Topical Review Article
Massive Soft Tissue Neurofibroma (Elephantiasis Neuromatosa): Case Report and Review of Literature
Journal of Child Neurology 1-7 ª The Author(s) 2015 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073815571635 jcn.sagepub.com
Fernando Santos Pinheiro, MD1, A. David Rothner, MD2, Manikum Moodley, MBChB, FCP, FRCP2, and Kenneth G. Zahka, MD3
Abstract The authors review the literature on massive soft tissue neurofibroma. The methods included a review of 71 reports (PubMed search 1929-2012) with a total of 91 massive soft tissue neurofibroma patients and illustration of clinical and radiological progression of massive soft tissue neurofibroma on a patient with neurofibromatosis type 1. The mean age at initial examination was 21 years. Tumor onset was mostly in childhood years. The commonest affected body segment was the lower extremity (46%), followed by head/neck (30%). Surgical management was pursued in the majority of cases (79%). Bleeding was a common complication (25%). Recurrence was described in 12%; multiple resections cases were described. Malignant transformation occurred in 5%. Although massive soft tissue neurofibroma may be present early in life, massive tumor overgrowth may take years. Predicting disease progression and/or benefit of surgical intervention early in the disease course is challenging. Recurrence and malignant transformation are possible. Massive soft tissue neurofibroma does not respond to chemotherapy or radiotherapy and is associated with life-threatening surgical complications. Keywords neurofibromatosis, massive soft tissue neurofibroma, elephantiasis, neuromatosa Received September 29, 2014. Accepted for publication January 15, 2015.
Neurofibomatosis type 1, also known as von Recklinghausen disease, is considered the most common cancer predisposition syndrome, affecting approximately 1:3000 births. Autosomal dominant mutations of the tumor suppressor gene neurofibromatosis type 1 results in impaired function of neurofibromin, a protein involved in inactivation of Ras-GTP pathways of cell proliferation, differentiation, and migration, ultimately leading to excessive Schwann cell overgrowth.1 Classically, NF type 1 patients develop multiple nerve sheath tumors known as neurofibromas. These are benign, slow-growing tumors which may involve virtually any body segment. Plexiform neurofibromas are almost exclusively seen in neurofibromatosis type 1, but localized cutaneous neurofibromas are the most common tumors in this condition. A rare variant—massive soft tissue neurofibroma—is characterized by local infiltration and extension to multiple nerve branches, as well as substantial overgrowth of adjacent soft tissue and skin,2-4 which distinguished it from its more benign variant, plexiform neurofibroma. Due to its striking presentation and severe dysmorphism, massive soft tissue neurofibroma is also labeled elephantiasis neuromatosa. Nevertheless it is still not clear in the literature whether peripheral nerve and massive soft tissue neurofibroma should be considered separate entities.
Massive soft tissue neurofibroma is exclusively associated with neurofibromatosis type 1. Although considered benign it shares similarities with malignant peripheral nerve sheath tumors such as local infiltration and cell mitogenesis. In addition, massive soft tissue neurofibroma is associated with significant morbidity and mortality and almost no response to conventional chemotherapy and radiotherapy. Surgery is eventually pursued, although bleeding may be a life-threatening complication as massive soft tissue neurofibromas are highly vascularized. Total resection is challenging depending on a tumor’s size and proximity to vital organs or large vessels, and recurrence after partial resection is not uncommon. In view of this dramatic condition, which severely impacts patient’s quality of life, the authors herein provide
1
Department of Neurology, Cleveland Clinic, Cleveland, OH, USA Pediatric Neurology, Cleveland Clinic Foundation, Cleveland, OH, USA 3 Pediatric Cardiology, Cleveland Clinic Foundation, Cleveland, OH, USA 2
Corresponding Author: Fernando Santos Pinheiro, MD, Department of Neurology, Cleveland Clinic, 9500 Euclid Ave S100-A, Cleveland, OH 44195, USA. Email: [email protected]
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muscle
plexiform neurofibroma diffuse neuromas t f
Figure 2. Magnetic resonance image of the lower limb: Axial T1weighted sequence of lower extremity with remarkable soft tissue outgrowth of the right leg with a heterogeneously hypo-intense to iso-intense mass. t and f bones: Tibia and Fibula, respectively; muscle: tibialis anterior.
Figure 1. Massive soft tissue overgrowth of the affected limb: Anteromedial (A) and lateral (B) view of the right leg. Compare the sizes of the calf and the ulcer scars on that limb. The venous malformation in the left leg is due to chronic venous insufficiency and heart failure.
a comprehensive review of the literature including 71 reports (91 patients). The authors also describe a case of a 22-year-old male with massive soft tissue neurofibroma of the leg.
Methods This manuscript involves a case report and review of the literature. The authors performed a PubMed search with the following terms: ‘‘elephantiasis neuromatosa,’’ ‘‘massive plexiform neurofibroma,’’ ‘‘giant plexiform neurofibroma,’’ ‘‘giant plexiform neuroma,’’ and ‘‘massive soft tissue neurofibroma.’’ The authors assumed such terms were used as synonyms of the same condition, since there is still controversy regarding the clinical and pathological definition related to massive soft tissue neurofibroma. A total of 71 publications from year 1929 to 2012, mostly case reports but also case series and reviews, with a total of 91 subjects, were included in the review. A few reports were excluded due to lack of data pertinent to diagnostic modalities, management, or pathologic data.
