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Cutaneous nerve hypertrophy
Pathology (1998), 30, pp. 422--424
CUTANEOUS NERVE HYPERTROPHY GRAHAM
H.
MASON*, TIM E. PITTt AND ERIC TA yt
Dorevitch Pathology* and Plastic and Reconstructive Surgery Service, Maroondahlt, Melbourne, Victoria, Australia
Summary We present a case of cutaneous nerve hypertrophy possibly secondary to scratching or other trauma. The patient was symptomatic and sought surgical treatment, despite no clinical lesion being evident. This type of change has not been previously reported in this clinical setting. There was no clinical evidence of multiple endocrine neoplasia-type 2b (MEN-2b). Awareness of this entity may avoid unnecessary surgery. Key words: Cutaneous nerve hypertropy, MEN-2b. Abbreviations: MEN-2b, multiple endocrine neoplasia-type 2b.
Accepted 28 May 1998
INTRODUCTION Nerve hypertrophy, also tenned 'dennal hypemeury'\ may be a cutaneous manifestation in multiple endocrine neoplasia-type 2b (MEN-2b)2 and may be seen in association with linear pigmentation of the trunk 3 . We report a case of cutaneous nerve hypertrophy in which there were severe symptoms of radiating pain, no clinical lesion and no associated conditions. CASE REPORT A 64 yr old Caucasian woman, previously well, presented with a painful, pruritic, ill-defined area of skin on the right upper medial back below the level of the scapula. It had been pruritic for 4 mo and painful for 2 moo The pain radiated down her right upper arm. There was no past history of note. There was no macroscopic lesion clinically and a 3 mm punch biopsy was taken from the most tender region. As this was reported as a plexiform neurofibroma, an initial excision was undertaken by a plastic surgeon. At operation the skin and subcutaneous tissue appeared normal. A second excision was done 2 wks later because of continuing symptoms and 'incomplete excision' of changes noted on the first excision specimen. Frozen sections were cut and, although nerve hypertrophy was still seen at peripheral resection lines, management was decided to be conservative and no further excision of the area was undertaken. Post-operative review of the patient showed that her symptoms were settling and were confined to the area over the scar. Twelve mo later the patient is well with only a slightly tender scar.
Fig. 1 Skin showing large nerve trunks with perineural thickening (H&E, original magnification X 13.2).
Initially a 3 mm punch biopsy was done followed by an excision of skin measuring 35 X 12 X 14 mm. There was a second skin excision undertaken, measuring 94 X 34 X 10 mm, with frozen section control. Histological findings Within the upper dennis of the initial 3 mm punch biopsy there were large tortuous nerve trunks with a thickened perineurium and associated mucin deposition (Fig. 1). These features were originally misinterpreted as suggestive of a plexiform neurofibroma within the dermis. In the first excision specimen the features were similar to those seen in the punch biopsy, although there was less perineural thickening. The hypertrophied nerves present (Fig. 2) were noted throughout papillary and reticular dermis, confinned with an SlOO stain, and extended to peripheral resection lines. The second excision specimen also showed hypertrophy of dennal nerves, although the degree of change was less at peripheral resection lines than in the centre of the specimen. In none of the specimens was there change of lichen simplex chronicus, the usual reaction pattern seen in skin secondary to chronic rubbing.
MATERIALS AND METHODS H&E staining was performed on fonnalin-fixed paraffin wax-embedded sections 4 p, thick. Immunohistochemical stain for S100 (Dako 1: 1000) was performed using the labelled streptavidin-biotin method on tissue sections of similar thickness.
PATHOLOGICAL FINDINGS Gross appearance The skin in all instances appeared macroscopically nonnal.
DISCUSSION At the time of the second resection it was appreciated that nerve hypertrophy may be a cutaneous manifestation of MEN-2b 2 . However there was no family history of medullary carcinoma of the thyroid or pheochromocytoma, and the patient had no clinical features to suggest multiple endocrine neoplasia syndrome. Genetic testing for gene carriage or calcitonin estimation were not however done.
