subcutaneous sarcoidosis: is it a specific subset of cutaneous sarcoidosis frequently associated...
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Subcutaneous sarcoidosis: Is it a specific subsetof cutaneous sarcoidosis frequently associated
with systemic disease?
Iftikhar Ahmed, MD, and Sujata R. Harshad, MD
Rochester, Minnesota
Background: Skin is involved in 25% of cases of sarcoidosis. The lesions are specific and nonspecificdepending on the presence or absence of granulomas, respectively. Specific lesions are not thought to haveprognostic significance and are not associated with systemic disease.
Objective: We sought to evaluate for the presence or absence of systemic disease in patients withsubcutaneous sarcoidosis.
Methods: With diagnostic criteria of subcutaneous sarcoidosis, 33 cases were identified in the literatureand 21 cases in our institutional database. A retrospective clinical and pathologic review of these cases wasconducted.
Results: Subcutaneous sarcoidosis is characterized by a peak incidence during the fourth decade; femalepredisposition; asymptomatic to slightly tender lesions typically involving the upper extremities; cutaneouslesional clustering and multiplicity; autoimmune disease associations at time of diagnosis in a subset ofcases; systemic disease associations at diagnosis in most patients, typically consisting of bilateral hilaradenopathy; and a favorable response to oral corticosteroid therapy.
Limitations: Retrospective analysis with inadequate documentation of therapeutic regimens and theirresponses in some cases is a limitation of this study.
Conclusions: The confirmatory diagnosis of subcutaneous sarcoidosis depends on identifying pannicularnoninfectious sarcoidal or epithelioid granulomas with minimal lymphocytic inflammation. Subcutaneoussarcoidosis is the only specific subset of cutaneous sarcoidosis frequently associated with systemic disease.( J Am Acad Dermatol 2006;54:55-60.)
Sarcoidosis is a multisystem granulomatousdisorder of unclear origin.1 Cutaneous involve-ment is seen in 25% of cases typically at disease
outset.1 Skin lesions are heterogeneous and classi-fied as specific and nonspecific on the basis of thepresence or absence of sarcoidal granulomas,
From the Department of Dermatology, Mayo Clinic.
Dr Harshad was a Visiting Clinician and is currently on faculty at
St John’s Medical College, Bangalore, India.
Funding sources: None.
Conflicts of interest: None identified.
Accepted for publication October 2, 2005.
Reprints not available from the authors.
Correspondence to: Iftikhar Ahmed, MD, Department of Der-
matology, Mayo Clinic, 200 First St SW, Rochester, MN 55905.
Published online December 5, 2005.
0190-9622/$32.00
ª 2005 by the American Academy of Dermatology, Inc.
doi:10.1016/j.jaad.2005.10.001
respectively.2 It is thought that specific skin lesionsdo not have prognostic significance and do notcorrelate with the presence of systemic disease.3,4
Herein, we present a retrospective review of pub-lished cases of sarcoidosis in which we identifiedsubcutaneous sarcoidosis on the basis of the diag-nostic criteria of Vainsencher and Winkelmann.5 Wealso present a retrospective review of the singlelargest series of cases of subcutaneous sarcoidosisdiagnosed and managed at our institution. Ourobservations conclusively demonstrate the strongassociation between subcutaneous lesions and sys-temic disease in sarcoidosis.
METHODSAfter receiving approval from our institutional
review board, our dermatopathology files werereviewed for the years 1966 to 2001 for all cases
55
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56 Ahmed and Harshad
filed under the diagnoses of sarcoidosis, nonspecificgranulomas, and granulomatous panniculitis.Routine hematoxylin and eosinestained sections ofall cases and any available specially stained tissuesections (Gram, Fite, acid-fast, and methenaminesilver stains) were examined. The selection criteriafor cases of subcutaneous sarcoidosis were basedon the criteria of Vainsencher and Winkelmann,5
including the identification of epithelioid or sarcoi-dal granulomaswithminimal lymphocytic inflamma-tion involving predominantly the panniculus, withnegligible involvement of the hypodermis (Fig 1).None of the cases selected showed evidence ofmicro-organisms (bacterial, fungal, ormycobacterial)either on tissue culture or with histologic specialstains. In addition, all the cases were negative forextraneous material on polarization microscopy ofroutine sections. A total of 21 cases were identified.The clinical and laboratory data of these patientswere recorded. None of the selected cases have beenreported previously from this institution.
