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Dermatology Diagnosis

Diagnosing A Painful Mass With A Genetic Component

A 21-year-old healthy-appearing woman presented to our clinic with a complaint of a chronically painful lump under the skin at the lateral aspect of her left ankle. She related a 10-year history of pain without any history of injury. She noted increased pain within the past few months, even to a slight touch.

The size of the lump and pain symptoms have progressively increased over time. She related intermittent shooting pain and a tingling sensation toward her fourth and fifth toes. Any degree of pressure and prolonged walking exacerbate the symptoms. Pain control measures consisted of various oral anti-inflammatories without adequate relief. She did not attempt other treatment measures.

The patient had denied any pertinent medical or surgical history. She denied the use of any medications. She also denied any significant family medical or social history.

On the physical exam, the patient had a large soft tissue mass to her right nare. She had many ephelides (freckles) on her face, neck and axilla. A light brown macule approximately 4 cm in size with smooth borders was present on her left wrist. She had a minimally antalgic gait pattern favoring the left foot.

A focused examination revealed an approximately 3 x 3 cm palpable mass to the posterolateral aspect of her left lower leg just proximal to the retromalleolar area. The mass was firm and slightly mobile in nature. No overlying skin changes were visible. The mass did not seem be continuous with the peroneal tendons as range of motion of the foot and ankle did not alter the appearance of the mass. The patient reported severe pain with palpation of the mass and exhibited a positive Tinel’s sign. The Valleix sign was negative. There was also mild tenderness to palpation of the Achilles tendon within the watershed area. Palpation elicited no pain at the Achilles insertion.

A complete set of radiographs of the left ankle revealed only a soft tissue density measuring 4.2 cm long to the anatomic location of interest without any associated calcifications or soft tissue edema. We ordered magnetic resonance imaging (MRI) (with and without contrast). The MRI findings were significant for a 1.1 x 1.3 x 2.4 cm fusiform lesion within the posterolateral ankle along the course of the sural nerve just lateral to the Achilles tendon. It demonstrated a central hypointense signal on T2 weighted sequences and avid homogeneous contrast enhancement. The radiologic impression was consistent with a benign-appearing nerve sheath tumor with neurofibroma favored as a diagnosis over schwannoma.

Key Questions To Consider

1. What is the diagnosis of this lump?
2. What is the differential diagnosis?
3. What are the key characteristics of this condition?
4. What is the treatment of this condition?

Answering The Key Diagnostic Questions

1. Neurofibromatosis type 1
2. Neurofibromatosis type 1, neurofibromatosis type 2, neurofibromatosis type 1-like syndrome (Legius syndrome), schwannomatosis
3. The patient had a firm 3 x 3 cm palpable mass at the posterolateral aspect of the left lower leg just proximal to the retromalleolar area. The mass did not seem be continuous with the peroneal tendons as range of motion of the foot and ankle did not alter the appearance of the mass.
4. Treating physicians may perform surgical excision of these tumors or reduce them with radiation therapy. Radiation and chemotherapy are options if cancer occurs.

A Guide To The Differential Diagnosis

Neurofibromatosis type 1 (NF1). The correct diagnosis is neurofibromatosis type 1. This typically appears during infancy and is characterized by multiple café-au-lait lesions, one or more neurofibromas, Lisch nodules, macrocephaly, short stature, cognitive deficits, optic gliomas, pheochromocytomas, and increased risks of malignant peripheral nerve sheath tumors, gastrointestinal stromal tumor, leukemia, breast cancer, rhabdomyosarcomas and osseous dysplasias. Genetic testing will reveal a mutation at the NF1 gene locus in chromosome band 17q11.2.

