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On-line version ISSN 1806-4841
An. Bras. Dermatol. vol.84 no.6 Rio de Janeiro Nov./Dec. 2009
Sclerosing perineurioma: case report and literature review*
Thiago Jeunon de Sousa VargasI; Maria Auxiliadora Jeunon SousaII; Ana Luisa Sobral Bittencourt SampaioIII; José Dib MouradIV; Geoffrey J. GolttliebVISpecialist in Dermatology, SBD, physician and preceptor, Service of Dermatology, Hospital Geral de Bonsucesso, Physician with Laboratório ID Investigação em Dermatologia S/C Ltda - Rio de Janeiro (RJ), Brazil
IISpecialist in Dermatology, SBD, Director of Laboratório ID Investigação em Dermatologia S/C Ltda, Retired Assistant Professor, Service of Dermatology, Faculdade de Ciências Médicas da Universidade do Estado do Rio de Janeiro - Rio de Janeiro (RJ), Brazil
IIISpecialist in Dermatology, SBD, Master studies under course, Service of Dermatology, Hospital Universitário Clementino Fraga Filho/Universidade Federal do Rio de Janeiro; Physician with Laboratório ID Investigação em Dermatologia S/C Ltda, - Rio de Janeiro (RJ), Brazil
IVMember of Brazilian Society of Surgical Dermatology; Master and Ph.D. in Surgery, Faculdade de Medicina da Universidade Federal do Rio de Janeiro; Retired Joint Professor, Department of General Surgery, Faculdade de Ciências Médicas da Universidade do Estado do Rio de Janeiro - Rio de Janeiro (RJ), Brazil
VCertified by American Board of Medical Specialties (United States) in Dermatopathology and Clinical Pathology; Director of Ackerman Academy of Dermatopathology, New York City, NY, USA
Sclerosing perineurioma is a rare benign neoplasm composed exclusively of perineural
differentiation cells spread in a dense fibrous stroma. It affects primarily
the skin of fingers and that of the palm of the hands. It appears as a hard
papule or nodule, normochromic and asymptomatic. A case of sclerosing perineurioma
in the left palm of a 16-year-old female is described, with detailed demonstration
of clinical aspects, histopathology and literature review published in the English
Sclerosing perineurioma is a rare benign neoplasm composed exclusively of perineural differentiation cells spread in a dense fibrous stroma. It affects primarily the skin of fingers and that of the palm of the hands. It appears as a hard papule or nodule, normochromic and asymptomatic. A case of sclerosing perineurioma in the left palm of a 16-year-old female is described, with detailed demonstration of clinical aspects, histopathology and literature review published in the English language.
Keywords: classification; dermatology; diagnosis; nerve sheath neoplasms; pathology
Sclerosing perineurioma is a rare benign neoplasm not very known by dermatologists, clinical pathologists and dermatopathologists, that affect preferably the skin of fingers and palmar regions. It has characteristic morphology both from the clinical and histopathological perspective, and it may be easily diagnosed by physicians who are familiar with the disease. We present next a case report and English speaking literature review.
Female 16-year-old patient came to the office presenting asymptomatic firm skin-colored nodule, measuring 1.5 x 1.0 cm, located on the left palmar region, close to the basis of middle finger, which had appeared 5 years before (Figure 1). The lesion was submitted to excision biopsy and sent for clinical pathology analysis. In sections stained with hematoxylin and eosin (H&E), there was symmetrical well circumscribed and non-encapsulated neoplasm, vertically oriented, with dense collagenous stroma (Figures 2 and 3). Amidst collagen bundles, there were cells that ranged in shape, some were rounded with easily detected cytoplasm (Figure 4), others were spindle-shaped and wavy (Figure 5). There were no pleomorphism, hyperchromasia or mitosis figures. Nervous fibers were seen amidst the stroma, some in direct contact with the neoplastic cells (Figure 6). There were also areas of low cellular density and prominent hyalinization of the stroma, in which there was predominance of elongated blood vessels with thin connective walls (Figure 7). The diagnosis was sclerosing perineurioma suggested by the lesion morphology and confirmed by immunehistochemical study, which showed positive response for cytoplasmatic pattern for epithelial membrane antigen (EMA) and negative response for protein S-100 (Figure 8).
