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THE JOURNAL OF INVESTIGATIVE DERMATOLOGY Vol. 44, No. 6 Copyright C 1965 by The Williams & Wilkins Co. Printed in U.S.A.

NECROBIOSIS LIPOIDICA: A HISTOPATHOLOGICAL AND HISTOCHEMICAL STUDY* HOWARD R. GRAY, M.D., JAMES H. GRAHAM, M.D. AND WAINE C. JOHNSON, M.D. Urbach (1), in 1932, described necrobiosislipoidica diabeticorum and 17 biopsy specimens lipoidica diabeticorum as a complication offrom 14 patients with lipoidica were studied. Also, biopsy material from 25 consecutive diabetes nwllitus. Oppenheim (2)later inpatients with annulare was studied. 1932, reported another patient with diabetes Clinical data was obtained from clinical records, who had the same cutaneous involvement andquestionaires, personal interviews, and examina- used the term dermatitis atrophicans lipoidestion of the patient. All specimens were fixed in 10% neutral buffered formalin and most of the diabetica. Since then dia-tissue was processed for routine paraffin-blocked beticorum has been generally the term used forsections. Multiple sections stained with hema- this skin disease associated with diabetes. Manytoxylin and eosin were examined from all patients. examples of necrobiosis lipoidica ot associatedSections of representative specimens from 5 pa- with diabetes have been reported (3—5) andtients each with necrobiosis lipoidica diaheticorum, necrobiosis lipoidica and were the incidence of associated diabetes is variouslyprepared by the following methods: periodic reported from 25 to 87% (6—10). Necrobiosisacid-Schiff (PAS) reaction, with and without lipoidica diabeticorum occasionally precedesdiastase digestion; colloidal iron reaction (12), clinical evidence of diabetes (6, 9). The estab-with and without bovine testicular hyaluronidase lishment of definite histopathologic criteria fordigestion for 1 hour at 37° C.; Snook's reticulum stain; Movat's pentachrome I stain (13); Gomori's the differentiation of necrobiosis lipoidica in thealdehyde-fuchsin technic; and the alcian blue diabetic or potential diabetic patient from nec-method. The pH of the working solutions, and robiosis lipoidica in the non-diabetic patientthe methods used in the aldehyde-fuchsin and would be a valuable adjunct in the early diag-alcian blue techniques and detailed interpretation nosis and management of these patients. of the results were similar to those described by Johnson and Helwig (14) and Johnson, Graham Rollins and Winkelman (11) in '1960 re-and Helwig (15). Frozen, sections were prepared ported identical clinical appearance but differ-from the forinalin-fixed tissue from 1 patient with ent histopathologic patterns in necrobiosisnecrobiosis lipoidica diabeticorurn, 3 patients with lipoidica in diabetic and non-diabetic patients. necrobiosis lipoidica and 1 patient with granulorna annulare, and these were stained with the oil red The present paper is a report of histopatho-O stain for fat. With the exceptions given, the logical and histochemical observations of biopsyprocedures were carried out as outlined in the material of necrobiosis lipoidica from patients"Manual of Histologic and Special Staining Tech- with and without diabetes. nics" (16). Clinical Data MATERIALS AND METHODS The clinical appearance of the lesions india- betic and nondiabetic patients was similar and For purposes of this report the term necrobio-clinical differentiation could not be made (Fig. 1 sis lipoidica diabeticorum is used to designate theand 2). The lesions appeared as brownish-red cutaneous disease occurring in patients with dia-patches with a central yellowish hue and varied betes, and necrobiosis lipoidica refers to the erup-in size and shape. The involved skin appeared tion in patients without diabetes. Twenty-one bi-shiny, waxy, and atrophic and the superficial blood opsy specimens from 13 patients with necrobiosisvessels were usually telangiectatic. Most of the This investigation was supported in part by re-lesions were slightly scaly and a few showed search training grant no. 2A-5289 (C2), from theulceration and scarring. About half of the patients National Institute of Arthritis and Metabolichad symmetrical involvement of the anterior as- Diseases, U. S. Public Health Service, Bethesda,pect of the legs. A few patients had involvement Maryland 20014. of only one leg, ankle or dorsal surface of the Presented by title at the Twenty-fifth Annualfoot. One patient with diabetes had a solitary le- Meeting of The Society for Investigative Derma-sion of the lateral aspect of the right upper arm and tology, Inc., San Francisco, Calif., June 21—23, 1964. Received for publication June 29, 1964. another had multiple lesions of the anterior aspects * From the Skin and Cancer Hospital of Phila-of the legs, left thigh and left hip. delphia, Department of Dermatology, Temple Necrobiosis Lipoidica Diabeticorun. The 13 University School of Medicine, Philadelphia, Pa.patients were all Caucasian. Twelve patients were 19107. female and one was male. The age of the pa- 369 370 THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

