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This is really two diseases. The solitary cutaneous form presents as a flesh colored nodule and simple surgical excision is curative.

The systemic form has a more sinister course and is associated with a symmetrical polyarthritis that behaves like a severe rheumatoid arthritis. It is symmetric, diffuse, progressive, and destructive with an arthritis mutilans, in approximately 20% to 50% of MR patients. There is a propensity for the distal interphalangeal joints of the hands but it can affect any joint. Patients may also have fever, weight loss, and malaise.

Routine laboratory tests are generally within normal limits, with the exception of elevated erythrocyte sedimentation rate and cholesterol levels in some patients. It is questionable whether this disease represents a paraneoplastic syndrome though there have been reported malignancies including breast carcinoma, leukemia, and metastatic cancer of unknown primary.


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Punched-out lesions on articular surfaces due to demineralization of the joints with relative sparing of the cartilage

Joint space widening and skin redundancy over the involved joints


Multicentric Systemic

Clin Rheumatol 1996;15:62-6.
Clin Dermatol 1993;11:107-11.

Multicentric reticulohistiocytosis (MR) is an extremely rare idiopathic disease that affects both skin and synovium

There is a predilection for women. Patients generally present in the fourth decade with cutaneous lesions and/or polyarthritis

Rings of papules (“coral beads”) along the nailfolds, which are characteristic

Multicentric reticulohistiocytosis with neurofibroma-like nodules

J Am Acad Dermatol 2001;44:373-5


Multicentric reticulohistiocytosis with arthritis and cardiac infiltration: regression following treatment for underlying malignancy Ann Rheum Dis 1992;51:815-7


GENERAL Diffuse mononucleated or multinucleated histiocytic giant cell infiltration throughout the dermis

The overlying epidermis is mildly hyperkeratotic with some atrophy and flattening of the rete ridges

Bands of collagen lie below the dermal-epidermal junction and separate the infiltrate from the epidermis

Periodic acid-Schiff-positive, diastase-resistant cytoplasm is eosinophilic and granular, which gives it a ground-glass appearance
Reticulohistiocytoma (solitary epithelioid histiocytoma): a clinicopathologic and immunohistochemical study of 44 cases.

Miettinen M, Fetsch JF.

Department of Soft Tissue Pathology, Armed Forces Institute of Pathology, Washington, DC.

Am J Surg Pathol. 2006 Apr;30(4):521-8. Abstract quote  

Reticulohistiocytoma and multicentric reticulohistiocytosis are designations for uncommon, incompletely characterized histiocytic proliferations of the skin or soft tissues.

In this study, we analyzed a uniform group of 44 lesions composed of epithelioid histiocytes, comprising a subset of lesions originally designated as reticulohistiocytoma, and propose designating them as "solitary epithelioid histiocytoma" (SEH), in line with the recently published classification proposal for histiocytic disorders. There were 26 males and 18 females with a median age of 35 years (range, 2.5-74 years).

All patients had a superficial, circumscribed, mildly elevated, solitary lesion (size range, 1.5-11 mm; median, 4 mm), located in the trunk wall (n=16), lower extremity (n=12), head and neck (n=8, including 2 in the oral cavity), upper extremity (n=6), penis (n=1), and an unspecified site (n=1).

Histologically, the lesions typically involved upper and mid-dermis and were not ulcerated. They were composed of large epithelioid histiocytes with a varying number of lymphocytes and neutrophils. The histiocytes had abundant, typically densely eosinophilic, cytoplasm and mostly mild, if any, nuclear atypia. Multinucleated forms with randomly oriented nuclei were also present. The histiocytes had low mitotic activity (range, 0-4 mitoses per 10 wide HPFs; median, 1 mitosis per 10 HPFs). The lesions contained varying numbers of CD3-positive T cells, whereas B lymphocytes, plasma cells, eosinophils, and mast cells were scant, if present at all. Immunohistochemically, the epithelioid histiocytes were positive for CD163, CD68, lysozyme (variably), and vimentin. They often had focal nuclear immunoreactivity for microphthalmia transcription factor, and they sometimes had focal reactivity for Factor XIIIa and S-100 protein. Membrane positivity for CD31, CD43, and CD45 was variable. The epithelioid histiocytes were consistently negative for CD3, CD20, CD30, HMB45, and keratins. All 12 patients with follow-up information had an uneventful clinical course with no recurrences (median, 13 years).

