Granulomatous Panniculitis in Erythema Nodosum Lars
F\l=o"\rstr\l=o"\m,MD, Richard K. Winkelmann, MD, PhD
A group of ten patients with granulomatous panniculitis was studied; five had erythema induratum of the tuberculous or the nontuberculous type and five had erythema nodosum. In both groups, histiocytic giant cells and lymphocytic inflammation of the fat were seen microscopically. Massive caseation was seen in the patients who had erythema induratum, but this was not a distinguishing feature between the tuberculous and the nontuberculous type. The clinical history in all instances was a reliable guide to diagnosis. No specific cause was found, and treatment was not specific. In granulomatous panniculitis, the clinical pattern of disease is confusing in view of the histologic findings, and the diagnosis can be made with confidence only if the clinical findings are carefully correlated to the course
any and
common
and noticeable clinical
histologie patterns. Although granuloma formation in the subcuta¬ neous fat may be a nonspecific patho¬ logic designation, most of our pa¬ tients with primary granulomatous panniculitis could be placed into two groups: erythema nodosum and erythema induratum of either the tuberculous
or
the nontuberculous
(nodular vasculitis) type. We studied these cases in detail in the hope of
clarifying the confusion in the di¬ agnosis of erythema nodosum when there are chronic granulomatous his¬ tologie findings and of determining the differences between erythema nodosum and erythema induratum.
of the disease.
OUR SERIES Clinical Data
classic granulomatous diseases of the subcutaneous fat include sarcoidosis, erythema induratum, and lipophagic granuloma. However, there is a group of patients with micro¬
The
scopic granulomatous panniculitis
in
whom the clinical pattern of disease is confusing in view of the histology. We have reviewed these cases in or¬ der to determine whether there are Accepted for publication Sept 19, 1974. From the Department of Dermatology, Mayo Clinic and Mayo Foundation, Rochester, Minn. Reprint requests to Section of Publications, 200 First St SW, Rochester, MN 55901 (Dr. F\l=o"\rstr\l=o"\m).
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The series consisted of ten patients who to the Mayo Clinic from 1964 to 1973 because of subcutaneous nodules in which there was a histopathologic pattern of granulomatous panniculitis. The number of nodules ranged from two to many, and these mainly involved the lower extrem¬ ities. Five patients had nodules that had the clinical appearance of erythema nodo¬ sum, and five had nodules that resembled those of erythema induratum (Table 1). All five patients with erythema nodosum were women. They had red to purple, pain¬ ful, or tender nodules that varied from 1 to 8 cm in diameter and were located mainly on the anterior surface of the legs (Fig 1, left). The temperature of the overlying skin was elevated. Some of the patients came
Fig 1.—Left, Erythematous nodules calves of a black (patient 9).
consistent with
erythema
nodosum
(patient 1). Right, Erythema induratum. Bluish brown lesions
on
Fig 2.—Top left, Lymphohistiocytic panniculitis with minimal septal or vessel disease (patient 1). Note giant cells at top of field (hematoxylin-eosin, original magnification x64). Top right, Focal histiocytic nodules in panniculus (patient 2) (hematoxylin-eosin, original magnification x 160). Bottom left, Diffuse granulomatous
panniculitis (patient 4) (hematoxylin-eosin, original magnification x100). Bottom right, Histiocytic, giant-cell, fibrotic reaction of panniculus (patient 5) (hematoxylin-eosin, original magnification X100).
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had
a
less
pronounced inflammatory
com¬
ponent of the overlying skin. All patients had bilateral nodules, although one patient (No. 3) had nodules that began unilater¬
ally. In some of the patients, nodules also developed on the calves and upper extrem¬
ities. There was no ulcération or suppura¬ tion of the nodules. Fever did not occur, but one patient (No. 4) had a subfebrile temperature of 37.5 C (99.5 F). The nodules appeared two weeks after withdrawal of a course of low-dose steroid for rheumatoid arthritis from which she had suffered for 25 years. The onset of nodules was related to the exacerbation of her basic disease. She was the only patient who had a joint complaint. One patient (No. 2) suffered from Hashimoto thyroiditis, and another (No. 5) had myxedema. The duration of the individual nodules varied from one to three months, and the duration of the disease process from 4 to 15 months. In three pa¬ tients (No. 1, 4, and 5), the nodules cleared without scarring or indentations, leaving slight hyperpigmentation and scaling only. Two patients (No. 2 and 3) had lesions on their last follow-up visit. The five patients with erythema indura¬ tum (three women and two men) had nod¬ ules that were more bluish-brown than red and were less tender (No. 6 through 9) or even
asymptomatic (No. 10), compared patients with erythema nodosum. overlying skin, which often was scaly, as
to the
The had
normal or almost normal tempera¬ ture. The nodules had a predilection for the calves (Fig 1, right) but occurred occasion¬ ally on the legs, thigh, and buttocks; one patient (No. 8) also had nodules on the up¬ per extremities and the trunk. One patient (No. 6) had a lesion that spontaneously drained colorless, watery fluid, and another patient (No. 7) had purulent material that discharged from an ulcerated nodule. None of these five patients had fever. One (No. 10) had been treated for carcinoma of the breast 28 years prior to the onset of leg nodules.