Neurofibromatosis type 2 (NF2). Neurofibromatosis type 2 typically appears at the start of adulthood. This disorder is characterized by bilateral vestibular schwannomas, intracranial meningiomas and/or ependymomas, spinal glioma, paraspinal schwannomas, cutaneous schwannomas, posterior subcapsular cataracts, pigmentary retinopathy, and an absence of typical café-au-lait spots. Genetic testing will reveal a mutation at the NF2 gene locus in chromosome band 22q11.

Neurofibromatosis type 1-like syndrome (Legius syndrome). This is characterized by the presence of café-au-lait spots, axillary freckling, macrocephaly, facial dysmorphism and perhaps learning difficulties. There is an absence of neurofibromas, optic pathway gliomas or other features of neurofibromatosis type 1. Genetic testing identifies a mutation in the SPRED1 gene in chromosome band 15q13.2.

Schwannomatosis. This typically appears in adulthood after the third decade of life and is characterized by multiple schwannomas and little or no skin pigmentation such as café-au-lait spots or intertriginous freckling. There is absence of splicing or missense mutations. Tumor biopsy uniformly demonstrates schwannoma.

Pertinent Insights On The Patient’s Post-Imaging Follow-Up And Surgery

The patient returned to the clinic three weeks later for follow-up as her MRI results were complete. Given the overall clinical picture, we further inquired if the patient had ever been diagnosed with neurofibromatosis. She had not but stated that several of her family members were affected by the disease, including her grandfather, father, two sisters, and several nieces and nephews. She related that they all differed in the severity of the disease manifestations. She revealed additional café-au-lait skin lesions on her torso and back.  

The assessment was neurofibroma versus schwannoma likely secondary to undiagnosed neurofibromatosis (type unknown). The plan was surgical excision of the mass with pathology evaluation, which she wished to pursue.

I used a standard dissection technique to excise the mass. Intraoperative findings revealed a well-circumscribed, fusiform yellow fibrous mass within the sural nerve sheath. The mass was free of any soft tissue attachment or adhesions other than a small tubular attachment at the proximal and distal most ends. The sural nerve was intact without any other notable pathology. There were no other identifiable changes to the surrounding soft tissue structures. After excising the mass in toto, I sent it to pathology for evaluation.
The patient had an unremarkable postoperative course and returned to full activity without restriction. She returned to our clinic for follow-up at one-month post-op with a well-healed surgical incision site at the operative site and improved symptoms with minimal intermittent tingling of the foot in the sural nerve distribution.

What The Pathology Evaluation Revealed

The microscopic description reveals sections containing a well-circumscribed lesion composed of spindle cells. There are two main types of areas and there are areas that are focal and loose with a pale matrix. The cells here have slender, wavy nuclei with occasional large and bizarre cells. Elsewhere in the lesion there is a more vesicular pattern but here the cells again have oval and wavy nuclei with more abundant dense red cytoplasm. Again, occasional bizarre cells are scattered throughout the lesion. Mitotic figures are not visible. Adjacent to this lesion is a section of peripheral nerve.  

Immunohistochemical stains for S100 and CD34 revealed positivity of the CD34 in the loose areas. However, the inner portion failed to show significant staining. The S100 staining was strong throughout. This pattern supports the diagnosis of schwannoma.

We discussed the case extensively with a pathologist regarding the report and final diagnosis due to an overall clinical picture exhibiting classic findings for neurofibromatosis type 1. Neurofibroma would be favored over schwannoma and this was consistent with the MRI report.The pathologist did report that the histopathology was significant for overlapping characteristics of schwannoma and neurofibroma, and that neurofibroma could not be ruled out.

What You Should Know About Neurofibromatosis Type 1

Neurofibromatosis is a rare genetic disorder that causes typically benign tumors of the nerves and growths in other parts of the body.1 Current diagnostic criteria originate from the National Institutes of Health Consensus Development Conference, during which authors proposed diagnostic criteria.2 Systemic manifestations vary widely among affected individuals. The three major types are NF1, NF2 and schwannomatosis.

