Perineurioma is a soft tissue tumor dervied from the peripheral nerve sheath tumor and composed exclusively of perineurial cells. These tumors can be divided broadly into two categories: a rare group of lesions with an intraneural localization (intraneural perineurioma), and a more common extraneural group of tumors arising in the soft tissues (perineurioma of soft tissue).
Epidemiology Disease Associations Pathogenesis Laboratory/Radiologic/Other Diagnostic Testing Gross Appearance and Clinical Variants Histopathological Features and Variants Special Stains/
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EPIDEMIOLOGY CHARACTERIZATION SYNONYMS Storiform perineurial fibroma
DISEASE ASSOCIATIONS CHARACTERIZATION NEUROFIBROMATOSIS 2
- Soft Tissue Perineurioma in a Patient With Neurofibromatosis Type 2: A Tumor not Previously Associated With the NF2 Syndrome.
Departments of *Pathology, and daggerOrthopaedics and Rehabilitation, Vanderbilt University Medical Center and Vanderbilt University School of Medicine, Nashville, TN.
- Am J Surg Pathol. 2006 Dec;30(12):1624-1629. Abstract quote
Neoplasms that commonly affect patients with neurofibromatosis type 2 (NF2) include schwannomas, meningiomas, astrocytomas, ependymomas, and neurofibromas. Perineuriomas are rare tumors of the peripheral nerve sheath that share some characteristics with meningioma. As in both NF2-associated and sporadic cases of schwannoma and meningioma, perineuriomas often harbor mutations or deletions of the NF2 gene. However, perineuriomas have not previously been reported in the clinical setting of NF2.
A 30-year-old man with a history of bilateral vestibular schwannomas, a parasagittal meningioma, an intraspinal ependymoma, and multiple other neoplasms involving both cranial and peripheral nerves (thereby fulfilling the diagnostic criteria for NF2) presented with an enlarging thigh mass. The diagnosis of cellular soft tissue perineurioma was confirmed by both immunohistochemical and ultrastructural analysis.
This case represents the first report of a soft tissue perineurioma arising in the setting of NF2.
Am J Surg Pathol. 2005 Sep;29(9):1164-1169. Abstract quote
Only two karyotypes of perineurioma have previously been reported, 46XX,del(10)(q22q24),der(10),del(22)(q11-12q?)/47, idem,+der(10) (in a sclerosing perineurioma of the finger) and 45,XX,add(14)(p13),-22,add(22)(q11.2) (in an intraneural perineurioma).
We investigated the clinicopathologic and cytogenetic findings in four consecutive perineuriomas in children, including two small (</=1 cm) digital sclerosing perineuriomas, a 2-cm intraneural perineurioma, and a 16-cm abdominal soft tissue perineurioma.
All lesions showed plump perineurial cells in a complex whorled configuration. Immunohistochemical (strong EMA immunostaining in all cases) and ultrastructural (in three of three lesions examined) evidence of perineurial differentiation was present. The sclerosing perineuriomas showed 46,XY,t(2;10)(p23;q24) and 47,XX,add(3)(q23),add(6)(q21),-5,-9,-10,-22,+mar1,+mar2,+mars; the intraneural tumor showed 46,XX,add(2)(q11.2),add(3)(q12); and the abdominal soft tissue perineurioma showed 46,XX,t(8;9)(q13;q22). Metaphase FISH analysis for an ALK gene rearrangement in the sclerosing perineurioma with t(2;10) was negative; the ALK signal remained on the der(2).
We conclude that perineuriomas display mostly simple karyotypes, characterized by one or few chromosomal rearrangements or numerical changes. In conjunction with the previously published sclerosing perineurioma karyotypes, the findings of chromosome 10 aberrations, t(2;10)(p23;q24) and monosomy 10 in two sclerosing perineuriomas, indicate that rearrangements and/or deletions of 10q are a consistent finding in this variant of perineurioma. The findings also expand previous assertions that chromosome 22 abnormalities are pathogenetic in perineurioma and suggest that diverse genetic tumorigenic mechanisms may exist, possibly depending on the subtype.
Soft tissue perineurioma: evidence for an abnormality of chromosome 22, criteria for diagnosis, and review of the literature.
Giannini C, Scheithauer BW, Jenkins RB, et al.
Am J Surg Pathol 1997;21:164–73.
The neurofibromatosis type 2 gene is mutated in perineurial cell tumors: a molecular genetic study of eight cases.
Lasota J, Fetsch JF, Wozniak A, Wasag B, Sciot R, Miettinen M.
Department of Soft Tissue Pathology, Armed Forces Institute of Pathology, 14th Street and Alaska Ave., Washington, DC 20306-6000, USA.
