Clinical and Experimental Dermatology 1991; 16: 287-291.
ADONIS 0307693691000577
Necrobiosis lipoidica and sarcoidosis K.GUDMUNDSEN, O.SMITH, P.DERVAN* AND F.C.POWELL Regional Centre of Dermatology and * Department of Pathology, Mater Misericordiae Hospital, Dublin 7, Ireland Accepted for publication \^ January 1991
her right shin about one year before presentation to us. The dyspnoea on exertion had been present for several We report the ease of a female patient with necrobiosis years, as had nocturnal wheeze and a productive cough in lipoidica of the lower legs and coexistent systemic and the morning. She had a previous history of tuberculosis cutaneous sarcoidosis. We review the six previously and had smoked 10-20 cigarettes a day for 30 years. reported patients with coexisting necrobiosis lipoidica There was no persona! or family history of diabetes and sarcoidosis. The associations between the granulo- mellitus. matous disorders of the skin, especially necrobiosis On examination, she had two clinically distinct types of lipoidica, sarcoidosis and granuloma annulare, are disskin lesions. In and about an old Caesarean-section scar cussed. The common pathogenetic features of these on her lower abdomen there were multiple, brownish, disorders are reviewed. slightly scaly dome-shaped papules (Fig. la). On her left shin there was a large patch with a central area of atrophic yellowish skin with prominent blood vessels and a dusky To our knowledge, the coexistence of necrobiosis lipoi- red border (Fig. lb). There was a similar but smaller dica diabeticorum (NLD) and sarcoidosis in the same lesion on her right shin. patient has been reported in only six patients to date'"** The clinical diagnoses of papular (scar) sarcoid and (Table 1). NLD has also been reported in association with necrobiosis lipoidica were confirmed histologically (Fig. other granulomatous-necrobiotic diseases, such as gra- 2). Random blood-sugar level, glucose-tolerance test, nuloma annulare (GA) and rheumatoid nodules. Sarcoi- serum calcium, ESR and angiotensin-converting-enzyme dosis has occasionally been found to coexist with GA, as levels were normal. well as with rheumatoid nodules, tuberculosis, Crohn's Investigation of her respiratory symptoms revealed disease and primary biliary cirrhosis. These associations findings consistent with pulmonary sarcoid and COAD. are of interest because they demonstrate the spectrum of Chest X-ray showed mediastinal adenopathy and mild cutaneous granulomatous reactions within the same diffuse interstitial lung disease, scarring of the left apex patient, and suggest that there may be a relationship in and pleuritic thickening of both apices consistent with old the pathogenesis of these diseases, which are distinctive tuberculosis. Pulmonary function tests revealed both a but show clinical and pathological similarities. We report restrictive lung disease (DLCO was 44% of predicted) here a case of a female patient with NLD of the lower legs and obstructive airways disease (FEVl was 53% of and coexistent systemic sarcoidosis with involvement of predicted, and FVC was 62% of predicted). Bronchosthe skin. We also review previously reported cases of copy and bronchio-alveolar lavage were normal. coexisting NLD and sarcoidosis, and discuss the associFor her pulmonary disease she was treated with oral ations between the granulomatous disorders of the skin. prednisone, initially at 40 mg daily reducing gradually over 4 months, and .salbutamol inhaler QID. On this regime her respiratory function improved symptomatiCase Report cally and objectively, and the papular (sarcoid) lesions in A 61-year-old woman presented to the Regional and about her abdominal scar cleared. The necrobiotic Centre of Dermatology at the Mater Hospital, complain- lesions on the lower legs have remained unchanged on ing of skin lesions on her shins and abdomen, and also of follow-up after 2 years. shortness of breath on exertion. She gave a history of having first developed skin lesions 13 years earlier along the scar of a Caesarean section, and on her left shin at Discussion about the same time. A further skin lesion developed on The patient reported here had two skin lesions which Correspondence: Dr F.C. Powell, Mater Hospital, Dublin 7, were clinically and histologically distinct. She had necrobiosis lipoidica diabeticorum (NLD) in the classic site on Ireland. Summary
287
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K.GUDMUNDSEN et al.
