Multicentric Reticulohistiocytosis a Unique Case with Pulmonary Fibrosis
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OBSERVATION Multicentric Reticulohistiocytosis A Unique Case With Pulmonary Fibrosis Kelly L. West, MD, PhD; Tom Sporn, MD; Puja K. Puri, MD Background: Multicentric reticulohistiocytosis (MRH) accompanied by notable lymphoid aggregates, a pattern is a rare disease of uncertain etiology that most com- of interstitial lung disease typical of systemic autoim- monly presents as a papulonodular cutaneous eruption mune and inflammatory conditions. accompanied by erosive polyarthritis. Although MRH is considered a systemic disorder in that it targets skin and Conclusions: These findings are notable because a joints, involvement of thoracic and visceral organs is un- histiocytic pulmonary infiltrate suggestive of direct pul- common. monary involvement by MRH is a rare event. In addi- tion, presentation of MRH in the setting of usual inter- Observations: A woman presented with diffuse cuta- stitial pneumonia is unique. These observations document neous nodules, and skin biopsy findings revealed clas- a new clinical and histopathologic presentation of MRH sic features of MRH. However, she also manifested se- that is significant for expanding the idea of MRH as a sys- vere pulmonary symptoms. A lung biopsy specimen temic disease while supporting the notion that MRH is showed prominent histiocytic infiltrates exhibiting the promoted by an inflammatory milieu. same characteristic morphologic features as those seen in her skin. Furthermore, the lung biopsy findings were significant for a pattern of usual interstitial pneumonia Arch Dermatol. 2012;148(2):228-232 ULTICENTRIC RETICULO- 50% of cases), hyperlipidemia (30%-58% of histiocytosis (MRH) is cases), and malignancy.11 a disease of unknown The association with malignancy is rela- etiology characterized tively common and has been reported in by diffuse skin lesions 15% to 31% of cases of MRH.12 Malig- and destructive polyarthritis. It was first de- nancy may be preceded by or be present M1 scribed in 1937 in a 35-year-old man with concomitantly with the cutaneous mani- a 6-month history of fevers, joint pain, and festations of MRH, and regression of MRH cutaneous nodules. The histiocytic nature has been reported subsequent to tumor of the disease was elucidated in 1944 by in- treatment.12 No single malignant process tralesional olive oil injection followed by bi- is implicated, and reported cases include opsy results demonstrating phagocytosis.2 melanoma, mesothelioma, lymphoma, and The term multicentric reticulohistiocytosis carcinomas of the penis, stomach, ovary, was coined in 1954,3 highlighting the sys- endometrium, breast, and cervix.13 temic, multicentric nature of the disease and The clinical differential diagnosis of its origin from cells of the reticuloendothe- MRH may be extremely broad. If erosive lial system. arthritis predominates, then rheumatoid Multicentric reticulohistiocytosis is rare, arthritis, psoriatic arthritis, Reiter syn- with approximately 200 cases reported in drome, and gout are major diagnostic con- the literature to date.4 The disease mani- siderations.5,14 If cutaneous lesions predomi- Author Affiliations: fests most commonly in middle-aged nate, the differential diagnosis may include Department of Pathology, Duke women, with a female predominance of ap- xanthomatosis, juvenile xanthogranuloma, University Medical Center, proximately 2:1 to 3:14,5 and an average age generalized eruptive histiocytosis, cutane- Durham (Drs West, Sporn, and at onset of 40 to 50 years.4,5 A few cases have ous Rosai-Dorfman disease, lepromatous Puri; and Center for Molecular 6,7 Biology and Pathology, been reported in children and pregnant leprosy, neurofibromatosis, and sarcoidosis, 8-10 5,15,16 Laboratory Corporation of women. Multicentric reticulohistiocyto- among others. When present, acral or America, Research Triangle Park sis has been associated with tuberculosis or facial nodules in MRH may help to narrow (Dr Puri), North Carolina. a positive tuberculin skin test result (12%- this differential diagnosis. ARCH DERMATOL/ VOL 148 (NO. 2), FEB 2012 WWW.ARCHDERMATOL.COM 228 ©2012 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 A B Figure 1. The patient presented with innumerable 1- to 5-mm cutaneous nodules that were prominent around the nail beds (A) and the perioral region (B). Histopathologic findings reveal a proliferation of large, A multinucleated histiocytic cells characterized by a 2-toned or a “ground-glass” cytoplasm that is finely granular and eosinophilic. Lymphocytes, plasma cells, mast cells, and eosinophils may be variably present in early lesions, but they decrease in number with time as lesions become in- creasingly fibrotic.15 