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 Table of Contents  
REVIEW ARTICLE
Year : 2018  |  Volume : 13  |  Issue : 3  |  Page : 195-201

Multicentric reticulohistiocytosis: A clinicoradiological review


1 Department of Radiodiagnosis, Post Graduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Dermatology and Venereology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
3 Department of Internal Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, India
4 Department of Histopathology, Post Graduate Institute of Medical Education and Research, Chandigarh, India

Date of Web Publication21-Aug-2018

Correspondence Address:
Dr. Anindita Sinha
Department of Radiodiagnosis, Post Graduate Institute of Medical Education and Research, Chandigarh - 160 012
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/injr.injr_151_17

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  Abstract 


Multicentric reticulohistiocytosis is a rare systemic disease described as a lipoid dermato-arthritis. Characteristic involvement includes multiple skin nodules and progressive arthritis. Involvement of skin, mucosa, and internal organs has been described. Predominant involvement of the distal interphalangeal joint occurs in the hands. Other joints involved are knee, shoulder, and hips. Rarely, vertebral involvement may also occur. A significant association with underlying solid organ as well as hematologic malignancies warrants a thorough workup and imaging screening. Diagnosis is based on histopathologic findings of histiocytic infiltration with multinucleated giant cells. Radiographic manifestations in the multiple joints are characterized by symmetrical destructive and erosive arthritis. Ultrasound of the hands may be helpful in detecting the nodules in characteristic periarticular distribution in early presentations. We describe the common and uncommon clinical and imaging features of early and late manifestations of the disease.

Keywords: Arthritis, histiocytosis, papules, skin


How to cite this article:
Sinha A, Dhungana S, Dipankar De, Prakash M, Sharma SK, Das A. Multicentric reticulohistiocytosis: A clinicoradiological review. Indian J Rheumatol 2018;13:195-201

How to cite this URL:
Sinha A, Dhungana S, Dipankar De, Prakash M, Sharma SK, Das A. Multicentric reticulohistiocytosis: A clinicoradiological review. Indian J Rheumatol [serial online] 2018 [cited 2019 Oct 18];13:195-201. Available from: http://www.indianjrheumatol.com/text.asp?2018/13/3/195/230571




  Introduction Top


Multicentric reticulohistiocytosis (MRH) is a rare systemic disorder classified as a type of non-Langerhans cell histiocytosis and is pathologically characterized by infiltration of the skin, mucosa, and synovium by multinucleated giant cells. The disorder is characterized by predominant cutaneous and joint manifestations. Cutaneous manifestations include progressive development of papules and nodular mucocutaneous lesions of varying sizes and numbers. The lesions may regress spontaneously and recur. Associated arthritic changes are symmetrical, predominantly involving the distal interphalangeal joints (DIPs) of the hand. The arthritic changes can be extensive and mutilating. Although rare, it affects multiple systems with reported pulmonary and cardiac associations. Few cases of musculoskeletal involvement with features such as myositis as well as visceral involvement have also been described.


  Definition and Categorization Top


The disease was first identified as a distinct clinical entity by Weber and Freudenthal as early as 1937.[1] The term MRH was suggested by Goltz and Laymon [2] in 1954, based on the multicentric involvement of the condition and histiocytic infiltration. It has been known by varying names such as lipoid dermato-arthritis, lipoid rheumatism, giant cell histiocytosis, and reticulohistiocytic granuloma.[3]

The Histiocyte Society classifies histiocytosis into three broad categories. Category I is Langerhans cell histiocytosis. Category II includes non-Langerhans cell histiocytosis, and Category III contains malignant histiocytosis.[4] The Category II is further subdivided into IIa (involving the dermal dendritic cells) and IIb (cell other than dermal dendritic cells and Langerhans cell). The MRH is classified under the latter group.


  Demography and Distribution Top


MRH is a rare condition and has only been described in a number of case reports and series. Exact distribution and etiopathogenesis of the disease are still not adequately studied. Only around 300 cases have been published in the literature. Most of the published reports are dermatologic rather than rheumatologic because of difficulty in the differentiation of disease from other common arthritic conditions, more so in the absence of the dermatologic manifestations.