Am J Pathol 2001 Apr;158(4):1223-9 Abstract quote
Perineurial cell tumors (PNTs) are rare neoplasms derived from or showing differentiation toward specialized lining cells of the nerve sheath, the perineurial cells.
In this study, we have evaluated neurofibromatosis type 2 (NF2) gene alterations in eight PNTs using archival formaldehyde-fixed, paraffin-embedded tissue. Two conventional soft-tissue PNTs from the upper back and chest wall, one retiform soft tissue variant from the scapular region, and five sclerosing PNTs from the fingers and palm were studied. All cases showed histological features of PNTs, and the neoplastic cells were positive for epithelial membrane antigen and negative for S100 protein. The coding sequences (exons 1 to 15) of the NF2 gene were polymerase chain reaction (PCR) amplified and evaluated for mutations by direct sequencing of the PCR products. Five NF2 point mutations, two in the 5'-untranslated region (UTR) and three in exons 3, 6, and 8, were identified in four of eight cases (50%) studied. Exon mutations resulted in changes of predicted amino acids sequences: Asp-->Asn at codon 83, Glu-->Asp at codon 182, and Leu-->Val at codon 241. In two cases (one with a missense mutation in codon 241), the same point mutation in the 5'-UTR at the nucleotide position 8958 was identified. A loss of heterozygosity (LOH) study was performed in three cases. LOH at the NF2 locus was found in one case with a mutation in the 5'-UTR. However, in another case with exon 8 and 5'-UTR mutations, deletion of one allele of the NF2 gene was previously documented by fluorescence in situ hybridization.
The coexistence of NF2 gene mutations and LOH at the NF2 locus indicates that the NF2 tumor suppressor gene is altered in PNTs by the two-hit mechanism.
CHARACTERIZATION General Intraneural
Intraneural neoplastic proliferation of perineurial cells with a ``(pseudo)onion bulb'' arrangement around a central axon
Extraneural More common arising in the soft tissues VARIANTS GASTROINTESTINAL
Am J Surg Pathol. 2005 Jul;29(7):859-65. Abstract quote
Benign peripheral nerve sheath tumors are uncommon in the gastrointestinal tract, and perineuriomas have not previously been reported to occur at this anatomic location.
In this study, we analyzed the clinicopathologic and immunohistochemical features of 10 perineuriomas arising in the intestine. Eight patients were female and 2 male (median age, 51 years; range, 35-72 years). Eight of the lesions were intramucosal perineuriomas presenting as small sessile polyps detected during colonoscopy; 6 of these 8 patients were asymptomatic and undergoing colorectal cancer screening. The remaining 2 cases were submucosal masses, one each located in the colon and jejunum. Of the mucosal polyps, six were located in the rectosigmoid or sigmoid colon and one each was detected in the descending colon and transverse colon. The polyps ranged from 0.2 to 0.6 cm (median, 0.4 cm) in greatest dimension. The colonic and jejunal masses measured 3 cm and 4.5 cm, respectively.
Histologically, the intramucosal perineuriomas were composed of uniform bland spindle cells having ovoid to elongated nuclei and pale indistinct cytoplasm, with no cytologic atypia, pleomorphism, or mitotic activity. The lesions had a fine collagenous stroma, demonstrated irregular borders with the adjacent lamina propria, and entrapped colonic crypts. Five cases exhibited hyperplastic changes in the adjacent or entrapped epithelium. The colonic submucosal tumor was microscopically well circumscribed, whereas the jejunal perineurioma showed focal infiltration through the muscularis propria into the subserosa. The stroma was collagenous in the colonic tumor and predominantly myxoid in the jejunal tumor. The spindle cells in the submucosal perineuriomas demonstrated tapered nuclei and elongated bipolar cytoplasmic processes.
All tumors except one were positive for epithelial membrane antigen (EMA); 4 of 10 expressed claudin-1 and 2 of 10 expressed CD34. All tumors were negative for S-100 protein, glial fibrillary acidic protein, neurofilament protein, smooth muscle actin, desmin, caldesmon, KIT, and pan-keratin. Electron microscopy was performed on the tumor lacking EMA expression, revealing typical features of perineurioma, namely, spindle cells with long bipolar cytoplasmic processes and prominent pinocytotic vesicles, surrounded by discontinuous basal lamina.
Clinical follow-up was available for 4 patients (median, 34 months; range, 8-53 months). No tumor recurred. In summary, perineuriomas may arise in the intestine, most often as intramucosal lesions detected as colorectal polyps with distinctive histologic features including entrapment of colonic crypts. Distinguishing perineuriomas from other spindle cell neoplasms of the gastrointestinal tract can be facilitated by immunostaining for EMA and claudin-1.
Perineurioma of the kidney. Report of a case with histologic, immunohistochemical, and ultrastructural studies.
Kahn DG, Duckett T, Bhuta SM.