Table 1. Reported cases of the coexistence of NLD and sarcoidosis
Site of NLD
Site of cutaneous sarcoidosis
Shin
legs, arms
Legs
cheeks, left car
Sbin
E. nodosum on both shins No details given Lower legs arms Both shins
left arm. forehead, back
Both shins
abdomen (scar)
Evidence for systemic sarcoidosis
Glucose tolerance
age sex (years)
Ref
BHL, pulmonary shadowing. decreasing DLCO iridocyclitis, BHL, Kveim rest positive BHL, Kveim test positive
GTT normal
35 F
Graham-Brown et al.^
GTT normal
42 F
Graham-Brown et al.^
blood glucose normal
61 F
Monk and DuVivier^
BHL, infiltrative changes in lung BHL, infiltrative changes in both lung fields. decreasing DLCO Mediastinal adenopatby, interstitial fibrosis, decreasing DLCO
blood glucose normal
46 F
Savin and Wilkinson'' Brungger"*
GTT normal
48 F
Dodd and Sarkany^
GTT normal
61 F
present case
BHL = bilateral hilar lymphadenopathy; GTT = glucose tolerance test; DLCO^trans-alveoIar diffusion of carbon monoxide.
Figure I. (a) Multiple papules in and around an old Caesarean-section scar, (b) Close-up of tbe plaque of necrobiosis lipoidica on tbe left shin.
the anterior aspect of the lower legs, and papules in an abdominal scar. The demonstration of sarcoidal granulomas in her abdominal-scar lesions drew attention to the possibility of systemic sarcoidosis. The finding in our patient of characteristic radiological and functional lung changes in association with cutaneous sarcoidal granulomas adequately fulfils the requirements for the diagnosis
of systemic sareoidosis. There was no evidence of diabetes mellitus, or impaired glucose tolerance. To our knowledge there have been five previous welldocumented reports of the coexistence of NLD and sarcoidosis in the same patient (Table 1). All of these patients were female, aged between 35 and 61 years. All had NLD on the legs, but the sites and manifestations of
NECROBIOSIS LIPOIDICA AND SARCOIDOSIS
289
Figure 2. (a) Histology of biopsy from abdominal scar, showing well-formed epithelioid granulomas with no degeneration of collagen, consistent with sarcoidosis (H&E x 126). (b) Histology from the lesion on the right shin showing collagen degeneration in the dermis surrounded by a chronic inflammatory-cell infiltrate including giant cells, consistent with necrobiosis lipoidica (H&E x 126).
the cutaneous sareoidosis were variable. In all cases, the cutaneous sarcoid consisted of papules or plaques (and was confirmed histologically by the presence of epithelioid granulomas in the dermis), except for that reported by Monk et al? in which there was a clinical diagnosis of erythema nodosum in association with systemic sarcoidosis. In addition, another case is mentioned by Savin and Wilkinson,' but no details were given. None of the patients reported had diabetes. Whether the coexistence of NLD and sarcoidosis in a patient is a true association or a coincidental occurrence is uncertain. Graham-Brown et al.^ remarked that because NLD and sarcoidosis are both relatively uncommon disorders, their coexistence in the same patients may suggest a pathogenetic relationship. They also note that both sarcoidosis and NLD have each been associated with granuloma annulare (GA), and that to find the remaining link between NLD and sarcoidosis is not unexpected. Monk et al.^ commented on the known associations of sarcoidosis with other granulomatous and necrobiotic diseases, and suggest that the necrobiotic granulomas, which include NLD, GA and rheumatoid nodules, may form a spectrum of similar disorders that overlap clinically and histologically. There is some circumstantial evidence to support a link between the granulomatous-necrobiotic disorders. Sarcoidosis has been reported to occur in the same patient in association with GA,^-^^ rheumatoid nodules,^ rheuma-
toid arthritis,'"" tuberculosis,'^ Crohn's disease" and primary biliary cirrhosis.'''-'' Fagen et al.^'' reported a group of patients with multi-organ granulomas whose features overlapped with those of sarcoidosis, primary biliary cirrhosis, coeliac disease, Sjogren's syndrome and mixed connective tissue disease. It may be difficult to distinguish histologically some cases of the epithelioidnodule type of GA from sarcoidosis.'' NLD has been reported in association with GA,'^"^" and both GA and rheumatoid nodules.^' In addition, 'atypical necrobiosis of the face and scalp' has been reported in association with systemic sarcoidosis.^^'^' The pallisading granulomatous type of NLD can closely resemble GA histologically.^''•^^ Classic NLD and cutaneous lesions of sarcoidosis may be easily differentiated clinically. However, there has been some confusion regarding lesions of the face and scalp, where the differential diagnosis might include NLD, annular sarcoid, GA and 'atypical NLD of the face and scalp'. True NLD at an atypical site, such as the face or scalp, may resemble sarcoidosis,"'' and lesions of the face or scalp in sarcoidosis have been reported as resembling NLD.^-" Classic NLD and sarcoidosis are also usually easily distinguished histologically. NLD consists of areas of necrobiosis of collagen surrounded by pallisading histiocytes in the lower dermis, but there is also a form, called the tuberculoid-type, in which pronounced granuloma-
290
K.GUDMUNDSEN et al.