Table 1.—Medical
Patient/Sex/ Age, yr
Laboratory Roentgenologic Findings The erythrocyte sedimentation rate was
moderately elevated in all patients except one (No. 9) (Table 2). The highest value, 62 mm in one hour, was seen in the patient with rheumatoid arthritis. The leukocyte count was slightly elevated in patient 3. One patient (No. 2) had hypercalcemia (calcium level, 12.6 mg/deciliter), hypophosphatemia (phosphate levels from 1.2 to 2.4 mg/dl), but normal urine calcium and phosphorus levels. The parathyroid hor¬ mone level was elevated to 64|iil/Eq/ml. There was no impairment of the kidney function, no kidney stones, and no signs of
Nodule Duration
Location of Nodules
Remarks
Erythema Nodosum
1/F/48
4
2-3
mo
>1 yr >8mo 5 wk
2/F/55 3/F/58 4/F/64
5/F/81
15
6/F/59
>10yr
7/F/64
>15yr
8/M/52 9/M/37
>20yr
3
9
Anterior surface of legs; wrists
mo
Legs, calves, arms Legs,calves Legs, forearms
mo
(?) 1 mo
Anterior surface of legs Erythema Induratum 6 wk Calves, thighs, buttocks 3 wk Calves, legs,
(?)
mo
Relapses
spring
in
Follow-up 2.5
mo,
lesions
healed
Dead,
cause
unknown
thighs
>4.5 yr
10/F/65
2 5
9
mo
Extremities, trunk Calves, thighs
mo mo
Calves, legs
mo
Exposed
to
tuberculosis
20 yr before Follow-up 4 mo, lesions
healed; mother had active tuberculosis
Table 2.—Results From Laboratory and Roentgenologic Examinations in Ten Patients With Granulomatous Panniculitis
Erythrocyte
Leukocytes,
ASO titer, Todd units
Patient
Sedimentation Rate, 1 hr
cu mm
1
40 29 43 62
6.700 6,400 11,300 9,600
40
5,100
Not done
27 32 32
6,400 8,800 10,400 5,900 6,700
12 Not done Not done Not done Not done
a
and
Disease Duration
and Clinical Data From Ten Patients With Granulomatous Panniculitis
History
10
28
50
Not done 50 125
Purified Protein Derivative Skin Test, TU* Positive (5) Not done
Negative (5) Not done
Negative (25) Positive (5) Positive (5) Not done Positive (5)
Negative (5)
Tuberculosis Chest
X-ray Normal Normal Normal Basal fibrosis Thickened
apical pleura
Normal Normal Normal Normal Normal
Culture, Sputum Negative Not done
Negative Not done
Negative Negative Not done
Negative Negative Not done
TU indicates tuberculin units.
bone disease. The test for sarcoidosis was negative, and follow-up examination one year later failed to show signs or symp¬ toms of sarcoidosis. The elevation in the serum calcium level was attributed to pri¬ mary hyperparathyroidism. The lupus erythematosus clot test was nonreactive in the two patients in whom it was performed. Test for antinuclear anti¬ body was positive (undiluted, mixed) in two patients (No. 4 and 7) and negative in two patients. Test for rheumatoid factor was negative in all four patients in whom it was carried out, including one (No. 4) who had rheumatoid arthritis. Serum amylase and lipase levels, which were mea¬ sured in one patient only, were normal, as was urine amylase in the three patients
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studied. Urinalysis gave normal results in all patients. Roentgenologic examination of the lungs showed normal findings in all pa¬ tients with the exception of two (No. 4 and 5), who demonstrated residual changes af¬
ter inflammatory processes in pleura or lungs. Roentgenologic examination of hands and feet was performed in two pa¬ tients only. In one of them, the result was normal. In the other (No. 4), there were changes typical of rheumatoid arthritis; no cystic bone changes were seen. Culture of urine for Mycobacterium tu¬ berculosis gave negative results in the four patients studied. Culture of biopsy specimens from the nodules showed no growth of aerobic or
pressions within three
months of isoniazid was contin¬ ued for 12 months. In patients 8 and 9, the treatment was instituted too recently to be
treatment, and the
treatment
adequately evaluated. The follow-up period in the series ranged from 2.5 months to 10 years, with 2.5 years the average. Six patients (No. 2, 3,6, 7,8, and 9) had lesions on their last fol¬ low-up examination.
Histopathologic Features
Fig 3.—Left, Epithelioid granulomas or tubercles, discrete and confluent, in multiple fat (hematoxylin-eosin, original magnification x100). Right, Diffuse granulomatous panniculitis with central caseation necrosis (patient 10). Multiple lobules and vessels are involved (hematoxylin-eosin, original magnification x 64). lobules
Granulomatous Erythema Nodosum.—All five patients demonstrated patchy inflam¬ mation of the subcutaneous fat lobules, with a lymphohistiocytic infiltrate. Oc¬ casional fat lobules showed diffuse in¬ volvement in which the lymphocytes pre¬ dominated. Lymphocytic infiltrates were observed about both the vessels and the in¬ dividual fat cells (Fig 2, top left). The
histiocyte-macrophage component always was
present in such
areas.
Focal
macro¬
phage infiltration about the fat cells was observed in all cases (Fig 2, top right). Masses of granulomatous nodules, or clearly demarcated masses of histiocyticepithelioid cells, involving the fat lobules represented the characteristic histopath¬ ologic observation indicative of granulo¬ matous panniculitis. Frequently, the gran¬ ulomas or tubercles were surrounded by lymphocytes, but occasionally they were not; this raised the question of the possi¬ bility of sarcoidosis (Fig 2, bottom left). Caseation
was never seen.
Giant cells
were
frequently observed in the tubercles or granulomas, and at times, they were the striking feature of the pathologic process. These were foreign-body giant cells with clumping of nuclei. No foreign material was
observed within
them, and results of
polaroscopy were negative in all cases. No
Fig 4.—Left, Granulomatous focus or tubercle in fat of patient with typical acute er¬ ythema nodosum (hematoxylin-eosin, original magnification x100). Right, Massive granulomatous panniculitis in subcutaneous fat lobule below dermal lesion of necrotizing and granulomatous vasculitis (hematoxylin-eosin, original magnification x100). anaerobic
bacteria, fungi,
or
yeast
or
mycobacteria (eight cases studied).