Fig 1. Epithelioid, or sarcoidal, granulomas with minimallymphocytic inflammation involving panniculus. Minimaldermal involvement is acceptable for diagnosis of sub-cutaneous sarcoidosis as long as panniculus is involved.(Hematoxylin-eosin stain; original magnification 3100.)
Fig 2. Multiple skin-colored, indistinct, subcutaneousnodules on back and ventral aspects of right forearm.Lesions had firm palpable quality. At patient evaluation,differential diagnosis included multiple lipomas.
RESULTSThe 21 patients whose cases were identified in
our database included 15 women and 6 men, with afemale:male ratio of 2.5:1. All the patients exceptone (from Latin America) were white. The mean agewas 46.3 years (range: 29-61 years). The duration ofdisease was known for 20 patients and was from1 week to 10 years at the time of diagnosis. A total of18 patients (90%) had disease duration longer than1 year. The family history was noncontributory for allpatients, and no obvious preceding cause was iden-tifiable in any patient.
The skin lesions were typically asymptomatic (12patients [57%]) to mildly tender (9 patients [43%])(Figs 2 and 3). The lesions were the color of normalskin in 6 of 20 patients (30%), erythematous in 10(50%), violaceous in 2 (10%), and hyperpigmented in2 (10%). Lesional multiplicity was usually observed([6 lesions in 18 of 21 patients [86%]). In 14 of these18 patients (78%), the dimensions of individuallesions were between 1 and 4 cm. Lesions werecharacteristically located on the extremities andusually bilateral and asymmetric (upper extremityin 21 patients, lower extremity in 16, trunk in 6,buttock in 2, and forehead in 1). In 20 of the 21patients (95%), more than one anatomic site wasinvolved, and all these patients had lesions on anupper extremity. Other types of lesions of sarcoido-sis coexisted with the subcutaneous lesions in 15patients (71%) and included plaques (6 patients),papules (4 patients), erythema nodosum (4 patients),and scar sarcoid (1 patient). In 16 of the 20 patients(80%) who had a systematic evaluation, a systemicdisease component was recognized at the timesubcutaneous sarcoidosis was diagnosed (Table I).All 16 of these patients had pulmonary involvement,which was documented with chest radiography.Bilateral hilar adenopathy was identified in 15 ofthe 16 patients (94%). In 6 of these cases,
Fig 3. Solitary large skin-colored subcutaneous noduleoverlying elbow joint. Lesion could be moved over jointand had firm palpable quality. At patient evaluation,differential diagnosis included inflamed bursa.
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Table II. Association between abnormallaboratory test results and abnormal chestradiographs in patients with subcutaneoussarcoidosis
Laboratory test
No. of patients with
abnormal (elevated)
result/total no. of
patients tested (%)
Abnormal chest
radiograph, no.
of patients
Angiotensin-convertingenzyme
3/11 (27) 3
Calcium 3/18 (17) 2Erythrocyte
sedimentation rate7/19 (37) 6
Gammaglobulin 3/11 (27) 1
Cases from Mayo Clinic database.
Table I. Systemic disease identified at outset in16 patients with subcutaneous sarcoidosis
Systemic disease No. of patients
Pulmonary 16Arthritis 3Peripheral neuropathy 2Renal 2Uveitis 2Parotitis 1Dactylitis 1Mucositis (nasal, oral, conjunctival) 3
Cases from Mayo Clinic database.