tous changes may develop.^^ Sarcoidosis is characterized by discrete well-formed epithelioid-cell granulomas; however, in some patients with skin lesions attributed to sarcoidosis necrobiotic changes may develop within the lesions.^'' Therefore, it may sometimes be difficult to distinguish between NLD and sarcoid histologically.^^-^^ Indeed, before the description of NLD as an entity by Oppenheim in 1929,^^ some cases of NLD (and GA) may have been labelled as 'scleroderma-like sarcoid' or 'tuberculosis with sclerodermatous changes.'^"-" Where there are two histological changes present it may be difficult to decide if one process is primary, and the other secondary, or indeed whether there are two different processes occurring. The difficulty is most apparent where sarcoidal changes cannot be established in organs other than the skin, as the diagnosis of sarcoidosis by definition depends on also finding characteristic clinical, radiological or histological evidence of sarcoidosis in the viscera.-^^ It has been appreciated that sarcoidal granulomas do occur, not uncommonly, in the skin in the absence of detectable systemic sarcoidosis, and these are clinically and histologically indistinguishable from those that occur in the skin of patients with systemic disease.-'^'-^ In addition, it is well known that infiltration by sarcoidal granulomas into areas of previously damaged skin, such as scars, can either be localized to the skin or a part of widespread disease.'^^•''^ It is uncertain, at this stage of our understanding of the pathogenesis of sarcoidal granulomas, whether the label of true 'cutaneous sarcoidosis' or 'sarcoidal tissue reaction' suits these lesions best. The pathogenesis of these cutaneous granulomatous reactions has been studied by several authors. Gange et al.^^ showed defective neutrophil migration in vivo into areas of traumatized skin in patients with NLD, sarcoidosis and GA. The cause of this defective neutrophil mobility is unknown in the majority of granulomatous disorders but the possibilities include increased levels of a serum factor that inactivates chemotactic factors, or directly inhibits the mobility or blood-vessel wall adherence of neutrophils.^^ Macrophage migration inhibitory factor (MIF)-like activity has been found in the sera of a significant number of patients with systemic sarcoidosis and of patients with GA.-"" Patients with NLD were also tested and the results were generally negative, although the number of patients involved was small.-"' Umbert and Winkelmann'' speculate that if the MIF-like activity were also present in the interstitial tissue of the skin, then it may contribute to the infiltration of mononuclear cells and the characteristic aggregation of histiocytes and epithelioid cells in lesions of cutaneous sarcoid and GA. Alternatively, both sarcoidosis and GA may be the result of a delayed-type cellular hypersensitivity reaction to an unknown antigen(s). Nodular deposition of fibrin outside the blood vessels in areas of necrobiosis and granulomas has been found in GA and sarcoidosis." Both
the tuberculin test and the mantoux test have occasionally produced typical lesions of GA.-'^ Umbert et al.^'' reported that patients with cutaneous sarcoidosis, and patients with GA, both have positive reactions to the tuberculin test, although patients with systemic sarcoidosis without cutaneous sarcoidosis give negative reactions. Histologically in NLD, well-developed vascular changes, especially endothelial proliferation and thickening of the wall, are found in the lesional skin of the majority of patients."** One theory holds that the dermal vasculopathy, perhaps itself due to an immune-complexmediated vasculitis, precedes and initiates the necrobiotic-granulomatous changes. Similar changes occur in the small blood vessels in NLD^' and GA.^^ It has been hypothesized that these changes may result from the significantly raised plasma levels offibronectin''*'and Factor-VIII-related antigen"^' which have been found in NLD without diabetes, generalized GA without diabetes and also in diabetes itself. In both NLD and GA the deposition of immunoglobulins and complement has been found in the walls of blood vessels,"*^**^ and the necrobiotic areas contain large amounts of fibrin orfibrinogen.^"^'^^Both NLD and some types of GA'*'' are associated with abnormalities of glucose metabolism. Clearly, therefore, there is clinical and histological overlap in the various cutaneous granulomatous disorders. In addition, the investigations cited above point to common serological, immunological and cellular abnormalities that may be found in patients with these disorders. The increasing number of patients reported with distinct coexisting cutaneous granulomas further support the hypothesis that these may represent a spectrum of related disorders. In patients with NLD, the possibility of associated DM is always considered and investigated appropriately. In addition, in view of the above reports, it seems prudent in patients with NLD at any site, to keep the possibility of associated systemic sarcoidosis in mind, and to carry out the appropriate clinical examination and laboratory tests.