Treatment and Course of Disease Two patients (No. 1 and 4) were treated with aspirin and bed rest only. One patient (No. 2) was given prednisone, 50 mg/day for eight days but did not obtain relief, and potassium iodide for 50 days was not effective in another (No. 3). In patient 5,
the nodules healed during iodide treat¬ ment. All patients with erythema indura¬ tum (No. 6 through 10) were treated with isoniazid, 5 mg/kg of body weight per day. Patient 6 had no response within six months of treatment. In another (No. 7), the disease did not respond to isoniazid therapy within three months; thereafter, the use of the drug was stopped because of severe diarrhea. In one patient (No. 10), the nodules healed, with formation of de-
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asteroid or Schaumann bodies were found. The giant cell-histiocyte masses replaced most of the fat lobules in two of the five cases (Fig 2, bottom right). Septal thick¬ ening was observed only in these two cases, and we believe that this reflects the diffuse granulomatous change within the fat lobule. Occasional polymorphonuclear leukocytes were observed in diffuse areas of involvement. In No. 5, many plasma cells were seen and some hyaline material, which was not amyloid, was found in the septae. No notable vascular changes
dermal observed. or
or
epidermal changes
were
Erythema Induratum, Tuberculous and (Nodular Vasculitis).—The long-standing nature of the lesions in these patients was demonstrated by dif¬ fuse granuloma formation in the fat (Fig 3, left). Caseation was the striking feature (Fig 3, right), both in the focal granulomas Nontuberculous
and in generalized granulomatous areas of the fat lobules. The caseation caused a loss of cell details and slight eosinophilia of the granulomatous areas, with some infil¬ tration by polymorphonuclear leukocytes. In all cases, the same lymphohistiocytic in¬ filtrate as seen in No. 1 through 5 was ob¬ served in some areas of the fat lobules. In addition to having granuloma formation, two patients had lymphocytic nodular masses alone in the fat lobules. Perivascular granuloma formation was ob¬ served about muscular vessels outside the fat lobules in two patients. Endarterial thrombosis of a large muscular artery was observed in one patient. Number 9 had a lymphohistiocytic patchy infiltrate and granulomas in the fat in the first biopsy specimen. Two years later, another biopsy specimen showed typical caseation and granuloma formation. In two patients with long histories of granuloma formation, fibrosis was present within the fat lobules.
COMMENT alone demon¬ clinical pattern similar to
Erythema nodosum strates
a
in our five patients with nodosum plus granuloma¬ erythema tous panniculitis. All five of our
that
seen
warm, erythematous nodules located on the ante¬ rior surface of the legs and lasting 4 to 12 weeks. Migration of the nodules was not observed. The lesions were
patients had tender,
bilateral in all patients. Although the duration of the nodules was longer than in typical erythema nodosum, the lesions did not have the bluish-
brown, painless, pigmented appear¬
ance with normal skin temperature that was seen in our patients who had erythema induratum or its nontuber¬ culous variant, nodular vasculitis. It is known that the duration of erythema nodosum varies according to the cause of the eruption, being longest when the cause is unknown and when triggered by sarcoidosis.1 None of our patients had evidence of sarcoidosis, though one (No. 2) may have had such evidence. The cause is unexplained in these cases, as often is true in long-standing erythema nodosum. The erythrocyte sedimentation rate corre¬ sponds generally to that seen in typi¬ cal erythema nodosum after the acute phase. The sex distribution is in agreement with that seen in erythe¬ ma nodosum. Similarly, erythema nodosum is a disease that is now seen
more
frequently in adults than it was
years ago.
Histopathologically, erythema
was no¬
dosum is characterized by a poly¬ morphous appearance of many ele¬ ments involving blood vessels, septae, and fat lobules, as pointed out by Löfgren and Wahlgren2 and Miescher.3 Acute septal inflammation around the veins is a characteristic finding. The cellular inflammation involving the veins may be predominantly lymphocytic or polymorphonuclear leukocytic. This inflammation may extend into the fat; when it does, extension is usually in areas contiguous to the ves¬ sel inflammation. Lymphocytic nod¬ ules in the panniculus are sometimes seen. Hemorrhage from the vessel in¬ flammation is characteristic. The sep¬ tal change may develop into a chronic granuloma with vascular granulation tissue proliferation, as in Vilanova and Pifiol's migratory panniculitis. The fat lobules may become the site not only of focal histiocytic "Miescher granulomas"4 (Fig 4, left) but also of larger massive granulomatous in¬ volvement, as was seen in our pa¬ tients. In these, the gross and histo¬
logie abnormalities persist longer,
and this may be considered as a chronic form of erythema nodosum. Histiocytic reaction has been con¬ sidered part of erythema nodosum, but this was never prominent enough so that granulomatous disease could be confused with it. Montgomery5 noted but did not comment on tuberculoid erythema nodosum. Lofgren and Wahlgren2 noted foci of histiocyt¬ ic granulomas in erythema nodosum. Although they discussed foreign-body giant cells, they did not emphasize the development of granulomatous disease. Michelson6 emphasized that the older lesions contained more histiocytes, but he did not consider the possibility that histiocytic granulo¬ mas could develop to the extent that erythema induratum or sarcoidosis would be considered in the diagnosis. "Nodular vasculitis" was the term used for the condition involving un¬ classified red, inflammatory nodular lesions of the legs in middle-aged women who had nonspecific granulo¬ matous histologie abnormalities of the vessels, fat, and septae. The use
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by Montgomery at al7 accepted by clinicians in all parts of the world, but the term has been so variously used that it now has come to mean nontuberculous erythema in¬
of this term
duratum. This limitation relates it to
specific pathologic changes, a specific
clinical constellation, and a classic chronic course. We believe that pa¬ tients 1 through 5 do not fit this cate¬ gory but that clinically, the condition is erythema nodosum with granulo¬ matous changes in the panniculus. The other five patients (No. 6 through 10) clinically and histologically may be considered as representing ery¬ thema induratum or its nontuber¬ culous variant, nodular vasculitis. The term "chronic erythema nodo¬ sum," which has been used to describe erythema nodosum of long duration, is descriptive but is confusing be¬ cause of the inclusion of such diseases as nodular vasculitis and erythema induratum,8 diseases that differ from erythema nodosum clinically as well as on immunofluorescence studies.910 Erythema nodosum migrans has been described as a variant of erythema nodosum, characterized by migrating nodules, the histologie abnormalities of which are those of typical ery¬ thema nodosum.1114 Vilanova and Piftol's subacute nodular migratory panniculitis shows the same clinical pattern and course as does erythema nodosum migrans but is considered to have distinct histopathologic find¬ ings,1517 differing from the granulo¬ matous panniculitis observed in the present series. The septal granuloma, the septal fibrosis, and the inflamma¬ tory destruction of fat with replace¬ ment by granulation tissue and pro¬ liferation of small blood vessels characterize migratory panniculitis. We contend that acute erythema nodosum, chronic and granulomatous erythema nodosum, and migratory panniculitis are all clinical forms of the same basic process. In the litera¬ ture, each form has its own separate
description, incorrectly implying a to¬ tally unique disease process.
addition to sarcoidosis and several other diseases that first appear as subacute nodules with granuloma formation were considered in the differential In
erythema induratum,
diagnosis of No.