Table III. Response to treatment of patients with subcutaneous sarcoidosis
Type of response
No. of
patients
Primary treatment
(No. of patients) Secondary treatment (No. of patients)
Complete remission(skin and systemic)
3 NSAIDs (3) None
Complete remission(skin) and partialremission (systemic)
5 Oral corticosteroids (5) Clofazimine 1 methotrexate 1 hydroxychloroquine(Plaquenil) (1); intralesional corticosteroids (1)
Remission (skin) withsubsequent recurrences
4 Oral corticosteroids (4) Methotrexate 1 NSAIDs (1)
Partial remission 2 NSAIDs Dapsone (1)
Cases from Mayo Clinic database.
NSAID, Nonsteroidal anti-inflammatory drug.
paratracheal adenopathy and pulmonary infiltrateswere also present. Pulmonary infiltrates were iden-tified in the one patient with no hilar adenopathy.Involvement of other organ systems was docu-mented subjectively and objectively (Table I).Various autoimmune disease associations werenoted at the outset in 6 of 21 patients (29%) andincluded Hashimoto thyroiditis in two patients,rheumatoid arthritis in two patients, and ulcerativecolitis, systemic lupus erythematosus, and sicca syn-drome in one patient each. Only one patient hadtwo coexisting autoimmune diseases (Hashimotothyroiditis and ulcerative colitis) at diagnosis.Laboratory abnormalities were not usually notedeither at diagnosis or on subsequent follow-up(Table II) and, when noted, they typically occurredin conjunction with abnormal radiographic findings.Adequate follow-up (mean 3.5 years; range 1 month-27 years and 10 months) was available for 14 patients(67%). Of these 14 patients, 12 (86%) had completeremission of the skin lesions (Table III), and for 9 ofthese patients, oral corticosteroids were the primarymodality of therapy. The dosage of corticosteroids
used was from 20 to 40 mg daily, and responses weretypically seen 4 to 8 weeks after the initiation oftherapy.
DISCUSSIONSarcoidosis is a multisystem granulomatous dis-
order of unclear cause.1 It is a global disease thataffects both sexes in all races and age groups. Thepeak incidence typically occurs between the secondand third decades, with a second peak occurring inwomen between the fourth and sixth decades.6 Inthe United States, the annual racial incidence is 10to 14/100,000 for Caucasians and 35.5 to 64/100,000for African Americans, with the highest incidence(107/100,000) among African American women age30 to 39 years.7,8
Cutaneous involvement is seen in 25% of cases ofsarcoidosis, typically at the time of diagnosis.1 Skinlesions are categorized into specific and nonspecificlesions on the basis of the presence or absence ofsarcoidal granulomas, respectively.2 It had beenassumed that specific skin lesions of sarcoidosishave no prognostic significance and are not
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Table IV. Features of 33 reported cases of subcutaneous sarcoidosis
Reference Sex/age, y Site of skin lesions Systemic disease
Darier and Roussy12 F/36 Trunk Enlarged LNs (axillary and inguinal)F/43 Trunk Enlarged LNs (axillary and inguinal)
Schaumann13 M/23 Trunk, extremities Enlarged LNs (hilar)Laplane14 F/51 Lower extremity Enlarged LNs (hilar)Gorl15 F/50 Trunk Parotitis, lung infiltrateGougerot et al16 M/70 Trunk, face, extremities Not reportedMaloney and Combes17 M/39 Trunk, buttock, lower extremity Not reported
F/11 Upper extremity Increased pulmonary markingsMarten and Warner18 M/21 Extremities Positive Kveim test, conjunctivitis, enlarged
