Malignant Peripheral Nerve Sheath Tumor in Neurofibromatosis

Type 1 Patient

Sudarsono

, Obdes Maharni Emputri

, Iswahyudi

, Indriasari

, Tati Herdawati

, Dyah Marianingrum

Department of Dermatovenereology, Raja Ahmad Tabib General Hospital, Tanjungpinang, Indonesia

Department of Ophthalmology, Raja Ahmad Tabib General Hospital, Tanjungpinang, Indonesia

Department of Surgery, Raja Ahmad Tabib General Hospital, Tanjungpinang, Indonesia

Department of Radiology, Raja Ahmad Tabib General Hospital, Tanjungpinang, Indonesia

Department of Pathology, Raja Ahmad Tabib General Hospital, Tanjungpinang, Indonesia

Keywords: neurofibromatosis type 1, malignancy, malignant peripheral nerve sheath tumor

Abstract: Malignant peripheral nerve sheath tumor (MPNST) is rare and highly aggressive neoplasm. Approximately

half of MPNST cases occur in association with neurofibromatosis type 1 (NF1). MPNST contribute

significantly in reducing life-span of neurofibromatosis type 1 patients. The only known definitive therapy

for MPNST is surgical resection with wide negative margins which may not be feasible in certain conditions

involving tumor size, location, and/or metastases. Therefore, early diagnosis of MPNST is mandatory to

increase the rate of successful surgical resection. We present a 36-year-old female with NF1, who had a

giant MPNST on the right arm. She died six months after diagnosis in spite of a surgical resection and

chemotherapy. This case report aimed to highlight the signs and symptoms of malignant peripheral nerve

sheath tumor and examinations that are needed to make an early diagnosis of MPNST especially in patients

with neurofibromatosis type 1.

1 INTRODUCTION

Neurofibromatosis type 1 (NF1) is an autosomal

dominant disorder characterized by neurofibromas,

cafe-au-lait spots, intertriginous freckling, bone

malformations, learning disabilities and iris

hamartomas. It is associated with mutation in NF1, a

tumor suppressor located on chromosome 17q11.2.

NF1 encodes neurofibromin, a protein of the ras-

signal transduction pathway (Zehou et al., 2013).

NF1 represents a major risk factor for development

of malignancy, particularly malignant peripheral

nerve sheath tumors (MPNST), optic gliomas, other

gliomas, and leukemias (Korf, 2005).

MPNST is a rare disease with an incidence of 1

in 1.000.000 in the general population. The

incidence of MPNST in patients with NF1 has been

estimated to be 2% to 5%. MPNST is considered

aggressive and is associated with a low survival rate

(Hwang et al., 2017). MPNST contribute

significantly in reducing life-span of NF1-patients

(Freidrich, 2007). We present a rare case of giant

MPNST with lung metastases in a patient with NF1.

2 CASE

A 36-year-old female presented with painful huge

mass on her right arm, which rapidly increased in

size within a four-year period. The mass had

restricted movement of the extremity without

neurological deficits. She also had multiple nodular

masses of different sizes almost covering her entire

body. These masses were initially seen in the head,

neck and upper extremities when she was 7 years

old. She also had multiple hyperpigmented macules

on her axilla and trunk when she was 3 months old.

None of her close relatives had similar signs and

symptoms.

Upon physical examination, a firm, tender soft

tissue mass with small necrotic area in right arm was

found. Size of the mass was about 13 cm x 9 cm x 9

cm (Figure 1). “Bag of worm” sensation was

negative on palpation. Multiple soft dome-shaped,

flesh-colored nodules with diameters ranging from

0,5 cm to 5 cm covering almost her entire body

(Figure 1). Multiple small to large cafe-au-lait

macules, more than six in number, with irregular

margins were seen on trunk. She also had multiple

Sudarsono, ., Emputri, O., Iswahyudi, ., Indriasari, ., Herdawati, T. and Marianingrum, D.

Malignant Peripheral Nerve Sheath Tumor in Neuroﬁbromatosis Type 1 Patient.

DOI: 10.5220/0008157403590362

In Proceedings of the 23rd Regional Conference of Dermatology (RCD 2018), pages 359-362

ISBN: 978-989-758-494-7

359

tiny hyperpigmented macules in her both axilla. Eye

examination revealed multiple Lisch nodules on the

iris of both eyes and the visual acuity were 6/12.