Department of Pathology, Olive View Medical Center, Sylmar, Calif.
Arch Pathol Lab Med 1993 Jun;117(6):654-7 Abstract quote
We report a perineurioma of the kidney.
A 66-year-old woman had a renal mass discovered as an incidental finding during the evaluation of hypertension and proteinuria. This neoplasm radiographically mimicked renal cell carcinoma, but the diagnosis of perineurioma was confirmed with histologic and ultrastructural studies.
Perineurioma is a recently described, rare, benign tumor of the peripheral nervous system composed of perineurial cells. Histologically, the differential diagnosis includes low-grade fibromyxoid sarcoma and other myxoid tumors.
SKIN CUTANEOUS SCLEROSING PERINEURIOMA OF THE DIGITS
Cutaneous sclerosing perineurioma of the digits: an uncommon soft-tissue neoplasm. Report of two cases with immunohistochemical analysis.
Canales-Ibarra C, Magarinos G, Olsoff-Pagovich P, Ortiz-Hidalgo C.
Department of Pathology, The American British Cowdray Hospital, Mexico City, Mexico, Department of Pathology, The British Hospital, Buenos Aires, Argentina, Department of Plastic Surgery, ABC Hospital, and Department of Histology, School of Medicine, Universidad Panamericana, Mexico City, Mexico.
J Cutan Pathol. 2003 Oct;30(9):577-581. Abstract quote
BACKGROUND: Cutaneous sclerosing perineurioma is a recently characterized, uncommon tumor composed of perineurial cells, which exhibits immunoreactivity for epithelial membrane antigen (EMA). These lesions occur preferentially in children and young adults and usually develop as dermal or subcutaneous nodules in the hands or palms.
METHODS: We report two cases of cutaneous sclerosing perineurioma in young patients without stigmata of neurofibromatosis. Histologically, these lesions were well-circumscribed masses and were characterized by a variable number of epithelioid and spindle cells with wavy nuclei end elongated cytoplasmic processes embedded in a dense collagen stroma.
RESULTS: These cells showed focal whorling formation, demonstrated robust immunoreactivity for EMA and CD99, and were uniformly negative for S-100 protein, actin (HHF-35), CD34, cytokeratin AE1-3, and CD57.
CONCLUSION: We comment on the differential diagnosis of fibrous cutaneous lesions based on immunohistochemistry.
Am J Surg Pathol. 2005 Jul;29(7):845-58. Abstract quote
Perineuriomas are uncommon benign peripheral nerve sheath tumors that include soft tissue, sclerosing, and intraneural variants. Fewer than 50 soft tissue perineuriomas have been reported to date, and the clinical significance of atypical histologic features is unknown.
To characterize these tumors further, 81 soft tissue perineuriomas received between 1994 and 2003 were retrieved from the authors' consult files. Hematoxylin and eosin sections were reexamined, immunohistochemistry was performed, and clinical details were obtained from referring physicians. Forty-three patients were female and 38 male (mean age, 46 years; range, 10-79 years). Tumor size ranged from 0.3 to 20 cm (mean, 4.1 cm) in greatest dimension.
Most patients presented with a painless mass. The tumors arose in a wide anatomic distribution: 36 lower limb, 19 upper limb, 15 trunk, 7 head and neck, 3 retroperitoneum, and 1 paratesticular. Forty-two tumors were situated primarily in subcutis, 25 in deep soft tissue, and 9 were limited to the dermis.
Nearly all cases were grossly well circumscribed; 12 showed focal microscopically infiltrative margins. Most tumors had a storiform and focally whorled growth pattern; 17 exhibited fascicular areas. Thirty-eight tumors were hypocellular, 15 were markedly hypercellular, and 7 showed alternating zones of hypocellularity and hypercellularity. Stroma was usually collagenous but in 17 tumors was predominantly myxoid, and in 16 was mixed collagenous and myxoid. Mitoses ranged from 0 to 13 per 30 high power fields (mean, 1); 53 tumors had no mitoses. Based on worrisome cytologic or architectural features, 14 cases were classified as atypical perineuriomas: 12 contained scattered pleomorphic cells, 1 showed an abrupt transition from typical morphology to a markedly hypercellular, fascicular area with cytologic atypia, and 1 exhibited diffuse infiltration of skeletal muscle.
All tumors were reactive for epithelial membrane antigen; 50 of 78 (64%) expressed CD34, 22 of 76 (29%) claudin-1, 16 of 77 (21%) smooth muscle actin, and 4 of 81 (5%) S-100 protein. All tumors were negative for glial fibrillary acidic protein, neurofilament protein, and desmin. Clinical follow-up was available for 43 patients (mean, 41 months; range, 6-146 months). Among tumors for which the status of surgical margins was known, 52% were widely excised, 31% were marginally excised, and 18% had positive margins. Only two tumors recurred locally (one of which was atypical): one recurred 10 years following primary excision; and one recurred twice, 5 and 9 years following excision. No tumor metastasized.