Nervous trunks and nervous fascicles
Nervous trunks are comprised by axons, Schwann cells and three support structures known as endoneurium, perineurium and epineurium (Figures 9 and 10). The endoneurium is comprised by very delicate collagen fibers, unseen by optical microscopy, but detectable by electron microscopy, that surround each set of axon and Schwann cell. Axons, Schwann cells and endoneurium form the nervous fascicles that, in turn, are surrounded by a lamellar structure known as perineurium. It is represented by one to six rows of flat cells (perineural cells) and variable amounts of connective tissue that comes in between these layers. The perineurium works as mechanical protection and individualized blood-brain barrier to each one of the nervous fascicles. The external component to the nervous trunks is the epineurium, dense fibrous tissue that is richly vascularized and responsible for maintaining the nervous fascicles close one to the other.
In the nervous roots of the spine, perineural cells are in continuity with pia-arachnoid membrane of the central nervous system, which also happens with the epineurium in relation to the dura 1. On the skin, there are not nervous trunks itself, but isolated nervous fascicles only, so that the perineurium can be in direct contact with the dermis.
History and definition of Perineurioma
Perineurioma was described for the first time in 1978. 2 Lazarus and Trombetta reported the findings of a soft part neoplasm excised from the gastrocnemic muscle of a 45-year-old man who had been originally diagnosed as having neurofibroma from sections stained with hematoxylin-eosin. Based on ultrastructural studies, these authors proved that this neoplasm was in fact a perineurioma and defined criteria for the perineural differentiation applicable to normal and pathological cells. Using electron microscopy, perineural cells show spindle formats, long and fine cytoplasmatic processes, well-formed tight junctions, incomplete external lamina, and characteristic granulous cytoplasm, full of picnotic vesicles, but with few mitochondriae and small amount of endoplasmatic reticulum. Some years later, it was shown that perineural cells are positive for EMA and negative for S-100 protein in immunohistochemical studies, excluding the need to resort to electron microscopy to confirm these cases in daily practice 3-5. Other antigens frequently expressed by these cells are GLUT-1, Claudin-1, collagen IV and laminin. Even though none of these antigens are absolutely specific, they are considered as markers of perineural differentiation within the appropriate morphological context.
Perineuriomas form a group of rare benign neoplasm of the nerve sheath comprised exclusively of perineural differentiation cells, in contrast with schwanomas, formed exclusively by Schwann cells, and neurofibromas, which present axons and a mixture of cell types, including Schwann cells, fibroblasts and cells similar to those that form the perineurium 6 . Lenahan and Gottlieb reported a tumor with two different components, one of which showed morphological and immunohistochemical aspects of neurofibroma, whereas the other showed aspects of perineurioma. The others classified the lesion descriptively as "benign neural neoplasm with characteristics of neurofibroma and perineurioma" 7. Perineuriomas are not associated with neurofibromatosis.
There are three main categories that comprise the group of neoplasms generically known as perineuriomas: intraneural perineurioma (PI), soft tissue perineurioma (PPM) and sclerosing perineurioma (PE). They all share the same immunohistochemical and ultrastructural profile, but can be distinguished by specificities in clinical and histological presentations.
Intraneural perineurioma was considered a degenerative neuropathy and designated in the past as a hypertrophic localized neuropathy, hypertrophic mononeuropathy or hypertrophic localized neurofibrosis, until Emory et al finally showed it as a neoplasm 8. Typically, there is a proliferation of spindle perineural cells in the nervous trunk and they are arranged in concentric structures around preexisting and compressed axons and Schwann cells. This pattern can be easily seen in cross-sections. The stereotyped clinical presentation is a patient below the age of 30 years with segmental thickness and dysfunction of the peripheral nervous trunk in one extremity.