1
through
5.
Deep
mycosis was excluded by PAS-stained
and methenamine silver-stained bi¬ opsy specimens in all cases and by culture of the biopsy specimen for fungus in three cases. Syphilis was excluded on the basis of sérologie
testing. Foreign-body granuloma was excluded by polaroscopy, which also excluded the possibility of poststeroid panniculitis (No. 4), in which biré¬ fringent crystals can be demonstrated in the subcutaneous tissue.18 Thor¬
ough work-up did not disclose signs or symptoms of lymphoma. Leprosy was not seriously considered because of
the absence both of dermal involve¬ ment and of inflammation of the nerves. Granulomatous vasculitis can extend into the fat, causing a granu¬ lomatous panniculitis (Fig 4, right) similar to that described in our series. However, in our patients, the dermis was free of inflammation. The vessel changes were minimal on serial sec¬ tions, thus excluding the possibility of thrombophlebitis. The absence of
blood vessel changes reduced the pos¬ sibility of pernio. There was no accen¬ tuation during the cold season. Weber-Christian syndrome and lipogranulomatosis subcutánea of Rothmann-Makai have different clinical features and have a characteristic histologie pattern in the later stage. In panniculitis associated with pan¬ creatic disease, the predominant fea¬ ture is fat necrosis, which can be surrounded by a mixed granuloma¬ tous infiltrate.
Our patients with cases of clinically typical erythema nodosum and the histologie features of granulomatous panniculitis would be confusing to most dermatologists. Both the clini¬ cian and histopathologist must be aware of this possibility because, in dealing with nodular lesions of the legs, erythema nodosum is not ex¬ cluded on the basis of granulomatous histologie findings, if the clinical course and quality of the lesions are typical of erythema nodosum. Chronic inflammation of the fat
lead to granuloma formation whether the cause is infectious, trau¬ can
matic, immunologie, or idiopathic as in many cases of erythema nodosum, nontuberculous erythema induratum,
and Weber-Christian disease. In most instances, the course of histopathologic events is acute inflammation related to leukocytic infiltrate and necrosis, the evolution of subacute in¬ flammation related to lymphocytes, and finally, histiocytic and giant cell infiltration of tissues yielding chronic
inflammatory changes.
Our series does not offer any new information on the cause of the dis¬ ease. At present, we believe that any of the known causes of erythema nodosum can evolve this pattern of disease based on the individual pa¬ tient response. In typical erythema nodosum, the histologie features are the same irrespective of the cause of the eruption.2 However, we believe that a prospective study of granulo¬ matous erythema nodosum should be made to search for unique causes.
References 1. Hannuksela M: Erythema nodosum with reference to sarcoidosis: A clinical study of 343 Finnish adult patients. Ann Clin Res 3(suppl 7):5-64, 1971. 2. L\l=o"\fgrenS, Wahlgren F: On the histo-pathology of erythema nodosum. Acta Derm Venereol 29:1-13, 1949. 3. Miescher G: Zur Histologie des Erythema nodosum. Acta Derm Venereol 27:447-468, 1947. 4. Miescher G: Zur Frage der Radi\l=a"\rkn\l=o"\tchen beim Erythema nodosum. Arch Dermatol Syph 193:251-256, 1951. 5. Montgomery H: Dermatopathology. New York, Harper & Row Publishers, 1967, vol 2, pp 676-679. 6. Michelson HE: Erythema nodosum. Arch Dermatol 77:546-553, 1958. 7. Montgomery H, O'Leary PA, Barker NW:
special
Nodular vascular diseases of the legs: Erythema induratum and allied conditions. JAMA 128:335\x=req-\ 341, 1945. 8. Fine RM, Meltzer HD: Chronic erythema nodosum. Arch Dermatol 100:33-38, 1969. 9. Salo OP, F\l=o"\rstr\l=o"\mL, Mustakallio KK, et al, cited in Hannuksela M: Erythema nodosum migrans. Acta Derm Venereol 53:313-317, 1973. 10. Tuffanelli, cited in Epstein WL: Erythema nodosum, in Samter M (ed): Immunological Diseases, ed 2. Boston, Little, Brown & Company, 1971, vol 2, pp 944-951. 11. B\l=a"\fverstedtB: Erythema nodosum migrans. Acta Derm Venereol 34:181-193, 1954. 12. B\l=a"\fverstedtB: Erythema nodosum migrans. Acta Derm Venereol 48:381-384, 1968. 13. Hannuksela M: Erythema nodosum migrans. Acta Derm Venereol 53:313-317, 1973.