MRH can present at any age, but the peak occurrence is seen in middle age with the average age of 40–50 years at presentation.[3],[5],[6] It is rarely seen in children and adolescence and old age with cases reported in as early as 6 years of age and as late as 86 years.[7],[8] MRH has shown a distinct female preponderance with the female: male ratio of 2–3:1. The condition is more commonly reported among the Caucasians (>80%); this, however, may be because of relatively higher reports from the developed countries.[3] A close association with autoimmune disorders and malignancy has been seen with concurrent underlying malignancy in 15%–30% of cases and autoimmune conditions in 5%–20% of cases.[9]

No definite familial predisposition to the condition is yet described. A very rare similar condition familial dermato-arthritic histiocytosis has been described in the literature in children and adolescents with similar clinical manifestations and association with glaucoma, uveitis, and cataracts. There have been inconsistent pathological findings, some showing and others lacking the characteristic feature of reticulohistiocytic granuloma.[10],[11]


  Clinical manifestations Top


Although a multisystem disorder, the clinical picture is dominated by cutaneous and joint involvement. Arthritis is the earliest manifestation of the condition and is characterized by joint pain and swelling. In the absence of cutaneous lesions, the condition is mistaken for more common entities such as rheumatoid arthritis (RA), psoriatic arthritis, and reactive arthritis with or without gout. The skin manifestations lag behind with latency reported to be from a few months up to 6 years (average 3 years)[3],[9] and can produce a diagnostic dilemma. The involvement of multiple other systems has been rarely mentioned.

Arthritis

Arthritis is the earliest manifestation in the majority of cases, and changes may be disproportionate to the symptoms (40%).[12] Patients typically present with progressive pain and swelling involving the joints. It is classically a symmetric polyarthritis with predominant involvement of small joints of the hands and wrist and closely mimics RA. The DIP is the most common joint involved. Other joints affected in order of frequency are knees, shoulders, hip, ankles, feet, elbows, and spine. Rarely, the temporomandibular joint may also be involved.[3],[13] Associated synovitis is seen with swelling and thickening of the synovium as well as the tendon sheaths.

The untreated condition shows initial rapid progression of the inflammatory changes with extensive bone destruction. The progression to arthritis mutilans occurs in as high as 45% of these cases. With the advancement in the treatment, mutilating arthritis is seen in around 12%.[3],[12],[14] The disease follows waxing and waning course with further erosions, destruction, and deformity and may progress to a severely debilitating condition. The disease gradually becomes inactive in 7–8 years with residual deformity.

In the absence of classical skin lesions, the condition mimics RA, and cases showing positive rheumatoid factor and anti-cyclic citrullinated peptide (CCP) antibodies have been reported.[15],[16] Since MRH is associated with multiple autoimmune conditions, it has been argued that the presence of RA factor and anti-CCP antibody may represent the coexistence of RA and MRH, rather than the manifestation of the MRH. Further, mutilating arthritis is very rare in RA (5%).[17]

Skin Manifestation

The skin manifestations follow arthritic changes. Less commonly skin changes and arthritis occur simultaneously (30%cases) or can even precede arthritis (30%).[12] The classical cutaneous manifestation of the MRH is of firm papulonodular lesions which are reddish brown to yellow and are symmetrically distributed [Figure 1]. The size varies from few millimeters to centimeters. They are typically distributed on the face, neck, ear, chest, arms, and hands. Ears are the most common site involved in the face. Typical involvement of the bridge of the nose and dorsal surface and the nail folds is seen in the hands. The papular lesions along the nail folds give the characteristic coral bead appearance. Associated longitudinal ridging of the nails may be seen with hyperpigmentation. The lesions may become confluent along the scalp margin, around the nose, nostrils, and the nailbeds and coalesce giving a cobble stone appearance.[3] The vermicular erythematous lesions around the nostrils are thought to be a characteristic of MRH.[11] These lesions rarely ulcerate.
Figure 1: (a) A 25-year-old female patient presenting with multiple skin-colored papules and nodular lesions involving the hands. (b) Soft tissue nodular radiopacities in the bilateral hands (arrows) and periarticular osteopenia and no joint space reductions or erosions in the patient with recent-onset disease. (c) Posteroanterior radiograph of bilateral hands in the same patient after 1 year showing arthritis mutilans. Extensive erosions of radioulnar joint and carpal and metacarpal bones with osteolysis of phalanges with distal tapering (arrow). Distal interphalangeal joint space involvement is out of proportion to proximal involvement