0031-3025198/040422-03 © 1998 Royal College of Pathologists of Australasia
CUTANEOUS NERVE HYPERTROPHY
Fig. 2 Skin with an abnormally enlarged nerve in the upper dermis (H&E, original magnification X 33).
Slides were reviewed by experts in neuropathology and dermatopathology. Although there were tumor-like areas, the overall consensus was that this represented fascicular nerve hypertrophy. In some enlarged nerves there was a neuromatous internal architecture and some nerves showed perineural fibrosis and mild chronic inflammation. Nerve hypertrophy within skin has been described in association with linear erythema and subsequent linear pigmentation on the trunk3 • This patient had a Marfanoid habitus and it was wondered if it was a forme fruste of MEN-2b, but without the endocrine tumors. In one instance reported4, linear erythema followed local trauma, so-called factitial dermatitis-eao Gio. However there was no histology described in that case report. Hypertrophied cutaneous nerves have also been described in prurigo nodularis, an exaggerated form of lichen simplex chroni-
cuss.
The histological differential diagnosis of cutaneous nerve hypertrophy, in addition to the above, also includes plexiform neurofibroma, plexiform schwannoma, traumatic neuroma, the plexiform variant of palisaded encapsulated neuroma and perineuroma. In plexiform neurofibroma there is irregular cylindrical or fusiform enlargement of a subcutaneous or deep nerve; they rarely arise in the dermis. There are numerous large nerve fascicles embedded in a cellular matrix and contain-
423
ing abundant mucin as well as collagen, fibroblasts and Schwann cells. Initially this proliferation of nerve fibres is confined within the epineurium of the involved nerve6• Plexiform schwannoma (plexiform neurilemmoma) shows circumscribed dermal nodules of Schwann cells with in areas, pallisading of nuclei and Verocay bodies. Antoni B type tissue, with more widely separated Schwann cells in a myxoid stroma, may also be presene. Solitary plexiform schwannomas, not associated with neurofibromatosis 7 , and agminate forms are described8 . In traumatic neuroma (acquired neuroma), which usually presents as a firm papule or nodule, interlacing fascicles of regenerating nerve fibres extend from the proximal end of a damaged nerve through an acquired defect in the perineurium 9 , into surrounding scar tissue. There may be concentric condensations of fibrous tissue around individual fascicles, giving the appearance of multiple separate nerves 10. The plexiform variant of palisaded encapsulated neuroma (solitary neuroma) also needs to be considered in the differential diagnosis. In addition to the plexiform growth pattern in the dermis, it shows fascicles of various sizes, frequently separated by clefts and composed of elongated cells containing spindied nuclei with tapered ends 11 . Perineurioma as a cause of localised hypertrophic neuropathy is described, but the histological changes of perineurioma are quite different. There are enlarged nerve fascicles divided by increased perineural connective tissue, with the abnormal fascicles composed of onion-bulb whorls. The latter are formed by concentric layers of cells 12. Subsequently one of us (GHM) has seen two cases of similar cutaneous nerve hypertrophy in re-excisions of malignant melanomas, where the nerve hypertrophy was some distance from the central scar. This feature could possibly be attributed to local trauma related to pruritus. In summary, cutaneous nerve hypertrophy in this clinical setting is likely to be an uncommon reaction to secondary scratching or other trauma. Awareness of this entity is important so as to avoid unnecessary surgery. ACKNOWLEDGEMENTS The authors offer their special thanks to Prof Z. Argenyi, University of Iowa, USA, Dr R. Kalnins, Austin and Repatriation Medical Centre, Austin Campus, Melbourne, Victoria, and Dr D. Weedon, Sullivan and Nicolaides Laboratory, Southport, Queensland, for assistance with the histological interpretation. Address for correspondence: G.H.M .. Dorevitch Pathology, 582 Heidelberg Rd, Fairfield, Vie 3078, Australia.
