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Dermatology > BENIGN NEOPLASMS
Multicentric Reticulohistiocytosis
Article Last Updated: Mar 10, 2008
AUTHOR AND EDITOR INFORMATION
Section 1 of 10  
Author: Ronald P Rapini, MD, Professor and Chair, Department of Dermatology, Professor of Pathology, University of Texas Medical School, MD Anderson Cancer Center
Ronald P Rapini is a member of the following medical societies: American Academy of Dermatology, American Dermatological Association, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Society for Investigative Dermatology, Southern Medical Association, and Texas Medical Association
Editors: Takeji Nishikawa, MD, Emeritus Professor, Department of Dermatology, Keio University School of Medicine; Director, Samoncho Dermatology Clinic; Managing Director, The Waksman Foundation of Japan Inc; Richard P Vinson, MD, Assistant Clinical Professor, Department of Dermatology, Texas Tech University School of Medicine; Consulting Staff, Mountain View Dermatology, PA; Rosalie Elenitsas, MD, Associate Professor of Dermatology, University of Pennsylvania School of Medicine; Director, Penn Cutaneous Pathology Services, Department of Dermatology, University of Pennsylvania Health System; Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University; William D James, MD, Paul R Gross Professor of Dermatology, University of Pennsylvania School of Medicine; Vice-Chair, Program Director, Department of Dermatology, University of Pennsylvania Health System
Author and Editor Disclosure
Synonyms and related keywords:
MRH, lipoid dermatoarthritis, lipoid rheumatism, giant cell reticulohistiocytosis, arthritis mutilans, arthritis
Background
Multicentric reticulohistiocytosis (MRH) is a rare disease in which papulonodular skin lesions containing a proliferation of true histiocytes (macrophages) are associated with arthritis. The arthritis involves the interphalangeal joints and becomes severe enough to cause severe destruction of the joints (known as arthritis mutilans) in 45% of cases (see Media File 1). The disease can involve the bones, the tendons, the muscles, the joints, and nearly any other organ (eg, eyes, larynx, thyroid, salivary glands, bone marrow, heart, lung, kidney, liver, gastrointestinal tract). It has been associated with an underlying internal malignancy in about one fourth of cases, suggesting that MRH may be a paraneoplastic condition. The proliferating histiocytes in this disease are thought to be reactive and are not themselves malignant. Also see Multicentric Reticulohistiocytosis. MRH has at least 10 synonyms (eg, lipoid dermatoarthritis), but multicentric reticulohistiocytosis is now clearly the preferred appellation. Goltz and Laymon proposed the name multicentric reticulohistiocytosis in 1954 to distinguish this disease from the occurrence of histologically identical solitary cutaneous nodules called reticulohistiocytomas, which are not at all associated with systemic disease. Skin nodules may be clinically confused with rheumatoid nodules, xanthomas, dermatofibromas, progressive nodular histiocytomas, juvenile xanthogranulomas, lepromatous leprosy, Farber disease (lipogranulomatosis), gouty tophi, and sarcoidosis. Usually, the clinical findings combined with histologic and radiographic findings allow an easy distinction. Solitary nodules identical to MRH can occur. These nodules are not associated with systemic disease and are called reticulohistiocytomas or reticulohistiocytic granulomas. The name MRH should not be confused with congenital self-healing reticulohistiocytosis, which is now considered to be a form of Langerhans cell histiocytosis (histiocytosis X). True malignant histiocytosis is extremely rare; however, in that disease, the histiocytes themselves are malignant (unlike MRH), and the condition is associated with lymphadenopathy, hepatosplenomegaly, and often a rapidly fatal course. Arthritis and skin lesions may also occur in osteoarthritis, rheumatoid arthritis, psoriatic arthritis, Reiter disease, lupus erythematosus, and gout. Osteoarthritis may produce firm nodules around the fingers but rarely elsewhere. None of these diseases has a polyarthritis that is as rapidly destructive as MRH. Patients with rheumatoid arthritis have severe involvement of the metacarpophalangeal (MCP) joints and the metatarsophalangeal joints rather than the interphalangeal joints, though the proximal interphalangeal (PIP) joints can be moderately involved, and osteoporosis develops. Psoriatic arthritis often involves the distal interphalangeal (DIP) joints. Reiter disease most commonly involves the lower extremities and the sacroiliac joints. Gouty erosions in joints are asymmetric. They progress slowly, and articular cartilage is preserved. Calcification of the tophi may be apparent.
The Medscape Arthritis and Rheumatoid Arthritis Resource Centers may be helpful. Medscape CME courses include Hematologic Malignancies and Anti-TNF-Directed Therapies in Rheumatoid Arthritis and Update on Rheumatoid Arthritis Therapies.