Case Report This is a 25-year-old man with no family history for neurofibromatosis was diagnosed with neurofibromatosis type 1 at age
5 after cafe´ au lait spots, cutaneous neurofibromas, axillary freckling, and increased swelling of the right lower extremity were noticed. At age 8 he underwent right epiphysiodesis in effort to halt leg overgrowth. Postoperatively, gait improved, but he eventually became wheelchair bound due to the heavy limb secondary to massive tumor overgrowth. Other comorbidities included hypoplastic right ventricle, pulmonary atresia and coronary fistula. He was treated with a Fontan operation. He also had below-average IQ. On exam, multiple cafe´ au lait macules and scattered 3-4 mm subcutaneous neurofibromas were noted. Cranial nerves, fundi, visual fields, and hearing were all normal. Lower extremity exam was significant for massive circumferential enlargement of the right leg, more prominent below the knee and extending down to the dorsum of his foot, measuring 81 39 cm. It was soft to touch, painless and the consistency resembled a ‘‘bag of worms.’’ The left leg had severe venous insufficiency secondary to the underlying hypoplastic cardiomyopathy (Figures 1A-1B). There was no ataxia, but gait was impaired by shuffling of right leg. Motor examination revealed normal strength, tone, and bulk except for the right leg, which was weak secondary to heavy leg weight and deconditioning. Sensory and cerebellar testing was normal. Magnetic resonance imaging (MRI) of the right lower extremity revealed a markedly enlarged right leg (Figure 2). There was diffuse enlargement of the distal half of the right leg with edema-like signal. An area of signal abnormality was seen in the more proximal portion of the posterior aspect of the right leg. It measured 2.9 1.3 4.0 cm and demonstrated enhancement, consistent with a neurofibroma. In addition, extensive signal abnormality was seen throughout the lower extremity, consistent with neurofibromas in all compartments. The osseous structures including bone marrow signal were intact. However there were multiple areas of contour abnormalities consistent with erosions from adjacent neurofibromas and
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Table 1. Summary Statistics Total Subjects
91
Age (y) Male Onseta Birth Infancy Childhood Adulthood Site Head/neck Upper extremity Trunk Lower extremity Imagingb Invasive only Noninvasive only Invasive and noninvasive No imaging Management Conservative Biopsy Resection Amputation Complicationc Recurrence Bleed Other No complication Malignant peripheral nerve sheath tumors Positive Negative Not applicabled
21 (0.25, 67) 57 (66%) 28 (39%) 5 (7%) 32 (45%) 6 (8%) 27 (30%) 8 (9%) 14 (15%) 42 (46%) 7 (8%) 55 (65%) 7 (8%) 15 (18%) 6 (7%) 12 (14%) 60 (68%) 10 (11%) 7 (12%) 14 (25%) 3 (5%) 34 (60%) 4 (5%) 69 (87%) 6 (8%)
Values are either mean (minimum, maximum) or count (%). a Infancy: 18 years. b Invasive: angiography, venography; noninvasive: computed tomography, magnetic resonance imaging, X-ray; no imaging: no imaging modality performed or described. c One patient experienced both recurrence and bleeding. d Not applicable: conservative management, no biopsy, or no pathology analysis.
dysplasia secondary to neurofibromatosis. The patient was also evaluated by vascular and orthopedic surgery teams for possible amputation of the limb, but he opted for conservative management.
Invasive imaging such as angiography, venography, and lymphangiography were rarely used. With regard to management, surgical approach was pursued in the majority (78%) of cases (of those, 14% had amputation, and 86% had partial or total tumor resection), while conservative management was reported in 7% of cases. Biopsy was the only intervention in 13% of the cases. Bleeding, reported as massive, was the most common complication related or not to surgical intervention (25%). Tumor recurrence was described in 12% of cases, and multiple resections due to recurrence were not rare. Malignant transformation into malignant peripheral nerve sheath tumors occurred in 4 cases (5%).
Discussion The majority of cases were noticed in early childhood (mean age 5.5 years among the childhood category); 1 case had evidence of the tumor before age 1 year.5 Although onset was early in life, surgical intervention was predominantly in adulthood (mean age 23.6 years for surgical intervention). In fact, early stages of neurofibromas have an unpredictable progression, and therefore surgical management may be deferred until the tumor progresses to massive proportions, significantly impacts quality of life and/or evolves into life-threatening conditions such as massive intratumor bleed. A substantial number of cases were published before 1990, and therefore advanced imaging studies were not available. Partial or total tumor resection was the commonest surgical intervention (86%) as an attempt to save the limb, but amputation is usually the most effective treatment, especially for limb tumors. Massive soft tissue neurofibroma are classically characterized as being highly vascularized tumors composed of friable vasculature prone to spontaneous bleeding events. Massive bleed, especially perioperatively, was a recurrent complication reported in the literature.6 Spontaneous massive bleed as the initial presentation of such tumors was also described involving the head, neck and trunk.7-10 It is also worth mentioning that under the ‘‘no complication’’ category the authors included cases where complications were not described; the authors assumed that if a significant complication had occurred it would have been mentioned. Malignant transformations to malignant peripheral nerve sheath tumors were rare (5%).11-13 Pathology was lacking in 17 reports (18%).
