Abstract
Neurofibromatosis type 1 (NF1) is an autosomal-dominant inherited disease affecting various parts of the body. Penetrance is almost complete but the phenotype varies considerably. Recently, mosaicism in NF1 has come into the focus of scientific interest. This report refers to a patient with orbitotemporal-confined neurofibromatosis who developed a rare skin tumor in the region.
- Neurofibromatosis
- NF1
- plexiform neurofibroma
- sphenoid wing dysplasia
- dermal cylindroma
- mosaicism
- rare tumor
Neurofibromatosis type 1 (NF1) is an autosomal-dominant inherited disease affecting about 1 in 2,700 individuals at birth (1). The gene product, called neurofibromin, acts as a tumor suppressor (2). The hallmark of disease are neurofibroma, i.e. benign peripheral nerve sheath tumors (3). These tumors preferentially develop in the integument (3). Other skin dysplasias, in particular pigmentation disorders, also proved to be characteristic for NF1 (4). However, NF1 is a multi-organ syndrome that relates to more than just the skin (5). Sphenoid wing dysplasia is a defining feature of neurofibromatosis type 1 (NF1) belonging to the large group of osseous findings in this disease (4). In the orbital region, several findings can be recorded constituting NF1 diagnosis, e.g. bone dysplasia, neurofibroma, optic nerve glioma and distinct lesions of the eye (6).
Cylindroma, a benign tumor affecting the skin (7), is thus far not a finding reported in NF1. This case report is about an individual affected by NF1-characteristic lesions predominantly confined to the skull, who developed a cylindroma, with special reference to applying diagnostic criteria for NF1.
Case Report
Medical history. A 57-year old woman was known as a patient in the Department of Oral and Craniomaxillofacial Surgery at the Eppendorf University Hospital, since her early childhood.
She was born with asymmetrically-appearing orbits associated with exophthalmos and soft tissue surplus of the orbital content on the right side. Soon after birth, the child developed ocular protrusion and depression of the affected eye. At the age of two years a craniotomy had been performed in the Department of Neurosurgery (UKE) because a retrobulbar tumor was suspected. However, intraoperatively no evidence of tumor growth could be found at this site. Medical reports were not informative about the biopsy of the situs at that time. Medical reports of the 12 year-old girl noted a right-sided pulsating exophthalmos, extremely depressed right eye and only one Café-au-lait (CAL) spot on the left abdominal skin.
At the age of 20 years, polymethylmethacrylate (Palavit®, Heraeus-Kulzer, Hanau, Germany) was formed as an individual implant in order to elevate the depressed eye. Obviously, this procedure took into account the enlarged orbit typically associated with plexiform neurofibroma of the orbit (8). Initially, the procedure appeared to function as a replacement for the missing bone level, but 4 weeks after insertion the patient developed an orbital abscess that forced explantation of the implant. Prior to this intervention, only mild abducens nerve paresis was recorded.
One year later, a rib transplant was chosen to restore the orbital floor in appropriate vertical dimension. This procedure proved to be successful. However, diplopia required for temporary coverage and repeated orthoptic interventions during the next years.
At the age of 23 years, tumor debulking was performed to reduce pressure on the displaced globe. Intraoperatively, neurofibroma was excised that adhered laterally and cranially to the globe. The rectus muscle appeared hypoplastic. The levator muscle was completely mixed with neurofibroma. This muscle was sub-totally resected and fixed to the frontal aponeurosis in a w-like fashion. Healing was uneventful, but correction of the stay sutures to raise the upper lid was necessary 6 month later.
At the age of 25 years, the patient underwent further orbital and eyelid surgery to reduce proptosis, relief from repeated progressive ptosis and elevate the eyeball. An orbitotomy was performed and the orbit was rotated from the medio-caudal malposition to a latero-cranial position (Figure 1D). Furthermore, lid-elevation via the permanent sutures was aligned with the eyelid fissure.
