. High cellularity with focal palisading can create diagnostic difficulties. Verocay bodies formation (palisading of nuclei with eosinophilic fibrillary cellular processes of schwann cells) are seen in Antoni A pattern. Sometimes more sections and deeper tissue block cutting may be required to highlight the Antoni A areas. Antoni B areas are less cellular than Antoni A, with prominence of loose edematous, collagenized, myxoid and cystic changes with inflammatory cells, particularly lymphocytes and histiocytes. Sparse thin wavy spindle or ovoid cells in myxoid substances help in the diagnosis.
- Other common histologic features of schwannomas are:
- Variable amount of collagen bundles (may resemblance to neurofibroma or solitary fibrous tumour)
- Variable size thick blood vessels with hyalinized walls and luminal thrombi, and dilated thin-walled stag-horn vasculature (seen in present case)
- Histiocyte-rich areas with xanthoma cells, siderophages and hemosiderin deposition.
- Focal nuclear atypia is common. Some Slow growing long-standing lesions may show degenerative changes/ancient change like marked nuclear pleomorphism with smudgy chromatin pattern.
- Intranuclear inclusions and cytoplasmic vacuolization may be seen (seen in present case)
- Mitoses are low to absent and without atypical forms, however, encapsulated cellular areas can show little more conspicuous mitotic activity, but without atypical forms, tumour necrosis and cytologic atypia.
- Peripheral capsular lymphoid aggregates and sparkling of lymphocytes in tumour can be seen.
- Extensive cystic change can be seen with a thin rim of a residual schwannoma.
- Ischemic necrosis and haemorrhage can be seen in a large encapsulated tumor, but no coagulative necrosis.
- Dense collagenisation and stromal hyalinization with hypocellularity may be seen. Foci of classic morphology should be searched to prevent misdiagnosis.
- Calcification/metaplastic bone formation may be seen.
6. In present case, tumor arising in thigh of a young and middle-aged individual female, along with solid sheets and fascicles of cellular spindle cells (some with elongated wavy tapered nuclei and eosinophilic cytoplasm), without Verocay bodies/palisading of nuclei, presence of perivascular whorls and hyalinization and diffuse positivity for S100 protein favor cellular schwannoma. Cellular schwannomas are uncommon but important to recognize, because it frequently mimic other spindle cell tumor. High cellularity, compact fascicular growth of spindle cells and occasional locally destructive behavior, including bone erosion, often prompt consideration of malignancy. Other features of cellular schwannoma are multi-nodularity or plexiform architecture, foamy histiocyte, thick fibrous capsule, with subcapsular or intra-tumoral lymphoid aggregates. Mitotic activity is usually low (limited to 5 per 10 HPFs); however, rare foci of higher mitotic activity can be seen in cellular areas. Ki67 index is commonly around 6% to 8%, however, it is not helpful to predict recurrence. Small foci of necrosis can be seen. Pleomorphism is not a feature of cellular schwannoma. Presence of mitotic activity and necrosis do not indicate malignancy if tumor is encapsulated and lacks striking pleomorphism. Diffuse strong positivity for S100 protein again argue against MPNST. Cellular schwannomas lack expression of smooth muscle actin, desmin, CD117 and DOG1, allowing exclusion of other important tumors in its differential diagnosis, leiomyosarcoma and GIST, respectively. Incomplete excision of cellular schwannomas may lead to recurrence, but never metastasize. The most important job of pathologist is to recognize this tumour as a benign entity rather than MPNST or synovial sarcoma or other sarcomas.
- Schwannomas (including all morphologic types) are strong and diffuse positive for S100 protein (both nuclei and cytoplasm staining)
- SOX10 also shows similar diffuse expression in nuclei
- Schwannomas are consistently positive for vimentin
- Some schwannomas can express glial fibrillary acidic protein (GFAP) and Cytokeratin. Cytokeratin AE1/AE3 and GFAP expression common in tumours of retroperitoneum, posterior mediastinum, and tumors from gastro-intestine tract. In peripheral sites, GFAP expression is rare, and CKAE1/AE3 has not been reported. CK AE1/AE3 expression due to cross-reactivity with GFAP.
- CD34 positive in fibroblasts at capsule and perivascular areas, but cellular areas are CD34 negative.
- Few perineurial cells on outer part of tumour can be immunoreactive for EMA
- CD68 can be positive in schwannoma due to high lysosomal content.
- Strong positivity for laminin and collagen type IV are due to abundant basement membrane material.
- Variable expression of neurofilaments is seen in schwannomas.
- Podoplanin (D2-40) and calretinin are diffuse and strong positive in most schwannomas.
- Schwannomas are negative for claudin-1 and GLUT1.
- Hybrid peripheral nerve sheath tumour express more than 1 markers in addition to S100.