Literature A total of 71 manuscripts (91 patients) were analyzed (Table 1). The mean age at initial exam was 21 years (3 months to 67 years). 66% of cases were male. The tumor onset was predominantly reported during childhood years (1 to 18 years of age), whereas in 39% of cases were present at birth. The commonest affected body segment was the lower extremity (46%), followed by head/neck (30%), trunk (including back, abdomen, and genitalia—15%), and upper extremity (9%). Imaging was the most used type of evaluation, plain X-ray was the main approach in earlier reports (before 1990), but was replaced by more advanced modalities such as computed tomography and MRI later on.
Genetics Neurofibromatosis type 1 affects approximately 1:3000 births worldwide.1 While 50% of cases are related to an autosomal dominant inheritance pattern, the other half is related to de novo mutation. Although neurofibromatosis type 1 is completely penetrant, there is a high variability in clinical manifestations even among family members or unrelated individuals carrying the exact same mutation. Neurofibromatosis type 1 is on chromosome 17q22 and encodes neurofibromin, a protein implicated in increasing cAMP synthesis and downregulating the Ras-GTP signaling pathway, which are important
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mediators of cell proliferation. Neurofibromatosis type 1 patients have 1 remaining functional allele of the neurofibromatosis type 1-tumor suppressor gene. The majority of neurofibromatosis type 1 gene mutations results from a variety of subtle changes such as nonsense, frameshift, missense mutations, or mutations that produce messenger ribonucleic acid splicing defects resulting in truncation of neurofibromin.14-16 Tumorigenesis is predicted to occur when a second somatic mutation disrupts the remaining functional copy of the neurofibromatosis type 1 allele—a condition known as loss of heterozygosity—and is seen in Schwann cells of neurofibromas.17 The hormonal environment also seems to play a critical role. Steroid hormone receptor expression and ligand mediated cell growth and survival are present in Schwann cells from neurofibromas, and with that in mind, animal studies have shown that only pregnant mice at the time of autologous implantation of skin-derived neural progenitors developed neurofibromas.18,19 The vast majority of peripheral nervous system tumors are derived from Schwann cells and their precursors.20 Histopathologic classification stratifies neurofibromas in 5 categories. The localized cutaneous variant is the most common, whereas the plexiform variant is pathognomonic of Neurofibromatosis type 1. Plexiform neurofibromas have the highest risk of malignant transformation among neurofibromas, and progression to malignant peripheral nerve sheath tumors is seen in 5-13% of cases.11,13 Massive soft tissue neurofibroma resemble the plexiform variant consisting of Schwann cells, perineural cells, mast cells, and fibroblasts which are sparsely distributed within a myxoid stroma. Due to unclear mechanisms, these large tumors appear to induce inappropriate growth of adjacent soft tissue and bone leading to clinical impairment disproportionate to the size of the neoplasm.21 They may also present with a very rich vascular system with friable vessel walls which can easily cause massive bleeds spontaneously or upon surgical intervention. Although it is the least common type of neurofibroma, massive soft tissue neurofibroma may also undergo malignant transformation. Massive soft tissue neurofibroma and plexiform neurofibromas tend to be clinically noticeable in 2 stages of life: A subtle enlargement of soft tissues is observed early in childhood with rapid and steady progression for several years followed by stabilization. The second period is during major hormonal changes, such as puberty and pregnancy,22 plexiform neurofibroma rarely develop after adolescence.23 Disfigurement is the most distressing disease manifestation.24 Many eventually opt for limb amputation or total tumor resection. Nevertheless, as noted, regrowth is often observed. Malignant transformation occurs when additional acquired somatic mutations involving tumor suppressor genes including p53, INK4a and p27, add to the neurofibromatosis type 1 -/- profile and lead to malignant peripheral nerve sheath tumors. Malignant peripheral nerve sheath tumors are very similar to atypical plexiform neurofibromas in early stages while in adulthood high grade malignant peripheral nerve sheath tumors predominates.11,13,25 Malignant transformation of plexiform neurofibromas and massive soft tissue neurofibroma is the major cause of
mortality in patients with neurofibromatosis type 1.26 Caregivers should be suspicious for malignant transformation when new onset of pain, neurologic deficit, or growth of a stable lesion ensues. In general, the risk of developing malignant peripheral nerve sheath tumors in neurofibromatosis type 1 patients with plexiform neurofibroma and massive soft tissue neurofibroma is 2-5%, but has been described as high as 30%,12 while the overall risk of malignancy in the neurofibromatosis type 1 population ranges around 10%.11,13,25,27,28 The overall life expectancy for individuals with neurofibromatosis type 1 is reduced by 15 years;27,29 malignancy and vasculopathy are the most important causes of early death in this population. The prognosis for malignant peripheral nerve sheath tumors is poor, with overall 5 to 10-year survival rates of 16-34% and 23% respectively. In addition, malignant peripheral nerve sheath tumors of neurofibromatosis patients are more prone to metastasis (39% vs 16% of patients without neurofibromatosis type 1), the most frequent site being the lung, followed by soft tissue, bone, and liver.26