Soft tissue perineuriomas behave in a benign fashion and rarely recur. Atypical histologic features (including scattered pleomorphic cells and infiltrative margins) seem to have no clinical significance and appear to be akin to those seen in ancient schwannoma and atypical (bizarre) neurofibroma.
HISTOLOGICAL TYPES CHARACTERIZATION GENERAL
Dermal, subcutaneous, or more deeply situated, usually well circumscribed (with or without a variably prominent hypocellular fibrous pseudocapsule) and of variable size (range, 1–20 cm)
Association with nerve is unusual
Bland, fusiform tumor cells arranged in whorls or interweaving fascicles, or they may show a storiform pattern
Cellular and nuclear atypia is rare and mitoses are only infrequently present
Variable amount of collagenous stroma may be present, often exhibiting pericellular cracking/clefting.
The Clinical and Histologic Spectrum of Cutaneous Fibrous Perineuriomas
Henry G. Skelton, M.D.; John Williams, CDR, M.C., U.S.N.; Kathleen J. Smith, M.D., M.C., U.S.N.
From the National Naval Medical Center, Bethesda, Maryland (J.W.); and Departments of Dermatology (K.J.S.) and Pathology (H.G.S.), University of Alabama at Birmingham, Birmingham, Alabama.
Am J Dermatopathol 2001;23:190-196 Abstract quote
Cutaneous fibrous perineuriomas (CFPs) and the closely related sclerotic perineuriomas are recently reported tumors.
We present nine additional cases of CFPs.
All tumors were small nodules on the extremities; however, they were not limited to a distal acral location as previously reported. In addition to tabulation of the histologic features, we performed a battery of immunohistochemical stains, including S-100 protein, CD34, cytokeratin, epithelial membrane antigen (EMA), KP-1, and collagen type IV.
Histologically, these tumors presented with sharp circumscription of their deep aspect, as previously reported, or were not circumscribed on any side. The cells ranged from plump and spindled with one or more nuclei to thin, elongated, spindled cells with slender nuclei. A variably fibrotic stromal matrix surrounded these components. Immunohistochemical staining showed EMA-positive staining of the cellular component, with collagen type IV–positive staining surrounding the cells. The tumor cells were negative for S-100 protein, factor XIIIa, CD34, cytokeratin, and KP-1.
The tumors reported here add to the clinical and histopathologic spectrum of CFPs.
Cutaneous fibrous perineurioma.
Smith K, Skelton H.
National Naval Medical Center, Bethesda, Maryland 20889-5600, USA.
J Cutan Pathol 1998;25:333–7. Abstract quote
Tumors of perineurial origin are rare. Three variants of perineuriomas have been described, a storiform perineurial fibroma, an intraneural perineurioma, and a recently described sclerosing perineurioma.
We present two patients with cutaneous fibrous perineurioma located in acral areas. Both tumors had a deep circumscribed margin with a prominent vascular component. They contained small round cells and spindle cells that express EMA and show membrane staining for type IV collagen.
Cutaneous fibrous perineuriomas fit within the spectrum of neurocristicly derived cellular proliferations.
- Granular perineurioma: the first report of a rare distinctive subtype of perineurioma.
Division of Pathology, School of Molecular Medical Sciences, University of Nottingham, Nottingham NG7 2UH, UK.
- Am J Dermatopathol. 2008 Apr;30(2):163-8. Abstract quote
Perineurioma represents a relatively recently described neoplasm in the spectrum of benign peripheral nerve sheath tumors composed of perineurial cells staining immunohistochemically positive for epithelial membrane antigen. Although intraneural, extraneural and sclerosing perineurioma, rare variants of perineurioma, do occur, and knowledge of them is important in the differential diagnosis of mesenchymal tumors of different lines of differentiation and more importantly if their clinical course differs from that of other perineuriomas.
We report herein the first case in the world literature of granular perineurioma arising in the dermal and subcutaneous tissues of the trunk of a 28-year-old female. The diagnosis was confirmed morphologically and immunohistochemically. More interestingly, 3 years later the patient complained of right lower extremity pain, for which magnetic resonance imaging studies showed an intraneural perineurioma confined to the sciatic nerve. The latter finding was confirmed both histopathologically and immunohistochemically to have exactly the same appearances of the original dermal and subcutaneous mass.
Neoplastic cells stained positively for epithelial membrane antigen and for the newly described antibodies claudin-1 and glut-1. Interestingly, the granular component of this large tumor (4.5 cm in maximum diameter) was negative for S100, but positive for NKI-C3.
The morphology, immunohistochemistry, and the clinical behavior for this tumor and the differential diagnoses are discussed.