Downloaded From: http://archderm.jamanetwork.com/ by a University of Michigan User on 06/20/2015
14. R\l=o"\cklH: Die Bedeutung der Histopathologie f\l=u"\rdie Diagnostik knotiger Unterschenkel\x=req-\
Dermatosen. Hautarzt 19:540-547, 1968. 15. Vilanova X, Pi\l=n~\olAguad\l=e'\JP: Hypodermite nodularie subaigu\l=e"\migratrice. Ann Dermatol Syphiligr 83:369-404, 1956. 16. Vilanova X, Pi\l=n~\olAguad\l=e'\J: Subacute nodular migratory panniculitis. Br J Dermatol
71:45-50, 1959. 17. Perry HO, Winkelmann RK: Subacute nodular migratory panniculitis. Arch Dermatol 89:170-179, 1964. 18. Hirokawa K, Nishido T, Okuda M: Post-
panniculitis with cerebral vascular and pulmonary complications: Report of an autopsy case. Acta Pathol Jap 22:565-579, 1972. steroid
F\l=o"\rstr\l=o"\m,MD, Richard K. Winkelmann, MD, PhD
A group of ten patients with granulomatous panniculitis was studied; five had erythema induratum of the tuberculous or the nontuberculous type and five had erythema nodosum. In both groups, histiocytic giant cells and lymphocytic inflammation of the fat were seen microscopically. Massive caseation was seen in the patients who had erythema induratum, but this was not a distinguishing feature between the tuberculous and the nontuberculous type. The clinical history in all instances was a reliable guide to diagnosis. No specific cause was found, and treatment was not specific. In granulomatous panniculitis, the clinical pattern of disease is confusing in view of the histologic findings, and the diagnosis can be made with confidence only if the clinical findings are carefully correlated to the course
any and
common
and noticeable clinical
histologie patterns. Although granuloma formation in the subcuta¬ neous fat may be a nonspecific patho¬ logic designation, most of our pa¬ tients with primary granulomatous panniculitis could be placed into two groups: erythema nodosum and erythema induratum of either the tuberculous
or
the nontuberculous
(nodular vasculitis) type. We studied these cases in detail in the hope of
clarifying the confusion in the di¬ agnosis of erythema nodosum when there are chronic granulomatous his¬ tologie findings and of determining the differences between erythema nodosum and erythema induratum.
of the disease.
OUR SERIES Clinical Data
classic granulomatous diseases of the subcutaneous fat include sarcoidosis, erythema induratum, and lipophagic granuloma. However, there is a group of patients with micro¬
The
scopic granulomatous panniculitis
in
whom the clinical pattern of disease is confusing in view of the histology. We have reviewed these cases in or¬ der to determine whether there are Accepted for publication Sept 19, 1974. From the Department of Dermatology, Mayo Clinic and Mayo Foundation, Rochester, Minn. Reprint requests to Section of Publications, 200 First St SW, Rochester, MN 55901 (Dr. F\l=o"\rstr\l=o"\m).
Downloaded From: http://archderm.jamanetwork.com/ by a University of Michigan User on 06/20/2015
The series consisted of ten patients who to the Mayo Clinic from 1964 to 1973 because of subcutaneous nodules in which there was a histopathologic pattern of granulomatous panniculitis. The number of nodules ranged from two to many, and these mainly involved the lower extrem¬ ities. Five patients had nodules that had the clinical appearance of erythema nodo¬ sum, and five had nodules that resembled those of erythema induratum (Table 1). All five patients with erythema nodosum were women. They had red to purple, pain¬ ful, or tender nodules that varied from 1 to 8 cm in diameter and were located mainly on the anterior surface of the legs (Fig 1, left). The temperature of the overlying skin was elevated. Some of the patients came
Fig 1.—Left, Erythematous nodules calves of a black (patient 9).
consistent with
erythema
nodosum
(patient 1). Right, Erythema induratum. Bluish brown lesions
on
Fig 2.—Top left, Lymphohistiocytic panniculitis with minimal septal or vessel disease (patient 1). Note giant cells at top of field (hematoxylin-eosin, original magnification x64). Top right, Focal histiocytic nodules in panniculus (patient 2) (hematoxylin-eosin, original magnification x 160). Bottom left, Diffuse granulomatous
panniculitis (patient 4) (hematoxylin-eosin, original magnification x100). Bottom right, Histiocytic, giant-cell, fibrotic reaction of panniculus (patient 5) (hematoxylin-eosin, original magnification X100).
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had
a
less
pronounced inflammatory
com¬
ponent of the overlying skin. All patients had bilateral nodules, although one patient (No. 3) had nodules that began unilater¬
ally. In some of the patients, nodules also developed on the calves and upper extrem¬
ities. There was no ulcération or suppura¬ tion of the nodules. Fever did not occur, but one patient (No. 4) had a subfebrile temperature of 37.5 C (99.5 F). The nodules appeared two weeks after withdrawal of a course of low-dose steroid for rheumatoid arthritis from which she had suffered for 25 years. The onset of nodules was related to the exacerbation of her basic disease. She was the only patient who had a joint complaint. One patient (No. 2) suffered from Hashimoto thyroiditis, and another (No. 5) had myxedema. The duration of the individual nodules varied from one to three months, and the duration of the disease process from 4 to 15 months. In three pa¬ tients (No. 1, 4, and 5), the nodules cleared without scarring or indentations, leaving slight hyperpigmentation and scaling only. Two patients (No. 2 and 3) had lesions on their last follow-up visit. The five patients with erythema indura¬ tum (three women and two men) had nod¬ ules that were more bluish-brown than red and were less tender (No. 6 through 9) or even
asymptomatic (No. 10), compared patients with erythema nodosum. overlying skin, which often was scaly, as
to the
The had
normal or almost normal tempera¬ ture. The nodules had a predilection for the calves (Fig 1, right) but occurred occasion¬ ally on the legs, thigh, and buttocks; one patient (No. 8) also had nodules on the up¬ per extremities and the trunk. One patient (No. 6) had a lesion that spontaneously drained colorless, watery fluid, and another patient (No. 7) had purulent material that discharged from an ulcerated nodule. None of these five patients had fever. One (No. 10) had been treated for carcinoma of the breast 28 years prior to the onset of leg nodules.