SEH is a benign, probably reactive, histiocytic proliferation of unknown etiology. It needs to be distinguished from Rosai-Dorfman disease, juvenile xanthogranuloma, a variety of granulomatous conditions, and some malignant neoplasms, including histiocytic sarcoma, melanoma, and epithelioid sarcoma.
Extranodal histiocytic sarcoma: clinicopathologic analysis of 14 cases of a rare epithelioid malignancy.

Hornick JL, Jaffe ES, Fletcher CD.

Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.

Am J Surg Pathol. 2004 Sep;28(9):1133-44. Abstract quote  

Histiocytic sarcoma is a rare malignant neoplasm that occurs in lymph nodes, skin, and the gastrointestinal tract. Many previously published cases were likely misdiagnosed examples of non-Hodgkin lymphoma. Only small numbers of bona fide examples exist in the world literature; cases arising primarily at extranodal sites are not well described and often seem to go unrecognized.

To characterize these tumors further, 14 extranodal histiocytic sarcomas were analyzed. Hematoxylin and eosin sections were reexamined, immunohistochemistry was performed, and clinical details were obtained from referring hospitals. Eight patients were female and 6 male (median age, 55 years; range, 15-89 years). All patients presented with a solitary mass, ranging in size from 1.8 to 12 cm (median 6.8 cm). Seven tumors arose in soft tissue (6 lower limb; 1 upper limb), 5 in the gastrointestinal tract (1 involving both stomach and colon, 1 ileum, 2 rectum, 1 anus), 1 in the nasal cavity, and 1 in the lung. Three gastrointestinal tract tumors also involved regional lymph nodes, and 1 involved the liver. Most cases had infiltrative margins.

The tumors were generally composed of sheets of large epithelioid cells with abundant eosinophilic cytoplasm, oval to irregular nuclei, vesicular chromatin, and large nucleoli. Binucleated cells were common, and 6 cases contained tumor giant cells. Mitoses ranged from 1 to 64 per 10 HPF (median 11 per 10 HPF). Necrosis was present in 8 cases. Nearly all tumors showed a striking inflammatory infiltrate, most often of neutrophils or lymphocytes. All cases were reactive for LCA, CD45RO, and CD68 (KP1 and PG-M1); 13 of 14 (93%) expressed CD4, 12 of 14 (86%) lysozyme, 8 of 10 (80%) CD31, 7 of 14 (50%) S-100 protein, and 5 of 14 (36%) focal CD1a. Two tumors showed weak, focal cytoplasmic positivity for CD30, and 1 for epithelial membrane antigen. The tumors were negative for ALK-1, CD21, CD35, CD3, CD20, CD34, myeloperoxidase, HMB-45, and keratins. Gastrointestinal tract cases were negative for c-kit and desmin. Six patients were treated with postoperative radiation and 7 with chemotherapy (CHOP or ProMACE-MOPP).

Follow-up was available for 10 patients (median, 24 months; range, 4 months to 11 years). Two tumors recurred locally, and 5 patients developed distant spread: 3 to lymph nodes, 1 to lung, and 1 to bone. At the last follow-up, 2 patients have died of disseminated disease, 4 and 5 months following initial diagnosis. The patients who died thus far had the largest primary tumors. Histiocytic sarcoma may arise primarily in soft tissue and shows reproducible histologic features, including abundant eosinophilic cytoplasm and a prominent inflammatory infiltrate. Metastatic carcinoma, metastatic melanoma, and large cell non-Hodgkin lymphomas should be excluded by immunohistochemistry.

Histiocytic sarcoma has the potential for an aggressive clinical course, most often with lymph node involvement. However, a subset of cases presenting with clinically localized disease have a favorable long-term outcome. Tumor size may be a prognostic factor.


Multicentric reticulohistiocytosis

Arthritis Rheum 1996;39:171-4.

Complete remission of multicentric reticulohistiocytosis with combination therapy of steroid, cyclophosphamide, and low-dose pulse methotrexate


J Rheumatol 1997;24:2250-3.

Severe multicentric reticulohistiocytosis: disease stabilization achieved with methotrexate and hydroxychloroquine

Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.

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Last Updated April 28, 2006

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