Fic. 1. Necrobiosis lipoidica diabeticorum in a 20 year old woman with diabetes for 6 years and skin lesions for 18 months. FIG. 2. Necrobiosis lipoidica in a 49 year old woman with skin lesions for 12 years tients at the time of the first biopsy examinationtients were Caucasian and 1 was a Negro. Thir- ranged from 18 to 75 years; the mean age wasteen patients were female and 1 was male. 44.7 years. The duration of necrobiosis lipoidicaThe age of the patients at the time of the first diabeticorum from onset to the time of the firstbiopsy examination ranged from 23 to 60 years. biopsy examination varied from 1 month to 5The mean age was 43.5 years. The duration of years; the mean duration was 21 months. Six pa-necrobiosis lipoidica prior to the first biopsy tients were known to have diabetes prior to theexamination varied from 9 months to 15 years; development of the ecrobiosis lipoidica diabeti-the mean duration was 7.9 years. All 14 patients comm. The duration of diabetes before develop-had negative laboratory tests for diabetes and ment of the skin lesions in 4 patients was knownmost patients had been tested at periodic intervals. and ranged from 1 to 14 years; the mean durationThe majority of patients had glucose tolerance was 6.1 years. Six patients developed cutaneoustests; a few had 2 hour post-prandial blood sugar lesions prior to the onset of clinical symptomsdeterminations; one patient not available for of diabetes mellitus, but laboratory evidence offurther investigation had only a urinalysis. Family diabetes was present at the time the diagnosis ofhistory from 11 patients was negative except for necrohiosis lipoidica diabeticorum was established. 1 patient whose maternal grandmother and mater- The duration of the skin lesion prior to the initialnal aunt had diabetes. diagnosis of diabetes ranged from 3 months to 11 Granuloma Annulare. Twenty-two patients were years; the mean duration was 2.8 years. The pa-Caucasian and 3 were Negro. Fifteen patients tient with skin lesions for 11 years had severalwere female and 10 were male. The age of the biopsy examinations performed before a histo-25 patients at the time of biopsy examination pathologic diagnosis of necrobiosis lipoidica dia-varied from 2 to 69 years. The mean age was beticorum was made. Nine years after onset a27.9 years. The disease had been present from borderline fasting blood sugar was reported, but1 week to 20 years prior to biopsy examination; not investigated. Two years later the patient wasthe mean duration was 2.4 years. Clinically, all studied and found to have a diabetic type ofthe patients had lesions characteristic of granu— glucose tolerance curve. Laboratory evidence ofloma annulare. The anatomical sites of the biopsy diabetes had probably been present several years.specimens in 23 patients were the lower extremi- One patient noted the onset of cutaneous lesionsties in 9; upper extremities in 10; buttocks in 2; at the time diabetes was initially detected, but theand the posterior aspect of the neck ad external diagnosis of necrobiosis lipoidica diabeticorumear in 1 each. was ot established until 4 years later. Family history revealed that 3 of 10 patients had close HISTOPATHOLOGIC OBSERVATIONS relatives with diabetes. Hematoxylin- and eosin-stained sections of Necrobiosis Lipoidica. Thirteen of the 14 pa-necrobiosis lipoidica generally showed similar NECEOBIOSIS LIPOIDICA 371 histopathologic changes in the diabetic andthe number of small blood vessels in the mid- non-diabetic patients, but certain differencescorium and deep corium was observed in 9 were observed. In lesions from both diabetic(47%) of the lesions. Groups of 3 to 6 capil- and non-diabetic patients the most prominentlaries were often observed associated with changes were in the coriurn with areas of nec-fibrosis and a perivascular infiltrate or inflam- robiosis, and a cellular infiltrate composed ofmatory cells (Fig. 5). variable numbers of lymphocytes, plasma cells, The superficial corium, mid-corium and deep histiocytes, epithelioid cells and giant cells.corium were all involved in 9 (69%) of the