Desmoplastic Melanomas Mimicking Neurofibromas.

Desmoplastic melanoma can be difficult to diagnose and on average have a significantly higher T stage at the time of diagnosis compared with conventional melanomas. Histologically, these tumors typically consist of spindle cells in a fibrous matrix. The spindle cells may display fibroblast and/or Schwann cell-like features. In this study, we describe the features of 12 cases of desmoplastic melanoma closely simulating neurofibroma. Although the spindle cells in these tumors may be indistinguishable from those of neurofibroma, features such as prominent fibroplasia (12/12), poor lateral circumscription (8/9), diffuse infiltration of subcutaneous tissue (7/9), and lymphoid aggregates (10/12) may be helpful clues to the diagnosis. No immunohistochemical markers were reliable in distinguishing neurofibroma-like desmoplastic melanomas from neurofibroma. Clinical follow-up was available in 8 cases, of which 4 were initially misdiagnosed as benign neoplasms and given no further re-excision. All 4 of these cases recurred; 2 of which showed transformation to a more aggressive phenotype.

Penile pacinian neurofibroma.

Pacinian neurofibroma (PNF) is a lobulated benign neural tumor with prominent structures resembling pacinian bodies. These tumors most commonly occur in areas where normal pacinian bodies are found, such as the hands and feet. Although pacinian bodies are common in the penis, no cases of penile PNF have been reported to date. We present a case of PNF on the dorsal glans penis of a 47-year-old man. The lesion presented as a single flesh-colored papule and the biopsy showed a dermal neurofibroma consisting of bland spindle cells with wavy nuclei, without mitoses or atypia, and some nodular structures with a concentric arrangement and a pacinian appearance. Immunohistochemistry demonstrated positivity for CD34 and Vimetin and negativity for Epithelial Membrane Antigen (EMA). S100 was highly positive in the most central areas of the pacinian-like nodules, while the periphery and non-nodular parts of the neurofibroma were less intensively expressed.

Immunohistochemical differentiation between spindle cell lipoma and neurofibroma of oral cavity using CD34 and SOX10.

Spindle cell lipoma (SCL), also called as pleomorphic adenoma, is a rare variant of lipoma histopathologically characterized by an admixture of mature fat cells with spindle cells and occasionally mast cells with myxoid connective tissue stroma and thick bends of birefringent collagen. Although buccal mucosa is the most common location for oral lipomas, for SCL, it is an exceedingly rare location. We report a case of an asymptomatic swelling of buccal mucosa that simulated the features of neurofibroma on histopathological examination, and the final diagnosis of SCL was made on the basis of immunohistochemical features. This is the first documentation of oral SCL using SOX10 to achieve the final diagnosis.

Distinguishing Neurofibroma From Desmoplastic Melanoma: The Value of p53.

Distinguishing desmoplastic melanomas (DMs) from neurofibromas (NFs) can be histologically challenging in some cases. To date, a reliable marker to differentiate the 2 entities has remained elusive. S100 subtyping and CD34 fingerprinting have been proposed, but controversy remains as to their reliability. Missense mutations in TP53 are often found in DMs, resulting in a dominant negative effect and paradoxical accumulation of the tumor suppressor protein p53. We hypothesized that p53 may be expressed differentially in DMs, making it a valuable tool in differentiating DMs from NFs. Using immunohistochemistry, we compared p53 protein expression in 20 DMs and 20 NFs retrieved from our tissue archives and stained with p53 antibody (Monoclonal, DO-7). Patients with DM included 18 men and 2 women (age, 36 to 95 y; mean, 70.5 y; median, 70 y). Fifteen (15/20) tumors occurred in head and neck area; 2 (2/20) on the trunk; and 3 (3/20) on the extremities. Patients with NF included 12 men and 8 women (age, 47 to 85 y; mean, 65.2 y; median, 69.5 y). Eleven (11/20) tumors occurred on the trunk, 6 (6/20) on the extremities, and 3 (3/20) on the head and neck area. A total of 19/20 (95%) DMs were positive for p53. DM Histo-scores ranged from 0 to 300 (mean, 203; median, 260). Nuclear accumulation of p53 was seen in all 19 positive DMs. None of the 20 NFs were positive for p53 (2-tailed t test P-value <0.0001). Detection of p53 by immunohistochemistry can help to distinguish DMs from NFs.