LNs (hilar)Schirmer19 M/18 Neck, trunk, extremities Enlarged LNs (hilar)Clayton and Wood20 M/41 Face, trunk, extremities Enlarged LNs (hilar)Gross et al*21 M/20 Heak, neck, trunk, extremities Uveitis, hepatosplenomegaly, enlarged
LNs (hilar)Scadding22 F/30 Upper extremity Enlarged LNs (hilar)Vainsencher and Winkelmann5 F/45 Upper extremity Not known
F/54 Extremities Uveitis, parotitis, neuritisM/44 Face, trunk, extremities Enlarged LNs (hilar), parotitis, dactylitis, lacrimal
gland involvementF/50 Upper extremity Enlarged LNs (hilar)
Boyd and Andrews*23 M/24 Extremities Enlarged LNs (hilar and paratracheal)Marzano et al24 F/33 Upper extremity Enlarged LNs (hilar), elevated ACE levelGirao et al25 M/37 Lower extremity Enlarged LNs (hilar and mediastinal), elevated
ACE levelKuramoto et al26 M/24 Lower extremity, buttocks Enlarged LNs (hilar)Weltfriend et al27 F/74 Extremities Enlarged LNs (hilar), elevated ACE levelKroll et al28 F/52 Upper extremity Enlarged LNs (hilar), interstitial pulmonary
infiltrates, parotitis, positive Kveim testGallimore et al29 F/65 Trunk Not reportedHiggins et al30 F/61 Trunk, buttocks Elevated ACE level, positive Kveim test, parotitisCurco et al31 F/60 Extremities Elevated ACE level, dactylitisOhi et al32 M/33 Lower extremity Elevated ACE level, lung granulomasLosada et al33 M/52 Upper extremity, trunk Elevated ACE level, enlarged LNs (hilar)Voelter-Mahlknecht et al34 M/30 Trunk, groin Elevated ACE level, enlarged LNs (mediastinal)Barnadas et al35 F/38 Extremities Abnormal pulmonary function testsMingins et al36 F/70 Trunk Elevated ACE levelRuiz de Erenchun et al37 M/61 Extremities Elevated ACE level, parotitis, enlarged LNs (hilar
and mediastinal)Shidrawi et al38 M/35 Head, neck, extremities Elevated ACE level, enlarged LNs (hilar),
pulmonary interstitial disease
Cases were identified with use of the criteria of Vainsencher and Winkelmann.5
ACE, Angiotensin-converting enzyme; F, female; LN, lymph node; M, male.
*African American.
correlated with the presence of systemic disease.3,4
In contrast, nonspecific lesions such as erythemanodosum have been shown to portend a favorableprognosis, because of the greater likelihood ofspontaneous resolution of the disease when theseskin lesions occur.9,10 Herein, we present data dem-onstrating a strong association between subcutane-ous sarcoidosis (a specific subset of cutaneoussarcoidosis) and systemic disease.
The skin lesions in sarcoidosis are protean andcommonly include macules, papules, nodules,
plaques, infiltrative scars, and lupus pernio.11
Atypical presentations include ulcerative, psoriasi-form, verrucous, ichthyosiform, hypopigmented,and erythrodermic type lesions.11 Subcutaneous in-volvement is diagnosed by identifying noninfectioussarcoidal or epithelioid granulomas with minimallymphocytic inflammation involving predominantlythe panniculus.5 With the use of these criteria, weretrospectively identified 33 cases of subcutaneoussarcoidosis reported in the literature (Table IV).5,12-38
The clinical details of these cases, in particular the
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relation to systemic disease, were collated and arepresented herein. In addition, we used the samecriteria to identify 21 cases of subcutaneous sarcoid-osis diagnosed and managed at our institution over adefined period.
