Peripheral Nerve Sheath Tumors in Patients With Neurofibromatosis Type 1: Morphological and Immunohistochemical Study.

BACKGROUND/AIM: The aim of the present investigation was to characterize the growth pattern and antigen profile of peripheral nerve sheath tumors (PNST) in a large series of tumors obtained from patients with Neurofibromatosis type 1 (NF1) focusing on morphological characteristics of diffuse plexiform neurofibroma (DPNF). MATERIALS AND METHODS: Tissue micro-array (TMA) analysis was applied to study 520 formalin-fixed, paraffin-embedded human PNST of 385 patients with confirmed NF1 diagnosis. PNST originated from all areas of the body and were classified as cutaneous neurofibroma (CNF, n=114), diffuse neurofibroma (DNF, n=109), DPNF (n=108), plexiform neurofibroma (PNF, n=110), and malignant peripheral nerve sheath tumor (MPNST, n=22). Histomorphology and antigen expression patterns of the tumors were determined [S100, epithelial membrane antigen (EMA), CD90, mast cell tryptase, and neurofilament]. RESULTS: Benign PNST showed significantly more S100-positive tumor cells than MPNST (p<0.001). EMA expression was most pronounced in perineurium of DPNF. The number of mast cells in CNF, DNF and DPNF was significantly higher compared to PNF and MPNST (p<0.001 for both comparisons, Mann-Whitney U-test). CONCLUSION: DPNF show some distinct cellular characteristics. A high number of EMA positive cells possibly indicates the dissemination of perineural cells to the surrounding tissue. Concerning mast cell density, DPNF resemble DNF and CNS rather than PNF. Close contact of tumor cells in DPNF, DNF and CNF with the immune system is a prerequisite for permanent immunological reactions in contrast to PNF in which tumor cells are partitioned from the immune system by the perineurium and blood-nerve barrier of blood vessels. It is assumed that these morphological distinctions may reflect in part the biological differences between the entities. While PNF is a known precancerous stage in NF1 patients, DPNF are not rated as such. Furthermore, the morphologic differences between benign nerve sheath tumors may be important for the efficacy of drugs to access tumor cells.

Multivacuolated mucin-filled cells: a unique cell characteristic of plexiform neurofibroma. A report of 11 cases.

The authors present 11 cases of plexiform neurofibroma (PN) that featured a very characteristic type of cell appearing as multivacuolated mucin-filled cells (MMFC). The 11 cases were obtained after reviewing 109 cases of PN. Six out of 10 patients showed clinical features of neurofibromatosis type 1. The size of PN ranged from 0.8 cm to 11.5 cm in the largest dimension. The lesions represented classical PN in all cases with myxoid, hypocellular stroma. The MMFC were found within the most myxoid tumorous nodules and were haphazardly located, typically featuring a variably sized, multivacuolated cytoplasm divided by fine septa with a small polygonal nucleus on one side, which was often compressed or slightly indented by the cytoplasmic mucous substances. In many cases, the cells resembled a soccer ball or a jellyfish. In all tested cases (n = 9), the MMFC stained for CD34; six cases were also positive with GLUT-1 antibody, and two cases expressed Claudin-1, whereas S-100 protein was negative. For comparison, we have reviewed a series of randomly selected non-PN, malignant peripheral nerve sheath tumors (MPNST) and of cases featuring non-neoplastic nerve trunks in our files, in which no MMFC were encountered. MMFC seem to be unique to myxoid areas of PN, where they occur in about 10% of cases. Their exact histogenesis is unclear but they might represent an intermediate type of cell between perineurial cells and fibroblasts. The awareness of this cell type in PN is especially important in limited (small) biopsy specimens where their recognition may provide a clue for the correct diagnosis.

Solitary plexiform neurofibroma of the stomach: a case report.

Plexiform neurofibroma (PN) of the digestive tract is very rare and usually part of the generalized syndrome of neurofibromatosis type 1 (von Recklinghausen disease). Solitary PN of the stomach is extremely rare and has not been reported in the literatures. Here we present a case of solitary PN of the stomach, which was not associated with von Recklinghausen disease. A 38-year-old male presented abdominal pain and distention for 7 d. The patient underwent endoscopy of the upper gastrointestinal tract, which revealed a 3.5 cm protruding and cauliflower-shaped mass with a shallow 1 cm central ulcer in the greater curvature of the stomach. The lesion was removed by laparoscopic surgery. Histological examination demonstrated characteristic histological findings of spindle-shaped cells. Immunohistochemical analysis showed that the tumor cells were positive for S-100 protein, but negative for CD34, KI-67, CD117, and actin. Based on histological findings, gastrointestinal stromal tumor could be excluded, and thus the case was confirmed as PN. We described the clinical features, physical examination, endoscopic findings, and histopathological examination of this case.