Results of immunohistochemical studies vary; however, in most cases, findings are posi- ␣ tive for CD68, CD45, CD4, HLA-DR, lysozyme, and 1- antitrypsin, whereas CD1a, S-100, CD20, and factor XIIIa generally do not stain.14 The histopathologic differential diagnosis includes soli- tary reticulohistiocytoma and diffuse cutaneous histiocy- tosis. Clinical pathologic correlation is necessary to dis- P tinguish between these entities. Immunohistochemical analysis may be helpful in differentiating MRH from other Figure 2. A computed tomographic scan of the chest was remarkable for 17 bilateral, predominantly lower lobe reticulation and honeycombing. A histiocytoses. For example, Langerhans cell histiocyto- indicates anterior; P, posterior. sis displays a characteristic immunohistochemical profile positive for S-100 and CD1a, whereas both of these im- high-titer positivity), a rheumatoid factor level of 109 IU munohistochemical stains yield negative findings in MRH. (reference level, Ͻ20 IU), and positive findings for anti-Ro and anti-La antibodies. Negative findings included nega- REPORT OF A CASE tive anti–double-stranded DNA, anti-Smith and anti- RNP antibodies, and levels of C3 and C4 within their ref- A 47-year-old African American woman was referred to erence ranges. An anti–crystalloid cardioplegia titer was our institution with several months of fever and joint pain, within the reference range on 2 separate occasions. morning stiffness, and cutaneous nodules. Family his- Radiographic imaging of her hands showed reactive peri- tory was notable for a sister with sarcoidosis and a mother ostitis with proliferative and erosive changes. Imaging of with rheumatoid arthritis. Physical examination re- the chest showed bilateral, predominantly lower lobe re- vealed multiple nontender cutaneous nodules ranging ticulation and honeycombing, which are characteristic fea- from 1 to 5 mm, primarily localized to the base of the tures of usual interstitial pneumonia (UIP) (Figure 2). nails of both hands but also noted around the perioral However, unusual radiographic findings included the pres- region, chin, chest, right thigh, and left upper arm ence of small bilateral pulmonary nodules and bilateral hi- (Figure 1). In some areas, the lesions had coalesced to lar and mediastinal lymphadenopathy. form plaques. In addition, she had diffuse bilateral swell- Given her constellation of findings (UIP, erosive ar- ing of the proximal interphalangeal, metacarpophalan- thritis, and serologic findings), she was initially given a geal, and wrist joints without apparent synovitis to sug- diagnosis of undifferentiated connective tissue disease. gest rheumatoid arthritis. She was treated with high-dose corticosteroids and leflu- Results of laboratory analyses were significant for an nomide, with little effect. Trials of methotrexate and aza- antinuclear antibody level of 1:2560 (corresponding to thioprine had to be discontinued owing to intolerance. ARCH DERMATOL/ VOL 148 (NO. 2), FEB 2012 WWW.ARCHDERMATOL.COM 229 ©2012 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 A B Figure 3. Skin biopsy specimen (hematoxylin-eosin). A, A low-power view (original magnification ϫ4) shows diffuse infiltration of the dermis by histiocytic cells and scattered multinucleated giant cells. B, On closer examination (original magnification ϫ40), the cells within the infiltrate exhibit finely granular, 2-toned cytoplasm. A biopsy of the cutaneous nodules was performed, and eral reports have observed nonspecific pulmonary patho- the specimen revealed a proliferation of large histio- logic findings, including hilar adenopathy,19,20 pulmo- cytes and multinucleated giant cells with ground-glass nary infiltrates,19,21,22 and pleural effusions.19,21-24 cytoplasm (Figure 3). Immunohistochemical staining To our knowledge, only 4 reports have shown pul- for CD68 highlighted the histiocytes, whereas staining monary involvement by MRH based on results of tissue for S-100 yielded negative results. Together, the clinical examination, and ours is the first to describe UIP coin- and histopathologic findings supported a diagnosis of cident with MRH. One case was that of a 56-year-old man MRH. A malignancy workup was recommended at this with multiple nodules in the lungs bilaterally that bi- point; however, it was not completed at our institution. opsy findings suggested were consistent with MRH.25 The To further characterize the patient’s pulmonary dis- second case was that of a 78-year-old man with nonspe- ease, a wedge biopsy specimen of the lung was ob- cific bilateral parenchymal disease and focal nodules.26 tained. Biopsy results showed prominent histiocytic ag- A transbronchial lung biopsy specimen was notable for gregates consisting of large cells and occasional a mixed