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Mucosal lesions are reported in 52% of cases in a study by Barrow and Holubar [3] and in 31% of cases in a review by Luz et al.[6] Frequently involved sites include oral and nasal mucosa, and the lesions are distributed along the lips, buccal mucosa, tongue, and gingival and nasal septum. Dysphagia secondary to esophageal involvement has been reported.[18] Involvement of the larynx has also been seen. Rare cases of vulvar and perianal involvement have been reported.[19],[20]

The papules, nodules, and erythematous rashes of MRH have shown distribution along the photo-exposed areas and may mimic photosensitive dermatitis. This photosensitive pattern of distribution of the lesions in MRH suggests that it may be associated with sunlight-induced Koebner phenomenon.[21] The closest differential diagnosis for this type of cutaneous manifestation of the MRH is dermatomyositis. Erythematous rashes along the neck resembling V-neck or shawl signs,[22] along with muscle weakness and inflammatory changes, mimicking dermatomyositis have been reported. The diagnosis can be confirmed by histopathology where MRH would demonstrate multinucleated giant cell infiltration.

Systemic manifestations

Although the clinical manifestation of MRH is dominated by its cutaneous and arthritic changes, many studies published show varied systemic involvement in the condition.

Pulmonary involvement has been very commonly associated with MRH (described in up to 20% of cases). Pulmonary findings described with MRH include pleural effusion, pleural thickening, airway infiltrates, mottling of lungs, as well as hilar and mediastinal lymphadenopathy.[5] Associated interstitial lung disease has also been described with a reported case of usual interstitial pneumonia which showed characteristic changes on biopsy.[23]

Cardiac involvement is less frequent. It may present with pericarditis, mostly fibrinous pericarditis which results in constrictive pericarditis, and may progress very rapidly and be fatal.[24] It may also present as acute or transient pericarditis as well as pericardial effusion. Myocardial involvement may occur with cardiomegaly.

Muscular involvement has been described predominantly in the form of muscle weakness and mimics dermatomyositis.[22],[24],[25] Histopathology of the muscle shows chronic nonspecific inflammatory changes.

Involvement of laryngeal, esophageal, and gastric involvement in the form of nodules is considered within the spectrum of mucosal lesions.[18],[20] Involvement of the submucosal tissue along the gastrointestinal tract and associated gastric ulcers has also been described [Figure 2].
Figure 2: Axial contrast-enhanced computed tomography of the abdomen of a patient with multicentric reticulohistiocytosis. Multiple areas of nodular mucosal thickening seen in the small bowel (*). Multiple nodular lesions are seen involving the skin (arrow)

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A presumed rare variant of MRH familial dermato-arthritic histiocytosis shows frequent association with uveitis, cataract, and glaucoma.[9]

Associated malignancies

Underlying malignancy has been detected in MRH in as high as 30% of cases. The associated malignancies include carcinomas (ovaries, stomach, colon, bronchus, and breast), melanoma, mesothelioma, leukemia, and lymphoma. Breast and ovarian malignancies and metastatic disease with unknown primary are associated with the condition.[26],[27] A case has been reported with past carcinoma breast with no current residual or recurrent malignancy presenting with MRH.[28] MRH may be a manifestation of paraneoplastic syndrome, due to the simultaneous remission of the symptoms with the response of malignancy to the chemotherapy and relapse of the symptoms with malignancy.[26]

Associated autoimmune diseases

The autoimmune conditions with MRH including Sjogren's syndrome, hypothyroidism, primary biliary cirrhosis, systemic sclerosis, systemic vasculitis, myositis, celiac disease, systemic lupus erythematosus, RA, and diabetes mellitus have been associated in 5%–20%.[29],[30],[31],[32]

Other conditions associated with MRH include hyperlipidemia (related to the xanthelasmas in MRH), tuberculosis (positive tuberculin tests are as high as 50% of cases), diabetes, and hypothyroidism.