Patients identified in the literatureOf the 33 patients with subcutaneous sarcoidosis
we identified in the literature, 17 were female and16 were male (Table IV). The female:male ratio was1:1. The mean age was 42.3 years (range: 11-74years). All the patients except two19,22 were white.The extremities were involved in 26 patients (78.8%)and included the upper and lower extremities in 14,the upper extremity in 7, and the lower extremity in5. Other sites of involvement included the trunk in15 patients; the face, head, and neck in 6; and thebuttocks and groin in 4. More than one anatomic sitewas involved in 19 patients (58%). A systemic diseasecomponent was present at the outset and identifiedin 29 patients (88%) at the time the diagnosis ofsubcutaneous sarcoidosis was established. It con-sisted of lymphadenopathy in 21 patients (hilar in 18,hilar plus other in 3, and other in 3), parotitis in 6,lung infiltrates in 4, uveitis in 2, dactylitis in 2, andconjunctivitis, abnormal pulmonary function tests,lacrimal gland involvement, and hepatosplenomeg-aly in 1 patient each. An increased level of angioten-sin-converting enzyme was observed in 11 of 13patients (85%), usually in the presence of a systemicdisease component.
Patients at our institutionFor the 21 patients with subcutaneous sarcoidosis
who were identified in our institutional database,the mean age (46.3 years) was close to that of thepatients reported in the literature, but in contrast tothe reported patients, our cohort was predominantlyfemale. Similar to the reported patients, most of ourpatients were also white (except for one Hispanicpatient). No preceding causative factor or pertinentfamily history was recorded for any patient. Otherfeatures shared by the reported patients and those inour cohort included the common location of lesionson the extremities, typically the upper extremities,and the association with a systemic disease compo-nent at disease outset, notably bilateral hilar ade-nopathy (Table I). We also observed the coexistenceof other types of lesions (specific and nonspecific) ofcutaneous sarcoidosis in two thirds of patients withsubcutaneous involvement. However, the subcuta-neous lesions represented most of the lesions inthese patients and were the principal reason forreferral to dermatology. The confirmatory diagnosisof subcutaneous sarcoidosis depends on, as it did for
all our patients, the histologic demonstration ofnoninfectious sarcoidal or epithelioid granulomaswith minimal lymphocytic inflammation within thepanniculus. In our cohort, an association of subcu-taneous sarcoidosis with various autoimmune dis-eases (not previously recognized) was noted at theoutset in 6 of 21 patients (29%). Laboratory abnor-malities, including angiotensin-converting enzymelevels, were not frequently identified (Table II), butwhen noted, they were typically found in conjunc-tion with abnormal radiographic findings. Adequatefollow-up (mean: 3.5 years) was available for 14 ofour 21 patients (67%), and therapeutic responses ofat least the skin lesions to oral corticosteroids wereobserved in all the patients for whom corticosteroidswere the primary modality of therapy (Table III). Thedosages of oral corticosteroids varied from 20 to 40mg daily and responses were typically observedwithin 4 to 8 weeks after the initiation of therapy. Inall, 5 patients received treatment with various non-steroidal antiinflammatory drugs and 3 of them hadcomplete remission of skin and systemic lesions,usually from 6 to 8 weeks after treatment was started.Various secondary treatment modalities were usedwhen partial responses of skin and systemic lesionsoccurred with oral corticosteroids and nonsteroidalantiinflammatory drugs or when skin lesions re-curred after having completely regressed with initialtherapy (Table III). However, because the responsesto these secondary therapeutic agents were notclearly documented in our patients, the details ofthese treatments are not described.
SummarySubcutaneous sarcoidosis is a specific subset of
cutaneous sarcoidosis of unclear origin character-ized by: (1) a peak incidence during the fourthdecade; (2) female predisposition; (3) asymptomaticto slightly tender subcutaneous lesions typicallyinvolving the upper extremities; (4) cutaneous le-sional multiplicity and clustering; (5) autoimmunedisease associations at the outset in a subset ofpatients; (6) strong association with a systemic dis-ease component at the outset of disease, notablybilateral hilar adenopathy; (7) noninfectious pannic-ular sarcoidal or epithelioid granulomas with mini-mal lymphocytic inflammation; and (8) a favorableresponse to oral corticosteroid therapy.
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