References
1. Weedon D. Skin Pathology. Edinburgh: Churchill Livingstone, 1997; 805. 2. Winkelman RK, Carney JA. Cutaneous neuropathology in multiple endocrine neoplasia, Type 2b, J Invest Dermatol 1982; 79: 307-12. 3. Guillet G, Gauthier Y, Tamisier JM, Geiaux M, Leroy JP, Texier L, Surleve-Bazeille JE. Linear cutaneous neuromas (dermatoneurie en stries): a limited phakomatosis with striated pigmentation corresponding to cutaneous hyperneury (featuring multiple endocrine neoplasia syndrome?). J Cutan Pathol 1986; 14: 43-8. 4. Silfen E, Wyre HW. Factitial dermatitis-Cao Gio. Cutis 1981; 28: 399-400. 5. Weedon D. Skin Pathology. Churchill Livingstone, Edinburgh, 1997; 638.
424
MASON
el
al.
6. Weedon D. Skin Pathology. Edinburgh: Churchill Livingstone, 1997; 808. 7. Kao OF, Laskin WB, Olson TO. Solitary cutaneous plexiform neurilemmoma (schwannoma). J Cutan Palhol 1988; 15: 318 (abstract). 8. Berger TO, Lapins NA, Engel ML. Agminated neurilemmomas. JAm Acad Dermatol 1987; 17: 891--4. 9. Reed R, Argenyi Z. Lever's Histopi;uhology of the Skin, 8th ed. Philadelphia: Lippincott-Raven, 1997; 997.
Pathology (1998), 30, November 10. Weedon D. Skin Pathology. Edinburgh: Churchill Livingstone, 1997; 804. 11. Argenyi Z, Cooper P, Santa Cruz D. Plexiform and other unusual variants of palisaded encapsulated neuroma. ] Cutan Pathol 1993; 20: 34-9. 12. Mitsumoto H, Wilbourn AJ, Ooren H. Perineurioma as the cause of localised hypertrophic neuropathy. Muscle Nerve 1980; 3: 403.
CUTANEOUS NERVE HYPERTROPHY GRAHAM
H.
MASON*, TIM E. PITTt AND ERIC TA yt
Dorevitch Pathology* and Plastic and Reconstructive Surgery Service, Maroondahlt, Melbourne, Victoria, Australia
Summary We present a case of cutaneous nerve hypertrophy possibly secondary to scratching or other trauma. The patient was symptomatic and sought surgical treatment, despite no clinical lesion being evident. This type of change has not been previously reported in this clinical setting. There was no clinical evidence of multiple endocrine neoplasia-type 2b (MEN-2b). Awareness of this entity may avoid unnecessary surgery. Key words: Cutaneous nerve hypertropy, MEN-2b. Abbreviations: MEN-2b, multiple endocrine neoplasia-type 2b.
Accepted 28 May 1998
INTRODUCTION Nerve hypertrophy, also tenned 'dennal hypemeury'\ may be a cutaneous manifestation in multiple endocrine neoplasia-type 2b (MEN-2b)2 and may be seen in association with linear pigmentation of the trunk 3 . We report a case of cutaneous nerve hypertrophy in which there were severe symptoms of radiating pain, no clinical lesion and no associated conditions. CASE REPORT A 64 yr old Caucasian woman, previously well, presented with a painful, pruritic, ill-defined area of skin on the right upper medial back below the level of the scapula. It had been pruritic for 4 mo and painful for 2 moo The pain radiated down her right upper arm. There was no past history of note. There was no macroscopic lesion clinically and a 3 mm punch biopsy was taken from the most tender region. As this was reported as a plexiform neurofibroma, an initial excision was undertaken by a plastic surgeon. At operation the skin and subcutaneous tissue appeared normal. A second excision was done 2 wks later because of continuing symptoms and 'incomplete excision' of changes noted on the first excision specimen. Frozen sections were cut and, although nerve hypertrophy was still seen at peripheral resection lines, management was decided to be conservative and no further excision of the area was undertaken. Post-operative review of the patient showed that her symptoms were settling and were confined to the area over the scar. Twelve mo later the patient is well with only a slightly tender scar.