Peripheral nerve sheath tumors of the breast.

Benign and malignant peripheral nerve sheath tumors can involve the breast, presenting as masses in the dermis, deep breast parenchyma or axillary soft tissue. Although the histologic features are frequently characteristic, diagnosis can be challenging on core needle biopsy, and the differential diagnosis includes a variety of other benign and malignant spindle cell lesions of the breast. Here, we review the key clinical and pathological features of breast schwannoma, neurofibroma, granular cell tumor, and malignant peripheral nerve sheath tumor.

An Intracardiac Mass in a Pregnant Woman Presenting With Ventricular Tachycardia.

A pregnant patient presented with symptomatic ventricular tachycardia. Echocardiography revealed a large intramyocardial mass. Surgical resection was attempted in conjunction with cryoablation of the surrounding myocardial tissue. Histologic examination of the resected mass revealed cardiac neurofibroma. To the best of our knowledge, this is the first report of cardiac neurofibroma in a pregnant patient in the absence of any neurocutaneous syndromes such as neurofibromatosis.

Transducer-like Enhancer of Split 1 as a Novel Immuno- histochemical Marker for Diagnosis of Synovial Sarcoma.

BACKGROUND: Synovial sarcoma is a mesenchymal neoplasm that accounts for around 10% of all soft tissue sarcomas. The diagnosis of synovial sarcoma can be a challenging task, particularly with small biopsy specimens. AIM: We investigated transducer-like enhancer of split 1 (TLE1), monoclonal antibody, expression by immunohistochemical analysis in a group of 74 synovial sarcoma cases, 20 cases of MPNST, 12 cases of neurofibroma, 15 cases of schwannoma, 5 cases of MFH, 10 cases of lieomyosarcoma and 10 cases of solitary fibrous tumor. MATERIALS AND METHODS: Whole tissue sections were examined: (39 biphasic and 35 monophasic). Nuclear immunoreactivity was scored as negative (<5% of cells positive), 1+(mild /5-25%), 2+ (moderate/25-50%), and 3+ (strong >50%). RESULTS: Overall, 71 (96%) of 74 synovial sarcomas were positive for TLE1, including 37 biphasic (95%) and 34 monophasic (97%) tumors. Other spindle cell tumors showed very low or absent staining of TLE1. CONCLUSIONS: We conclude that TLE1 is a sensitive marker and can be a useful diagnostic marker for synovial sarcoma, particularly the monophasic forms.

A neurogenic tumor containing a low-grade malignant peripheral nerve sheath tumor (MPNST) component with loss of p16 expression and homozygous deletion of CDKN2A/p16: a case report showing progression from a neurofibroma to a high-grade MPNST.

Development of malignant peripheral nerve sheath tumors (MPNSTs) is a stepwise process that involves the alteration of many cell cycle regulators and the double inactivation of the NF1 gene. Inactivation of the TP53 gene and deletion of the CDKN2A/p16 gene are known to play an important role in the process. Herein, we present a 19-year-old man with a familial history of neurofibromatosis type 1, in whom the tumor arose from the intercostal nerve and showed 3 components: a neurofibroma, a low-grade MPNST, and a high-grade MPNST. Loss of p16 expression and homozygous deletion of the CDKN2A/p16 gene were observed in both the low-grade and the high-grade MPNST. In contrast to low-grade MPNSTs, high-grade MPNSTs generally tend to lose expression of p16 and harbor homozygous deletion of the CDKN2A/p16 gene. Loss of p16 expression and homozygous deletion of the CDKN2A/p16 gene in low-grade MPNST in our case might be related to its progression to high-grade MPNST. To the best of our knowledge, this is the first study correlating the p16 expression status and CDKN2A/p16 gene alteration in low-grade MPNSTs.

Isolated diffuse episcleral neurofibroma.

AIMS: To report a rare case of isolated diffuse episcleral neurofibroma and to discuss possible differential diagnoses. CASE REPORT: A 37 year old Caucasian female was found to have an epibulbar tumour arising from the superior aspect of her left eye. Clinical examination revealed a 12 mm × 8 mm "salmon pink" coloured lesion. RESULTS: A biopsy was performed and histopathologic examination and subsequent systemic evaluation showed it to be a rare case of isolated diffuse episcleral neurofibroma. CONCLUSION: There are many differential diagnoses for an epibulbar lesion and neurofibroma should be added to these. Even though a small risk of malignant transformation exists, we recommend a conservative approach for slow growing lesions.