Table 1.—Medical
Patient/Sex/ Age, yr
Laboratory Roentgenologic Findings The erythrocyte sedimentation rate was
moderately elevated in all patients except one (No. 9) (Table 2). The highest value, 62 mm in one hour, was seen in the patient with rheumatoid arthritis. The leukocyte count was slightly elevated in patient 3. One patient (No. 2) had hypercalcemia (calcium level, 12.6 mg/deciliter), hypophosphatemia (phosphate levels from 1.2 to 2.4 mg/dl), but normal urine calcium and phosphorus levels. The parathyroid hor¬ mone level was elevated to 64|iil/Eq/ml. There was no impairment of the kidney function, no kidney stones, and no signs of
Nodule Duration
Location of Nodules
Remarks
Erythema Nodosum
1/F/48
4
2-3
mo
>1 yr >8mo 5 wk
2/F/55 3/F/58 4/F/64
5/F/81
15
6/F/59
>10yr
7/F/64
>15yr
8/M/52 9/M/37
>20yr
3
9
Anterior surface of legs; wrists
mo
Legs, calves, arms Legs,calves Legs, forearms
mo
(?) 1 mo
Anterior surface of legs Erythema Induratum 6 wk Calves, thighs, buttocks 3 wk Calves, legs,
(?)
mo
Relapses
spring
in
Follow-up 2.5
mo,
lesions
healed
Dead,
cause
unknown
thighs
>4.5 yr
10/F/65
2 5
9
mo
Extremities, trunk Calves, thighs
mo mo
Calves, legs
mo
Exposed
to
tuberculosis
20 yr before Follow-up 4 mo, lesions
healed; mother had active tuberculosis
Table 2.—Results From Laboratory and Roentgenologic Examinations in Ten Patients With Granulomatous Panniculitis
Erythrocyte
Leukocytes,
ASO titer, Todd units
Patient
Sedimentation Rate, 1 hr
cu mm
1
40 29 43 62
6.700 6,400 11,300 9,600
40
5,100
Not done
27 32 32
6,400 8,800 10,400 5,900 6,700
12 Not done Not done Not done Not done
a
and
Disease Duration
and Clinical Data From Ten Patients With Granulomatous Panniculitis
History
10
28
50
Not done 50 125
Purified Protein Derivative Skin Test, TU* Positive (5) Not done
Negative (5) Not done
Negative (25) Positive (5) Positive (5) Not done Positive (5)
Negative (5)
Tuberculosis Chest
X-ray Normal Normal Normal Basal fibrosis Thickened
apical pleura
Normal Normal Normal Normal Normal
Culture, Sputum Negative Not done
Negative Not done
Negative Negative Not done
Negative Negative Not done
TU indicates tuberculin units.
bone disease. The test for sarcoidosis was negative, and follow-up examination one year later failed to show signs or symp¬ toms of sarcoidosis. The elevation in the serum calcium level was attributed to pri¬ mary hyperparathyroidism. The lupus erythematosus clot test was nonreactive in the two patients in whom it was performed. Test for antinuclear anti¬ body was positive (undiluted, mixed) in two patients (No. 4 and 7) and negative in two patients. Test for rheumatoid factor was negative in all four patients in whom it was carried out, including one (No. 4) who had rheumatoid arthritis. Serum amylase and lipase levels, which were mea¬ sured in one patient only, were normal, as was urine amylase in the three patients
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studied. Urinalysis gave normal results in all patients. Roentgenologic examination of the lungs showed normal findings in all pa¬ tients with the exception of two (No. 4 and 5), who demonstrated residual changes af¬
ter inflammatory processes in pleura or lungs. Roentgenologic examination of hands and feet was performed in two pa¬ tients only. In one of them, the result was normal. In the other (No. 4), there were changes typical of rheumatoid arthritis; no cystic bone changes were seen. Culture of urine for Mycobacterium tu¬ berculosis gave negative results in the four patients studied. Culture of biopsy specimens from the nodules showed no growth of aerobic or
pressions within three
months of isoniazid was contin¬ ued for 12 months. In patients 8 and 9, the treatment was instituted too recently to be
treatment, and the
treatment
adequately evaluated. The follow-up period in the series ranged from 2.5 months to 10 years, with 2.5 years the average. Six patients (No. 2, 3,6, 7,8, and 9) had lesions on their last fol¬ low-up examination.
Histopathologic Features
Fig 3.—Left, Epithelioid granulomas or tubercles, discrete and confluent, in multiple fat (hematoxylin-eosin, original magnification x100). Right, Diffuse granulomatous panniculitis with central caseation necrosis (patient 10). Multiple lobules and vessels are involved (hematoxylin-eosin, original magnification x 64). lobules
Granulomatous Erythema Nodosum.—All five patients demonstrated patchy inflam¬ mation of the subcutaneous fat lobules, with a lymphohistiocytic infiltrate. Oc¬ casional fat lobules showed diffuse in¬ volvement in which the lymphocytes pre¬ dominated. Lymphocytic infiltrates were observed about both the vessels and the in¬ dividual fat cells (Fig 2, top left). The
histiocyte-macrophage component always was
present in such
areas.
Focal
macro¬
phage infiltration about the fat cells was observed in all cases (Fig 2, top right). Masses of granulomatous nodules, or clearly demarcated masses of histiocyticepithelioid cells, involving the fat lobules represented the characteristic histopath¬ ologic observation indicative of granulo¬ matous panniculitis. Frequently, the gran¬ ulomas or tubercles were surrounded by lymphocytes, but occasionally they were not; this raised the question of the possi¬ bility of sarcoidosis (Fig 2, bottom left). Caseation
was never seen.
Giant cells
were
frequently observed in the tubercles or granulomas, and at times, they were the striking feature of the pathologic process. These were foreign-body giant cells with clumping of nuclei. No foreign material was
observed within
them, and results of
polaroscopy were negative in all cases. No
Fig 4.—Left, Granulomatous focus or tubercle in fat of patient with typical acute er¬ ythema nodosum (hematoxylin-eosin, original magnification x100). Right, Massive granulomatous panniculitis in subcutaneous fat lobule below dermal lesion of necrotizing and granulomatous vasculitis (hematoxylin-eosin, original magnification x100). anaerobic
bacteria, fungi,
or
yeast
or
mycobacteria (eight cases studied).