Fig. 1 Skin showing large nerve trunks with perineural thickening (H&E, original magnification X 13.2).
Initially a 3 mm punch biopsy was done followed by an excision of skin measuring 35 X 12 X 14 mm. There was a second skin excision undertaken, measuring 94 X 34 X 10 mm, with frozen section control. Histological findings Within the upper dennis of the initial 3 mm punch biopsy there were large tortuous nerve trunks with a thickened perineurium and associated mucin deposition (Fig. 1). These features were originally misinterpreted as suggestive of a plexiform neurofibroma within the dermis. In the first excision specimen the features were similar to those seen in the punch biopsy, although there was less perineural thickening. The hypertrophied nerves present (Fig. 2) were noted throughout papillary and reticular dermis, confinned with an SlOO stain, and extended to peripheral resection lines. The second excision specimen also showed hypertrophy of dennal nerves, although the degree of change was less at peripheral resection lines than in the centre of the specimen. In none of the specimens was there change of lichen simplex chronicus, the usual reaction pattern seen in skin secondary to chronic rubbing.
MATERIALS AND METHODS H&E staining was performed on fonnalin-fixed paraffin wax-embedded sections 4 p, thick. Immunohistochemical stain for S100 (Dako 1: 1000) was performed using the labelled streptavidin-biotin method on tissue sections of similar thickness.
PATHOLOGICAL FINDINGS Gross appearance The skin in all instances appeared macroscopically nonnal.
DISCUSSION At the time of the second resection it was appreciated that nerve hypertrophy may be a cutaneous manifestation of MEN-2b 2 . However there was no family history of medullary carcinoma of the thyroid or pheochromocytoma, and the patient had no clinical features to suggest multiple endocrine neoplasia syndrome. Genetic testing for gene carriage or calcitonin estimation were not however done.
0031-3025198/040422-03 © 1998 Royal College of Pathologists of Australasia
CUTANEOUS NERVE HYPERTROPHY
Fig. 2 Skin with an abnormally enlarged nerve in the upper dermis (H&E, original magnification X 33).
Slides were reviewed by experts in neuropathology and dermatopathology. Although there were tumor-like areas, the overall consensus was that this represented fascicular nerve hypertrophy. In some enlarged nerves there was a neuromatous internal architecture and some nerves showed perineural fibrosis and mild chronic inflammation. Nerve hypertrophy within skin has been described in association with linear erythema and subsequent linear pigmentation on the trunk3 • This patient had a Marfanoid habitus and it was wondered if it was a forme fruste of MEN-2b, but without the endocrine tumors. In one instance reported4, linear erythema followed local trauma, so-called factitial dermatitis-eao Gio. However there was no histology described in that case report. Hypertrophied cutaneous nerves have also been described in prurigo nodularis, an exaggerated form of lichen simplex chroni-
cuss.