The patient was lost to follow-up during the next 9 years. At the age of 33 years, neurological investigation documented amblyopia of the affected eye combined with paralysis of the abducens nerve and advanced paresis of oculomotorius nerve. The patient showed neither a sufficient number of CAL spots nor any Lisch nodule. However, two cardinal findings to establish NF1 diagnosis were already known: sphenoid wing dysplasia and plexiform neurofibroma. Both findings were strictly unilateral, i.e. confined to the right orbit and lid. At that time, a segmental neurofibromatosis was brought into discussion regarding the appropriate diagnosis in this case.
At the age of 41 years, the enucleation of the blind, proptotic eye was performed and the patient was supplied with a prosthesis. Three years later, re-growth of tumor impaired retention of prosthesis. Tumor debulking was performed creating new space for the eye prosthesis (Figure 1A and B). The tumor proved to be a diffuse neurofibroma, WHO grade I (Figure 3B), together with scar tissue including scar neuromas. The next attendance to our outpatient clinic was her current visit to clarify a neoplasm of her scalp (Figure 2A).
Physical findings. Upon admission, the 57-year-old female patient was in good general condition. She wore an eye patch to cover her unsightly right orbital region. She complained about a tumor that had developed during the last months in the skin of her skullcap. She disclosed the tumor region from covering hair and a mushroom-like tumor was exposed on the right paramedian parietal region. The skin covering the tumor did not contain visible hair, showed intact integument without signs of inflammation, distinct borders and regular skin perfusion. On palpation, the tumor was firm and could not be moved on the underlay. Physical investigation could not clarify the differential diagnosis of peripheral nerve sheath tumor and other tumors of the integument.
The right orbital region of the face was enlarged due to soft tissue tumor palpable in the whole region. The circular margins of the palpable diffuse neurofibroma exceeded slightly the orbit border. The eye was replaced by a prosthesis that fairly fit into the orbit cavity. However, she could not move the ipsilateral eye lids. The excretory function of the lachrymal gland was ineffective to moisten the prosthesis' surface due to locally invasive growth of the repeatedly resected plexiform neurofibroma and probably also as a consequence of tumor surgery. A distinct pulsating exophthalmos was noted indicating sphenoid wing dysplasia. CAL spots were absent all over her skin except for one abdominal spot. No axillary or inguinal freckling was noted. The left eye showed no iris hamartoma. Clinical findings revealed two major criteria for diagnosing NF1, but strictly locally confined findings supported the former assumption of segmental distribution of the disease. The patient's family history showed no evidence of NF1-affected ancestors. The patient had no children. The patient showed a reduced vision of the left eye (0.2 to 0.4) not explainable by refraction, photorefractive media or fundus findings (Department of ophthalmology, UKE).
Radiology. Magnetic resonance imaging (MRI) and computed tomography studies performed during the last 11 years confirmed the congenital dysplasia of right orbital roof with herniation of temporal lobe into the orbit that explain the ipsilateral pulsating exophthalmos (Figure 1C). The well-known right fronto-basal gliosis zone showed no alteration of size comparing present findings with MRI taken at the age of 50 and 54 years. MRI reveals soft tissue contrast enhancement of the former retrobulbar region (about 4.4×1.0×0.8 cm3) in size. This lesion borders to the right cavernosus sinus. Currently, there is no evidence for focal areas of signal intensity. The previously described bilateral leukoencephalopathy has not changed during the last 4 years. MRI shows a small exophytic tumor of right paramedian fronto-parietal region. The skull is not affected in the region of the exophytic tumor of the skullcap.
Treatment. In local anesthesia, the tumor was completely excised and the defect was covered by primary intention. Healing was uneventful.
Histology. Initial diagnosis was basal cell carcinoma. However, careful investigation of the specimen disclosed irregularly puzzle-like associated basaloid cell islands surrounded by wide hyalinized membranes with focal tubular structures indicative of dermal cylindroma (Figure 3A).