Soft tissue perineurioma
Soft tissue perineurioma has its peak of incidence in middle-aged subjects and it is more frequent on the subcutaneous tissue of the extremities, scapular or pelvic area and the trunk. However, approximately 30% of the cases involve deeper soft parts, including many located in the peritoneal cavity, whereas there are rare cases of dermal location. Tumor size is variable, ranging from few millimeters to many centimeters. They are comprised by spindle cells with long fine and delicate cytoplasmatic prolongations and show major variability of architectural patterns, among which there are storiform, fascicular, reticular, plexiform, infiltrative and myxoid 6,9,10. Zelger made a hypothesis that some cases related with myxoid tumor of the nerve sheath (nerve sheath myxoma) are in fact perineuriomas 11. Curiously, a case of perineurioma partially comprised by granular cells was reported and all cells of the neoplasm were positive for EMA, GLUT-1 and claudin-1, regardless of the morphology (granular cells or not). 12
Sclerosing perineurioma was described for the first time in 1997 by Fetsch and Miettinen in a series of 19 patients 13. In a study carried out in the database Medline/ Pubmed, we identified other 23 cases reported in the English-speaking literature and none in Portuguese 14-26. Table I sums up the clinical information of all these cases. Absence of single correct clinical diagnosis or even the inclusion of sclerosing perineurioma in the list of differential diagnosis in all cases previously reported shows that dermatologists are not familiar with this neoplasm.
PE is presented as a papule, nodule or small painless tumor, skin-colored, measuring 0.3 to 8.0 cm (mean = 2.7 cm, median = 2.9 cm) in the largest dimension and preferably on the fingers and hand palms. It affects men and women (M:F ratio = 1.3), and subjects of all ages, between 7 and 67 years (mean = 25.7; median = 23 years). Lesions are normally solitary, but one case with two lesions (right hand palm and left index finger) and another one with multiple lesions (hands and forearms) have been reported 16,26. In the histopathology analysis, it presents as a benign neoplasm, vertically oriented, relatively symmetrical and well circumscribed, even though not encapsulated. Stroma is densely sclerotic and cells have two different forms, both commonly present in the same lesion. One of them is spindle-shaped and wavy, sometimes associated with fine cytoplasmatic processes; the other one is rounded and epithelioid, with evident cytoplasm. The nuclei are normally small, with dense chromatin and undifferentiated nucleolus. Mitoses figures are rare or absent and there is no nuclear pleomorphism. As a result of large amount of collagen, it does not seem to be densely cellular when observed under small magnification. Cells are placed amidst the collagen bundles and are arranged in individual units, small nests, in rows and in rounded formations. In some lesions, dilated blood vessels on thin walls and nervous fascicles are present amidst the neoplasm. Be attentive to some neoplastic cells placed very close and sometimes even touching the perineurium of preexisting nervous fibers, an observation which was not highlighted in previous publications and that can be helpful to define the diagnosis. Some mast cells may be frequently found. Recently, an adipocytic component was reported in an isolated case, which apart from that, had all typical characteristics of PE 25.
Two cases in 1998 and other six in 2001 were reported under the nomenclature of "fibrous cutaneous perineurioma". According to the analysis of published microphotographies, we would have interpreted these cases as PE 27,28. However, we have not included them in the present review considering the divergent opinion of the authors.
Differently from PPM, PE show a very constant morphological pattern, as we can see by analyzing previous publications about the neoplasm. Even though it is always important to consider the differential diagnosis frequently reported for this lesion - among which sclerotic fibroma, dermatofibroma, angiofibroma, tendon sheath fibroma, fibrosing tenosynovial tumor of giant cells, trichodiscoma, neurofibroma, glomus tumor, epithelioid sarcoma and meningioma, none of them is a real consideration in most cases of PE. If a dermatologist is familiar with the morphological aspects of the lesion, the correct diagnosis may be strongly suggested and immunohistochemical and/or ultrastructural studies should be performed for confirmation purposes.
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Mailing Address: Conflict of interest: None * Study carried
out at Dermatopathology Laboratory ID Investigação em Dermatologia
S/C Ltda, Rio de Janeiro (RJ), Brazil and at Ackerman Academy of Dermatopathology,
New York (NY), USA.
Thiago Jeunon de Sousa Vargas
Rua Barão de Mesquita, 200 Ap. 901. Tijuca
20540 003 Rio de Janeiro
21 2234 0722
Conflict of interest: None
* Study carried out at Dermatopathology Laboratory ID Investigação em Dermatologia S/C Ltda, Rio de Janeiro (RJ), Brazil and at Ackerman Academy of Dermatopathology, New York (NY), USA.