Evaluation and Management In 1948 Holt and Wright30 described the radiologic features of neurofibromatosis. Although not pathognomonic, these findings are often strongly suggestive of the disease, such as spinal scoliosis, tibial peudoarthrosis, sphenoid wing hypoplasia, erosive bone lesions contiguous to neurofibromas, overgrowth of 1 or more bones associated with elephantiasic soft tissues and intraosseous cystic lesions.31 Advanced imaging modalities such as MRI is the exam of choice for diagnostic and monitoring purposes.2,32-34 T2-weighted MRI of massive soft tissue neurofibroma presents as hyperintense signal with central low attenuation. MRI is also important in the screening for malignant peripheral nerve sheath tumors by identifying areas with features of hemorrhage or necrosis. It is still controversial whether MRI should be performed as part of the assessment of neurofibromatosis type 1 patient for early diagnostic purposes, especially before clinical suspicion has not even arisen. The fact is that clinical management rarely changes when early imaging findings are noticeable. Furthermore normal MRI findings would not preclude subsequent development of neurofibromas. Besides, increased costs and anxiety of patient and family should also be taken into consideration. As always, other diagnosis should be considered, especially with individuals without a clear neurofibromatosis status (Table 2). Positron emission tomography (PET) scan is another imaging modality being recently implemented for distinction of benign and malignant tumors;25,35-41; 3D segmentation and computerized volumetric techniques combined with whole-body MRI have also been studied to determine tumor burden in this population.33 Nevertheless, differentiating malignant peripheral nerve sheath tumors from massive soft tissue neurofibroma is only fully possible through histopathologic analysis. Although surgery remains the only available treatment for massive soft tissue neurofibroma, complete resection of large,
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Table 2. Massive Soft Tissue Neurofibroma—Differential Diagnosis. Differential diagnosis 1. Congenital Maffucci Sd Klippel-Trenaunay Sd Proteus syndrome 2. Acquired 2.1 Infectious Filariasis (Wuchereria bancrofti) Repeated strep infection Tuberculosis 2.2 Noninfectious Podoconiosis Chronic lymphedema
assessment in light of the dramatic dysmorphic body changes should always be in mind, as social withdrawal is commonly observed. Genetic counseling should be available for patients and their family members.
Conclusion
infiltrative masses is usually unsatisfactory. Early surgical intervention has been proposed as an alternative to slow the progression of neurofibromas,42 even though it is challenging to predict natural progression. And problematically, resection and debulking of invasive plexiform neurofibroma is associated with recurrence in up to 40% of cases.43 Therapeutic angiography with artery embolization prior to surgery, especially for highly vascularized tumors, may be an alternative to prevent major bleed, as noted, a common surgical complication.6 With respects to medical management, most of the common chemotherapy regimens have proven to be ineffective.44-46 Several studies are in place targeting inactivation of the Ras-protein signaling pathway and other unrelated approaches such as angiogenesis inhibitors and cell differentiation inducers.47 Imatinib, a tyrosine-kinase inhibitor has also showed promising results in a recent phase 2 trial,48 by targeting c-kit, a proto-oncogene protein involved with neurofibromin signaling pathways. Pegyleted interferon-alpha-2b, an antiangiogenic and antiproliferative agent, is also in process for a phase 2 trial after preliminary data showed clinical and radiographic improvement of unresectable, progressive, symptomatic or life-threatening plexiform neurofibroma in a pediatric population.45-47 Finally tamoxifen, a selective estrogen receptor modulator, has demonstrated potent tumorigenesis inhibition in mice orthotopically xenografted with human malignant peripheral nerve sheath tumors.18,19,49 Nevertheless, plexiform neurofibroma and its variants have different morphology and invasive tendencies which impair accurate therapy impact in clinical trials;45 it is hard to infer whether massive soft tissue neurofibroma progression would be prevented by the abovementioned chemotherapeutic agents in light of its distinct growth pattern and genotype. Radiotherapy is contraindicated for plexiform neurofibroma due to risk of malignant transformation.11,50 As mentioned above, recurrence is common (in the range of 50%), as tumors can rarely be removed entirely, even when resection occurs early in life while small in size and somewhat restricted.42,51,52 Complications are mostly related to compression of surrounding structures, massive bleeds secondary to vasculopathy or surgical intervention, and pain. Psychosocial
Massive soft tissue neurofibroma is a rare disorder affecting only patients with neurofibromatosis type 1. Although initial findings of the disease are noticed during the first years of life, it is hard to predict its progression or whether surgery is beneficial in early stages. Therefore close supervision is paramount. Massive tumor overgrowth may take years to decades to develop and patients end up being surgically evaluated in adulthood. Surgical intervention is associated with the risk of massive bleed, but considering the risk of malignant transformation and poor response to conventional chemotherapy and radiotherapy, one should consider intervention as soon as feasible. Author Contributions FSP performed the study concept and design, acquisition of data, analysis, and interpretation. ADR performed the study concept, study supervision, and critical revision of the manuscript. MM performed the critical revision of the manuscript for important intellectual content. KZ performed the critical revision of the manuscript and acquisition of data.
Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The authors received no financial support for the research, authorship, and/or publication of this article.