Vascular wall cells contribute to tumourigenesis in cutaneous neurofibromas of patients with neurofibromatosis type 1. A comparative histological, ultrastructural and immunohistochemical study.

UNLABELLED: Neurofibromas are benign nerve sheath tumours. They occur sporadically, singly or few in number, and in neurofibromatosis type 1 (NF1), an autosomal inherited disease. These tumours are composed of different cell types, e.g. nerve cells (axons and axon sheaths), Schwann cells, mast cells, and fibroblasts. The local control of tumour growth in NF1 is poorly understood. Identification of cell markers could provide new information on the processes that are involved in tumour growth. MATERIALS AND METHODS: NF1 patients were diagnosed according to the revised NF1 diagnostic criteria proposed by the US National Institute of Health. Fifteen cutaneous neurofibromas from eight patients (origin: trunk and face) were excised, immediately immersion-fixed in Bouin's fixative and embedded in paraffin. Six micrometre thin sections were incubated with a variety of neuronal markers, connective tissue and glial cell markers, neurotrophic factors and their receptors. In addition, material was fixed, embedded and further processed for light and electron microscopic studies. RESULTS: The tumours were composed of different cell types, e.g. nerve cells (axons and axon sheaths), Schwann cells, mast cells, compartmentalising cells and fibroblasts. Neuronal markers were identified in axons (neuron-specific protein gene product 9.5, PGP9.5), in several cell types (neurofilament protein-200 kDa, NF-200) and glial cells (protein S-100, S-100). In glial cells the immunoreactivity for fibroblast surface protein (FSP) was scanty, low for cyclic 2,3-nucleotide 3'-phosphodiesterase (CNPase), strong for glucose transporter 1 (Glut-1) but lacking for glial fibrillary acidic protein (GFAP). Schwann cells and so-called compartmentalising cells exhibited immunoreactivity for neurotrophin receptor protein TrkA (TrkA) and glial cell-derived neurotrophic factor (GDNF). GDNF receptor α-1 (GFR-α1) exhibited distinct immunoreactivity in single axons, in Schwann cells, and with lower intensity in some perineurial sheet cells. No immunoreactivity was observed for the low-affinity neurotrophin receptor protein p75(NTR), high-affinity receptor protein TrkB (TrkB), high-affinity receptor protein TrkC (TrkC), the neurotrophin 3 (NT-3), and the brain-derived neurotrophic factor (BDNF). CONCLUSION: Human cutaneous neurofibromas displayed a pattern of neurotrophic factors and their receptor immunoreactivity, which is characteristic of differentiated non-malignant tumours, and exhibited some differences from that established in developing and differentiated control Schwann cells (probably involved in the pathogenesis of the neurofibromas), as well as tumour cells in the process of differentiation. Neurofibromas are highly vascularized tumours and possess activated endothelial cells and pericytes. We presume that most of the hyperplastic structural components of a neurofibroma are generated from activated pericytes and smooth muscle cells of the small tumour vessels which possess qualities of adult stem cells.

Intrapulmonary neurofibroma independent of neurofibromatosis type 1.

Intrapulmonary neurofibromas without neurofibromatosis type 1 are rare-so rare that only 11 cases have been reported previously. This case report describes a 37-year-old woman who was otherwise healthy. Chest radiography and computed tomography showed a solitary nodule, 20 mm diameter, in the left lung. The tumor was removed and examined. It was not encapsulated but was covered with an intact bronchial mucosa and lacked a clear partition into two areas of Antoni A (a palisading cellular component) and Antoni B (a loose myxoid component). Tumor cells were strongly positive for neuron-specific enolase and S-100 protein. These data characterized the tumor as a rare benign neurofibroma. The patient shows no sign of recurrence after 12 months of follow-up. We reviewed and characterized surgically resected cases of intrapulmonary neurofibroma without neurofibromatosis type 1 especially in comparison with cases of endotracheobronchial neurofibroma.

Hyaluronan in intra-operative edema of NF1-associated neurofibromas.

