Introduction
Peripheral nerve sheath tumors constitute a diverse group of neoplasms that are derived from cells accompanying peripheral nerve fibers. These include Schwann cells that form the innermost layer of endoneurium, characterised cytologically by wavy nuclei and expression of S100 protein; perineurial cells, nerve sheath dendritic cells as well as fibroblasts.1
In the recent 2020 WHO Classification, nerve sheath tumours included under benign category are schwannoma, neurofibroma, perineurioma, granular cell tumour, nerve sheath myxoma, solitary circumscribed neuroma and hybrid nerve sheath tumour. These tumours exhibit a wide range of diagnostically challenging cytomorphologic features like spindle cells, hypercellularity, myxoid change, epithelioid morphology and degenerative atypia and hence differential diagnoses with leiomyoma, fibromatosis, solitary fibrous tumor and low-grade fibromyxoid sarcoma, at times, becomes difficult. Malignant peripheral nerve sheath tumor (MPNST), malignant granular cell tumour and malignant perineurioma are the malignant counterparts and can be confused with high-grade soft tissue neoplasms, i.e., synovial sarcoma, fibrosarcoma, leiomyosarcoma, sarcomatoid carcinoma, and melanoma.2 Therefore, a comprehensive clinicopathological, morphological and immunohistochemical approach is necessary for arriving at definitive diagnosis.
Materials and Methods
It was a 3 years retrospective and 2 years prospective study from 2015-2020 conducted in the Department of Pathology of JawaharLal Nehru Medical College, AMU, Aligarh. Prior ethical approval and clearance was taken from the University Ethical Review Board. Informed consent was taken in all cases. History and clinical findings were collected from the archives of Histopathology and Cytopathology Lab and both FNA as well as Imprint smears were included in the Cytopathology cases. The biopsies and resected histopathological specimen were fixed in 10% neutral buffered formalin and processed routinely and stained by H and E staining.
Immunohistochemical staining was done using automated VENTANA BENCHMARK XT. The immunophenotypic panel of markers which were used in the study to differentiate and categorise the peripheral nerve sheath tumours were- S100, EMA, Pan CK, Desmin, SMA, TLE -1, HMB -45, GLUT -1, CD 31, CD 34 and Ki 67.
Results
A total of 82 cases of Peripheral Nerve Sheath Tumours (PNSTs) were subjected to FNAC over a period of 5 years (2015-2020) accounting for 45.8% of the total soft tissue tumours. Out of 82 cases, 70 (85.4 %) were diagnosed as benign and 12 (14.6 %) as malignant. The male to female ratio was 1.5:1. Cytologically diagnosed cases were confirmed on histopathology and after the application of immunohistochemistry. Benign cases comprised of Neurofibroma (52.5%) and Schwannoma (47.5%) and their variants namely plexiform neurofibroma, cellular neurofibroma, cellular schwannoma and ancient schwannoma while malignant cases included MPNST.
Neurofibroma (38 cases – 46.4%)
It was seen over a wide age range with maximum cases in 2nd decade. With a male to female ratio of 1.9:1, head and neck region was the most common site. Clinically, most tumours were slow growing and painless, solitary lesions with a soft to rubbery consistency. The mean size was around 2-3 cm. On Cytopathology, low to moderate cellularity was seen, comprising of sheets as well as singly scattered spindle cells with characteristic wavy nuclei set in a pink matrix background were seen. Grossly, the tumours were lobulated or well circumscribed masses. Most of them were skin covered with glistening, tan white cut surface. Microscopic examination revealed small bland spindle cells with wavy nuclei and cytoplasmic processes set in a loose myxoid stroma. No mitosis or necrosis was seen. The differential on histopathological examination was Schwannoma and S100 was diffusely positive in all the cases . Grossly, plexiform neurofibroma showed enlarged tortuous and fusiform nerves and microscopically disordered proliferation of Schwann cells in a myxoid matrix was seen.
Figure 1
a: Clinical Photograph of a patient showing swelling on the back of neck; b: FNA smear showing sheets as well as singly dispersed bland spindle cells. H & E (x100); c: Section showing skin covered tissue with underlying tissue showing proliferation of spindle cells; d: Section showing small bland spindle cells set in a loose stroma. H & E (x400); e: S100 showing diffuse cytoplasmic positivity.
Figure 2
a: Clinical Photograph of a 24 years old female patient showing swelling on the extensor aspect of forearm; b: FNA smear showing cluster of spindle cells with characteristic wavy nuclei. H & E (x400); c: Section showing compact Antoni A areas alternating with loosely arranged Antoni B areas. H & E (x40); d: S100 showing diffuse cytoplasmic positivity (x400).
