Posterior Calf Mass

A 43-year-old woman presents with a slow growing left posterior calf mass. Gross examination of the resected specimen shows a circumscribed and encapsulated 7.5 x 4.5 x 3.5 cm mass. Upon sectioning, the tumor exhibits a tan to yellow cut surface without necrosis.

Master List of Diagnoses

  • Leiomyoma
  • Leiomyosarcoma
  • Low-grade fibromyxoid sarcoma
  • Malignant peripheral nerve sheath tumor
  • Neurofibroma
  • Schwannoma
  • Spindle cell melanoma
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This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2017, Case 20, and is schwannoma of the calf.

Criteria for Diagnosis and Comments

Sections show a well-circumscribed tumor surrounded by a fibrous capsule (the capsule might not be sampled in every section submitted), displaying two distinct morphologies. There are more cellular areas (also known as Antoni-A) composed of spindle cells with eosinophilic cytoplasm, indistinct cytoplasmic borders, and wavy nuclei with tapered ends arranged in compact fascicles. Tumor nuclei aligned in two rows separated by eosinophilic fibrillary processes forming structures known as Verocay bodies are noted. In between Antoni-A zones there are hypocellular areas known as Antoni-B. These areas contain haphazardly arranged spindle cells set in a loose myxoid stroma with delicate collagen fibers, microcystic changes, and inflammatory cells. Numerous ectatic vessels with irregular lumens and hyalinized walls are noted especially in the Antoni-B areas. These features are consistent with a diagnosis of schwannoma.

Schwannoma (or neurilemmoma) is a benign peripheral nerve sheath tumor with a predilection for the head and neck area and the flexor surfaces of extremities. The tumor affects all ages (more common in adults) and does not favor a gender. Schwannomas occur usually as solitary and sporadic tumors. In 3% of cases, they occur in association with neurofibromatosis type 2 and in 2% with schwannomatosis; in these contexts, the tumors may be multiple. Inactivating mutations involving the NF2 gene are seen in schwannomas associated with neurofibromatosis type 2 and have also been described in about 2/3 of sporadic schwannomas. Loss of merlin expression (the protein product of NF2 gene) is seen in almost all schwannomas suggesting that alternative epigenetic mechanisms may be involved in cases with intact NF2 gene.

Schwannomas are slow growing tumors and are usually not painful unless they are large. Schwannomas arise in association with a peripheral nerve and they are freely movable except on the long axis of the nerve that is involved. Schwannomas originating or extending into the spinal canal may cause neurologic symptoms due to compression of adjacent nerves.

On gross examination, schwannomas are surrounded by a true capsule composed of epineurium. Schwannomas are usually smaller than 5.0 cm in diameter; larger tumors may be seen in the retroperitoneum. On cut surface, the tumor is white to yellow and may show cystic degeneration.

Histologic examination shows the classic alternation of a cellular component (Antoni-A) and a loose myxoid component (Antoni-B). Schwannomas may contain glands and benign epithelial structures. A rare variant with small lymphocyte-like Schwann cells arranged concentrically around a collagen core with the appearance of giant pseudorosettes has been described as neuroblastoma-like schwannoma. Large schwannomas of long-standing duration may display degenerative changes in the form of cyst formation, calcification, hemorrhage, and hyalinization. Notably, these tumors, referred to as ancient schwannomas, demonstrate marked cytologic atypia in the form of large pleomorphic nuclei with hyperchromasia and multilobation; however, they lack mitotic activity. Cellular variant of schwannoma contains exclusively Antoni-A areas and lacks Verocay bodies. The cells are arranged in short fascicles and whorls but also in long herringbone fascicles reminiscent of the pattern seen in malignant peripheral nerve sheath tumor (MPNST), fibrosarcoma, or leiomyosarcoma with which cellular schwannoma may be confused. A plexiform pattern may be seen in about 5% of schwannomas. In contrast to plexiform neurofibroma, which is considered pathognomonic for neurofibromatosis type 1, plexiform schwannoma is only weakly associated with neurofibromatosis type 1 or type 2.

All schwannomas express strongly and diffusely S100 and Sox10, which serve as diagnostic markers. In addition, positivity for GFAP and keratin may be seen in schwanommas, especially the retroperitoneal ones. Schwannomas, including the cellular variant, are benign tumors characterized by an indolent behavior. Malignant transformation of schwannomas has been described; however, it is exceedingly rare. When it occurs, it tends to be in the form or epithelioid MPNST or angiosarcoma.

Differential diagnosis of schwannoma includes neurofibroma, MPNST, leiomyoma, leiomyosarcoma, low-grade fibromyxoid sarcoma/hyalinizing spindle cell tumor with giant rosettes (LGFMS/HSCT) and spindle cell melanoma.