Perineurial cell tumor (perineurioma) with granular cells.
Diaz-Flores L, Alvarez-Arguelles H, Madrid JF, Varela H, Gonzalez MP, Gutierrez R.
Department of Anatomy and Pathology, Faculty of Medicine, University of La Laguna, Santa Cruz de Tenerife, Islas Canarias, Spain.
J Cutan Pathol 1997 Oct;24(9):575-9 Abstract quote
A form of benign cutaneous tumor with perineurioma findings and with the presence of associated granular cells is described.
The two cases studied consisted of whorls made up of a high number of circumferentially arranged flattened cells, with perineurial characteristics, including bipolar cell processes, pinocytotic vesicles, a basal lamina, a positive immunoreactivity for EMA, and absence of immunostaining for S-100 protein. The granular cells, enclosed within the whorls, contained densely packed vesicles, particles with an apparently solid core, as well as membrane-limited vacuoles with disintegrating cellular organelles and electron-dense amorphous material.
While failing to demonstrate any immunoreactivity for EMA, the granular cells showed positivity for S-100 protein, which supports their Schwann-cell origin.
Due to its morphological and immunohistochemical characteristics, this peculiar form of tumor can be considered as a perineurioma with perineurial cell whorls and granular cell changes occurring in associated Schwann cells at the center of the whorls.
Intraneural reticular perineurioma of the neck.
De La Jarte-Thirouard AS, Jacquier I, De Saint-Maur PP.
Departments of Pathology, and Otorhinolaryngology, Hopital Saint-Antoine, APHP, Paris, France.
Ann Diagn Pathol 2003 Apr;7(2):120-3 Abstract quote
Perineuriomas are infrequent tumors that may be intraneural or extraneural in soft tissue with no apparent relation with a nerve. Some cases of soft tissue perineurioma may have a retiform pattern, but this pattern has not been described to date in intraneural perineurioma.
We report a case of a unique perineurioma arising in a nerve of the neck that had a distinctive reticular pattern and was intraneural. The patient was a 21-year-old woman who had a lump on the left side of the neck abutting the vena jugularis. The tumor had features of both reticular perineurioma and intraneural perineurioma with pseudo-onion bulb pattern.
The tumor cells were positive for epithelial membrane antigen. The patient is free of tumor 6 months after operation.
Ann Diagn Pathol. 2005 Aug;9(4):197-201. Abstract quote
A case of low-grade malignant perineurioma presenting as a mass in the thigh is described. The patient was a 76-year-old woman with an enlarging painful mass on her right lateral thigh over the past 2 months. Thorough clinical and radiological studies did not reveal any evidence of tumor elsewhere. The patient underwent fine needle aspiration of the mass, which revealed pleomorphic spindle cells in small clusters or dispersed as single cells within myxoid stroma, cytologically consistent with a high-grade sarcoma. At surgery, the tumor was found to be entirely confined within the muscle.
Grossly, the tumor measured 6.5 cm in greatest diameter and showed a gray-white fleshy cut surface that was well circumscribed but unencapsulated. Histologic examination showed a highly cellular spindle cell proliferation embedded within myxoid stroma. The tumor cells showed mild to moderate nuclear pleomorphism with minimal mitotic activity. No evidence of hemorrhage or necrosis was noted. The tumor irregularly invaded the surrounding skeletal muscle. Immunohistochemical studies showed weak membranous positivity for epithelial membrane antigen and focal cytoplasmic positivity for CD34; stains for smooth muscle actin, cytokeratin AE1/AE3, desmin, CD56, H-caldesmon, calponin, and S-100 protein were negative. Electron microscopy showed cells with thin, elongated cytoplasmic processes extending along connective tissue in a parallel, onion-like arrangement and prominent subplasmalemmal pinocytotic activity.
The marked pleomorphism displayed on fine needle aspiration observed in this case can lead to a mistaken diagnosis of high-grade sarcoma resulting in unnecessarily aggressive management.
Malignant peripheral nerve sheath tumor with perineurial differentiation: 'malignant perineurioma'.
Rosenberg AS, Langee CL, Stevens GL, Morgan MB.
Department of Pathology, University of South Florida College of Medicine, USA Department of Dermatology, University of South Florida College of Medicine, USA James Haley V. A. Hospital, Tampa, Florida, USA.
J Cutan Pathol 2002 Jul;29(6):362-7 Abstract quote
BACKGROUND: Although benign tumors derived from the nerve sheath perineurial cell have been described from a variety of anatomic sites and are known to be a component of a number of benign neoplasms, malignant nerve sheath tumors of perineurial origin are exceedingly uncommon.
METHODS: We report an unusual case of a 70-year-old male who presented with a rapidly growing mass of the left arm, subsequently shown to be a malignant nerve sheath tumor with perineurial differentiation. A brief microscopic differential diagnosis and review of the literature are discussed.
