Dermatology Unit, Department of Medicine, Ahmadu Bello University and Teaching Hospital, Zaria.
Adeiza Mukhtar Abdulmajid.
Infectious Disease Unit, Department of Medicine, Ahmadu Bello University and Teaching Hospital, Zaria.
Correspondences to: Dr. Abdullahi Umar, Department of Medicine P.M.B 06, Ahmadu Bello University Teaching Hospital, Shika-Zaria. Email: firstname.lastname@example.org
|Neurofibromatosis type 1 (NF-1) is a relatively common autosomal dominant inherited disorder, with patient at increased risk of developing both benign and malignant tumours. Even though the manifestations of NF-1 affects mainly the nervous system, other organs and tissues in the body can as well be affected with patient presenting to different medical and surgical specialist at different times. We present a 33 years old woman with NF-1 who developed progressive paraparesis, cough, chest pain and shortness of breath. Further clinical and laboratory evaluation revealed spinal cord compression, massive right sided pleural effusion with an Intrathoracic mass. Histology showed malignant peripheral nerve sheath tumour (MPNST).However outcome was unfavourable and mortality was thought to be as a result of late presentation and extensive nature of the disease. We report this case because of the rare association of MPNST with NF-1.|
Key-words: *Neurofibromatosis type 1 *malignant peripheral nerve sheath tumours (MPNST) *Autosomal dominant disorder *Paraparesis
Neurofibromatosis type 1 was first described by Frederic von Recklinghausen in 1882. It is a relatively common inherited disorder that affects about 1 in 2500 to 1 in 3000 people worldwide with no sex or ethnic variation (1).
Even though it is a benign tumour but malignant peripheral nerve sheath tumours (MPNST) may occur with an incidence of 0.16% in patients with neurofibromatosis type 1, compared to incidence of 0.001% in the general population (2,3). Patients are also at risk of developing other associated tumours such as; optic pathway glioma, glioblastoma, gastrointestinal stromal tumour, breast cancer, leukaemia, phaeochromocytoma etc.1.
Both the peripheral and central nervous system are affected in NF-1. Plexiform neurofibromas affects large nerves, plexi, spinal roots, sympathetic nerves, or small peripheral nerve fibres. This may results in pain and erosion of the neural foramen or cord compression at multiple levels (4).
In NF-1, the thorax and lungs can be affected in several ways such as cutaneous and subcutaneous neurofibromas on the chest wall, kyphoscoliosis, ribbon deformity of the ribs, Intrathoracic neoplasms and interstitial lung disease (5).
This case is reported because of the rarity of MPNST in
association with NF-1 presenting with Intrathoracic tumour and cord compression syndrome.
A 33 year old woman with NF-1 on follow up at the neurology and plastic surgery clinic presented with a four months history of progressive paraparesis, associated numbness, paraesthesia and low back pain with no history of trauma to the back. She had associated history of both faecal and urinary incontinence but no history of headache, convulsions or loss of consciousness. There was no visual or hearing abnormalities and there was no family history of neurofibromatosis.
A month prior to presentation, she developed insidious onset of cough, productive of whitish mucoid, non-bloody sputum with associated right sided dull aching chest pain and progressive breathlessness with reduced exercise tolerance. There was no orthopnoea or Paroxysmal nocturnal dyspnoea, no leg swellings and no palpitations. No history of contact with a known open pulmonary tuberculosis case and was never treated for pulmonary tuberculosis before. She had history of high grade intermittent fever with chills and rigors noticed two weeks before presentation. There was no drenching night sweat but she had significant weight loss. No history of cigarette smoking or exposure to organic and inorganic dust. Review of gastrointestinal tract system essentially unremarkable. No family history of neurofibromatosis.
She was not diabetic or hypertensive and there was no risk factor for HIV infection and no previous exposure to ionizing radiation.