Pathophysiology
The details of the etiology are unknown. The old name lipoid dermatoarthritis reflects the previous assumption that the disease might be a storage disease because some patients had hypercholesterolemia and xanthelasma, but these findings are now thought to have been an unrelated coincidence. The disease is now thought to be mainly related to a proliferation of true histiocytes (macrophages that are derived from monocytes), which have a characteristic abundant eosinophilic ground-glass cytoplasm. This proliferation may be a paraneoplastic response to an underlying malignancy in at least a fourth of cases.
Frequency
International
Worldwide, MRH is very rare. The average dermatologist, rheumatologist, or orthopedist will see at most 1-2 cases in an entire career.
Mortality/Morbidity
The disease can cause considerable morbidity, mainly related to the occurrence of severe arthritis. This arthritis can come and go, but it can be very severe in about 45% of cases. The skin lesions also have the potential for spontaneous resolution.
- MRH may become inactive after several years, often after about 8 years.
- Morbidity or mortality can occur from the underlying malignancy. Even after the disease remits, some patients are left with crippling, deformed joints or a disfigured leonine facies.
Race
MRH affects all races, but about 88% of the reported cases have been in white patients.
Sex
Like many other rheumatologic diseases, females are affected more often than men. The ratio of women to men for MRH is 3:1.
Age
MRH can be found in teenagers or in elderly persons, but it most commonly begins in early middle age, with the average age of onset at about 43 years.
History
- About one half of patients initially develop polyarthritis. One fourth of patients first develop the skin papules and the nodules. Another one fourth of patients develop skin and joint manifestations at the same time.
- Skin lesions are usually asymptomatic.
- One third of patients complain of pruritus.
- Arthritis may wax and wane, but it can rapidly become severe.
- About one third of patients have constitutional symptoms, such as weakness, weight loss, and fever.
Physical
- Skin lesions are skin colored to reddish brown.
- Lesions vary from papules that are 1-2 mm in diameter to nodules that are several centimeters in diameter.
- Papules and lesions may be isolated from one another, or they may be clustered, sometimes giving a cobblestone appearance (see Media File 3).
- The Koebner phenomenon has been reported, wherein trauma to the skin gives rise to new lesions.
- Skin lesions more commonly occur on the upper half of the body, but other areas can be involved.
- Face and hands (90%)
- Ears (76%)
- Forearms (55%)
- Elbows (40%)
- Scalp (40%)
- Mucosal surfaces, such as the lips, the tongue, the gingiva, and the nasal septum (50%)
- Several miscellaneous nail changes have been described, but most are due to adjacent arthritis.
- About one third of patients have been reported to have xanthelasma, but whether or not this is related to MRH is unclear.
- MRH is a polyarthritis involving a wide variety of joints.
- Hands (76%)
- Knees (73%)
- Shoulders (64%)
- Wrists (64%)
- Hips (61%)
- Ankles (58%)
- Elbows (58%)
- Feet (58%)
- Spine (52%)
Causes
Most cases of MRH are of unknown cause, but, in about 28% of cases, the disease appears to be caused by a paraneoplastic disorder related to an underlying malignancy. MRH precedes the development of cancer in 73% of cases. Whether the malignancy is truly related to MRH is debated for several reasons.
- No consistent type of neoplasm is associated with MRH. Most of the reported specific cancer types are reported less than 5 times each in the literature.
- Because MRH is rare, a reporting bias exists in the literature toward reporting those cases with underlying malignancy, especially previously unreported malignancies. Some of these associations may be a coincidence.
- The activity of the arthritis and the skin lesions of MRH may or may not be correlated with the eradication of the cancer, unlike some paraneoplastic disorders where removal of the malignancy may produce improvement in the paraneoplastic findings.
- Some patients with MRH have been extensively studied or an autopsy has been performed with no evidence of cancer.
- MRH has been reported with cancer of the breast (scirrhous, intraductal, unspecified types), cervix, colon (adenocarcinoma), stomach (adenocarcinoma), lung (bronchogenic carcinoma, mesothelioma of pleura), bronchus, larynx, ovary (medullary carcinoma, adenocarcinoma),1 lymphoma, leukemia, sarcoma (omentum, axilla), and melanoma. MRH has also been reported with cancers of unknown primary.
Leprosy
Other Problems to be Considered
Rheumatoid nodules
Progressive nodular histiocytomas
Farber disease (lipogranulomatosis)
Gouty tophi
Osteoarthritis
Rheumatoid arthritis
Gout
Lab Studies
- About one half of patients may have an elevated erythrocyte sedimentation rate or anemia.
- Some patients have thyroid function abnormalities.
- About 6% of patients have diabetes.
- One third of patients have hypercholesterolemia, often associated with xanthelasma, but this seems to be unrelated to MRH.
- Rheumatoid factor is characteristically negative, but it has been reported to be positive in at least 4 cases.