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Massive Soft Tissue Neurofibroma (Elephantiasis Neuromatosa): Case Report and Review of Literature
Journal of Child Neurology 1-7 ª The Author(s) 2015 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073815571635 jcn.sagepub.com
Fernando Santos Pinheiro, MD1, A. David Rothner, MD2, Manikum Moodley, MBChB, FCP, FRCP2, and Kenneth G. Zahka, MD3
Abstract The authors review the literature on massive soft tissue neurofibroma. The methods included a review of 71 reports (PubMed search 1929-2012) with a total of 91 massive soft tissue neurofibroma patients and illustration of clinical and radiological progression of massive soft tissue neurofibroma on a patient with neurofibromatosis type 1. The mean age at initial examination was 21 years. Tumor onset was mostly in childhood years. The commonest affected body segment was the lower extremity (46%), followed by head/neck (30%). Surgical management was pursued in the majority of cases (79%). Bleeding was a common complication (25%). Recurrence was described in 12%; multiple resections cases were described. Malignant transformation occurred in 5%. Although massive soft tissue neurofibroma may be present early in life, massive tumor overgrowth may take years. Predicting disease progression and/or benefit of surgical intervention early in the disease course is challenging. Recurrence and malignant transformation are possible. Massive soft tissue neurofibroma does not respond to chemotherapy or radiotherapy and is associated with life-threatening surgical complications. Keywords neurofibromatosis, massive soft tissue neurofibroma, elephantiasis, neuromatosa Received September 29, 2014. Accepted for publication January 15, 2015.
Neurofibomatosis type 1, also known as von Recklinghausen disease, is considered the most common cancer predisposition syndrome, affecting approximately 1:3000 births. Autosomal dominant mutations of the tumor suppressor gene neurofibromatosis type 1 results in impaired function of neurofibromin, a protein involved in inactivation of Ras-GTP pathways of cell proliferation, differentiation, and migration, ultimately leading to excessive Schwann cell overgrowth.1 Classically, NF type 1 patients develop multiple nerve sheath tumors known as neurofibromas. These are benign, slow-growing tumors which may involve virtually any body segment. Plexiform neurofibromas are almost exclusively seen in neurofibromatosis type 1, but localized cutaneous neurofibromas are the most common tumors in this condition. A rare variant—massive soft tissue neurofibroma—is characterized by local infiltration and extension to multiple nerve branches, as well as substantial overgrowth of adjacent soft tissue and skin,2-4 which distinguished it from its more benign variant, plexiform neurofibroma. Due to its striking presentation and severe dysmorphism, massive soft tissue neurofibroma is also labeled elephantiasis neuromatosa. Nevertheless it is still not clear in the literature whether peripheral nerve and massive soft tissue neurofibroma should be considered separate entities.
Massive soft tissue neurofibroma is exclusively associated with neurofibromatosis type 1. Although considered benign it shares similarities with malignant peripheral nerve sheath tumors such as local infiltration and cell mitogenesis. In addition, massive soft tissue neurofibroma is associated with significant morbidity and mortality and almost no response to conventional chemotherapy and radiotherapy. Surgery is eventually pursued, although bleeding may be a life-threatening complication as massive soft tissue neurofibromas are highly vascularized. Total resection is challenging depending on a tumor’s size and proximity to vital organs or large vessels, and recurrence after partial resection is not uncommon. In view of this dramatic condition, which severely impacts patient’s quality of life, the authors herein provide
1
Department of Neurology, Cleveland Clinic, Cleveland, OH, USA Pediatric Neurology, Cleveland Clinic Foundation, Cleveland, OH, USA 3 Pediatric Cardiology, Cleveland Clinic Foundation, Cleveland, OH, USA 2
Corresponding Author: Fernando Santos Pinheiro, MD, Department of Neurology, Cleveland Clinic, 9500 Euclid Ave S100-A, Cleveland, OH 44195, USA. Email: [email protected]
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muscle
plexiform neurofibroma diffuse neuromas t f
Figure 2. Magnetic resonance image of the lower limb: Axial T1weighted sequence of lower extremity with remarkable soft tissue outgrowth of the right leg with a heterogeneously hypo-intense to iso-intense mass. t and f bones: Tibia and Fibula, respectively; muscle: tibialis anterior.
Figure 1. Massive soft tissue overgrowth of the affected limb: Anteromedial (A) and lateral (B) view of the right leg. Compare the sizes of the calf and the ulcer scars on that limb. The venous malformation in the left leg is due to chronic venous insufficiency and heart failure.
a comprehensive review of the literature including 71 reports (91 patients). The authors also describe a case of a 22-year-old male with massive soft tissue neurofibroma of the leg.
Methods This manuscript involves a case report and review of the literature. The authors performed a PubMed search with the following terms: ‘‘elephantiasis neuromatosa,’’ ‘‘massive plexiform neurofibroma,’’ ‘‘giant plexiform neurofibroma,’’ ‘‘giant plexiform neuroma,’’ and ‘‘massive soft tissue neurofibroma.’’ The authors assumed such terms were used as synonyms of the same condition, since there is still controversy regarding the clinical and pathological definition related to massive soft tissue neurofibroma. A total of 71 publications from year 1929 to 2012, mostly case reports but also case series and reviews, with a total of 91 subjects, were included in the review. A few reports were excluded due to lack of data pertinent to diagnostic modalities, management, or pathologic data.