Physical examination revealed an acute on chronically ill-looking young woman in respiratory distress (tachypnoeic, oxygen saturation of 88% on room air). She was pale, not cyanosed and had no significant peripheral lymphadenopathy.Multiple cutaneous neurofibromas, cafe´-au-lait macules, and skinfold freckling with plexiform neurofibromas were seen. [Figure 1]
Her pulse rate was 120 per minute regular, full volume, blood pressure was 100/70mmHg supine with distended external jugular veins. Apex beat was displaced at 6th LICS lateral to mid-clavicular line, non-heaving and heart sounds were normal first and second with no murmurs. Respiratory rate was 32 cycles per minute with reduced chest movement on the right hemi thorax and trachea deviated to the left. Percussion note was stony dull over the right hemi thorax where breath sound was vesicular with reduced intensity. Coarse crepitations were heard over the left infra-clavicular and infra-axillary areas.
On examining the central nervous system she had spastic paraparesis with hypereflexia and ankle clonus. There was loss of sensation to both fine and crude touch and a sensory level at T4/T5. She has non tender hepatomegaly with no ascites.
Laboratory results showed normal blood sugar and electrolytes. HIV antibodies were negative and full blood count was normal. Pulmonary tuberculosis screen were negative (sputum AFB, gene xpert/RIF). Chest x-ray showed right sided pleural effusion with a mass on the right hemi thorax. Chest CT scan could not be done for financial reasons. Abdominal/chest ultrasound scan done showed hepatomegaly of 16.2cm with a well-defined right lower lung mass, right sided pleural effusion and anterior abdominal wall subcutaneous nodules. [Figure 2]
Diagnostic pleural fluid tap showed a haemorrhagic and exudative pleural effusion. A biopsy of the Intrathoracic mass was taken and histology report showed a cellular tumour growing in sheets with vague fascicular pattern, it was composed of markedly pleomorphic round to spindle cells including giant forms with oval to wavy nuclei, prominent nucleoli, coarse chromatin pattern and scanty to moderate cytoplasm. Mitoses (9p10hpf) and foci of necrosis were noted. The stroma was scanty to moderate and fibromyxoid. These findings were suggestive of malignant peripheral nerve sheath tumour (MPNST). [Figure 3] With these findings, a diagnosis of neurofibromatosis type 1 associated with malignant peripheral nerve sheath tumour of the thoracic spinal nerves was made complicated by a malignant pleural effusion and superior vena caval obstruction.
She had supplemental oxygen therapy and intercostal tube drainage of the effusion but died of progressive respiratory failure while awaiting the histology report.
Comment Format of referencing Havard or APHA style?
Neurofibromatosis type 1 or von Recklinghausen?s disease is an autosomal dominant disorder of the ectoderm and mesoderm characterized mainly by the presence of neurofibromas, cafe-au-lait spots, and pigmented hamartomas in the iris (Lisch nodules) (6). According to national institute of health (NIH) consensus criteria for diagnosis of neurofibromatosis type 1 , Two or more of the following clinical features are sufficient toestablish a diagnosis of neurofibromatosis type 1:? Six or more cafe-au-lait macules (>0.5 cm at largestDiameter in a prepubertal child or >1.5 cm in post-pubertalIndividuals), ? Axillary freckling or freckling in inguinal regions, ? Two or more neurofibromas of any type or one or more plexiform neurofibromas, ? Two or more Lisch nodules (iris hamartomas), ? A distinctive osseous lesion (sphenoid wing dysplasia, long-bone dysplasia), ? an optic pathway glioma, ? A first-degree relative with neurofibromatosis type 1 diagnosed by the above criteria (1).
The NF-1 gene is located on chromosome 17q11 which functions as tumour suppressor gene and encodes for the protein Neurofibrin (6), which is predominantly expressed in neurons, Schwann cells and astrocytes.
Oncogenic mutations in Ras genes or inactivation of NF-1 gene leads to a permanentstimulation of a cascade of signals and excessive cell division, leading to the formation of tumours (7). The mutation of tumour suppressor NF-1 gene increases the risk for the development of other malignancies mainly derived from the neural crest such as malignant schwannoma, neurofibrosarcoma, intracranial glioma, and phaeochromocytoma in patients with NF-1 (6).