RESULTS: Histologic sections show a partially circumscribed tumor of atypical spindle cells arranged in sweeping fascicles embedded in a myxoid matrix with focal whorling. Nuclear pleomorphism was evident among scattered typical and atypical mitotic figures (mean mitotic index of 7/10 high-power fields). The immunophenotypic profile consisted of only vimentin and epithelial membrane antigen (EMA) positivity, while antibodies to S-100, CD34, smooth muscle actin, and pankeratins were negative. Ultrastructural features included spindle cells with long cytoplasmic processes invested by interrupted basal lamina and pinocytotic vesicles, consistent with perineurial differentiation.
CONCLUSIONS: While the histogenic source of the benign perineurioma, the perineurial cell has only rarely been described in conjunction with malignant tumors. All cases to date have shown EMA-positive and S-100-negative atypical spindled cells arranged in fascicles embedded in a myxoid matrix. In addition to immunohistochemistry, ultrastructural examination may be necessary to support the diagnosis. The diagnostic differential includes melanoma, spindle cell squamous cell carcinoma, atypical fibroxanthoma, leiomyosarcoma, and conventional malignant peripheral nerve sheath tumor, most commonly of Schwannian differentiation. Recognizing perineurial differentiation is important since few cases have been reported to date and the biological potential of these neoplasms is not known.
A case of perineurioma with prominent myxoid changes.
Lopez JI, Elizalde JM.
Arch Anat Cytol Pathol 1992;40:220–2. RETICULAR
Reticular Perineurioma A Distinctive Variant of Soft Tissue Perineurioma
J. Frans Graadt van Roggen, etal.
Am J Surg Pathol 2001;25:485-493 Abstract quote
Soft tissue perineurioma is a relatively recently characterized, uncommon tumor composed of perineurial cells exhibiting immunoreactivity for epithelial membrane antigen (EMA). These lesions occur preferentially in adults and may arise in a wide variety of anatomic sites.
We report the clinicopathologic, immunohistochemical, and ultrastructural features of six cases of a poorly recognized morphologic variant of soft tissue perineurioma, characterized by a highly distinctive reticular growth pattern.
Four of the patients were women, two were men (age range, 34–61 yrs; median, 43 yrs). Four of the cases arose in the subcutis of the upper extremity; three were located distally (thumb, finger, palm), whereas one was situated more proximally near the elbow region. One case each was located in the gingiva and subcutaneous tissue of the inguinal region, respectively. In those cases in which clinical information was available (n = 5), the lesions were asymptomatic and had been present from 4 months to 10 years before resection. Tumor size ranged from 1.5 cm to 10 cm (median size, 4.25 cm).
Microscopically the lesions demonstrated a predominantly lace-like or reticular growth pattern composed of anastomosing cords of fusiform cells with bipolar cytoplasmic processes and palely eosinophilic cytoplasm. Nuclei were centrally placed, ovoid to fusiform in shape, and no mitoses were seen. Transition to more cellular areas was focally present in all cases. The stroma was variably collagenous to myxoid. Immunohistochemically all six cases stained positively for EMA but not for S-100 protein. Two cases demonstrated focal positive cytoplasmic staining for cytokeratin, whereas one case was focally desmin positive. Ultrastructural examination of two tumors showed typical features of perineurial cells. Follow up (available in only two cases) showed no evidence of recurrence.
Reticular perineurioma of soft tissue represents an unusual morphologic variant within the perineurioma group, which should be distinguished from myoepithelial tumors, extraskeletal myxoid chondrosarcoma, and myxoid synovial sarcoma.
Ann Diagn Pathol. 2005 Oct;9(5):293-4. Abstract quote
Retiform perineurioma is a rare distinct histologic subtype of benign soft tissue perineurioma.
We report 1 case of retiform perineurioma with a superficial invasion of the adjacent skeletal muscle. The patient was a 34-year-old woman with a neoplasm located between the deltoid muscle and the biceps.
Histologically, the tumor was nonencapsulated, composed exclusively of perineurial cells without cytologic and tissue atypia. There were focal areas in which the neoplastic cells infiltrated the muscle tissue, widely separating the bundles.
This case may represent a diagnostic pitfall as it can be confused with a malignant perineurioma.
- Hybrid peripheral nerve sheath tumors: Schwannoma-perineurioma and neurofibroma-perineurioma. A report of three cases in extradigital locations.
Kazakov DV, Pitha J, Sima R, Vanecek T, Shelekhova K, Mukensnabl P, Michal M.
Sikl's Department of Pathology, Charles University, Medical Faculty Hospital, 30460 Pilsen, Czech Republic.