Treatment and Course of Disease Two patients (No. 1 and 4) were treated with aspirin and bed rest only. One patient (No. 2) was given prednisone, 50 mg/day for eight days but did not obtain relief, and potassium iodide for 50 days was not effective in another (No. 3). In patient 5,
the nodules healed during iodide treat¬ ment. All patients with erythema indura¬ tum (No. 6 through 10) were treated with isoniazid, 5 mg/kg of body weight per day. Patient 6 had no response within six months of treatment. In another (No. 7), the disease did not respond to isoniazid therapy within three months; thereafter, the use of the drug was stopped because of severe diarrhea. In one patient (No. 10), the nodules healed, with formation of de-
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asteroid or Schaumann bodies were found. The giant cell-histiocyte masses replaced most of the fat lobules in two of the five cases (Fig 2, bottom right). Septal thick¬ ening was observed only in these two cases, and we believe that this reflects the diffuse granulomatous change within the fat lobule. Occasional polymorphonuclear leukocytes were observed in diffuse areas of involvement. In No. 5, many plasma cells were seen and some hyaline material, which was not amyloid, was found in the septae. No notable vascular changes
dermal observed. or
or
epidermal changes
were
Erythema Induratum, Tuberculous and (Nodular Vasculitis).—The long-standing nature of the lesions in these patients was demonstrated by dif¬ fuse granuloma formation in the fat (Fig 3, left). Caseation was the striking feature (Fig 3, right), both in the focal granulomas Nontuberculous
and in generalized granulomatous areas of the fat lobules. The caseation caused a loss of cell details and slight eosinophilia of the granulomatous areas, with some infil¬ tration by polymorphonuclear leukocytes. In all cases, the same lymphohistiocytic in¬ filtrate as seen in No. 1 through 5 was ob¬ served in some areas of the fat lobules. In addition to having granuloma formation, two patients had lymphocytic nodular masses alone in the fat lobules. Perivascular granuloma formation was ob¬ served about muscular vessels outside the fat lobules in two patients. Endarterial thrombosis of a large muscular artery was observed in one patient. Number 9 had a lymphohistiocytic patchy infiltrate and granulomas in the fat in the first biopsy specimen. Two years later, another biopsy specimen showed typical caseation and granuloma formation. In two patients with long histories of granuloma formation, fibrosis was present within the fat lobules.
COMMENT alone demon¬ clinical pattern similar to
Erythema nodosum strates
a
in our five patients with nodosum plus granuloma¬ erythema tous panniculitis. All five of our
that
seen
warm, erythematous nodules located on the ante¬ rior surface of the legs and lasting 4 to 12 weeks. Migration of the nodules was not observed. The lesions were
patients had tender,
bilateral in all patients. Although the duration of the nodules was longer than in typical erythema nodosum, the lesions did not have the bluish-
brown, painless, pigmented appear¬
ance with normal skin temperature that was seen in our patients who had erythema induratum or its nontuber¬ culous variant, nodular vasculitis. It is known that the duration of erythema nodosum varies according to the cause of the eruption, being longest when the cause is unknown and when triggered by sarcoidosis.1 None of our patients had evidence of sarcoidosis, though one (No. 2) may have had such evidence. The cause is unexplained in these cases, as often is true in long-standing erythema nodosum. The erythrocyte sedimentation rate corre¬ sponds generally to that seen in typi¬ cal erythema nodosum after the acute phase. The sex distribution is in agreement with that seen in erythe¬ ma nodosum. Similarly, erythema nodosum is a disease that is now seen
more
frequently in adults than it was
years ago.
Histopathologically, erythema
was no¬
dosum is characterized by a poly¬ morphous appearance of many ele¬ ments involving blood vessels, septae, and fat lobules, as pointed out by Löfgren and Wahlgren2 and Miescher.3 Acute septal inflammation around the veins is a characteristic finding. The cellular inflammation involving the veins may be predominantly lymphocytic or polymorphonuclear leukocytic. This inflammation may extend into the fat; when it does, extension is usually in areas contiguous to the ves¬ sel inflammation. Lymphocytic nod¬ ules in the panniculus are sometimes seen. Hemorrhage from the vessel in¬ flammation is characteristic. The sep¬ tal change may develop into a chronic granuloma with vascular granulation tissue proliferation, as in Vilanova and Pifiol's migratory panniculitis. The fat lobules may become the site not only of focal histiocytic "Miescher granulomas"4 (Fig 4, left) but also of larger massive granulomatous in¬ volvement, as was seen in our pa¬ tients. In these, the gross and histo¬
logie abnormalities persist longer,
and this may be considered as a chronic form of erythema nodosum. Histiocytic reaction has been con¬ sidered part of erythema nodosum, but this was never prominent enough so that granulomatous disease could be confused with it. Montgomery5 noted but did not comment on tuberculoid erythema nodosum. Lofgren and Wahlgren2 noted foci of histiocyt¬ ic granulomas in erythema nodosum. Although they discussed foreign-body giant cells, they did not emphasize the development of granulomatous disease. Michelson6 emphasized that the older lesions contained more histiocytes, but he did not consider the possibility that histiocytic granulo¬ mas could develop to the extent that erythema induratum or sarcoidosis would be considered in the diagnosis. "Nodular vasculitis" was the term used for the condition involving un¬ classified red, inflammatory nodular lesions of the legs in middle-aged women who had nonspecific granulo¬ matous histologie abnormalities of the vessels, fat, and septae. The use
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by Montgomery at al7 accepted by clinicians in all parts of the world, but the term has been so variously used that it now has come to mean nontuberculous erythema in¬
of this term
duratum. This limitation relates it to
specific pathologic changes, a specific
clinical constellation, and a classic chronic course. We believe that pa¬ tients 1 through 5 do not fit this cate¬ gory but that clinically, the condition is erythema nodosum with granulo¬ matous changes in the panniculus. The other five patients (No. 6 through 10) clinically and histologically may be considered as representing ery¬ thema induratum or its nontuber¬ culous variant, nodular vasculitis. The term "chronic erythema nodo¬ sum," which has been used to describe erythema nodosum of long duration, is descriptive but is confusing be¬ cause of the inclusion of such diseases as nodular vasculitis and erythema induratum,8 diseases that differ from erythema nodosum clinically as well as on immunofluorescence studies.910 Erythema nodosum migrans has been described as a variant of erythema nodosum, characterized by migrating nodules, the histologie abnormalities of which are those of typical ery¬ thema nodosum.1114 Vilanova and Piftol's subacute nodular migratory panniculitis shows the same clinical pattern and course as does erythema nodosum migrans but is considered to have distinct histopathologic find¬ ings,1517 differing from the granulo¬ matous panniculitis observed in the present series. The septal granuloma, the septal fibrosis, and the inflamma¬ tory destruction of fat with replace¬ ment by granulation tissue and pro¬ liferation of small blood vessels characterize migratory panniculitis. We contend that acute erythema nodosum, chronic and granulomatous erythema nodosum, and migratory panniculitis are all clinical forms of the same basic process. In the litera¬ ture, each form has its own separate
description, incorrectly implying a to¬ tally unique disease process.
addition to sarcoidosis and several other diseases that first appear as subacute nodules with granuloma formation were considered in the differential In
erythema induratum,
diagnosis of No.