Case Report This is a 25-year-old man with no family history for neurofibromatosis was diagnosed with neurofibromatosis type 1 at age
5 after cafe´ au lait spots, cutaneous neurofibromas, axillary freckling, and increased swelling of the right lower extremity were noticed. At age 8 he underwent right epiphysiodesis in effort to halt leg overgrowth. Postoperatively, gait improved, but he eventually became wheelchair bound due to the heavy limb secondary to massive tumor overgrowth. Other comorbidities included hypoplastic right ventricle, pulmonary atresia and coronary fistula. He was treated with a Fontan operation. He also had below-average IQ. On exam, multiple cafe´ au lait macules and scattered 3-4 mm subcutaneous neurofibromas were noted. Cranial nerves, fundi, visual fields, and hearing were all normal. Lower extremity exam was significant for massive circumferential enlargement of the right leg, more prominent below the knee and extending down to the dorsum of his foot, measuring 81 39 cm. It was soft to touch, painless and the consistency resembled a ‘‘bag of worms.’’ The left leg had severe venous insufficiency secondary to the underlying hypoplastic cardiomyopathy (Figures 1A-1B). There was no ataxia, but gait was impaired by shuffling of right leg. Motor examination revealed normal strength, tone, and bulk except for the right leg, which was weak secondary to heavy leg weight and deconditioning. Sensory and cerebellar testing was normal. Magnetic resonance imaging (MRI) of the right lower extremity revealed a markedly enlarged right leg (Figure 2). There was diffuse enlargement of the distal half of the right leg with edema-like signal. An area of signal abnormality was seen in the more proximal portion of the posterior aspect of the right leg. It measured 2.9 1.3 4.0 cm and demonstrated enhancement, consistent with a neurofibroma. In addition, extensive signal abnormality was seen throughout the lower extremity, consistent with neurofibromas in all compartments. The osseous structures including bone marrow signal were intact. However there were multiple areas of contour abnormalities consistent with erosions from adjacent neurofibromas and
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Table 1. Summary Statistics Total Subjects
91
Age (y) Male Onseta Birth Infancy Childhood Adulthood Site Head/neck Upper extremity Trunk Lower extremity Imagingb Invasive only Noninvasive only Invasive and noninvasive No imaging Management Conservative Biopsy Resection Amputation Complicationc Recurrence Bleed Other No complication Malignant peripheral nerve sheath tumors Positive Negative Not applicabled
21 (0.25, 67) 57 (66%) 28 (39%) 5 (7%) 32 (45%) 6 (8%) 27 (30%) 8 (9%) 14 (15%) 42 (46%) 7 (8%) 55 (65%) 7 (8%) 15 (18%) 6 (7%) 12 (14%) 60 (68%) 10 (11%) 7 (12%) 14 (25%) 3 (5%) 34 (60%) 4 (5%) 69 (87%) 6 (8%)
Values are either mean (minimum, maximum) or count (%). a Infancy: 18 years. b Invasive: angiography, venography; noninvasive: computed tomography, magnetic resonance imaging, X-ray; no imaging: no imaging modality performed or described. c One patient experienced both recurrence and bleeding. d Not applicable: conservative management, no biopsy, or no pathology analysis.
dysplasia secondary to neurofibromatosis. The patient was also evaluated by vascular and orthopedic surgery teams for possible amputation of the limb, but he opted for conservative management.
Invasive imaging such as angiography, venography, and lymphangiography were rarely used. With regard to management, surgical approach was pursued in the majority (78%) of cases (of those, 14% had amputation, and 86% had partial or total tumor resection), while conservative management was reported in 7% of cases. Biopsy was the only intervention in 13% of the cases. Bleeding, reported as massive, was the most common complication related or not to surgical intervention (25%). Tumor recurrence was described in 12% of cases, and multiple resections due to recurrence were not rare. Malignant transformation into malignant peripheral nerve sheath tumors occurred in 4 cases (5%).
Discussion The majority of cases were noticed in early childhood (mean age 5.5 years among the childhood category); 1 case had evidence of the tumor before age 1 year.5 Although onset was early in life, surgical intervention was predominantly in adulthood (mean age 23.6 years for surgical intervention). In fact, early stages of neurofibromas have an unpredictable progression, and therefore surgical management may be deferred until the tumor progresses to massive proportions, significantly impacts quality of life and/or evolves into life-threatening conditions such as massive intratumor bleed. A substantial number of cases were published before 1990, and therefore advanced imaging studies were not available. Partial or total tumor resection was the commonest surgical intervention (86%) as an attempt to save the limb, but amputation is usually the most effective treatment, especially for limb tumors. Massive soft tissue neurofibroma are classically characterized as being highly vascularized tumors composed of friable vasculature prone to spontaneous bleeding events. Massive bleed, especially perioperatively, was a recurrent complication reported in the literature.6 Spontaneous massive bleed as the initial presentation of such tumors was also described involving the head, neck and trunk.7-10 It is also worth mentioning that under the ‘‘no complication’’ category the authors included cases where complications were not described; the authors assumed that if a significant complication had occurred it would have been mentioned. Malignant transformations to malignant peripheral nerve sheath tumors were rare (5%).11-13 Pathology was lacking in 17 reports (18%).