Surgery for atypical plexiform neurofibromas of the trunk in NF1 with high standardised uptake value (SUV) in positron-emission tomography (PET) expressing podoplanin: a long-term follow-up.

A 23-year-old female with an established diagnosis of neurofibromatosis type 1 (NF1) was found to have two tumours in her trunk. These showed high uptake value in positron-emission/computerized tomography (PET) scans, and were suspected to be malignant peripheral nerve sheath tumours (MPNST). The extirpated tumours proved to be atypical plexiform neurofibromas. Slight to moderate podoplanin expression of the tumour cells was noted in areas of fibrillary growth. Six years following surgery, there is neither evidence of local tumour recurrence nor development of MPNST. Current studies on atypical neurofibroma in NF1 suggest podoplanin expression in subtypes of transformed Schwann cells, resembling schwannoma-like areas in neurofibroma. This marker may be useful in distinguishing different Schwann cell populations in NF1.

Identification of growth hormone receptor in plexiform neurofibromas of patients with neurofibromatosis type 1.

OBJECTIVE: The aim of this study was to investigate the presence of growth hormone receptor in plexiform neurofibromas of neurofibromatosis type 1 patients. INTRODUCTION: The development of multiple neurofibromas is one of the major features of neurofibromatosis type 1. Since neurofibromas commonly grow during periods of hormonal change, especially during puberty and pregnancy, it has been suggested that hormones may influence neurofibromatosis type 1 neurofibromas. A recent study showed that the majority of localized neurofibromas from neurofibromatosis type 1 patients have growth hormone receptor. METHODS: Growth hormone receptor expression was investigated in 5 plexiform neurofibromas using immunohistochemistry. RESULTS: Four of the 5 plexiform neurofibromas were immunopositive for growth hormone receptor. CONCLUSION: This study suggests that growth hormone may influence the development of plexiform neurofibromas in patients with neurofibromatosis type 1.

Identification of growth hormone receptor in plexiform neurofibromas of patients with neurofibromatosis type 1

OBJECTIVE: The aim of this study was to investigate the presence of growth hormone receptor in plexiform neurofibromas of neurofibromatosis type 1 patients. INTRODUCTION: The development of multiple neurofibromas is one of the major features of neurofibromatosis type 1. Since neurofibromas commonly grow during periods of hormonal change, especially during puberty and pregnancy, it has been suggested that hormones may influence neurofibromatosis type 1 neurofibromas. A recent study showed that the majority of localized neurofibromas from neurofibromatosis type 1 patients have growth hormone receptor. METHODS: Growth hormone receptor expression was investigated in 5 plexiform neurofibromas using immunohistochemistry. RESULTS: Four of the 5 plexiform neurofibromas were immunopositive for growth hormone receptor. CONCLUSION: This study suggests that growth hormone may influence the development of plexiform neurofibromas in patients with neurofibromatosis type 1.

Oral plexiform neurofibroma not associated with neurofibromatosis type I: case report.

An unusual case of isolated plexiform neurofibroma arising in the oral cavity without other clinical manifestations or family history of neuro-fibromatosis-1 (NF-1) is described. The tumor was histopathologically analyzed and an immunohistochemical panel comprising S-100 protein, epithelial membrane antigen (EMA), collagen IV, and CD34 was performed. Typical features of plexiform neurofibroma characterized by enlarged nerve fascicles composed of elongated nuclei and scant cytoplasm cells were identified. Subjacent to the oral epithelium, tactile-like bodies were also detected. On the basis of this report, we would like to emphasize that plexiform neurofibroma can occur in the oral cavity as a benign isolated tumor in patients without other stigmata of NF-1.

Dendritic cell neurofibroma with pseudorosettes: a report of 18 cases of a distinct and hitherto unrecognized neurofibroma variant.