The tumor suppressor disorder neurofibromatosis type 1 (NF1) is associated with development of multiple neurofibromas which may grow intraneurally as plexiform neurofibromas (PNF) or intracutaneously (CNF). Upon surgery neurofibromas may show prominent swelling hindering skin-edge approximation. To assess whether the water binding glycosaminoglycan hyaluronan is involved in intra-operative swelling, 51 neurofibromas from 33 NF1-patients were investigated. Hyaluronan was histologically demonstrated and was quantified by ELISA. Molecular weight of hyaluronan was determined by gel filtration. Further, hyaluronan content was measured in cultivated Schwann cells and fibroblasts. Clinically, 67% of PNF were associated with moderate or severe intra-operative swelling, whereas only 36% of CNF showed this feature. Significantly higher levels of hyaluronan content were found in PNF compared to CNF (P < 0.05). Mast cell density did not correlate with any of the parameters. Molecular weight of hyaluronan in PNF and CNF ranged from higher than 106 Da to approximately 105 Da. Fibroblasts produced less hyaluronan than Schwann cells. The findings support the view that hyaluronan plays an important role in intra-operative swelling in neurofibroma surgery.

Solitary neurofibroma of the gingiva with prominent differentiation of Meissner bodies: a case report.

BACKGROUND: Oral neurofibromas are peripheral nerve sheath tumors, similar to schwannomas. Histological variations in oral neurofibromas are relatively uncommon. CASE PRESENTATION: Here, we present a case of unique variation in the observed characteristics of a neurofibroma, with no relation to neurofibromatosis type-1 or von Recklinghausen disease of the skin. The neurofibroma was observed in the right mandibular gingiva of a 32-year-old Japanese woman. Histologically, it differed from conventional neurofibromas in that the tumor was composed of a mixture of fine fibrillary collagen in sheets and/or cords of neoplastic Schwann cells containing numerous clusters of Meissner bodies. Histologically, these bodies were in contact with neoplastic Schwann cells. The Meissner bodies were immunopositive for S-100 protein, neuron-specific enolase, and vimentin, but were negative for calretinin. CD34-positive spindle cells were observed around the Meissner bodies. No recurrence or signs of other tumors have been observed in the patient for 5 years after tumor resection. CONCLUSION: To the best of our knowledge, no formal descriptions of sporadic, solitary neurofibromas containing numerous Meissner bodies occurring in the oral cavity are available in literature. We believe that an uncommon proliferation of Meissner bodies, as seen in the present case, may result from aberrant differentiation of neoplastic Schwann cells.

Differential expression of angiogenic factors in peripheral nerve sheath tumors.

It is difficult to differentiate some malignant peripheral nerve sheath tumors (MPNST) from benign peripheral nerve sheath tumors (BPNST) histologically, and to predict the clinical outcome of patients with MPNST. In this study, the expression of VEGF and MVD were evaluated immunohistochemically in 22 cases of MPNST, 14 of neurofibroma and 19 of schwannoma and correlation of the staining grade of VEGF or MVD and the various clinical factors were analyzed, and statistically evaluated. Levels of VEGF mRNA expression were also determined with real-time RT-PCR. Statistically higher positive staining for VEGF was observed in MPNST compared to neurofibroma (P=0.004) and schwannoma (P<0.001). Even low grade MPNST showed higher VEGF positive staining than neurofibroma. Moreover, high VEGF expression statistically correlated with the poor prognosis of the patients with MPNST (P=0.015). Although MVD in MPNST was significantly higher than that in neurofibroma (P=0.038) and schwannoma (P<0.001), MVD could not predict the prognosis of the patients with MPNST. Although VEGF mRNA expression tended to be higher in MPNST compared to neurofibroma, the difference was not significant. Levels of VEGF protein expression serve as a novel diagnostic and prognostic tools for peripheral nerve sheath tumors.

The controversial nosology of benign nerve sheath tumors: neurofilament protein staining demonstrates intratumoral axons in many sporadic schwannomas.