Capillary-endothelial proliferation with thick-13 specimens in which the entire thickness of ening of the vessel walls and narrowing of thethe coriuni was present for evaluation. Six lumina was frequently observed in the midbiopsy specimens were removed too superficially corium and deep corium. and it was not possible to evaluate all levels Necrobiosis Lipoidica Diabeticorun't. Hema-of the corium. The necrobiotic areas were limited toxylin- and eosin-stained sections from 19 ofto the superficial coriuni and mid corium in 2 the 21 specimens from the 13 patients with dia-(15%); deep corium in 1 (8%); and to the betes showed histopathologic changes character-mid-corium and deep corium in 1 (8%). istic of active lesions (Fig. 3). The other 2 bi- Necrobiosis Lipoidica. Hernatoxylin- and opsy specimens were from healed lesions, 1 ofeosin-stained section of the 17 biopsy specimens which occurred spontaneously and the otherfrom 14 patients without diabetes showed a occurred after intralesional corticosteroid in-characteristic pattern of histopathologic fea- jections. Both healed lesions showed only fibro-tures. Epidermal changes were often striking. sis of the corium. The was essentiallyAtrophy of the epidermis and associated flat- normal in most of the specimens. Parakerotosistening of the rete ridges was noted in 7 was present in 3 (16%) of the 19 specimens and(41%) of the specimens (Fig. 6). Slight hyper- a slight acanthosis in 1 (5%). Necrobiotic areaskeratosis was present in only 1 (6%) of the were present in all 19 specimens but the degreespecimens. Acanthosis and parakeratosis were of necrobiosis varied. The necrobiotic changesnot observed. All 17 specimens showed areas of were minimal in 2 (11%) of the specimens.necrobiosis. The degree of necrobiotic change Fragmented nuclei were usually present in thevaried but usually was well developed. Frag- areas of necrobiosis. A basophilic staining sub-mented nuclei were usually present in the nec— stance was present in the necrobiotic areas inrobiotic areas. A basophilic staining substance 11 (58%). A inflammatory infiltrate was oftenwas present in the areas of necrobiosis in only located about areas of necrobiosis and sections3 (18%) of the 17 specimens. A prominent from 7 (37%) of the specimens showed a prom-palisaded arrangement of the inflammatory inent palisaded arrangement of the cells. Lym-infiltrate about the necrobiotic areas was noted phocytes were usually abundant in all the sec-in 4 (24%) of the specimens. Lymphocytes tions. A prominent plasma cell infiltrate waswere present in all sections, and the subcutane- present in 5 (26%) of the specimens. Epithelioidous fat was usually involved with the inflam-. cells were noted in 12 (63%) and tuberclematory infiltrate. A prominent plasma cell in- formation in 8 (42%). Multinucleated giantfiltrate was noted in 9 (53%) of the specimens cells were present in 13 (68%) of the specimens,(Fig. 7). Epithelioid cells and well-developed but only 3 of the 13 showed more than a raretubercles were present in 12 (71%) of the or occasional giant cell. The giant cells werespecimens. Giant cells were noted in 15 (88%) of the foreign body, Langhans, and occasion-of the specimens and large numbers were often ally Touton type. Perivascular inflammationpresent (Fig. 8). Foreign body, Langhans and was usually present and frequently the walls ofoccasionally Touton type giant cells were ob- the blood vessels were involved. In the sec-served. Capillary-endothelial proliferation and tions with subcutaneous fat present, infiltrationthickening of the vessel walls with narrowing with inflammatory cells was observed. Narrow-of the lumina was occasionally noted (Fig. 7). ing of capillary lumina with endothelial prolif-A perivascular inflammatory infiltrate was eration and thickening of the vessel wallsoften present and this frequently involved the frequently occurred in the mid-corium andwalls of the blood vessels. A pronounced in- deep corium (Fig. 4). A pronounced increase increase in the number of capillaries in the mid- 372 THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