References I. Graham-Brown RAC, Shuttleworth D, Sarkany I. Coexistence of sarcoidosis and necrobiosis lipoidica; a report of two cases. Clinical and Experimental Dermatology 1985; 10: 274-278. 2. Monk BE, DuVivier AWP. Necrobiosis lipoidica and sarcoidosis. Clinical and Experimental Dermatology 1987; 12: 294-295. 3. Savin JA, Wilkinson DS. Sarcoidosis. In: Rook A, Wilkinson DS, Ebling FJG, Champion RH, Burton JL, eds. Textbook of Dermatology, 4th edn. Oxford: Blackwell Scientific Publications, 1986: 1755-1986. 4. Brungger A. Hautsarkoidose unter dem Bild einer Necrobiosis lipoidica. Hautarzt 1987; 38: 238-240. 5. Dodd HJ, Sarkany I. Necrobiosis lipoidica and sarcoidosis. British Journal of Dermatology 1988; 33: 117-118.
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6. Umberi P, Winkelmann RK. Granuloma annulare and sarcoido- 27. Mehregan AH, Pinkus H. Necrobiosis lipoidica with sarcoid reaction Archives of Dermatology 1961; 83: 143-145. sis. British Journal of Dermatology 1977; 97: 481-486. 7. Dicken CH, Carrington SG, Winkelmann RK. Generalized 28. Saxe N, Benarar SR, Bok L, Gordon W. Sarcoidosis with leg ulcers and annular face lesions. Archives ofDermatology 1984; 120: granuloma annulare. Archives of Dermatology 1969; 99: 556-563. 93-96. 8. Harrison P, Shuster S. Granuloma annulare and sarcoidosis. British Journal of Dermatology 1979; 100: 231. 29.Oppenheim M. Eigentumliche disseminerte Degeneration des Uindegewebes der Haut bei einem Diabetiker. Zentralblatt fiir 9. Fallahi S, Deaver-Collins R, Miller RK, Halle JT. Coexistence of Haut- und Geschlechtskrankheiten 1929-30; 32: 179. rheumatoid arthritis and sarcoidosis. Journal of Rheumatology iy84; 11:526-529. 30. Ellis FA, Kirby-Smitb H. Necrobiosis lipoidica and granuloma annulare; a comparative study. Archives of Dermatology and 10. Thompson WR, Ferenzi GW. Sarcoidosis and rheumatoid Syphtlology 1942; 45: 40-60. arthritis. Illinois Medical Journal 1966; 129: 239-242. 11. Putkonen T, Virkkunen M, Wager O. Joint involvement in 31. Gray Wood M, Beerman II. Necrobiosis lipoidica, granuloma annulare and rheumatoid nadule. Journal of Investigative Dermasarcoidosis with special reference to the coexistence of sarcoidosis tology 1960; 34: 139-147. and r\\e\i.mato\diTXhnt\s. Acta Rheumalica Scandinavica 1965; U: 53-61. 32. James DG. Dermatological aspects of sarcoidosis. Quarterly Journal of Medicine 1959; 28: 109-129. 12. Maycock RL, Bertrand P, Morrison CE, Scott LH. Manifestations of sarcoidosis; analysis of 145 patients and a review of nine 33. Hanno R, Needleman A, Eiferman RA, Callen JP. Cutaneous sarcoidal granulomas and the development of systemic sarcoidoseries selected from the literature. American Journal of Medicine sis. Archives of Dermatology 1981; 117: 203-207. 1963; 35: 67-89. 13. Oakley JR, Lawrence DAS, Fiddian RV. Sarcoidosis associated 34. Rowland-Payne CME, Meyrick Thomas RH, Black MM. From silica granuloma to scar sarcoidosis. Clinical and Experimental with Crohn's disease of the ileum, mouth and esophagus. Journal Dermatology 1983; 8: 171-175. of the Royal Society of Medicine 1983; 76: 1068-1071. 14. Maddrey WC. Sarcoidosis and primary biliary cirrhosis; asso- 35. Gange RW, Black MM, Carington P. L^efective neutropbil ciated disorders.' New England Journal of Medicine 1983; 308: migration in granuloma annulare, necrobiosis lipoidica and .588-590. sarcoidosis. Archives of Dermatology 1979; 115: 32-35. 