Schwannomas are benign peripheral nerve sheath tumors believed to be composed purely of cells with ultrastructural features of Schwann cells; these tumors are believed to develop eccentrically from the surface of nerves and not to contain axons, other than immediately beneath the capsule. This concept has recently been disputed in cases associated with neurofibromatosis type 2. The usual presence of intratumoral axons in neurofibromas is said to allow easy distinction from schwannomas. Eighty sporadic schwannomas (20 conventional, 20 cellular, 20 ancient, 10 gastric, and 10 plexiform) were retrieved from the authors' files. Hematoxylin-and-eosin stained slides were reviewed, diagnoses were confirmed and all tumors were stained for S-100 protein and neurofilament protein (NFP). The amount (rare, focal, multifocal, and diffuse) and distribution (central and/or peripheral) of axons within the tumors were analyzed. All tumors were strongly and diffusely positive for S-100 protein (nuclear and cytoplasmic staining). NFP-positive axons were identified in 11 of 20 (55%) conventional schwannomas (2 rare, 4 focal, 3 multifocal, and 2 diffuse; 5 central, 4 peripheral, and 2 central and peripheral) and in 15 of 20 (75%) cellular schwannomas (3 rare, 6 focal, and 6 multifocal; 12 central, 1 peripheral, and 2 central and peripheral). Of the 20 ancient schwannomas, 7 cases (35%) showed intratumoral axons, highlighted by NFP immunostaining (1 rare, 4 focal, 1 multifocal, and 1 diffuse; 4 peripheral, 2 central, and 1 central and peripheral). Most cases of gastric schwannoma showed no evidence of intratumoral axons; 9 cases (90%) were negative for NFP and only 1 case (10%) was positive (focal and central). Seven of 10 cases (70%) of plexiform schwannomas were negative for NFP, whereas only 3 cases (30%) showed positive axons (2 multifocal and 1 focal; 3 central). The unexpected but quite frequent presence of intratumoral axons in schwannomas argues against conventional views of these lesions' pathogenesis as an eccentric encapsulated lesion and raises the possibility that a more diverse cell population, perhaps more closely resembling neurofibromas, may constitute these neoplasms. Although NFP-positive axons were most often present in the conventional and cellular variants of schwannoma, their presence was also observed in a minority of ancient, gastric and plexiform schwannomas. Differentiation between neurofibroma and schwannoma in cases with overlapping cytoarchitectural features should not be based solely on the presence or absence of NFP-positive axons within a given tumor.

Cellular neurofibroma with atypia mimics sarcoma: report of a case with immunohistochemical staining pattern analysis and literature review.

A case of two sporadic cellular neurofibromas with atypia and one widespread hyalinization neurofibroma of the lumbar spine in a 51-year-old man without evidence of neurofibromatosis-1 is reported. Cellular neurofibroma with atypia is an unusual variant. The definite criteria for low-grade and high-grade malignant peripheral nerve sheath tumors as well as cellular neurofibroma are not well defined in the literature. The clinical significance of atypical cellular neurofibroma has rarely been systematically studied. To our knowledge, the concomitance of cellular architecture and cytologic atypia is rarely documented, and this is a rare report of atypical cellular neurofibroma. The recognition of this entity is of great importance to both pathologists and clinicians because atypical cellular neurofibroma is clever at masquerading both histologically and cytologically as a sarcoma; therefore, a precise diagnosis of this variant is essential because of the differences in treatment and clinical behavior between benignancy and malignancy. We also examined the immunohistochemical characteristics of CD34 positive cells and focal high expression of p53 up to 73% encountered in our case. To our knowledge, seldom have series or case reports elucidated this phenomenon.

Pure sclerotic neurofibroma: a neurofibroma mimicking sclerotic fibroma.

BACKGROUND: Neurofibroma (NF) is a benign tumor of the nerve sheath. Several variants of NF have been described. PURPOSE: We report a case of NF with sclerotic changes resembling sclerotic fibroma (SF). METHODS AND RESULTS: The patient was a 61-year-old man who had an asymptomatic cutaneous lesion on the right scapular region. Physical examination revealed a pedunculated, white-to-pinkish nodule that had a firm consistency, spherical morphology, and smooth surface. Microscopically, the nodule showed a well-circumscribed, nonencapsulated dermal tumor composed of scant cells and thick collagen bundles with prominent clefts. The tumor cells were immunoreactive for vimentin and S100 protein. The patient was diagnosed as having pure sclerotic NF. To our knowledge, only five cases of NF with SF-like pattern have been previously published, and in two this pattern was pure. CONCLUSION: It is important to recognize this exceptional type of NF because it may be easily confused with SF, as well as with a wide variety of neoplasms or hamartomatous conditions containing similar sclerotic pattern.