Neurofibromas are benign peripheral nerve sheath tumors with three main variants: localized, plexiform, and diffuse. They may be circumscribed but are usually not encapsulated. Classic histology includes a myxoid matrix containing cells with wavy nuclei, wire-like strands of collagen, and increased number of mast cells. In contrast to schwannoma, neurofibroma lacks Antoni-A and -B areas and does not mark diffusely with S100.

MPNST are malignant tumors with differentiation toward various elements of the nerve sheath. They may be confused with schwannoma, especially the cellular variant. In contrast to cellular schwannoma, MPNST demonstrates geographic areas of necrosis, higher grade atypia and increased mitotic activity. In addition, MPNSTs lack the diffuse expression of S100 characteristic of schwannoma, which is another helpful diagnostic clue.

Leiomyoma and leiomyosarcoma are tumors with smooth muscle differentiation. As such, they are composed of tightly packed fascicles of spindle cells with elongated cigar-shaped nuclei and eosinophilic cytoplasm resembling schwannoma, particularly the cellular variant. In contrast to schwannoma, leiomyoma and leiomyosarcoma are not encapsulated tumors, lack Verocay bodies, and are negative or only focally positive for S100.

LGFMS/HSCT contains alternating hypo- and hypercellular zones with epitheliod and spindle cells, which may resemble the Antoni-A and -B areas of schwannoma. In addition, some cases demonstrate distinctive giant rosettes with a central core containing coarse and haphazardly distributed collagen reminiscent of the pseudorosettes in neuroblastoma-like schwannoma. Key distinguishing features from schwannoma include large size (usually larger than 6.0 cm), lack of circumscription and encapsulation, expression of MUC4, and negative S100 staining. Recently, the t(7;16)(q32-34;p11) translocation involving the FUS-CREB3L2 genes was found in 90% of cases.

Spindle cell melanoma may also enter the differential diagnosis due to spindle cell morphology and expression of S100. In contrast to schwannomas, they demonstrate higher grade atypia, increased mitotic activity and an infiltrative growth pattern.

  1. Which of the following histologic features is most characteristic for schwannoma?
    1. Cytologic atypia
    2. Encapsulation
    3. Increased mitotic activity
    4. Increased number of mast cells.
    5. Tumor necrosis
  2. Which of the following immunohistochemical stains is most useful in differentiating schwannoma from malignant peripheral nerve sheath tumor?
    1. Desmin
    2. EMA
    3. MUC4
    4. Myoglobin
    5. S100
  3. Which of the following statements is most accurate in schwannoma?
    1. Almost all schwannomas demonstrate inactivating mutations of NF2 gene.
    2. Almost all schwannomas lack expression of merlin.
    3. Malignant transformation is common.
    4. Plexiform variant of schwannoma is pathognomonic for neurofibromatosis type 1.
    5. Plexiform variant of schwannoma is pathognomonic for neurofibromatosis type 2.


  1. Antinheimo J, Sankila R, Carpén O, Pukkala E, Sainio M, Jääskeläinen J. Population-based analysis of sporadic and type 2 neurofibromatosis-associated meningiomas and schwannomas. Neurology. 2000;54(1):71-76.
  2. Fletcher CD, Davies SE. Benign plexiform (multinodular) schwannoma: a rare tumour unassociated with neurofibromatosis. Histopathology. 1986;10(9):971-980.
  3. McMenamin ME, Fletcher CD. Expanding the spectrum of malignant change in schwannomas: epithelioid malignant change, epithelioid malignant peripheral nerve sheath tumor, and epithelioid angiosarcoma. Am J Surg Pathol. 2001;25(1):13-25.
  4. Suchak R, Luzar B, Bacchi CE, Maguire B, Calonje E. Cutaneous neuroblastoma-like schwannoma: a report of two cases, one with plexiform pattern, and a review of the literature. J Cutan Pathol. 2010;37(9):997-1001.
  5. Reid R, de Silva MV, Paterson L, Ryan E, Fisher C. Low-grade fibromyxoid sarcoma and hyalinizing spindle cell tumor with giant rosettes share a common t(7;16)(q34;p11) translocation. Am J Surg Pathol. 2003;27(9):1229-1236.
  6. White W, Shiu MH, Rosenblum MK, Erlandson RA, Woodruff JM. Cellular schwannoma. A clinicopathologic study of 57 patients and 58 tumors. Cancer. 1990;66:1266-1275.


Aleodor A. Andea, MD, MBA
Surgical Pathology Committee
University of Michigan
Ann Arbor, MI

Answer Key

  1. Encapsulation (b)
  2. S100 (e)
  3. Almost all schwannomas lack expression of merlin. (b)