1
through
5.
Deep
mycosis was excluded by PAS-stained
and methenamine silver-stained bi¬ opsy specimens in all cases and by culture of the biopsy specimen for fungus in three cases. Syphilis was excluded on the basis of sérologie
testing. Foreign-body granuloma was excluded by polaroscopy, which also excluded the possibility of poststeroid panniculitis (No. 4), in which biré¬ fringent crystals can be demonstrated in the subcutaneous tissue.18 Thor¬
ough work-up did not disclose signs or symptoms of lymphoma. Leprosy was not seriously considered because of
the absence both of dermal involve¬ ment and of inflammation of the nerves. Granulomatous vasculitis can extend into the fat, causing a granu¬ lomatous panniculitis (Fig 4, right) similar to that described in our series. However, in our patients, the dermis was free of inflammation. The vessel changes were minimal on serial sec¬ tions, thus excluding the possibility of thrombophlebitis. The absence of
blood vessel changes reduced the pos¬ sibility of pernio. There was no accen¬ tuation during the cold season. Weber-Christian syndrome and lipogranulomatosis subcutánea of Rothmann-Makai have different clinical features and have a characteristic histologie pattern in the later stage. In panniculitis associated with pan¬ creatic disease, the predominant fea¬ ture is fat necrosis, which can be surrounded by a mixed granuloma¬ tous infiltrate.
Our patients with cases of clinically typical erythema nodosum and the histologie features of granulomatous panniculitis would be confusing to most dermatologists. Both the clini¬ cian and histopathologist must be aware of this possibility because, in dealing with nodular lesions of the legs, erythema nodosum is not ex¬ cluded on the basis of granulomatous histologie findings, if the clinical course and quality of the lesions are typical of erythema nodosum. Chronic inflammation of the fat
lead to granuloma formation whether the cause is infectious, trau¬ can
matic, immunologie, or idiopathic as in many cases of erythema nodosum, nontuberculous erythema induratum,
and Weber-Christian disease. In most instances, the course of histopathologic events is acute inflammation related to leukocytic infiltrate and necrosis, the evolution of subacute in¬ flammation related to lymphocytes, and finally, histiocytic and giant cell infiltration of tissues yielding chronic
inflammatory changes.
Our series does not offer any new information on the cause of the dis¬ ease. At present, we believe that any of the known causes of erythema nodosum can evolve this pattern of disease based on the individual pa¬ tient response. In typical erythema nodosum, the histologie features are the same irrespective of the cause of the eruption.2 However, we believe that a prospective study of granulo¬ matous erythema nodosum should be made to search for unique causes.
References 1. Hannuksela M: Erythema nodosum with reference to sarcoidosis: A clinical study of 343 Finnish adult patients. Ann Clin Res 3(suppl 7):5-64, 1971. 2. L\l=o"\fgrenS, Wahlgren F: On the histo-pathology of erythema nodosum. Acta Derm Venereol 29:1-13, 1949. 3. Miescher G: Zur Histologie des Erythema nodosum. Acta Derm Venereol 27:447-468, 1947. 4. Miescher G: Zur Frage der Radi\l=a"\rkn\l=o"\tchen beim Erythema nodosum. Arch Dermatol Syph 193:251-256, 1951. 5. Montgomery H: Dermatopathology. New York, Harper & Row Publishers, 1967, vol 2, pp 676-679. 6. Michelson HE: Erythema nodosum. Arch Dermatol 77:546-553, 1958. 7. Montgomery H, O'Leary PA, Barker NW:
special
Nodular vascular diseases of the legs: Erythema induratum and allied conditions. JAMA 128:335\x=req-\ 341, 1945. 8. Fine RM, Meltzer HD: Chronic erythema nodosum. Arch Dermatol 100:33-38, 1969. 9. Salo OP, F\l=o"\rstr\l=o"\mL, Mustakallio KK, et al, cited in Hannuksela M: Erythema nodosum migrans. Acta Derm Venereol 53:313-317, 1973. 10. Tuffanelli, cited in Epstein WL: Erythema nodosum, in Samter M (ed): Immunological Diseases, ed 2. Boston, Little, Brown & Company, 1971, vol 2, pp 944-951. 11. B\l=a"\fverstedtB: Erythema nodosum migrans. Acta Derm Venereol 34:181-193, 1954. 12. B\l=a"\fverstedtB: Erythema nodosum migrans. Acta Derm Venereol 48:381-384, 1968. 13. Hannuksela M: Erythema nodosum migrans. Acta Derm Venereol 53:313-317, 1973.
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14. R\l=o"\cklH: Die Bedeutung der Histopathologie f\l=u"\rdie Diagnostik knotiger Unterschenkel\x=req-\
Dermatosen. Hautarzt 19:540-547, 1968. 15. Vilanova X, Pi\l=n~\olAguad\l=e'\JP: Hypodermite nodularie subaigu\l=e"\migratrice. Ann Dermatol Syphiligr 83:369-404, 1956. 16. Vilanova X, Pi\l=n~\olAguad\l=e'\J: Subacute nodular migratory panniculitis. Br J Dermatol
71:45-50, 1959. 17. Perry HO, Winkelmann RK: Subacute nodular migratory panniculitis. Arch Dermatol 89:170-179, 1964. 18. Hirokawa K, Nishido T, Okuda M: Post-
panniculitis with cerebral vascular and pulmonary complications: Report of an autopsy case. Acta Pathol Jap 22:565-579, 1972. steroid