FIG. 3. Necrobiosis lipoidica diabeticorum showing areas of necrobiosis, palisading of in- flammatory cells about the necrobiotic areas and capillary-endothelial proliferation. H & E, x50. FIG. 4. Necrobiosis lipoidica diabeticorum showing capillary-endothelial proliferation, thickening of the vessel walls and narrowing of the lumina. H & E, x620. NECROBIOSIS LIPOIDICA 373 c flt4flib&Lt

t rit,

,.1 ; ,•—-.-.•• — • - • - - •:- —r -- / — -• •1 -

FIG.5. Necrobiosis lipoidica diabeticorum showing groups of capillaries (arrows) near area of necrobiosis. H & E, X 97. FIG. 6. Necrobiosis lipoidica showing of the epidermis and flattening of the rete ridges. Elastic fibers stain dark and are absent in the areas of necrobiosis. Aldehyde-fuchsin stain pH 1.7, X 60. 374 aTHE JOURNAL''r OFnat INVESTIGATIVE waaaaa DERMATOLOGY

'Sft Fi. 7. Necrobiosis lipoidica with a plasma cell infiltrate about a capillary showing endo- thelial proliferation and thickening of the vessel wall. H & E, X 410. Fx. 8. Necrobiosis lipoidica showing multinucleated giant cells, lymphocytes and plasma cells. H & E, X 410. NECROBIOSIS LIPOIDICA 375 corium and deep corium was noted in only 2 HISTOCHEMICAL STUDIES (12%) of the specimens. The groups of 3 to 6 capillaries in the sections of these 2 specimens Necrobiosis lipoidica diabeticorum, necrobi- were surrounded by an infiltrate of inflamma-osis lipoidica and granulonta annulare showed similar histochemical properties but some varia- tory cells. tion in degree of change was observed. The The superficial corium, mid-corium, and deep corium were involved in 13 (87%) of thenecrobiotic areas did not show a significant 15 specimens in which the full thickness ofamount of glycogen but contained some the coriunt was present in the sections. ThePAS-positive diastase-resistant material. This superficial corium and mid-corium were in-latter substance cannot definitely be identified volved in 1 (7%) of these 15 specimens andbut may represent a mucopolysaccharide or the other 1 (7%) showed changes limited to thepolysaccharide-protein complex. Capillaries of the mid corium and deep coriurn contained PAS- mid-corium and deep corium. Granuloma Annulare. Hematoxylin- and eosin-positive diastase-resistant material in the vessel stained sections of 25 biopsy specimens fromwalls and in some examples this substance was 25 patients with granuloma annulare werewithin the lumina (Fig. 12). This reaction of the capillaries was striking in necrobiosis studied (Fig. 9). The epidermal changes con- sisted of a slight in 5 (20%) oflipoidica diabeticorum, and less common and less the specimens, parakeratosis in 1 (4%) andpronounced in necrobiosis lipoidica and granu- slight acanthosis in 2 (8%). Areas of necrobio-lorna annulare. The basophilic staining material sis were present in all 25 specimens, but thein areas of necrobiosis was alcian blue positive changes were minimal in 2 (8%). The degreeat pH 2.5 and negative at pH 0.4, and colloidal of the necrobiotic changes present varied fromiron positive and hyaluronidase-labile. These minimal to prominent. Fragmented nuclei wereresults indicate that the mucinous substance occasionally present in the areas of necrobiosis.is hyaluronic acid. The