  Investigations Top


Imaging

Radiological evaluation is of immense importance to make an early diagnosis of the condition. Radiology also helps identify the systemic involvement and screen for malignancy [Table 1].
Table 1: Radiological manifestations of multicentric reticulohistiocytosis

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The radiological findings in MRH are of symmetric polyarthritis with predilection for the hands. Symmetric well-circumscribed sharply marginal erosions rapidly progress to involve the entire joint surface with associated joint space widening and subchondral resorptions.[13],[33] Periarticular osteopenia is rare, unlike RA. Erosions show predilection for the DIP. Periosteal reaction is minimal or absent. No associated osteoporosis or osteoproliferative lesions are seen.[34]

The articular lesions of MRH show initial rapid progression with joint destruction and mutilation [Figure 1]b and [Figure 1]c. The radiological findings are generally out of proportion to the clinical findings. There is foreshortening of the fingers and telescoping, eventually leading to opera glass deformity. The mutilation may resemble the changes of psoriatic arthritis; however, only 5% of the psoriatic arthritis progresses to mutilation.

Apart from hands, similar articular erosions may also be seen involving the foot, ankle, knee joints, shoulders, elbows, and spine [Figure 3]. The cervical region is more commonly involved in the spine. Atlantoaxial subluxation has been found to be frequently associated. There is symmetric involvement of the bilateral costovertebral joints and the sacroiliac joints. Bony ankylosis has been described in the sacroiliac and costovertebral joints.[35] This ankylosis generally lacks subchondral sclerosis.
Figure 3: Anteroposterior radiograph of the shoulders in a patient with a 20-year history of the disease showing bilaterally symmetric erosions of the humeral heads and glenoid (arrows) with decreased joint space

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Apart from osseous changes, plain radiographs may also at times demonstrate cutaneous changes in the form of soft tissue thickening and nodularity [Figure 2].

One of the closest differential diagnoses is RA. MRH results in extensive mutilation and destruction in contrast to RA where mutilation is rare and is seen in 5% of cases.[17]

Psoriatic arthritis involves the DIP, lacks the symmetric distribution of MRH, and less frequently progresses to mutilation. Similarly, reactive arthritis is also asymmetric with a predilection to the lower limb. Both psoriatic arthritis and reactive arthritis are associated with periosteal new bone formation which is rarely seen in MRH.[36]

Erosive osteoarthritis typically shows central bony erosions unlike MRH where the erosions are marginal. There is associated narrowing of the joint space.

Gouty arthritis is predominantly bilateral, but more often asymmetric. The erosions in the gout are marginal and show typical overhanging margins with sclerosis. Associated soft tissue changes may be prominent. Bone density and joint space are generally preserved until late [Table 2].
Table 2: Radiological differential diagnosis of multicentric reticulohistiocytosis

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Ultrasound (USG) is useful to detect early erosions. Associated synovial thickening, joint effusion, and swelling of tendon sheaths are apparent on USG [Figure 4]. USG may also be useful for screening of the systemic involvement such as detection of pleural and pericardial effusions as well as screening for malignancies.
Figure 4: Ultrasound showing hypertrophic synovium (*) involving the metacarpophalangeal and proximal interphalangeal joint with erosions in the proximal and middle phalanges (↑↑)

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Computed tomography and magnetic resonance imaging (MRI) are helpful to identify the associated systemic pathologies. The early pulmonary changes include effusions, pleural thickening, infiltrates, and mediastinal adenopathy. MRI may be useful in identifying the myopathy; however, the findings are highly nonspecific [Figure 5].
Figure 5: Coronal T2-weighted magnetic resonance imaging of the bilateral knees showing hyperintensities in distal vastus medialis (arrows). Erosions of femoral condyles with bone marrow edema (arrowhead) and cartilage loss (cross) are also seen with minimal effusion

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Since the association of MRH with malignancy has been reported in as high as 30% of cases, a diagnosed case of MRH may require a thorough imaging evaluation to rule out the possibility of malignancy.