- Occasionally, patients have had paraproteinemia, cold agglutinins, cryoglobulinemia, or hypergammaglobulinemia.
- Synovial fluid findings are variable, and reports exist of elevated counts of neutrophils or mononuclear cells.
Imaging Studies
- Routine radiographs of joints may be helpful. Changes are most commonly seen in the interphalangeal joints (PIP or DIP).
- Bilaterally symmetric, sharply circumscribed erosions spread from the margins to the joint surfaces.
- Separation of the bone ends often occurs, but no subchondral sclerosis and little or no periosteal reaction are seen.
- Osteoporosis is mild or absent.
- Erosions in osteoarthritis begin centrally rather than at the joint margins.
- In psoriatic arthritis and Reiter disease, erosions are asymmetric and have poorly defined margins; the erosions are also associated with periosteal new bone formation.
- MRI2 and CT scanning3 have been reported to be helpful, but they are not needed in most cases.
- Gallium scans and bone scans have been used in the past; however, recommending them routinely is difficult because of their nonspecificity.
Histologic Findings
The papulonodules of the skin and the larynx consist of a diffuse infiltration of true histiocytes (macrophages) that tend to have abundant ground-glass (nonfoamy) cytoplasm. When the skin lesions are present, skin is the easiest site from which to obtain a biopsy specimen. Sometimes these histiocytes are found after blind biopsies of synovium in patients with unclassified arthritis, who lack the skin lesions.4 The characteristic histiocytes can be huge or bizarre, and they may be multinucleated. Varying numbers of lymphocytes or eosinophils may be present. The cytoplasm of the histiocytes stains with the periodic acid-Schiff (PAS) stain. Although positive staining with Sudan black B and scarlet red indicates the presence of lipid within these cells, they are not usually foamy to the degree found in many other histiocytic disorders. The cells stain with the usual macrophage markers, such as lysozyme, CD68, MAC387, or human alveolar macrophage-56 (HAM-56). Staining for S-100, CD1a, CD34, factor XIIIa, or alpha-1-antitrypsin is typically negative.
Medical Care
No therapy consistently improves MRH. After an average course of 8 years, patients often go into remission, but considerable joint destruction may have already occurred. Many different drugs have been used. (A common quip is that those diseases for which many treatment options exist often have no particular useful therapy.) None of these is covered in great detail here because of the lack of uniformly accepted therapy. The response to therapy is difficult to determine because of the rarity of the disease, lack of controlled studies, and tendency for the remission to complicate evaluation of efficacy. Most of the previously reported therapies include the following:
- First-line therapies
- Systemic corticosteroids (eg, prednisone, prednisolone, dexamethasone high-dose pulse)
- Intralesional corticosteroids (eg, triamcinolone acetonide)
- Nonsteroidal anti-inflammatory drugs (eg, aspirin, indomethacin)
- Second-line therapies
- Psoralen plus ultraviolet light (PUVA)
- Antimalarials (eg, chloroquine, hydroxychloroquine5)
- Cyclophosphamide6
- Chlorambucil
- Azathioprine
- Vincristine
- Methotrexate5, 6, 7
- Topical nitrogen mustard
- Antitumor necrosis factor-alpha drugs8 (eg, etanercept,9 infliximab10)
- Bisphosphonate drugs (eg, alendronate, zoledronic acid11)
- Concomitant combinations of several of the above therapies5
Surgical Care
- Orthopedic surgery may be useful for joint deformities.
- General surgeons and other surgeons may be needed to excise internal malignancies that may occur.
Consultations
- Dermatologists and rheumatologists often see patients with MRH.
- Oncologists or surgeons may be needed if internal malignancy occurs.
- Other specialists are occasionally needed if internal organs are involved.
Complications
- Even after the disease remits, some patients are left with crippling, deformed joints or a disfigured leonine facies.
Prognosis
- After an average course of 8 years, patients often go into remission. The disease can cause considerable morbidity, mainly related to the occurrence of severe arthritis. The arthritis can come and go, but it can be very severe in about 45% of cases.
- Morbidity or mortality can occur from the underlying malignancy.
Patient Education
Medical/Legal Pitfalls
- Failure to perform an evaluation for an internal malignancy is a pitfall. Because some patients with MRH may have an underlying malignancy, evaluation for a possible malignancy is important. Patients ought to have at least a good review of systems to direct appropriate additional studies.