reactions were more Basophilic staining material in the necrobioticpronounced and consistently positive in granu- areas was observed in 20 (80%) of the speci-loma annulare, less in necrobiosis lipoidica diabeticorum and least in necrobiosis lipoidica. mens. Palisading of fibrocytic and epithelioid cells about necrobiotic areas was well developedThe aldehyde-fuchsin stain revealed a decrease in 10 (40%) of the examples (Fig. 10). Pen-to absence of elastic fibers in the areas of nec- vascular inflammation extended throughout therobiosis (Fig. 6). Mast cells were often observed corium and involved the subcutaneous fat,in the areas of inflammation. Snook's reticulum stain showed a network of argyrophilic fibers when present. The cellular infiltrate consisted predominantly of lymphocytes and only a rarelocated in areas of inflammation. The areas of plasma cell was observed. Epithelioid cells andnecrobiosis stained yellow similar to that of usually only a few giant cells were noted in 13collagen with Movat's pentachrome I stain. Frozen sections for oil red 0 fat stain revealed (52%) of the specimens (Fig. 11). Tubercle formation was observed in 8 (32%) of thepositive material in the areas of necrobiosis in specimens. Capillaries in the mid-corium andthe tissue examined from necrobiosis lipoidica deep corium occasionally showed slight endo-diabeticorum, necrobiosis lipoidica and granu- thelial proliferation and thickening of thelorna annulare. vessel walls. A prominent increase in the num- ber of capillaries with grouping was observed COMMENT in 9 (36%) of the examples of granuloma Lesions of necrobiosis lipoidica diabeticorum annulare. and necrobiosis lipoidica appeared clinically The superficial coriurn, mid-corium and deepidentical. The present study revealed no signi- corium were all involved in 11 (65%) of 17ficant differences in the age of the patients at specimens in which the entire thickness of thethe time of the first biopsy examination. Pa- corium was present. The superficial corium wastients with necrobiosis lipoidica had their skin involved in 1 (6%) of these 17 specimens; thelesions for a mean of 7.9 years prior to the superficial corium and mid-corium in 4 (24%);first biopsy examination compared to a mean and the changes were limited to the deepof 21 months in patients with necrobiosis corium in 1 (6%). lipoidica diabeticorum. Therefore, it appears 376 THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

Fia. 9. Granuloma annulare showing areas of necrobiosis and a perivascular lymphocytic infiltrate. H & E, X 50. Fia. 10. Granuloma annulare showing an area of necrobiosis with basophilic staining sub- stance within a necrobiotic area. Prominent palisading of the cellular infiltrate about the necrobiotic area is present. H & E, X 50. NECROBIOSIS LIPOIDICA 377

ft I

Fw.11. Granuloma annulare showing giant cells. H & E, >< 135 FIG. 12. Necrobiosis lipoidica diabeticorum showing PAS-positive and diastase-resistant material in the capillary wall and lumen. PAS with diastase digestion, >< 510. 378 ThEJOURNAL OF INVESTIGATIVE DERMATOLOGY

TABLE I Comparative histo pathologic changes

Histopathologic Changes NecjbisipLioidica Necrobiosis Lipoidica Granuloma Annulare