Ann Diagn Pathol. 2005 Feb;9(1):16-23. Abstract quote
We present three cases of subcutaneous tumors with hybrid features of schwannoma-perineurioma (one case) and neurofibroma-perineurioma (two cases), which occurred in two women aged 50 and 52 years and one man aged 52. Locations included the scapular area, skin overlying breast and knee area. The tumors were 1.5, 4 and 5 cm in largest diameter. None of the patients had signs of neurofibromatosis. All tumors were surgically removed, and patients remained disease-free for 1 to 4 years.
The classification of the lesion into schwannoma-perineurioma and neurofibroma-perineurioma rested on histopathological and immunohistochemical findings. An ultrastructural study was performed in one case of neurofibroma-perineurioma.
All cases were studied for mutation of the NF2 gene, and in one case (neurofibroma-perineurioma) a point mutation was detected in exon 15 of the gene.
- Cutaneous lipomatous sclerosing perineurioma.
CIPAX-Medicina Diagnostica, Sao Jose dos Campos, SP, Brazil.
- Am J Dermatopathol. 2008 Jun;30(3):291-4. Abstract quote
Sclerosing perineurioma is a variant of extraneural soft tissue perineurioma that occurs in the distal extremities of young adults. They are composed of small, plump, spindle-shaped, or epithelioid perineurial cells that coexpress epithelial membrane antigen (EMA), glut-1, claudin 1, collagen type IV, laminin, and are negative for S-100 protein. Once locally excised, sclerosing perineurioma does not recur or metastasize. Adipocytic component has been observed occasionally in peripheral nerve sheath tumors. In particular, only one report has previously detailed histopathological features of a superficial soft tissue perineurioma harboring lipomatous areas.
Herein, we report a unique case of sclerosing perineurioma showing adipocytic component. Knowledge of this phenomenon is important to reach a correct diagnosis and to avoid unnecessary aggressive local excision.
Fine-needle aspiration cytology of sclerosing perineurioma.
Lee LH, Bos GD, Marsh WL Jr, Wakely PE Jr.
Ann Diagn Pathol. 2004 Apr;8(2):80-6. Abstract quote
Sclerosing perineurioma is a recently described rare benign nerve sheath tumor. The cytopathology of this neoplasm has, to our knowledge, not previously been described.
We report the fine needle aspiration cytopathology of sclerosing perineurioma, discuss potential pitfalls in cytologic interpretation, and compare the aspirate with the corresponding resection specimen.
CHARACTERIZATION Immunoperoxidase EMA+
Epithelial membrane antigen expression by the perineurium of peripheral nerve and in peripheral nerve tumours.
Theaker JM, Gatter KC, Puddle J.
Histopathology 1988;13:171–9. CD34 30% to 40% of soft tissue perineuriomas may be CD34 positive (Christopher Fletcher, personal observation) CLAUDIN-1
Expression of claudin-1, a recently described tight junction-associated protein, distinguishes soft tissue perineurioma from potential mimics.
Folpe AL, Billings SD, McKenney JK, Walsh SV, Nusrat A, Weiss SW.
Am J Surg Pathol 2002 Dec;26(12):1620-6 Abstract quote
Perineuriomas are rare benign soft tissue tumors having an immunophenotype paralleling the normal perineurial cell [S-100 protein negative and epithelial membrane antigen (EMA) positive]. Because EMA expression in perineuriomas may be focal and/or faint, there is continued interest in the development of new markers of perineurial differentiation. Perineurial cells differ from almost all other mesenchymal cell types by virtue of their formation of tight junctions. In the course of evaluating a group of novel tight junction-associated proteins, we noted high levels of expression of claudin-1 by normal perineurial cells and have systematically extended these observations to perineuriomas.
Twelve EMA-positive/S-100-negative perineuriomas were retrieved from our consultation archives and compared with 39 tumors in the differential diagnosis of perineurioma (seven dermatofibrosarcoma protuberans, eight low-grade fibromyxoid sarcomas, three desmoplastic fibroblastomas, seven fibromatoses, nine neurofibromas, and five schwannomas).
All cases were immunostained for claudin-1 using standard avidin-biotin technique. Cases were scored as 3+ (>50% positive cells), 2+ (25-50% positive cells), and 1+ (5-24% positive cells). In all cases positive internal controls in the form of epithelium, normal perineurium, or endothelial cells were present.
Positive staining for claudin-1 was visualized in a distinctly particulate pattern along the cell membrane. Cytoplasmic staining was infrequent and was not scored as positive.
Claudin-1 expression was present in 11 of 12 (92%) perineuriomas studied (seven at 3+, three at 2+, and one at 1+). In all but two cases, the degree of claudin expression was equal to or greater than the corresponding EMA immunostain.