15. Karlish AJ, Thompson RPH, Williams R. A case of sarcoidosis 36. Umbert P, Belcher RW. Winkelmann RK. Lymphokines (MIF) in the serum of patients with sarcoidosis and cutaneous granuloma and primary biliary cirrhosis. Lancet 1969; ii: 599. annulare. British Journal of Dermatology 1976; 95: 481-485. 16. Fagan EA, Moore-Gillon JC, Turner-Warwick M. Multiorgan granulomas and mitochondral antibodies. New England Journal of 37. Umbert P, Winkelmann RK. Granuloma annulare: direct immunofluorescence study. British Journal of Dermatology 1976; 95: Medicine 1983; 308: 572-575. 487-492. 17. Umbert P, Winkelmann RK. Histologic, ultrastructural and histochemical studies of ganuloma annulare. Archives of Dermato- 38. Beer WE, Wilson-Jones E. Granuloma annulare following tuberculin heaf tests. Transactions of the St John's Hospital Dermatologilogy 1977; 113: 1681-1686. cal Society 1966; 52: 68-70. 18. Schwartz ME. Necrobiosis lipoidica and granuloma annulare. Archives of Dermatology 1982; 118: 192-193. 39.Binazzi M, Simonetti S. Granuloma annulare, necrnbiosis lipoi19. Cohen IJK. Necrobiosis lipoidica and granuloma annulare. dica and diabetic disease. International Journal of Dermatology Journal of the American Academy of Dermatology 1984; 10: 1231988; 27: 576-579. 124. ' 40. Koh MS, Majewski BBJ, Barter S, Rhodes EL. Increased plasma fibronectin in diabetes mellirus, necrobiosis lipoidica and wide20. Binazzi M, Simonetti S. Atypical disseminated granuloma annuspread granuloma annulare. Clinical and Experimental Dermatolare co-existing with necrobiosis lipoidica in a diabetic patient. logy 1984; 9: 293-297. Annali Italiani di Dermatologia Clinica e Sperimentale 1987; 41: 61-66. 41. Majewski BBJ, Koh MS, Barter S, Rhodes EL. Increased factor Vlll-related antigen in necrobiosis lipoidica and widespread 21. Burton JL. Granuloma annulare, rheumatoid nodules and necrogranuloma annulare witbout associated diabetes. British Journal hiosis lipoidica. British Journal of Dermatology 1977; 97 (Suppl. of Dermatology 1982; 107: 641-645. 15): 52-54. 22. Savin JA. Diabetes mellitus, sarcoidosis, Pnecrobiosis lipoidica. 42. Jorizzo JL, Olansky AJ, Stanley RJ. Superficial ulcerating necrobiosis in rheumatoid arthritis. Archives ofDermatology 1982; Proceedings of the Royal Society of Medicine 1969; 62: 10. 118:255-259. 23. Anderson KE. Systemic sarcoidosis with necrobiosis lipoidicalike .scalp lesions. Acta Dermato-Venereologica (Stockholm) 1977; 43.Dahl MV, Ullman S, Goltz RW. Vasculitis in granuloma annulare. Archives of Dermatology 1977; 113: 463-467. 57: 367-369. 24. Muller SA, Winkelmann RK. Necrobiosis lipoidica diabeti- 44. Dahl MV, Ullman S, Goltz RW. Vasculitis in granuloma annulare {abstTdct). Journal ofInvestigative Dermatology 1976; 67: 564-565. corum; histopathologic study of 98 cases. Archives of Dermatology 1966; 94: l-IO. ' " 45. Ullman S, Dahl MV. Necrobiosis lipoidica: an immunofluorescent study. Archives of Dermatology 1977; 113: 1671-1673. 25. llarman RRM. Necrobiotic granulomas. British Journal of Dermatology 1977; 97 (Suppl. 15); 54-55. 46. Muhlemann MF, Williams DRR. Localized granuloma annulare is associated with insulin-dependent diabetes mellitus. British 26. Wilson-Jones E. Necrobiosis lipoidica presenting on the fate and .scalp. Transactions of the St John's Hospital Dermatological Society Journal of Dermatology 1984; HI: 325-329. 1971; 57: 202-220."