The authors present 18 cases of a hitherto unrecognized variant of cutaneous neurofibroma. The tumors presented in adults (10 occurred in men and eight occurred in women) as a solitary, well-circumscribed, superficial lesion located in the dermis measuring 3 to 17 mm (mean size, 6.2 mm). The tumors formed oval-shaped masses that ran perpendicular to the epidermis. In the deep part of the tumor there was multinodular arrangement with two types of cells: Type I cells were small, dark, lymphocyte-like cells with a slightly irregular nucleus and inconspicuous cytoplasm. Type II cells were larger, with pale-staining vesicular nuclei, with frequent invaginations and intranuclear inclusions, and had copious clear eosinophilic cytoplasm that formed a stellate growth pattern, which was poorly visible on hematoxylin and eosin staining. Type I cells were grouped concentrically around type II cells and formed pseudorosettes. Most of the type I and type II cells were S-100 protein and CD57 positive, and various proportions of both cell types were CD56 and PGP9.5 positive. All cells were chromogranin A, synaptophysin, glial fibrillary acidic protein, cytokeratins, CD1a, CD21, CD31, alpha-smooth muscle actin, muscle-specific actin, desmin, and HMB-45 negative. CD34 stained intralesional fibroblasts. Antibody to epithelial membrane antigen stained only the perineurium around the tumor masses, suggesting that the tumors arose inside the nerve sheath. No signs of neurosecretory granules were present at ultrastructural level. None of the lesions recurred and none metastasized over a mean follow-up of 8.1 years.

Perineuroma. A frequently unrecognized entity with emphasis on a plexiform variant.

AIMS: The present series describes six cases of perineurioma, a rare and frequently unrecognized entity, including one case with an unusual plexiform growth pattern. METHODS: Retrospective clinicopathologic study of six perineuriomas. RESULTS: All lesions occurred on the upper extremities or shoulders of adults, five in females. Histologically, all six cases of perineurioma had been initially unrecognized or misdiagnosed as dermatofibroma, fibroma of tendon sheath, neurofibroma, schwannoma, or naevus, respectively. Scanning magnification revealed well circumscribed, dermal to subcutaneous lesions without capsule formation. Besides characteristic onion bulbs", i.e. concentric whorls of epithelioid to spindle-shaped cells, there was great variation of histomorphologic features: single nodules or plexiform architecture; a few to many concentric whorls; five to several dozens of cell layers in concentric whorls; high to low cellularity; round/oval to spindle-shaped/wavy cells/nuclei; delicate to prominent collagen; variable mucin, sclerosis, and/or intralesional clefts. Immunohistochemically, all lesions were consistently positive for EMA, ultrastructurally (1 case) with evidence of perineurial differentiation such as slender and elongated, bipolar cytoplasmic processes with discontinuous basal lamina, prominent pinocytosis and desmosome-like junctions. CONCLUSION: Our series documents that cutaneous and subcutaneous perineurioma is frequently unrecognized or misinterpreted and may occasionally show a plexiform growth pattern. The differential diagnosis of plexiform variants includes a variety of plexiform lesions such as naevi, neurofibroma, schwannoma, etc. Historically, similar plexiform lesions seem to have been published as nerve sheath myxoma/neurothekeoma, Pacinian neurofibroma or perineurial myxoma. This terminology is imprecise and confusing and, thus, should be avoided in favour of the correct term of perineurioma.

Plexiform neurofibroma with and without associated malignant peripheral nerve sheath tumor: a clinicopathologic and immunohistochemical analysis of 54 cases.

Plexiform neurofibroma (PNF) is an important part of the diagnostic criteria for neurofibromatosis type 1 (NF1) and is a known precursor lesion of malignant peripheral nerve sheath tumor (MPNST). We studied the clinicopathologic features of 54 cases of PNF for which the hematoxylin- and eosin-stained slides and paraffin blocks were available and adequate clinical follow-up could be obtained. In addition, in all cases, a representative section of the PNF and, when present, MPNST, was evaluated immunohistochemically with an antibody for p53 (DO7). The cohort included 28 male patients and 26 female patients, with an age range from 4 to 79 years (mean, 27 yr). Of these 54 patients, 46 (85%) met the strict diagnostic criteria for NF1. Thirty-nine patients had PNF alone; 15 patients had an MPNST arising from the PNF (PNF/MPNST). Those patients with PNF/MPNST tended to be older (38 yr vs. 22 yr) and to have larger tumors (10.5 cm mean vs. 7.4 cm mean) than those with PNF alone. In 9 patients (23%) of 39 with PNF alone, local recurrence developed, whereas in 7 patients (47%) of 15 with PNF/MPNST, recurrent MPNST developed, and metastases developed in 3 (20%) of the 15. Immunohistochemically, only 1 case (2.5%) of 39 cases of PNF alone stained for p53. On the other hand, 12 (80%) of 15 cases of PNF/MPNST showed p53 immunoreactivity in the MPNST component, 2 of which also showed staining in the PNF areas. In conclusion, we found that the vast majority of patients with PNF met the strict diagnostic criteria for NF1. The immunohistochemical detection of intranuclear p53 protein is common in the malignant areas of PNF/MPNST but is rare in the PNF regions. The rarity of p53 staining in the PNF regions precludes its use in predicting those tumors that are likely to progress to MPNST.