Neurofibromatosis is an inherited disorder or the product of a gene mutation. It is caused by two separate abnormal genes and may be inherited from parents who have neurofibromatosis or may be the result of a mutation in the sperm or egg cells. Neurofibromatosis is considered an autosomal dominant disorder. The gene for NF1 is located on chromosome 17. The gene for NF2 is located on chromosome 22. Children have a 50 percent chance of inheriting the genes that cause neurofibromatosis if the parent has neurofibromatosis. The type of neurofibromatosis the child inherits will be the same as that of the parent. Therefore, if the parent has NF1, there will be a 50 percent chance the child will have NF1. If the parent has NF2, there will be a 50 percent chance the child will have NF2.

Keys To Treating And Managing Neurofibromatosis Type 1

Pediatricians should screen children with neurofibromatosis type 1 for any of the aforementioned clinical manifestations, especially with a family history of the disease. Document and investigate any unusual growth patterns, physical findings, or sexual development. Order blood tests or X-ray imaging if there are any concerns. Healthy children with neurofibromatosis type 1 usually have annual or biannual exams. Adults with neurofibromatosis type 1 who are otherwise generally healthy usually have annual examinations.

There is no known treatment or cure for neurofibromatosis and no known effective screening strategies. Treating physicians may excise tumors or reduce them with radiation therapy. Early surgery is better as malignant tumors can metastasize. Radiation and chemotherapy are options if cancer occurs. Early detection is the best approach as the condition can cause serious complications and reduce life expectancy. Discuss with patients the risks and benefits of surgery as surgery may cause further injury to nerves and additional neurological problems. A cochlear implant or auditory brainstem implant may help some who have hearing loss. A team of specialists that may be involved in care could include a pediatrician, geneticist, neurologist, dermatologist, eye specialist, orthopedist, oncologist and psychologist. Online support groups are also available.

In Conclusion

It is critical for the podiatric clinician to be able to identify systemic manifestations of the various disease processes in the population and work up these patients appropriately within their scope of practice. This patient presented for the evaluation of a painful mass, which ultimately led to surgical intervention for symptomatic relief but more importantly prompted the cascade of referrals to appropriate providers for formal diagnosis and management of her condition.

Dr. Elebrashi is a third-year resident at Maricopa Medical Center in Phoenix.

Dr. Fishco is a faculty member of the Podiatry Institute and is in private practice in Phoenix. He is a Fellow of the American College of Foot and Ankle Surgeons.

1.     Huson SM. The neurofibromatoses: differential diagnosis and rare subtypes. In: Ferner RE, Huson SM, Evans DG (eds). Neurofibromatoses in Clinical Practice, First Edition. Springer-Verlag London Limited, 2011, pp. 1-46.
2.     Ferner RE. Neurofibromatosis 1. In: Ferner RE, Huson SM, Evans DG (Eds.) Neurofibromatoses in Clinical Practice, First Edition. Springer-Verlag London Limited, 2011, pp. 1-46.
3.     Friedman JM, Pagon RA, Adam MP, et al. Neurofibromatosis 1. University of Washington, Seattle. 2014. Available at .
4.     National Human Genome Research Institute (NHGRI). Learning about Neurofibromatosis. Available at . Published August 16, 2016.
5.     American Association of Neurological Surgeons. Neurofibromatosis. Available at .
6.     Genetics Home Reference. Neurofibromatosis type 1 and type 2. Available at Published October 5, 2015.  
7.     Perry A, Brat DJ. Practical Surgical Neuropathology: A Diagnostic Approach. Elsevier Health Sciences, Philadelphia, 2010, p. 435.  
8.     Rodrigues LO, Batista PB, Goloni-Bertollo EM, et al. Neurofibromatoses: Part 1 - Diagnosis and differential diagnosis. Arq Neuropsiquiatr. 2014; 72(3):241-50.

Dermatology Diagnosis
By Yehia Elebrashi, DPM, and William Fishco, DPM, FACFAS
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