ADONIS 0307693691000577
Necrobiosis lipoidica and sarcoidosis K.GUDMUNDSEN, O.SMITH, P.DERVAN* AND F.C.POWELL Regional Centre of Dermatology and * Department of Pathology, Mater Misericordiae Hospital, Dublin 7, Ireland Accepted for publication \^ January 1991
her right shin about one year before presentation to us. The dyspnoea on exertion had been present for several We report the ease of a female patient with necrobiosis years, as had nocturnal wheeze and a productive cough in lipoidica of the lower legs and coexistent systemic and the morning. She had a previous history of tuberculosis cutaneous sarcoidosis. We review the six previously and had smoked 10-20 cigarettes a day for 30 years. reported patients with coexisting necrobiosis lipoidica There was no persona! or family history of diabetes and sarcoidosis. The associations between the granulo- mellitus. matous disorders of the skin, especially necrobiosis On examination, she had two clinically distinct types of lipoidica, sarcoidosis and granuloma annulare, are disskin lesions. In and about an old Caesarean-section scar cussed. The common pathogenetic features of these on her lower abdomen there were multiple, brownish, disorders are reviewed. slightly scaly dome-shaped papules (Fig. la). On her left shin there was a large patch with a central area of atrophic yellowish skin with prominent blood vessels and a dusky To our knowledge, the coexistence of necrobiosis lipoi- red border (Fig. lb). There was a similar but smaller dica diabeticorum (NLD) and sarcoidosis in the same lesion on her right shin. patient has been reported in only six patients to date'"** The clinical diagnoses of papular (scar) sarcoid and (Table 1). NLD has also been reported in association with necrobiosis lipoidica were confirmed histologically (Fig. other granulomatous-necrobiotic diseases, such as gra- 2). Random blood-sugar level, glucose-tolerance test, nuloma annulare (GA) and rheumatoid nodules. Sarcoi- serum calcium, ESR and angiotensin-converting-enzyme dosis has occasionally been found to coexist with GA, as levels were normal. well as with rheumatoid nodules, tuberculosis, Crohn's Investigation of her respiratory symptoms revealed disease and primary biliary cirrhosis. These associations findings consistent with pulmonary sarcoid and COAD. are of interest because they demonstrate the spectrum of Chest X-ray showed mediastinal adenopathy and mild cutaneous granulomatous reactions within the same diffuse interstitial lung disease, scarring of the left apex patient, and suggest that there may be a relationship in and pleuritic thickening of both apices consistent with old the pathogenesis of these diseases, which are distinctive tuberculosis. Pulmonary function tests revealed both a but show clinical and pathological similarities. We report restrictive lung disease (DLCO was 44% of predicted) here a case of a female patient with NLD of the lower legs and obstructive airways disease (FEVl was 53% of and coexistent systemic sarcoidosis with involvement of predicted, and FVC was 62% of predicted). Bronchosthe skin. We also review previously reported cases of copy and bronchio-alveolar lavage were normal. coexisting NLD and sarcoidosis, and discuss the associFor her pulmonary disease she was treated with oral ations between the granulomatous disorders of the skin. prednisone, initially at 40 mg daily reducing gradually over 4 months, and .salbutamol inhaler QID. On this regime her respiratory function improved symptomatiCase Report cally and objectively, and the papular (sarcoid) lesions in A 61-year-old woman presented to the Regional and about her abdominal scar cleared. The necrobiotic Centre of Dermatology at the Mater Hospital, complain- lesions on the lower legs have remained unchanged on ing of skin lesions on her shins and abdomen, and also of follow-up after 2 years. shortness of breath on exertion. She gave a history of having first developed skin lesions 13 years earlier along the scar of a Caesarean section, and on her left shin at Discussion about the same time. A further skin lesion developed on The patient reported here had two skin lesions which Correspondence: Dr F.C. Powell, Mater Hospital, Dublin 7, were clinically and histologically distinct. She had necrobiosis lipoidica diabeticorum (NLD) in the classic site on Ireland. Summary
287
288
K.GUDMUNDSEN et al.
Table 1. Reported cases of the coexistence of NLD and sarcoidosis
Site of NLD
Site of cutaneous sarcoidosis
Shin
legs, arms
Legs
cheeks, left car
Sbin
E. nodosum on both shins No details given Lower legs arms Both shins
left arm. forehead, back
Both shins
abdomen (scar)
Evidence for systemic sarcoidosis
Glucose tolerance
age sex (years)
Ref
BHL, pulmonary shadowing. decreasing DLCO iridocyclitis, BHL, Kveim rest positive BHL, Kveim test positive
GTT normal
35 F
Graham-Brown et al.^
GTT normal
42 F
Graham-Brown et al.^
blood glucose normal
61 F
Monk and DuVivier^
BHL, infiltrative changes in lung BHL, infiltrative changes in both lung fields. decreasing DLCO Mediastinal adenopatby, interstitial fibrosis, decreasing DLCO
blood glucose normal
46 F
Savin and Wilkinson'' Brungger"*
GTT normal
48 F
Dodd and Sarkany^
GTT normal
61 F
present case
BHL = bilateral hilar lymphadenopathy; GTT = glucose tolerance test; DLCO^trans-alveoIar diffusion of carbon monoxide.