7. Variety of spindle cell tumor fall in the differential diagnosis of schwannomas. Neurofibroma are uncapsulated and lacks Antoni A pattern of schwannomas. Schwannomas with prominent Antoni B areas can look very similar to neurofibroma. Neurofibroma composed of mixture of Schwann cells (S 100 positive, but less striking compared to schwannoma), fibroblasts (CD34 positive), perineurial cells (EMA positive), axons, and variable inflammatory elements, such as mast cells and lymphocytes. Podoplanin (D2-40) is diffusely positive in most schwannomas, compared to very few cases of neurofibromas are positive for Podoplanin (D2-40). Also calretinin stain stronger in schwannoma while it is focal in neurofibromas. Factor XIIIa stain stronger in neurofibroma while weak in schwannomas. Malignant Peripheral Nerve Sheath Tumor (MPNST) are often larger and more deep-seated than schwannoma. Cells of MPNST are monomorphic spindle to highly pleomorphic. Mitotic activity is high and easy to appreciate. Geographic necrosis common. S100 protein expression is negative or patchy/focal only, however lower grade MPNST may show good S100 positivity. Diffusely S100 positive should be strongly consider for cellular schwannomas. Cellular, plexiform, and ancient schwannomas are mimicker of MPNST. Epithelioid MPNST contains larger nuclei with prominent macronucleoli. Malignant/Metastatic Melanoma should be considered in dermal based tumours. Past history of melanoma is reaching the diagnosis. Melanoma usually lack Antoni A and Antoni B areas. Important clue is junctional activity. Spindle cell melanoma may be relatively bland, but often shows at least focal nuclear atypia and mitotic activity. Epithelioid melanoma cells are often cytologically malignant with prominent eosinophilic “cherry red” nucleoli. Strong expression of S100 protein and SOX10 are another pitfall. Expression of HMB-45, MART1/Melan-A, MiTF, tyrosinase are helpful to rule out cellular schwannoma and MPNST. Focal expression can be seen in HMB-45 and MART1/Melan-A. Desmoplastic melanomas are commonly negative for HMB-45 and MART-1, so strong diffuse S100 positivity in spindle cells easily mistaken for schwannoma, also reverse may occur. Pleomorphic Hyalinizing Angiectatic Tumor (PHAT) has predilection for foot, ankle, and leg. PHAT is little similar to ancient schwannoma, but PHAT is S100 protein negative. CD34 is positive in around 50% of cases. Significant risk of local recurrence with simple excision. Leiomyoma is generally looks pink on low power and lack Antoni A and Antoni B areas. Leiomyoma composed of fascicles of plump eosinophilic spindle cells with cigar-shaped nuclei. Focal areas may show epithelioid morphology and variable degree of hyalinization and myxoid changes. Leiomyomas are positive for smooth muscle actin (SMA), caldesmon, and desmin while negative for S 100 protein. Perineurioma is a benign neoplasm with perineurial differentiation and the presence of 22q deletions. Perineurioma occur in neural and soft tissue location. Intraneural perineuriomas are very slow growing localized solitary expansion of peripheral nerves. Histologically, intraneural perineuriomas are characterized by a complex perineurial cell proliferation, extending into the endoneurium and concentrically surrounding individual nerve fibers and endoneurial capillaries producing characteristic “pseudo-onion bulbs” appearance. Soft tissue perineuriomas are not associated with nerve and are usually well circumscribed or capsulated tumor. Slender cells with very delicate, overlapping elongated cellular processes, arranged in loose fascicles or whorls is the typical pattern. Pleomorphic cells and limited infiltration may be seen. Abundant myxoid change, creating a microcystic or reticular pattern. On immunohistochemistry, EMA is membranous positive in most perineuriomas. Claudin 1 and GLUT1 stain perineuriomas but neither of these markers is entirely specific.
8. Surgical excision with sparing of nerve is generally curative and recurrences are rare. However, deep-seated, and cellular examples may recur.
9. Malignant changes are extremely rare. A diagnosis of malignancy requires documented origin of the malignant component from a preexisting schwannoma, which is usually epithelioid MPNST. They are high-grade tumours, with enlarged epithelioid cells with prominent nucleoli in an otherwise typical schwannoma suggests early malignant change. Angiosarcoma arising in schwannoma has also been reported and usually has an epithelioid component. Keratin positivity is common, and S100 protein positivity is patchy rather than diffuse. High tumour related mortality is seen.
10. Some histologic features are difficult to assess in a core biopsy especially capsule and palisading pattern. Use of clinical findings like duration of swelling, associated pain, site and location (superficial or deep), relevant radiology findings and use of S 100 immunostain prevent a misdiagnosis of schwannoma as a sarcoma. Schwannoma show more homogeneous neoplastic proliferation of mature Schwann cells with diffuse strong S100 positivity.
References: Rodriguez FJ, Folpe AL, Giannini C, Perry A. Pathology of peripheral nerve sheath tumors: diagnostic overview and update on selected diagnostic problems. Acta Neuropathol. 2012 Mar;123(3):295-319. doi: 10.1007/s00401-012-0954-z. Epub 2012 Feb 12. PMID: 22327363; PMCID: PMC3629555.