Literature A total of 71 manuscripts (91 patients) were analyzed (Table 1). The mean age at initial exam was 21 years (3 months to 67 years). 66% of cases were male. The tumor onset was predominantly reported during childhood years (1 to 18 years of age), whereas in 39% of cases were present at birth. The commonest affected body segment was the lower extremity (46%), followed by head/neck (30%), trunk (including back, abdomen, and genitalia—15%), and upper extremity (9%). Imaging was the most used type of evaluation, plain X-ray was the main approach in earlier reports (before 1990), but was replaced by more advanced modalities such as computed tomography and MRI later on.
Genetics Neurofibromatosis type 1 affects approximately 1:3000 births worldwide.1 While 50% of cases are related to an autosomal dominant inheritance pattern, the other half is related to de novo mutation. Although neurofibromatosis type 1 is completely penetrant, there is a high variability in clinical manifestations even among family members or unrelated individuals carrying the exact same mutation. Neurofibromatosis type 1 is on chromosome 17q22 and encodes neurofibromin, a protein implicated in increasing cAMP synthesis and downregulating the Ras-GTP signaling pathway, which are important
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mediators of cell proliferation. Neurofibromatosis type 1 patients have 1 remaining functional allele of the neurofibromatosis type 1-tumor suppressor gene. The majority of neurofibromatosis type 1 gene mutations results from a variety of subtle changes such as nonsense, frameshift, missense mutations, or mutations that produce messenger ribonucleic acid splicing defects resulting in truncation of neurofibromin.14-16 Tumorigenesis is predicted to occur when a second somatic mutation disrupts the remaining functional copy of the neurofibromatosis type 1 allele—a condition known as loss of heterozygosity—and is seen in Schwann cells of neurofibromas.17 The hormonal environment also seems to play a critical role. Steroid hormone receptor expression and ligand mediated cell growth and survival are present in Schwann cells from neurofibromas, and with that in mind, animal studies have shown that only pregnant mice at the time of autologous implantation of skin-derived neural progenitors developed neurofibromas.18,19 The vast majority of peripheral nervous system tumors are derived from Schwann cells and their precursors.20 Histopathologic classification stratifies neurofibromas in 5 categories. The localized cutaneous variant is the most common, whereas the plexiform variant is pathognomonic of Neurofibromatosis type 1. Plexiform neurofibromas have the highest risk of malignant transformation among neurofibromas, and progression to malignant peripheral nerve sheath tumors is seen in 5-13% of cases.11,13 Massive soft tissue neurofibroma resemble the plexiform variant consisting of Schwann cells, perineural cells, mast cells, and fibroblasts which are sparsely distributed within a myxoid stroma. Due to unclear mechanisms, these large tumors appear to induce inappropriate growth of adjacent soft tissue and bone leading to clinical impairment disproportionate to the size of the neoplasm.21 They may also present with a very rich vascular system with friable vessel walls which can easily cause massive bleeds spontaneously or upon surgical intervention. Although it is the least common type of neurofibroma, massive soft tissue neurofibroma may also undergo malignant transformation. Massive soft tissue neurofibroma and plexiform neurofibromas tend to be clinically noticeable in 2 stages of life: A subtle enlargement of soft tissues is observed early in childhood with rapid and steady progression for several years followed by stabilization. The second period is during major hormonal changes, such as puberty and pregnancy,22 plexiform neurofibroma rarely develop after adolescence.23 Disfigurement is the most distressing disease manifestation.24 Many eventually opt for limb amputation or total tumor resection. Nevertheless, as noted, regrowth is often observed. Malignant transformation occurs when additional acquired somatic mutations involving tumor suppressor genes including p53, INK4a and p27, add to the neurofibromatosis type 1 -/- profile and lead to malignant peripheral nerve sheath tumors. Malignant peripheral nerve sheath tumors are very similar to atypical plexiform neurofibromas in early stages while in adulthood high grade malignant peripheral nerve sheath tumors predominates.11,13,25 Malignant transformation of plexiform neurofibromas and massive soft tissue neurofibroma is the major cause of
mortality in patients with neurofibromatosis type 1.26 Caregivers should be suspicious for malignant transformation when new onset of pain, neurologic deficit, or growth of a stable lesion ensues. In general, the risk of developing malignant peripheral nerve sheath tumors in neurofibromatosis type 1 patients with plexiform neurofibroma and massive soft tissue neurofibroma is 2-5%, but has been described as high as 30%,12 while the overall risk of malignancy in the neurofibromatosis type 1 population ranges around 10%.11,13,25,27,28 The overall life expectancy for individuals with neurofibromatosis type 1 is reduced by 15 years;27,29 malignancy and vasculopathy are the most important causes of early death in this population. The prognosis for malignant peripheral nerve sheath tumors is poor, with overall 5 to 10-year survival rates of 16-34% and 23% respectively. In addition, malignant peripheral nerve sheath tumors of neurofibromatosis patients are more prone to metastasis (39% vs 16% of patients without neurofibromatosis type 1), the most frequent site being the lung, followed by soft tissue, bone, and liver.26