Mutation analysis. NF1 mutation analysis in the patient's blood was performed by exon scanning and revealed no genetic alteration.
Discussion
The present report describes the coincidence of a solitary and rare tumor of the skin appendages in a patient with a hereditary disorder with preferred infestation of the skin by nerve sheath tumors. However, the close relation of both findings to branches of the trigeminal nerve, in particular the supraorbital nerve, is striking. With respect to orbital tumor treatment, the long-lasting history of the patient represents the typical course of the disease with orbito-temporal plexiform neurofibroma in NF1 (9).
(A) and (B): Details of photos of the patient at the time of plexiform neurofibroma reduction (2003) (A: en face, B: in profile). (C): Detail of axial magnetic resonance imaging showing the deformed orbit without globe and hyperechoic space occupying masses filling-up the deformed right orbit. (D): Plain radiograph of the patient's orbital region shows the enlarged empty orbit and osteosynthesis plates and screws typical for the time of surgery (1982), cropped image.
(A): Closed-up photograph of the exophytic scalp tumor that proved to be a cylindroma. (B): Photograph of the excised scalp tumor after transection in the tumor center. (C): Cropped image of scalp tumor depicted on coronal section of magnetic resonance imaging.
Histology of cylindroma (2015) and plexiform neurofibroma (2003). (A) Cylindroma: circumscribed dermal tumor composed of irregularly shaped islets of basaloid cells surrounded by broad hyaline membranes (red), Periodic acid–Schiff. (B): Plexiform-diffuse neurofibroma: tumor composed of elongated cells with wavy contours and collagen fibres partly growing within the perineurium of a nerve fascicle (large arrow), partly invading neighbouring fat- and muscle tissue (short arrows), haematoxylin and eosin; scale bars=100 μm.
Dermal cylindroma. Dermal cylindroma is a rare benign tumor of the skin appendages. The tumor shows preference for manifestation in the head and neck region (7). The tumor is well-known as a sporadic finding, predominantly as a solitary lesion in women of medium to higher ages. Much rarer are cylindromas as part of a family clustering of affected individuals. In the latter type autosomal-dominant inherence is known and the tumors may develop early in life and in multiple regions (10). Cylindromas are usually small lesions but occasionally a confluent lesion of enormous size can appear in the scalp and adjacent skin, the so-called turban tumor (11). The well-differentiated tumor is composed of both apocrine and eccrine glands. Probably, the tumor arises from primitive antecessors of sweat glands with pluripotent differentiation. However, recent findings point to the human hair bulge as the origin of cylindroma development (12).
In some cases the cylindroma occurs in association with further tumors derived from skin appendages, e.g. spiradenoma or trichoepithelioma, allowing diagnosis of Brooke-Spiegler syndrome (11, 13). Malignant transformation of cylindroma is exceptionally rare but well-documented (14, 15). Calvarial defects do not necessarily imply malignant transformation of cylindroma (11, 16). However, follow-on requirements for resection procedure allow for complete excision of the neoplasm and minimizes the risk for local recurrence and bone invasion (17). Genetic analysis has revealed mutations of the CYLD gene locus (chromosome 16q12-q13) both in sporadic and inherent type of cylindroma (10). Clinical differential diagnosis may be difficult in cases with disseminated cutaneous cylindromas simulating neurofibromatosis (18, 19).
The macroscopic appearance of cylindroma is a firm gummy knot measuring a few millimeters up to some centimeters in diameter. Colour of the exophytic tumor is pink to red and occasionally bluish. The microscopic appearance is a dermal tumor with no direct contact to the epidermis. The tumor is composed of multiple nests of adenoid cells. Theses nests are encased by prominent hyaline membranes predominantly composed of collagen IV-containing extracelluar matrix. This predominant feature resembles the microscopic aspect of basal membranes. The cell cluster shows a characteristic structure: Basophil palisade-like organized cells are localized peripherally in these tumor cell clusters whereas centrally located are cells with pale cytoplasm. Both inside and outside the tumor cell clusters small tubular lumina are distinguished that define the name of the tumor. Malignant cylindroma show cellular and nuclear polymorphous features not found in the essentially benign tumors (20).