Epidermal atrophy None 41% None Involvement of superficial coriumand 15% 7% 30% mid corium only Mucinous substance in necrobioticareas 58% 18% 80% Palisading about necrobiotic areas Prominent in 37%Prominent in 24%Prominent in 40% Plasma cells Prominent in 26%Prominent in 53%Prominent in 0% Giant cells 68% 88% 52% Tubercle formation 42% 71% 32% Capillary-endothelial proliferationandOften pronouncedUsually slightUsually slight thickening of vessel wall changes changes changes Increased number of capillaries inmidProminent in 50%Prominent in 12%Prominent in 36% corium and deep corium

that the oiset of the skii lesiois occurred at ain riecrobiotic areas of tissue specirneris from slightly yonnger age in patients without dia-diabetic arid riori-diabetic patients. Promirient betes. This differs from the observatiois ofpalisaded arrangement of inflammatory cells Rollins and Wirikelmari (11) who rioted aabout areas of riecrobiosis was observed iri younger age at onset in patients with diabetes.specimeris removed from 37% of patients with our study, the sex iriciderice was the samediabetes, as compared to 24% from patients with orily 1 male patient in each group. Rollinswithout diabetes. A prominent plasma cell iri- and Wirikelmari (11) rioted 43% of the patientsfiltrate, tubercles arid giant cells were more studied with diabetes to be males and 7% ofcommori in riecrobiosis lipoidica thari iri riec- the patients without diabetes to be males. robiosis lipoidica diabeticorum. Capillary-endo- Our observatioris revealed definite quantita-thelial proliferatiori arid thickening of the tive histopathologic and histochemical differ-vessel wall arid groups of small blood vessels erices between riecrobiosis lipoidica diabeti-present in the mid-corium arid deep corium corum and riecrobiosis lipoidica (Table I).were more proriouriced in riecrobiosis lipoidica Significant epidermal atrophy was noted in sec-diabeticorum as compared to the vascular tions from 7 (41%) of the specimeris of riecro-chariges in riecrobiosis lipoidica. biosis lipoidica. Sectioris of riecrobiosis lipoidica We fourid the histopathologic differerices iri diabeticorum showed rio sigriificarit epidermalriecrobiosis lipoidica diabeticorum arid riecrobi- changes. Rollins and Wirikehnari (11) reportedosis lipoidica to be fairly coristant, and objec- rio sigriificarit differerices in the epidermis intive determiriatiori of the preserice of abserice of riecrobiosis lipoidica diabeticorum and riecrobio-diabetes was ordinarily possible. Material from sis lipoidica, although they rioted that an oc-1 patient with diabetes showed the pattern casiorial specimen from rioridiabetic patientsusually seeri iri riecrobiosis lipoidica arid secti&ns showed a slight degree of atrophy. Our obser-from a specimeri of 1 riori-diabetic patient pre- vations revealed no sigriificarit differerices in theserited the pattern of riecrobiosis lipoidica extent rior in the locatiori of the riecrobioticdiabeticorum. The diabetic patient was a 61 areas preserit iri the diabetic and riori-diabeticyear old female and the skin disease had been patients. Rollins arid Wirikelmari (11) observedpreserit for 1 year. Diabetes was first detected more prominent areas of riecrobiosis iri diabeticat the time the skin disease was diagnosed. The patieritsBasophilic stairiirig material, withriori-diabetic patierit was a 53 year old female histochemical properties of hyaluroriic acid, waswith riecrobiosis lipoidica of 4 years' duratiori observed in riecrobiotic areas from 58% of thearid rio laboratory evidence of diabetes mellitus. specimeris from diabetic patients and iri orilyThere was no family history of diabetes. 18% from riori-diabetic patients. Tfsirig selective It must be emphasized that experience gained staining technics Rollins and Wirikelman (11)by studying sectians of the 2 cutaneous dis- reported a general absence of mucinous materialeases is riecessary iri order to histologically NECROBIOSIS LIPOIDICA 379