Figure I. (a) Multiple papules in and around an old Caesarean-section scar, (b) Close-up of tbe plaque of necrobiosis lipoidica on tbe left shin.
the anterior aspect of the lower legs, and papules in an abdominal scar. The demonstration of sarcoidal granulomas in her abdominal-scar lesions drew attention to the possibility of systemic sarcoidosis. The finding in our patient of characteristic radiological and functional lung changes in association with cutaneous sarcoidal granulomas adequately fulfils the requirements for the diagnosis
of systemic sareoidosis. There was no evidence of diabetes mellitus, or impaired glucose tolerance. To our knowledge there have been five previous welldocumented reports of the coexistence of NLD and sarcoidosis in the same patient (Table 1). All of these patients were female, aged between 35 and 61 years. All had NLD on the legs, but the sites and manifestations of
NECROBIOSIS LIPOIDICA AND SARCOIDOSIS
289
Figure 2. (a) Histology of biopsy from abdominal scar, showing well-formed epithelioid granulomas with no degeneration of collagen, consistent with sarcoidosis (H&E x 126). (b) Histology from the lesion on the right shin showing collagen degeneration in the dermis surrounded by a chronic inflammatory-cell infiltrate including giant cells, consistent with necrobiosis lipoidica (H&E x 126).
the cutaneous sareoidosis were variable. In all cases, the cutaneous sarcoid consisted of papules or plaques (and was confirmed histologically by the presence of epithelioid granulomas in the dermis), except for that reported by Monk et al? in which there was a clinical diagnosis of erythema nodosum in association with systemic sarcoidosis. In addition, another case is mentioned by Savin and Wilkinson,' but no details were given. None of the patients reported had diabetes. Whether the coexistence of NLD and sarcoidosis in a patient is a true association or a coincidental occurrence is uncertain. Graham-Brown et al.^ remarked that because NLD and sarcoidosis are both relatively uncommon disorders, their coexistence in the same patients may suggest a pathogenetic relationship. They also note that both sarcoidosis and NLD have each been associated with granuloma annulare (GA), and that to find the remaining link between NLD and sarcoidosis is not unexpected. Monk et al.^ commented on the known associations of sarcoidosis with other granulomatous and necrobiotic diseases, and suggest that the necrobiotic granulomas, which include NLD, GA and rheumatoid nodules, may form a spectrum of similar disorders that overlap clinically and histologically. There is some circumstantial evidence to support a link between the granulomatous-necrobiotic disorders. Sarcoidosis has been reported to occur in the same patient in association with GA,^-^^ rheumatoid nodules,^ rheuma-
toid arthritis,'"" tuberculosis,'^ Crohn's disease" and primary biliary cirrhosis.'''-'' Fagen et al.^'' reported a group of patients with multi-organ granulomas whose features overlapped with those of sarcoidosis, primary biliary cirrhosis, coeliac disease, Sjogren's syndrome and mixed connective tissue disease. It may be difficult to distinguish histologically some cases of the epithelioidnodule type of GA from sarcoidosis.'' NLD has been reported in association with GA,'^"^" and both GA and rheumatoid nodules.^' In addition, 'atypical necrobiosis of the face and scalp' has been reported in association with systemic sarcoidosis.^^'^' The pallisading granulomatous type of NLD can closely resemble GA histologically.^''•^^ Classic NLD and cutaneous lesions of sarcoidosis may be easily differentiated clinically. However, there has been some confusion regarding lesions of the face and scalp, where the differential diagnosis might include NLD, annular sarcoid, GA and 'atypical NLD of the face and scalp'. True NLD at an atypical site, such as the face or scalp, may resemble sarcoidosis,"'' and lesions of the face or scalp in sarcoidosis have been reported as resembling NLD.^-" Classic NLD and sarcoidosis are also usually easily distinguished histologically. NLD consists of areas of necrobiosis of collagen surrounded by pallisading histiocytes in the lower dermis, but there is also a form, called the tuberculoid-type, in which pronounced granuloma-