Malignant peripheral nerve sheath tumour (MPNST) as seen is this case is a rare and aggressive sarcoma that arises from the nerve sheath or shows features of nerve sheath differentiation, with an incidence of 0.001% in the general population as against incidence of 0.16% in patients with neurofibromatosis type 1 (2, 3).These tumours represent about 3?10% of all soft-tissue sarcomas, with majority of cases seen in individuals with neurofibromatosis type 1 (1). MPNST can arise anywhere within the body but more commonly seen in the extremities, head, and neck (2, 3). The index case had Intrathoracic and spinal involvement though in the literature, Intrathoracic MPNST is uncommon (8).
The cumulative lifetime risk of developing MPNST in a patient with NF-1 is about 8?13%9. The risk of developing this severe form of sarcoma is increased 20-fold in the area of an existing internal plexiform neurofibroma (1), which was noticed in this case.
Other risk factors for development of MPNST include previous radiation therapy which our patient has never had, and large germline mutations encompassing the entire NF1 gene (micro deletions) (1).
The index case met 4 of the 6 major diagnostic criteria for NF-1 though only 2 are needed namely; >6 cafe´ -au-lait macules, skinfold freckling, 1 plexiform neurofibromas and >2 cutaneous neurofibromas. She didn?t have osseous dysplasia, iris hamartomas and optic glioma. On the other hand, neurofibromatosis type 2 (NF-2) is characterized by bilateral vestibular schwannoma. Both conditions have high de novo mutation rates and carry a high risk of tumour formation, though NF-1 carries a higher risk of high-grade malignancy (10).
The median age for sporadic MPNST is between 30 and 60 years, and that for NF-1-associated MPNST is seen in much younger age group between 20 and 40 years (11), as seen in this case at 33 years.Patients with MPNST presents
with a rapidly enlarging mass that may be painful or cause local neurological symptoms such as weakness or paraesthesia. This case presented with progressive bilateral lower limb weakness that may be related to spinal cord compression by MPNST, but a dumb bell neurofibroma may also compress on the spinal nerves.
Exertional dyspnoea, cough and chest pain that may be related to the rapidly enlarging Intrathoracic tumour with pleural effusion, mediastinal shift and superior vena cava obstruction as shown in the above index case are obvious manifestations of Intrathoracic MPNST associated with NF-1.
Magnetic resonance imaging is considered the most useful imaging modality which helps to characterize the anatomical extent of the tumour for subsequent surgical intervention. Flourodeoxyglucose-positron emission tomography (FDG-PET) has been employed to differentiate between benign neurofibromas from MPNST in patients with NF-1, with relatively high specificity (12). However these advanced imaging modalities were not available or affordable in our centre.
Histology remains the most readily available diagnostic tool for MPNST, even though the histologic features may rather be non-specific (13). Histological features of MPNST may composed of monotonous spindle cells arranged in intersecting fascicles. Pleomorphic variants also exist as seen in the index case. Compared to benign neurofibromas, MPNST usually shows a marked increase in tumour cellularity, pleomorphism, and mitotic activity and have a more organized cellular growth pattern, with less extracellular matrix material (13).
The most effective treatment for MPNST requires complete surgical excision. Even with surgical excision, 5-year overall survival rates are poor and MPNST represents a substantial cause of mortality in individuals with NF-1 (1). Radiotherapy may delay recurrence but has little effect on long-term survival (14). Doxorubicin can be used as single-agent standard chemotherapy for soft tissue sarcoma in adults, but has a poor response rate of 12% (15). Furthermore, the presence of NF-1 is one of the most significant poor prognostic factors with use of chemotherapy against MPNST (16).
The late presentation of this case and the extensive nature of the disease at presentation contributed to the poor outcome.
- Angela C H, David H G. Neurofibromatosis type 1: a multidisciplinary approach to care. Lancet Neurol2014; 13: 83443.
- Yamaguchi, U., Hasegawa, T., Hirose, T., Chuman, H., Kawai, A.et al. Low grade malignant peripheral nerve sheath tumour: varied cytological and histological patterns. J ClinPathol 2003; 56: 826?830.
- Rekhi B, Abhijeet I, Rajiv K, Maria AD, Rajesh D, Nirmala A. J. Malignant peripheral nerve sheath tumors: Clinicopathological profile of 63 cases diagnosed at a tertiary cancer referral center in Mumbai, India. Indian J PatholMicrobiol. 2010; 53: 611-618.