Therapy of choice is local excision with safety margins. Small cylindroma can be eradicated with carbon dioxide laser (21). Multiple cylindroma may require for extensive plastic surgical multi-step procedures (7, 11).
Prognosis differs with respect to sporadic or inherited type of disease (20). A rare complication of cylindroma is tumorous erosion of calvaria (11) and growth of tumor inside the cranial cavity (16). An adequate resection technique allows the prognosis of tumor-free follow-up (17).
Segmental type of NF1. NF1 is an autosomal-dominantly transmitted genetic disease with a high rate of spontaneous mutations, calculated to be about 50% (4). The locus of the NF1 gene is chromosome 17q11.2 (22). NF1 shows a plethora of symptoms and findings that have complicated a unifying classification over many years. Early phenotype-related classifications also paid attention to the probably rare, but repeated observation on patients who showed typical combinations of findings diagnostic for NF1 strictly restricted to a certain part of the body. This constellation was termed segmental neurofibromatosis. Later on, Riccardi classified neurofibromatosis sub-types according to clinical findings. Within his classification the segmental phenotype was termed NF type V (23). Nowadays NF1 restricted to a compartment of the body should be addressed as mosaic NF1 (24-28). Nevertheless, the term ‘segmental’ neurofibro-matosis is informative in many medical disciplines to adequately describe this condition, in particular in the field of surgery (29). Indeed, at present, surgical therapy for plexiform neurofibroma does not have to consider whether the individual is localized or generalized affected by the NF1 mutation. However, it should be emphasized that ‘mosaicism’ of a genetic disease is not equivalent to ‘segmental’, given the well-known restriction of NF1 mutations to a sub-group of cells with a distribution within the body not restricted to an anatomically-defined region. Indeed, mosaic NF1 is estimated to be a common condition (30). Early estimates of prevalence were 0.006% in France (31) to 0.0018% in Italy (32). The approximate prevalence of mosaic NF1 is calculated to 10% of all NF1 patients, but is probably underestimated due to individuals not diagnosed as having this sub-type of disease (29). Currently, prevalence is calculated 1: 36.000-40.000 individuals (0.0006–0.0027%), as derived from published reports (28).
Many reports on mosaic NF1 lack genetic testing (28). With respect to clinically-based data on mosaic NF1 phenotypes, the localization of the plexiform neurofibroma to the orbital region appears to be exceptionally rare. Ruggieri et al. (33) identified in their study on ophthalmological manifestations in patients with segmental NF1 only 3 individuals with scalp temporal/orbital PNF and explicitly noted that the tumors were ‘sparing the skull bone including the orbit’ (33). Tanito et al. (34) detailed bone deformities in 3 out of 58 patients of their study on mosaic neurofibromatosis type 1 but did not report on topographical data. All PNF were unilateral and all bone deformities were associated with PNF. Lisch nodules were rarely diagnosed in this study (34). Listernick et al. (30) analyzed 23 patients with segmental NF1 and noted one patient with sphenoid dysplasia and PNF of the upper eyelid. This patient had also Lisch nodules in the eye ipsilateral to the PNF (30). Unilateral Lisch nodules may precede the diagnosis of segmental NF1 in rare cases (35). Montard et al. described a further case with orbitotemporal PNF (36). These authors assumed segmental NF1 occurring in their patient due to localized growth of the nerve sheath tumor.
Conclusion
Coincidence of cylindroma and mosaic NF1 in the same dermatome have not yet been described. It is likely that both genetic events developed independently. Future studies on NF1 should pay attention to associated skin tumors in NF1-affected individuals.
- Received September 16, 2015.
- Revision received October 7, 2015.
- Accepted October 21, 2015.
- Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