differentiate the lesiois iithediabetic aidrespectively are reported. The cutaieous lesiois ioi-diabetic patieIt. Some overlap of histo-ii diabetic aid ioi-diabetic patieits are clini- pathologic patteits occur aid at times the dif-cally identical but show quantitative histo- ferentiatioi is difficult. Biopsy examinatioi andpathologic aid histochemical differences. Prom- determination of the preseice of the diabeticiIeit palisading of inflammatory cells about or ioi-diabetic histopathologic pattern cai othynecrobiotic centers, mucinous material ii areas serve as an adjuict to a complete medicalof iecrobiosis, aid alterations of the capil- history, physical examinatioi and appropriatelaries ii the mid-corium and deep corium were laboratory studies. more commothy observed in iecrobiosis lipoid- Necrobiosis lipoidica diabeticorum and iec-ica diabeticorum. Epidermal atrophy, giant robiosis lipoidica may represent 2 different dis-cells, tubercle formatioi and a prominent ease processes, but the ideitical clithcal pic-plasma cell infiltrate were observed more oftei ture, similar clinical course aid overlapping ofii necrobiosis lipoidica. Histopathologic differ- histopathologic features indicate that the 2 coi'-entiatioi of the cutaneous lesions in the dia- ditiops probably represent the same basic proc-betic or potential diabetic patient from the ess. The histopathologic differeices observed areirnn-diabetic patient can usually be made. Ex- probably due to factors ii the host response ofceptiois to the usual histopathologic pattern diabetic or potential diabetic patients aid non-occur aid microscopic differeitiation does not diabetic patients. The chaiges noted in thereplace the medical history, physical examina- capillaries in necrobiosis lipoidica diabeticorumtioi and appropriate laboratory tests, but cai are known to occur ii the skin (17—19) andserve as ai important adjuict in evaluating other orgai systems ii patients with diabetesthe patient's disease. (10, 20, 21). Alteratiois ii the compositioi of REFERENCES serum proteins have beei reported ii patieits 1. tJrbach, E.: Beitrage zu einer physiologischen with diabetes and are thought to play a role und pathologischen Chemie der Haut: X. ii the development of the vascular changes Mitteilung. Eine neue diabetische Stoff- wechseldermatose: Nekrobiosis lipoidica Di- (10, 22). abeticorum. Arch. Derm. u. Syph., 166:273, It is probable that granulomatosis disciformis 1932. 2. Oppenheim, M.: TJber eine bisher nicht chronica et progressiva as described by beschriebene, mit eigentumlicher lipoider Meischer aid Leder (23) and necrobiosis lipoid- Degeneration der Elastica und des Binde- ica are the same disease process (11). gewebes einhergehende chronische Derma- tose bei Diabetes mellitus (Dermatitis A number of extensive studies of granuloma atrophicans lipoides diabetica). Arch. Derm. airnulare have been reported (7, 24—26) and u. Syph., 166:576,1932. comparisons of microscopic features with nec- 3. Belote, G. H. and Welton, D. G.: Necrobiosis without diabetes. Arch. Derm. (Chicago), robiosis lipoidica have also beei made (7, 26— 40:887,1939. 27). The histo pathologic changes present in 4. Traub, E. F.: Necrobiosis lipoidica diabeti- graiuloma aimulare closely resemble those seen corum without diabetes. Arch. Derm. (Chi- cago), 42:693,1940. ii iecrobiosis lipoidica diabeticorum, aid histo-5. Dowling, G. B.: Non-diabetic necrobiosis pathologic differentiatian betweei the two may lipoidica. Brit. J. Derm. 58:75,1946. 6. Hildebrand, A. G., Montgomery, H. and not be possible (Table I). The more common Rynearson, E. H.: Necrobiosis lipoidica superficial involvement of the corium and diabeticoruin. Arch. Intern. Med. (Chicago), mucinous material ii areas of necrobiosis ii 66:851, 1940. 7. Ellis, F. A.and Kirby-Smith, H.: Necrobiosis grarniloma airnulare were features of value ii lipoidica and granuloma annulare. Arch. making a histopathologic differentiatioi from Derm. (Chicago), 45:40,1942. 8. Hare, P. J.: Necrobiosis lipoidica. Brit. I iwcrobiosis lipoidica diabeticorum. Aiother dif- Derm., 67: 365, 1955. ferential feature was the pronouiced capillary 9. Smith, J. G. Jr.: Necrobiosis lipoidica: A dis- change ii the mid-corium aM deep corium in ease of changing concepts. Arch. Derm. (Chicago), 74: 280, 1956. necrobiosis lipoidica diabeticorum. 10. Engel, M. F. and Hammack, W. J.: Necro- biosis lipoidica diabeticorum: a biochemical, SUMMARY histochemical, and electrophoretic study. Arch.Derm. (Chicago), 78: 73, 1958. The histopathologic and histochemical fea- 11.Rollins, T. G. and Winkelmann, R. K.: Necro- tures of necrobiosis lipoidica diabeticorum aid biosis lipoidica granulomatosis: necrobiosis lipoidica diabeticorum in the nondiabetic. iecrobiosis lipoidica in 13 and 14 patients Arch. Derm. (Chicago), 82:537,1960. 380 THEJOURNAL OF INVESTIGATIVE DERMATOLOGY