Claudin-1 expression was not noted in any cases of dermatofibrosarcoma protuberans, low-grade fibromyxoid sarcoma, desmoplastic fibroblastoma, or fibromatosis. Six of nine cases of neurofibroma contained a significant number of claudin-1-positive cells that were thought to be perineurial in origin, based on the staining of long, delicate cytoplasmic processes. One of four schwannomas contained a subpopulation of perivascular, dendritic, claudin-1-positive cells of presumed perineurial lineage.
This is the first study to document expression of claudin-1 in perineurial cells and suggests a role for claudin-1 immunohistochemistry in the diagnosis of perineuriomas.
Although claudin-1 should not replace EMA in the diagnosis of perineurioma, we think that it may play a valuable adjunctive role in difficult cases. In particular, claudin-1 is often a more robust marker than EMA in a given perineurioma. Claudin-1 is not expressed within the lesional cells of the mesenchymal tumors that enter into the differential diagnosis of perineurioma.
Electron microscopy (EM)
Abundant collagenous stroma and exhibit the typical features of perineurial cells:
(1) elongated tapering nuclei with peripheral condensation of heterochromatin
(2) extensive thin cytoplasmic processes with prominent pinocytotic vesicles, frequently arranged along the cell membrane
(3) scattered rudimentary intercellular junctions
(4) an incomplete and variably thin basement membrane
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES GENERAL
Perineurioma: an uncommon soft tissue neoplasm distinct from localized hypertrophic neuropathy and neurofibroma.
Tsang WY, Chan JK, Chow LT, Tse CC.
Institute of Pathology, Queen Elizabeth Hospital, Hong Kong.
Am J Surg Pathol 1992 Aug;16(8):756-63 Abstract quote
Perineurial cells, which normally surround the nerve fascicles within a nerve, can be distinguished from Schwann cells by their immunoreactivity for epithelial membrane antigen (EMA) and lack of reactivity for S-100 protein.
We report two cases of perineurioma, a tumor composed exclusively of perineurial cells and distinct from other nerve sheath tumors. The first case involved a deep, soft-tissue mass of the neck, and the second involved a tumor located in the infraclavicular subcutaneous tissue. Both tumors were well circumscribed.
Histologically, they were hypocellular and composed of spindle cells possessing elongated nuclei and bipolar, wavy, slender, strikingly elongated cytoplasmic processes, disposed in a background of collagen in the form of short bundles and whorls. In the first case, there were frequent calcospherites and remnants of a small nerve at the periphery. The spindle cells stained for EMA but not S-100 protein, chromogranin, neuron-specific enolase or Leu-7.
Ultrastructurally, they possessed long cytoplasmic processes with incomplete basal lamina and occasional pinocytotic vesicles. Axons were not identified. Review of the literature shows that genuine perineuriomas are rare, and most cases reported as such are merely examples of localized hypertrophic neuropathy, a mononeuropathy characterized by fusiform swelling of a nerve, usually in the extremities. The involved segment in localized hypertrophic neuropathy contains distended fascicles composed of whorls of perineurial cells and fibrous tissue entrapping residual axons, probably representing a hyperplastic reaction to nerve damage.
The term perineurioma should be reserved for the neoplasm composed only of perineurial cells and presenting as a soft tissue tumor.
PROGNOSIS AND TREATMENT CHARACTERIZATION
Low-grade malignant perineurioma of the paravertebral column, transforming into a high-grade malignancy.
Karaki S, Mochida J, Lee YH, Nishimura K, Tsutsumi Y.
Departments of Orthopedic Surgery, Tokai University School of Medicine, Isehara, Japan.
Pathol Int 1999 Sep;49(9):820-5 Abstract quote
A demarcated 6 x 5 cm right paravertebral tumor at the level of T6 in a 39-year-old male was removed surgically. Histologically, the tumor consisted of monomorphous benign-looking, low-cellular spindle cells embedded in desmoplastic stroma. Ten years later, the tumor recurred locally with metastasis to systemic organs, including the occipital skin. Malignancy was histologically evident by the increased cellularity, cellular atypia and mitotic activity. The patient died of respiratory failure at the age of 49. Retrospectively reviewed, the primary lesion was low-grade fibrosarcoma-like spindle cell tumor, with secondary transformation into a highly malignant form.
The differential diagnoses included sclerosing epithelioid fibrosarcoma, low-grade fibromyxoid sarcoma and malignant peripheral nerve sheath tumor. Immunohistochemically, the spindle cells in the primary and recurrent tumors consistently expressed epithelial membrane antigen, vimentin, type 4 collagen and laminin. The tumor cells in the present case showed a differentiation toward perineurial cells, which are normally positive for these immunohistochemical markers. Hence, the appropriate diagnostic term should be 'malignant perineurioma', a subtype of malignant peripheral nerve sheath tumor.
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Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fifth Edition. Mosby Elesevier 2008
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