Chest x-ray examination was normal.

Based on anamnesis and physical examination,

the differential diagnosis of the enlarging mass were

MPNST and plexiform neurofibroma (PN). The

patient underwent wide excision under general

anesthesia. Histopathology evaluation revealed

overall features of MPNST composed of

pleomorphic spindle cells with hyperchromatic

nuclei and mitotic activity (more than 20 mitoses per

10 high-power field) arranged curlicue and whorls

(Figure 2). Infiltration of the tumor cells into the

surrounding soft tissue and area of necrosis was

noted. Immunohistochemical analysis revealed a

scattered positive staining uptake in the cells with S-

100 antibody.

During follow-up, three months later, she

presented with enlarging mass of 6 cm x 8 cm in her

right axilla. Fine needle aspiration biopsy of the

mass revealed disease progression presence of

mitotic cells dominance, including some

pleomorphic malignant spindle cell proliferation.

CT-scan examination of axilla and lung revealed

solid mass of 6,2 cm x 8,3 cm x 6,1 cm on axilla and

multiple nodules on lung suggestive lung metastases.

We referred the patient to oncology surgeon and she

received two cycles of chemotherapy (ifosfamide)

without any improvement. She died six months after

diagnosis.

Figure 1: (A) A huge soft tissue mass with multiple neurofibromas in right arm. (B) Leomorphic spindle cells with

hyperchromatic nuclei and mitotic activity.

3 DISCUSSION

The term MPNST currently describes a

heterogeneous group of malignant tumors that

possibly arise from cells of the nerve sheath

(Freidrich et al., 2007). MPNST may appear de novo

or develop from the malignant transformation of a

benign neural neoplasm, generally a PN.

Approximately half of MPNST cases occur in

association with NF1 (Cunha et al., 2012).Leroy et

al (2001) reported the prevalence of MPNST was

approximately 4% in patients with NF1.In our

patient, MPNST occurred in association with NF1.

A diagnosis of NF1 was confirmed by the presence

of four clinical manifestations that met the National

Institutes of Health (NIH) consensus criteria.

In NF1 patients, one allele of Nf1 is inactivcated.

PN is initiated when a second-hit mutation

inactivates the remaining functional Nf1 gene,

resulting in a loss of neurofibromin expression and

Ras hyperactivation. This enhanced Ras signalling

promotes the proliferation and invasive behavior of

the neoplastic cells and their production of factors

that recruit other Nf1 happloinsufficient cell types

into the nascent neurofibroma. The subsequent loss

of additional tumor suppressor genes (p53, cyclin

D1-cyclin-dependent kinase (CDKN2A), phosphate

and tensin homologue (PTEN), retinoblastoma

(Rb)), amplification of key growth factor receptor

genes (epidermal growth factor receptor (EGFR),

ErbB2, C-Met, platelet-derived growth factor

receptor (PDGFRα), KIT), mutation of polycomb

repressive complex 2 (PRC2) components and

alteration of key cytoplasmic signaling pathways

then leads to the development of MPNST derived

from the the neoplastic Schwann cells within the

neurofibroma (Carroll, 2016).

MNPST may arise at any age with no gender

predilection (Farid et al., 2014).Patients with NF1

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usually present at a slightly earlier age than those

with sporadic MPNST (Goldblum et al., 2014). The

median age for sporadic MPNST is between 30 and

60 years, and that for NF1- associated MPNST is

between 20 and 40 years (Farid et al., 2014). Our

case was a 36-year-old female.

MPNST usually presents as a progressively

enlarging mass with pain and, later neurological

symptoms such as weakness and paresthesias.

Symptoms are present for months before the

malignant neoplasm is identified correctly (Farid et

al., 2014; Leroy et al., 2001).Most MPNST arise in

association with major nerve trunks, including the

sciatic nerve, brachial plexus, and sacral plexus.

Consequently, the most common anatomic sites

include the proximal portions of the upper and lower

extremities and the trunk. Few MPNST arise in the

head and neck (Goldblum et al., 2014). de

Vasconcelos et al. (2017) reported the extremities

(58%) as the most common affected sites, followed

by trunk (32%) and head and neck (10%) (de

Vasconcelos et al., 2017). MPNST is usually large,

averaging more than 5 cm in diameter and has a

fleshy, opaque, white-tan surface marked by areas of

secondary hemorrhage and necrosis (Goldblum et

al., 2014).de Vasconcelos et al. (2017) reported the

mean tumor sizes were 15,8±8,2 cm (range, 3-47

cm).