The histological differential diagnosis of cutaneous nerve hypertrophy, in addition to the above, also includes plexiform neurofibroma, plexiform schwannoma, traumatic neuroma, the plexiform variant of palisaded encapsulated neuroma and perineuroma. In plexiform neurofibroma there is irregular cylindrical or fusiform enlargement of a subcutaneous or deep nerve; they rarely arise in the dermis. There are numerous large nerve fascicles embedded in a cellular matrix and contain-
423
ing abundant mucin as well as collagen, fibroblasts and Schwann cells. Initially this proliferation of nerve fibres is confined within the epineurium of the involved nerve6• Plexiform schwannoma (plexiform neurilemmoma) shows circumscribed dermal nodules of Schwann cells with in areas, pallisading of nuclei and Verocay bodies. Antoni B type tissue, with more widely separated Schwann cells in a myxoid stroma, may also be presene. Solitary plexiform schwannomas, not associated with neurofibromatosis 7 , and agminate forms are described8 . In traumatic neuroma (acquired neuroma), which usually presents as a firm papule or nodule, interlacing fascicles of regenerating nerve fibres extend from the proximal end of a damaged nerve through an acquired defect in the perineurium 9 , into surrounding scar tissue. There may be concentric condensations of fibrous tissue around individual fascicles, giving the appearance of multiple separate nerves 10. The plexiform variant of palisaded encapsulated neuroma (solitary neuroma) also needs to be considered in the differential diagnosis. In addition to the plexiform growth pattern in the dermis, it shows fascicles of various sizes, frequently separated by clefts and composed of elongated cells containing spindied nuclei with tapered ends 11 . Perineurioma as a cause of localised hypertrophic neuropathy is described, but the histological changes of perineurioma are quite different. There are enlarged nerve fascicles divided by increased perineural connective tissue, with the abnormal fascicles composed of onion-bulb whorls. The latter are formed by concentric layers of cells 12. Subsequently one of us (GHM) has seen two cases of similar cutaneous nerve hypertrophy in re-excisions of malignant melanomas, where the nerve hypertrophy was some distance from the central scar. This feature could possibly be attributed to local trauma related to pruritus. In summary, cutaneous nerve hypertrophy in this clinical setting is likely to be an uncommon reaction to secondary scratching or other trauma. Awareness of this entity is important so as to avoid unnecessary surgery. ACKNOWLEDGEMENTS The authors offer their special thanks to Prof Z. Argenyi, University of Iowa, USA, Dr R. Kalnins, Austin and Repatriation Medical Centre, Austin Campus, Melbourne, Victoria, and Dr D. Weedon, Sullivan and Nicolaides Laboratory, Southport, Queensland, for assistance with the histological interpretation. Address for correspondence: G.H.M .. Dorevitch Pathology, 582 Heidelberg Rd, Fairfield, Vie 3078, Australia.
References
1. Weedon D. Skin Pathology. Edinburgh: Churchill Livingstone, 1997; 805. 2. Winkelman RK, Carney JA. Cutaneous neuropathology in multiple endocrine neoplasia, Type 2b, J Invest Dermatol 1982; 79: 307-12. 3. Guillet G, Gauthier Y, Tamisier JM, Geiaux M, Leroy JP, Texier L, Surleve-Bazeille JE. Linear cutaneous neuromas (dermatoneurie en stries): a limited phakomatosis with striated pigmentation corresponding to cutaneous hyperneury (featuring multiple endocrine neoplasia syndrome?). J Cutan Pathol 1986; 14: 43-8. 4. Silfen E, Wyre HW. Factitial dermatitis-Cao Gio. Cutis 1981; 28: 399-400. 5. Weedon D. Skin Pathology. Churchill Livingstone, Edinburgh, 1997; 638.
424
MASON
el
al.
6. Weedon D. Skin Pathology. Edinburgh: Churchill Livingstone, 1997; 808. 7. Kao OF, Laskin WB, Olson TO. Solitary cutaneous plexiform neurilemmoma (schwannoma). J Cutan Palhol 1988; 15: 318 (abstract). 8. Berger TO, Lapins NA, Engel ML. Agminated neurilemmomas. JAm Acad Dermatol 1987; 17: 891--4. 9. Reed R, Argenyi Z. Lever's Histopi;uhology of the Skin, 8th ed. Philadelphia: Lippincott-Raven, 1997; 997.
Pathology (1998), 30, November 10. Weedon D. Skin Pathology. Edinburgh: Churchill Livingstone, 1997; 804. 11. Argenyi Z, Cooper P, Santa Cruz D. Plexiform and other unusual variants of palisaded encapsulated neuroma. ] Cutan Pathol 1993; 20: 34-9. 12. Mitsumoto H, Wilbourn AJ, Ooren H. Perineurioma as the cause of localised hypertrophic neuropathy. Muscle Nerve 1980; 3: 403.