Figure 3
a: FNA smear showing cluster of malignant spindle cells with increased nucleocytoplasmic ratio, prominent nucleoli and scant cytoplasm against a hemorrhagic background. H & E (x400); b: Section showing marked nuclear atypia, hyperchromasia and irregular nuclear membrane. H & E (x400); c: S100 showing focal cytoplasmic positivity (x400); d: Vimentin showing strong cytoplasmic positivity; e: Ki67 index >40%; f: INI 1 showing nuclear positivity (x100); g: H3K27me3 showing diffuse nuclear positivity (x400)
Table 1
Comparative analysis of incidence, age, sex and site distribution of peripheral nerve sheath tumors
|
|
Number of cases |
Age (in years) |
M:F ratio |
Site |
|
Vahini., 2015 3 |
32.38% |
21-30 |
1:1 |
Head and neck |
|
Harpal et al. 20164 |
10.5% |
11-30 |
0.9:1 |
- |
|
Naik et al., 2018 5 |
13.27% |
61-70 |
0.6:1 |
Head and neck |
|
Present study,2020 |
45.8% |
11-20 |
1.48:1 |
Head and neck |
Schwannoma (32 cases – 39%)
Schwannoma showed a female preponderance presenting in the 3rd decade with head and neck as the most commonly involved site (62.5%). FNA smears showed clusters of bland spindle cells with wavy pointed nuclei. Grossly, the tumours were mostly solitary, well-circumscribed, and encapsulated. Microscopically, there were compact Antoni A areas with cells showing moderate amount of eosinophilic cytoplasm and elongated tapered nuclei with occasional nuclear palisading (Verocay bodies), alternating with loosely arranged Antoni B areas. Diffuse nuclear as well as cytoplasmic S100 positivity was seen with greater intensity in Antoni A areas. One case of cellular schwannoma showed cellular Antoni A areas and no Verocay bodies or Antoni B areas. Scattered aggregates of foamy macrophages along with increased mitotic activity and focal atypia were also seen. There were 2 cases of ancient Schwannoma showing hyalinisation, nuclear atypia and hemosiderin deposition.
Malignant peripheral nerve sheath tumour (12 cases- 14.6%)
MPNST occurred in the second and third decade of life, with a male to female ratio of 2:1, in the head and neck region and lower extremity. Almost all patients presented with a palpable swelling which was painful in 60% cases. The mean size was about 6 cm. On Cytopathology, the smears were highly cellular showing clusters of malignant spindle cells with increased nucleocytoplasmic ratio, prominent nucleolus and scant cytoplasm against a hemorrhagic and necrotic background. Grossly, it was a large infiltrative tumour seen in association with major nerves. On microscopy, tumours were composed of fascicles of alternating hyper- and hypo-cellular spindle-shaped cells with hyperchromatic nuclei and pale wavy cytoplasm along with areas of geographical necrosis and increased mitotic activity. Immunohistochemically, SMA, EMA, vimentin and Pan CK were negative and focal S100 positivity was seen. H3K27me3, SOX10 and INI1 were applied also applied. FNCLCC grading was done and 6 tumours were grade 2 while remaining 6 were grade 3. Staging was done using AJCC system. 6 tumours were Stage II and 6 were Stage III.
Discussion
Neurofibroma and schwannoma are common benign peripheral nerve sheath tumours that occur as isolated sporadic lesions or in syndromic association with Neurofibromatosis.6 The incidence of MPNSTs is 0.001%.7
The frequent sites of involvement of benign peripheral nerve sheath tumours were the head and neck.8 Maximum cases of neurofibroma in our study were also located in head and neck region and were commonly seen in the second decade with a high male to female ratio. In a study by Rao BS.,et al., 20169 neurofibroma constituted 8 cases (44.4%) out of 18 cases of peripheral nerve sheath tumours with male predominance, similar to our study while Naik V., et al.,20185 reported a much higher incidence of 80%.Cimino -Mathews AM.,201110 reported that scattered nuclear atypia can be seen in neurofibroma but necrosis and brisk mitotic activity were absent, a finding similar to our study. In few cases, mild nuclear pleomorphism was seen but frank mitosis and necrosis were absent.
Bishop JA., 201111 observed that although schwannomas can occur at any age but most commonly involve patients in the age group 20-50 years and are often located in the head and neck and extremities. In our study, schwannoma also showed site predilection for head and neck with maximum incidence in the third decade and a female predilection. Schaefer and Fletcher CD.,2015,12 also observed that middle aged women are more commonly affected. Bishop JA.,2011 11 also observed that cellular schwannomas can be confused with sarcomas especially MPNST because of high cellularity and mitosis but strong and diffuse positive S100 staining was very reassuring. We did face this problem with cellular and ancient schwannomas, but a strong and uniform S100 positivity confirmed the diagnosis.
MPNST showed equal distribution in head and neck and lower extremity and were more commonly seen in males. All 12 cases were seen in the second and third decade.
Fisher C.,201113 observed that the commonest sites of MPNST are proximal limbs, trunk, or head and neck and younger age at presentation is associated with Neurofibomatosis type 1 with a peak in 4th decade. In our study, none of the patients clinically showed any signs and symptoms of NF-1. We also observed herringbone pattern in one of the cases. This was in accordance with report published by Hirose T.,et al., 199814 in which he described MPNSTs to have a herringbone pattern with wavy, serpiginous buckled nuclei with scant cytoplasm. A study by Senthilkumar AC.,201915 also highlighted focal areas with rhabdoid differentiation. However, in our study, we have included only those cases that exhibited spindled morphology.
Conclusion
Tumors arising from peripheral nerves may cause difficulties in diagnosis, in classification and in management. There is a wide differential diagnosis, especially with malignant tumours in which overlap with other spindle cell tumours is seen. Hence, a clinical as well as cyto-histopathological correlation is necessary along with judicious use of immunohistochemistry to arrive at a definitive diagnosis.