Our case presented with painful huge mass

(13 cm x 9 cm x 9 cm) on proximal portion of the

upper extremity without neurological symptoms.

Most MPNST are aggressive with a high

likehood of local recurrence and distant metastases.

The local recurrence rate varies from 40% to 65%

and the metastatic rate from 40% to 68%. They

frequently metastasize to the lung followed by bone,

liver, brain, soft tissue, skin and retroperitoneum.

Three months after surgical resection, our patient

developed local recurrence in the axilla and lung

metastases.

Fluorodeoxyglucose positron emission

tomography (PET-CT) is of great value in

monitoring lesions with the potential for malignant

transformation in NF1 (Batista et al., 2015).

Increased uptake was found to be characteristic of

MPNST (Korf, 2005). Due to the frequency and

severity of MPNST associated to NF1, PET-CT scan

could be useful in the following situations: a) when

the plexiform tumor growth is inconsistent with the

child’s growth track; b) in the presence of

neurological deficit, c) changes in tumor texture; and

finally d) when patient reports an inexplicable and

progressive pain (Batista et al., 2015).

Histologic features of MPNST are composed of

monotonous spindle cells arranged in intersecting

fascicles. Pleomorphic variants also exist. At low

power, alternating hyper- and hypocellular areas

may be present, often with hypercellular areas

localized in close proximity to blood vessels.

Compared with benign neurofibromas, MPNST

usually demonstrate a marked increase in tumor

cellularity, pleomorphism, and mitotic activity and

show a more organized cellular growth pattern, with

less extracellular matrix material (Farid et al., 2014).

S-100 protein has been the classic and the most

widely used antigen for documenting nerve sheath

differentiation. Between 50% and 90% of MPNST

express the antigen but usually focally only

(Goldblum et al., 2014).Our patient had

histopathological and immunochemical findings

similar to the earlier findings and diagnosis of

MPNST was made.

Current treatment of MPNST is similar to

treatment of soft tissue sarcomas as a whole and

relies primarily on local control measures. The only

known definitive therapy for MPNST is surgical

resection with wide negative margins, which may

not feasible due to variables such as tumor size,

location, and/or metastases. The role of adjuvant

radiation and chemotherapy is not defined (Kim et

al., 2017). Chemotherapy is usually preferred for

metastatic disease and may be also useful in the

preoperative management in order to decrease the

size in patients with inoperable tumors. Radiation

therapy is recommended for positive microscopic

margins providing local control and delaying the

onset of recurrence (Pourtsidis et al., 2014). Our

patient underwent excision and chemotherapy was

given after local recurrence and distant metastases of

the tumor to the lung.

MPNST are very aggressive tumors and all

current treatments have shown poor results. The

five-year overall survival rate of patients with

MPNST ranges between 34% and 58%, with several

studies suggesting that prognosis in the setting of

NF1 may be worse (Dunn et al., 2013).A meta-

analysis testing the effect of NF1 status on MPNST

by Kolberg et al. (2012) showed a significantly

worse outcome in NF1 patients (Kolberg et al.,

2013). de Vasconcelos et al. (2017) showed the

presence of NF1 and tumor size (greater than 10 cm)

had a significant negative impact on overall survival.

The five-year overall survival was 18% for NF1

associated and 40% for sporadic MPNST (de

Vasconcelos, et al., 2017). Our patient died six

months after diagnosis in spite of a surgical

resection and chemotherapy. She had NF1 status and

huge tumor size (13 cm x 9 cm x 9 cm) that

associated with poor prognostic.

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361

4 CONCLUSION

Patients with NF1 need careful follow up because of

the possibility of hidden carcinomas such as MPNST

underneath the neurofibromas. Clinicians should be

alert to unexpected growth of a pre-existing

neurofibroma, particulary a plexiform neurofibroma,

or the occurrence of unexplained pain with/without

neurological symptoms such as weakness and

paresthesias. Fluorodeoxyglucose PET-CT should be

used in suspicious lesion with the potential for

malignant transformation in NF1. Early diagnosis of

MPNST is mandatory to increasing the successful of

surgical resection

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