Evaluation and Management In 1948 Holt and Wright30 described the radiologic features of neurofibromatosis. Although not pathognomonic, these findings are often strongly suggestive of the disease, such as spinal scoliosis, tibial peudoarthrosis, sphenoid wing hypoplasia, erosive bone lesions contiguous to neurofibromas, overgrowth of 1 or more bones associated with elephantiasic soft tissues and intraosseous cystic lesions.31 Advanced imaging modalities such as MRI is the exam of choice for diagnostic and monitoring purposes.2,32-34 T2-weighted MRI of massive soft tissue neurofibroma presents as hyperintense signal with central low attenuation. MRI is also important in the screening for malignant peripheral nerve sheath tumors by identifying areas with features of hemorrhage or necrosis. It is still controversial whether MRI should be performed as part of the assessment of neurofibromatosis type 1 patient for early diagnostic purposes, especially before clinical suspicion has not even arisen. The fact is that clinical management rarely changes when early imaging findings are noticeable. Furthermore normal MRI findings would not preclude subsequent development of neurofibromas. Besides, increased costs and anxiety of patient and family should also be taken into consideration. As always, other diagnosis should be considered, especially with individuals without a clear neurofibromatosis status (Table 2). Positron emission tomography (PET) scan is another imaging modality being recently implemented for distinction of benign and malignant tumors;25,35-41; 3D segmentation and computerized volumetric techniques combined with whole-body MRI have also been studied to determine tumor burden in this population.33 Nevertheless, differentiating malignant peripheral nerve sheath tumors from massive soft tissue neurofibroma is only fully possible through histopathologic analysis. Although surgery remains the only available treatment for massive soft tissue neurofibroma, complete resection of large,
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Table 2. Massive Soft Tissue Neurofibroma—Differential Diagnosis. Differential diagnosis 1. Congenital Maffucci Sd Klippel-Trenaunay Sd Proteus syndrome 2. Acquired 2.1 Infectious Filariasis (Wuchereria bancrofti) Repeated strep infection Tuberculosis 2.2 Noninfectious Podoconiosis Chronic lymphedema
assessment in light of the dramatic dysmorphic body changes should always be in mind, as social withdrawal is commonly observed. Genetic counseling should be available for patients and their family members.
Conclusion
infiltrative masses is usually unsatisfactory. Early surgical intervention has been proposed as an alternative to slow the progression of neurofibromas,42 even though it is challenging to predict natural progression. And problematically, resection and debulking of invasive plexiform neurofibroma is associated with recurrence in up to 40% of cases.43 Therapeutic angiography with artery embolization prior to surgery, especially for highly vascularized tumors, may be an alternative to prevent major bleed, as noted, a common surgical complication.6 With respects to medical management, most of the common chemotherapy regimens have proven to be ineffective.44-46 Several studies are in place targeting inactivation of the Ras-protein signaling pathway and other unrelated approaches such as angiogenesis inhibitors and cell differentiation inducers.47 Imatinib, a tyrosine-kinase inhibitor has also showed promising results in a recent phase 2 trial,48 by targeting c-kit, a proto-oncogene protein involved with neurofibromin signaling pathways. Pegyleted interferon-alpha-2b, an antiangiogenic and antiproliferative agent, is also in process for a phase 2 trial after preliminary data showed clinical and radiographic improvement of unresectable, progressive, symptomatic or life-threatening plexiform neurofibroma in a pediatric population.45-47 Finally tamoxifen, a selective estrogen receptor modulator, has demonstrated potent tumorigenesis inhibition in mice orthotopically xenografted with human malignant peripheral nerve sheath tumors.18,19,49 Nevertheless, plexiform neurofibroma and its variants have different morphology and invasive tendencies which impair accurate therapy impact in clinical trials;45 it is hard to infer whether massive soft tissue neurofibroma progression would be prevented by the abovementioned chemotherapeutic agents in light of its distinct growth pattern and genotype. Radiotherapy is contraindicated for plexiform neurofibroma due to risk of malignant transformation.11,50 As mentioned above, recurrence is common (in the range of 50%), as tumors can rarely be removed entirely, even when resection occurs early in life while small in size and somewhat restricted.42,51,52 Complications are mostly related to compression of surrounding structures, massive bleeds secondary to vasculopathy or surgical intervention, and pain. Psychosocial
Massive soft tissue neurofibroma is a rare disorder affecting only patients with neurofibromatosis type 1. Although initial findings of the disease are noticed during the first years of life, it is hard to predict its progression or whether surgery is beneficial in early stages. Therefore close supervision is paramount. Massive tumor overgrowth may take years to decades to develop and patients end up being surgically evaluated in adulthood. Surgical intervention is associated with the risk of massive bleed, but considering the risk of malignant transformation and poor response to conventional chemotherapy and radiotherapy, one should consider intervention as soon as feasible. Author Contributions FSP performed the study concept and design, acquisition of data, analysis, and interpretation. ADR performed the study concept, study supervision, and critical revision of the manuscript. MM performed the critical revision of the manuscript for important intellectual content. KZ performed the critical revision of the manuscript and acquisition of data.
Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The authors received no financial support for the research, authorship, and/or publication of this article.
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