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tous changes may develop.^^ Sarcoidosis is characterized by discrete well-formed epithelioid-cell granulomas; however, in some patients with skin lesions attributed to sarcoidosis necrobiotic changes may develop within the lesions.^'' Therefore, it may sometimes be difficult to distinguish between NLD and sarcoid histologically.^^-^^ Indeed, before the description of NLD as an entity by Oppenheim in 1929,^^ some cases of NLD (and GA) may have been labelled as 'scleroderma-like sarcoid' or 'tuberculosis with sclerodermatous changes.'^"-" Where there are two histological changes present it may be difficult to decide if one process is primary, and the other secondary, or indeed whether there are two different processes occurring. The difficulty is most apparent where sarcoidal changes cannot be established in organs other than the skin, as the diagnosis of sarcoidosis by definition depends on also finding characteristic clinical, radiological or histological evidence of sarcoidosis in the viscera.-^^ It has been appreciated that sarcoidal granulomas do occur, not uncommonly, in the skin in the absence of detectable systemic sarcoidosis, and these are clinically and histologically indistinguishable from those that occur in the skin of patients with systemic disease.-'^'-^ In addition, it is well known that infiltration by sarcoidal granulomas into areas of previously damaged skin, such as scars, can either be localized to the skin or a part of widespread disease.'^^•''^ It is uncertain, at this stage of our understanding of the pathogenesis of sarcoidal granulomas, whether the label of true 'cutaneous sarcoidosis' or 'sarcoidal tissue reaction' suits these lesions best. The pathogenesis of these cutaneous granulomatous reactions has been studied by several authors. Gange et al.^^ showed defective neutrophil migration in vivo into areas of traumatized skin in patients with NLD, sarcoidosis and GA. The cause of this defective neutrophil mobility is unknown in the majority of granulomatous disorders but the possibilities include increased levels of a serum factor that inactivates chemotactic factors, or directly inhibits the mobility or blood-vessel wall adherence of neutrophils.^^ Macrophage migration inhibitory factor (MIF)-like activity has been found in the sera of a significant number of patients with systemic sarcoidosis and of patients with GA.-"" Patients with NLD were also tested and the results were generally negative, although the number of patients involved was small.-"' Umbert and Winkelmann'' speculate that if the MIF-like activity were also present in the interstitial tissue of the skin, then it may contribute to the infiltration of mononuclear cells and the characteristic aggregation of histiocytes and epithelioid cells in lesions of cutaneous sarcoid and GA. Alternatively, both sarcoidosis and GA may be the result of a delayed-type cellular hypersensitivity reaction to an unknown antigen(s). Nodular deposition of fibrin outside the blood vessels in areas of necrobiosis and granulomas has been found in GA and sarcoidosis." Both
the tuberculin test and the mantoux test have occasionally produced typical lesions of GA.-'^ Umbert et al.^'' reported that patients with cutaneous sarcoidosis, and patients with GA, both have positive reactions to the tuberculin test, although patients with systemic sarcoidosis without cutaneous sarcoidosis give negative reactions. Histologically in NLD, well-developed vascular changes, especially endothelial proliferation and thickening of the wall, are found in the lesional skin of the majority of patients."** One theory holds that the dermal vasculopathy, perhaps itself due to an immune-complexmediated vasculitis, precedes and initiates the necrobiotic-granulomatous changes. Similar changes occur in the small blood vessels in NLD^' and GA.^^ It has been hypothesized that these changes may result from the significantly raised plasma levels offibronectin''*'and Factor-VIII-related antigen"^' which have been found in NLD without diabetes, generalized GA without diabetes and also in diabetes itself. In both NLD and GA the deposition of immunoglobulins and complement has been found in the walls of blood vessels,"*^**^ and the necrobiotic areas contain large amounts of fibrin orfibrinogen.^"^'^^Both NLD and some types of GA'*'' are associated with abnormalities of glucose metabolism. Clearly, therefore, there is clinical and histological overlap in the various cutaneous granulomatous disorders. In addition, the investigations cited above point to common serological, immunological and cellular abnormalities that may be found in patients with these disorders. The increasing number of patients reported with distinct coexisting cutaneous granulomas further support the hypothesis that these may represent a spectrum of related disorders. In patients with NLD, the possibility of associated DM is always considered and investigated appropriately. In addition, in view of the above reports, it seems prudent in patients with NLD at any site, to keep the possibility of associated systemic sarcoidosis in mind, and to carry out the appropriate clinical examination and laboratory tests.
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