12. Mc Manus, J. F. A. and owry, R. W.: Stain- microangiopathy in human toes with em- ing Methods: Histologic and Histochemical, phasis on the ultrastructural change in der- pp. 133—135. New York, Paul B. Hoeber, Inc., mal capillaries. Amer. J. Path., 45:41,1964. Medical Book Dept., Harper and Row, 1960. 20. Goldberg, A. I. and Rosenberg, W. A.: Necro- 13. Movat, H. Z.: Demonstration of all connective biosis lipoidica diabeticorum with intercapil- tissue elements in a single section. Arch. lary glomerulosclerosis. Arch. !Derm. (Chi- Path. (Chicago), 60:289,1955. cago), 71:642,1955. 14. Johnson, W. C. and Helwig, E. B.: Histo-21. LeCompte, P. M.: Vascular lesions in diabetes chemistry of the acid mucopolysaccharides mellitus. J. Chronic. Dis., 2:178,1955. of skin in normal and in certain pathologic22. Engel, M. F. and Smith, J. G. Jr.: The patho- conditions. Amer. J. Clin. Path., 40:123, genesis of necrobiosis lipoidica. Arch. Derm. 1963. (Chicago), 82:791,1960. 15. Johnson, W. C., Graham, J. H. and Helwig,23. Miescher, G. and Leder, M.: Granulomatosis E. B.: Histochemistry of the acid muco- disciformis chronica et progressiva (Aty- polysaccharides in cutaneous calcification. J. pische Tuberkulose), Dermatologica, (Suppl. Invest. Derm., 42:215,1964. 97) 25—34, 1948. 16. Armed Forces Institute of Pathology. Manual24. Prunty, F. C. and Montgomery, H.: Granu- of Histologic and Special Staining Technics, loma annulare. Arch. Derm. (Chicago), 46: ed. 2. New York, The Blakiston Division, 394, 1942. McGraw-Hill Book Company, Inc., 1960. 25. Goodman, M. H. and Ketron, L. W.: Granu- 17. Aagenaes, 0. and Moe, H.: Light- and Elec- loma annulare. Arch. Derm. (Chicago), 33: tron-microscopic study of skin capillaries of 473,1936. diabetics. Diabetes, 10:253,1961. 26. Wood, M. G. and Beerman, H.: Necrobiosis 18. Handelsman, M. B., Morrione, T. G. and lipoidica, granuloma annulare, and rheuma- Ghitman, B.: Skin vascular alterations in toid nodule. J. Invest. Derrn., 34:139,1960. diabetes mellitus. Arch. Intern. Med. (Chi-27. Laymon, C. W. and Fisher, I.: Necrobiosis cago), 110:108,1962. lipoidica (diabeticorum?).Arch.Derm. (Chi- 19. Banson, B. B. and Lacy, P. E.: Diabetic cago), 59:150, 1949.