Histopathology

Histopathology is the gold standard for the diagnosis of MRH. The pathological involvement is characterized by infiltration by cells of reticulohistiocytic granuloma. These cells include multinucleated histiocytic giant cells and mononuclear histiocytes [Figure 6]. These granulomatous aggregations have been mentioned along with gastric ulcer bases, perinephric fat, and colostomy stomas.[37] These typical cells of MRH stain positively with periodic acid–Schiff after diastase digestion. These multinucleated histiocytic giant cells have eosinophilic cytoplasm and are fine and granular with ground-glass appearance and multiple vesicular nuclei with distinct nuclear membrane and prominent nucleoli. The nuclei may be haphazardly arranged or may be in clusters and tend to prefer the central location. Mononuclear histiocytes are seen as round-to-oval cells with finely granular cytoplasm. Cells showing transitional features between the mononuclear histiocytes and giant cells are also seen.[3]
Figure 6: (a and b) Skin biopsy from a papulonodular lesion on the dorsal aspect of the hand showing large collections of pink histiocytes in the dermis. High power view of histiocytes with abundant eosinophilic cytoplasm dissecting the dermal collagen. Occasional multinucleated cells are also seen

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The temporal progression of these granulomas has been proposed with early dense infiltration of the lymphocytes, eosinophils, and histiocytes, with progressive appearance of the giant cells followed by the disappearance of the giant cells and appearance of fibroblasts later in the disease and finally the development of fibrosis.

Immunohistochemical (IHC) study helps in differentiating MRH from other histiocytic proliferations. The MRH cells are positive for vimentin, CD68, MAC387, and CD45 and negative for S-100 and CD34 and Factor XIIIa factor. This IHC pattern helps differentiate MRH from Type I/II dendrocytes or Langerhans cells. Of these, the expression of CD68 has been included as an essential criterion for the diagnosis of MRH.[38]

Laboratory investigations are generally noncontributory. Anemia and elevated erythrocyte sedimentation rate have been reported. Isolated reports of positive rheumatoid factor, anti-CCP, antinuclear antibodies, tumor necrosis factor-alpha exist.[39]

Treatment

MRH is an aggressive disease and may progress to a severely debilitating condition if untreated. No definite consensus, on treatment, is available owing to the rarity of studies and controlled trials. The condition has been variably treated with nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, and various immunomodulators and immunosuppressive drugs (methotrexate, cyclophosphamide, hydroxychloroquine, azathioprine, etc.). Biological agents such as etanercept, adalimumab, and infliximab have also been used in some instances.

The NSAIDs and steroids cause symptomatic relief with no definite impact on the disease progression. The drugs such as methotrexate, chlorambucil, and cyclophosphamide have shown a variable degree of remission of arthritis and skin lesions. Methotrexate is considered to be more effective for arthritic changes and chlorambucil and cyclophosphamide for the skin lesions. Cases showing remission on azathioprine and leflunomide have also been reported.[39],[40],[41] Treatment with biological agents (etanercept, adalimumab, and infliximab) have shown response in many of the reviewed cases.[39] They are found to be more useful in the refractory cases.

Improvements have also been reported with the use of bisphosphonates including alendronate, zoledronate, and pamidronate.

Because of the variable efficacy of the drugs on arthritic and cutaneous manifestation as well as on symptomatic improvement, combination regimens are useful. The response to the treatment is found to be best in early disease.


  Conclusion Top


MRH is a rare systemic disease with predominant cutaneous and arthritic manifestations. The significance of the condition lies in the fact that it is very aggressive and progresses to a debilitating condition. MRH is mistaken for more common arthropathies and cutaneous conditions and thus wrongly treated. A high index of suspicion is required for early diagnosis. The progression of the disease can be halted and possibility of the deformities reduced if the condition is treated early. A possibility of MRH should be kept in the appropriate clinical setting with supportive radiological findings and confirmed with histopathology.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Lonsdale-Eccles AA, Haworth AE, McCrae FC, Young-Min SA. Successful treatment of multicentric reticulohistiocytosis with leflunomide. Br J Dermatol 2009;161:470-2.  Back to cited text no. 41
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