- Failure to rule out other forms of arthritis is a pitfall. MRH may be mistaken for other forms of arthritis. Because MRH can be severely mutilating in some cases, the diagnosis should be considered for patients with severe arthritis. Because many other forms of arthritis are often treated in a similar way, missing the diagnosis in the early stages may not have serious consequences.
| Media file 1:
Nodules on a hand with deformed joints from arthritis due to multicentric reticulohistiocytosis. |
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| Media file 3:
Cobblestone papules on the eyelid and papules on the forehead. |
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| Media file 4:
Low-power view of the histologic features of a biopsy sample of large histiocytes and multinucleated giant cells in the dermis. |
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| Media file 5:
High-power view of the histologic features of large histiocytes in the dermis. |
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| Media file 6:
Brown immunoperoxidase staining for lysozyme in histiocytes. |
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- Kishikawa T, Miyashita T, Fujiwara E, Shimomura O, Yasuhi I, Niino D, et al. Multicentric reticulohistiocytosis associated with ovarian cancer. Mod Rheumatol. Oct 2007;17(5):422-5. [Medline].
- Yamada T, Kurohori YN, Kashiwazaki S, Fujibayashi M, Ohkawa T. MRI of multicentric reticulohistiocytosis. J Comput Assist Tomogr. Sep-Oct 1996;20(5):838-40. [Medline].
- Kamel H, Gibson G, Cassidy M. Case report: the CT demonstration of soft tissue involvement in multicentric reticulohistiocytosis. Clin Radiol. Jun 1996;51(6):440-1. [Medline].
- Kroot EJ, Weel AE, Hazes JM, Zondervan PE, Heijboer MP, van Daele PL, et al. Diagnostic value of blind synovial biopsy in clinical practice. Rheumatology (Oxford). Feb 2006;45(2):192-5. [Medline].
- Cash JM, Tyree J, Recht M. Severe multicentric reticulohistiocytosis: disease stabilization achieved with methotrexate and hydroxychloroquine. J Rheumatol. Nov 1997;24(11):2250-3. [Medline].
- Liang GC, Granston AS. Complete remission of multicentric reticulohistiocytosis with combination therapy of steroid, cyclophosphamide, and low-dose pulse methotrexate. Case report, review of the literature, and proposal for treatment. Arthritis Rheum. Jan 1996;39(1):171-4. [Medline].
- Rentsch JL, Martin EM, Harrison LC, Wicks IP. Prolonged response of multicentric reticulohistiocytosis to low dose methotrexate. J Rheumatol. May 1998;25(5):1012-5. [Medline].
- Shannon SE, Schumacher HR, Self S, Brown AN. Multicentric reticulohistiocytosis responding to tumor necrosis factor-alpha inhibition in a renal transplant patient. J Rheumatol. Mar 2005;32(3):565-7. [Medline].
- Lovelace K, Loyd A, Adelson D, Crowson N, Taylor JR, Cornelison R. Etanercept and the treatment of multicentric reticulohistiocytosis. Arch Dermatol. Sep 2005;141(9):1167-8. [Medline].
- Sellam J, Deslandre CJ, Dubreuil F, Arfi S, Kahan A. Refractory multicentric reticulohistiocytosis treated by infliximab: two cases. Clin Exp Rheumatol. Jan-Feb 2005;23(1):97-9. [Medline].
- Mavragani CP, Batziou K, Aroni K, Pikazis D, Manoussakis MN. Alleviation of polyarticular syndrome in multicentric reticulohistiocytosis with intravenous zoledronate. Ann Rheum Dis. Oct 2005;64(10):1521-2. [Medline].
- Barrow MV, Holubar K. Multicentric reticulohistiocytosis. A review of 33 patients. Medicine (Baltimore). Jul 1969;48(4):287-305. [Medline].
- Brackenridge A, Bashir T, Wheatley T. Multicentric reticulohistiocytosis and pregnancy. BJOG. May 2005;112(5):672-3. [Medline].
- Kovach BT, Calamia KT, Walsh JS, Ginsburg WW. Treatment of multicentric reticulohistiocytosis with etanercept. Arch Dermatol. Aug 2004;140(8):919-21.
- Luz FB, Gaspar AP, Ramos-e-Silva M, Carvalho da Fonseca E, Villar EG, Cordovil Pires AR, et al. Immunohistochemical profile of multicentric reticulohistiocytosis. Skinmed. Mar-Apr 2005;4(2):71-7. [Medline].
- Mody GM, Cassim B. Rheumatologic manifestations of malignancy. Curr Opin Rheumatol. Jan 1997;9(1):75-9. [Medline].
- Rapini RP. Multicentric reticulohistiocytosis. Clin Dermatol. Jan-Mar 1993;11(1):107-11. [Medline].
- Tajirian AL, Malik MK, Robinson-Bostom L, Lally EV. Multicentric reticulohistiocytosis. Clin Dermatol. Nov-Dec 2006;24(6):486-92. [Medline].
- Trotta F, Castellino G, Lo Monaco A. Multicentric reticulohistiocytosis. Best Pract Res Clin Rheumatol. Oct 2004;18(5):759-72.
Multicentric Reticulohistiocytosis excerpt Article Last Updated: Mar 10, 2008
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