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Chin Med J (Taipei) 1997;59:269-73.
Department of Pathology, Veterans General Hospital-Kaohsiung, Kaohsiung, Taiwan, R.O.C.
A case of cutaneous Rosai-Dorfman disease (sinus histiocytosis with massive lymphadenopathy) manifestating as a recurrent breast tumor is reported. The tumor occurred on the left breast of a 35-year-old woman. Before arriving at the correct diagnosis, four biopsies had been performed with various diagnoses of chronic inflammation, plasma cell mastitis and inflammatory pseudotumor. Numerous typical histiocytes with lymphophagocytosis appeared in the final excised specimen, and a correct diagnosis was made. Ultrastructural examination revealed no evidence of Birbeck granule. The literature concerning Rosai-Dorfman disease manifestating as breast tumor is reviewed. Since the diagnosis is often overlooked in the absence of lymphadenopathy, a high index of suspicion is required to recognize this rare cutaneous Rosai-Dorfman disease.
[Chin Med J (Taipei) 1997;59:269-73.]
Keywords: breast, Rosai-Dorfman disease, skin
Received: January 31, 1996.
Accepted: December 24, 1996.
Address reprint requests to: Dr. Jyh-Seng Wang, Department of Pathology, Veterans General Hospital-Kaohsiung, 386, Ta-Chung 1st Rd., Kaohsiung, Taiwan, R.O.C.
Rosai-Dorfman disease, with its synonym of sinus histiocytosis with massive lymphadenopathy, is a distinct clinicopathological entity first described by Rosai and Dorfman in 1969 [1]. While lymphadenopathy is the most striking manifestation, an extranodal lesion occurs in up to 43% of all cases, with the skin being the most common site [2]. However, Rosai-Dorfman disease confined strictly to the skin is rare [3]. It is even more rare with the lesion limited exclusively to the skin of breast and presenting as a breast tumor [4]. This report concerns a case of a young woman with cutaneous Rosai-Dorfman disease manifestating as a recurrent breast tumor and reviews the literature concerning similar clinical manifestations.
A 35-year-old woman presented with a 3-year history of multiple left breast nodules. The nodules were located in the inner upper quadrant of the left breast, with the largest one measured 5x2x1 cm, and the other satellite nodules measured 0.5-1.5 cm in greatest dimension. The nodules had irregular margins and erythematous overlying skin without ulceration. There was no palpable lympha-denopathy. Breast cancer was suspected clinically. However pathological report of the excised specimen was chronic mastitis composed predominantly of mature plasma cells infiltrating in fibrotic stroma. The patient was free of disease after total excision of the tumors.
Two and half years later, the patient noticed progressively enlarged multiple breast nodules over the same region of the breast. Physical examination revealed a 5.0x4.5 cm indurated plaque accompanied by several satellite nodules around the previous surgical scar area. There was no palpable lymphadenopathy. Clinical diagnosis was recurrent breast cancer. However, thoracic computerized tomography scan showed subepidermal and subcutaneous tumor without mammary gland involvement or Iymphadenopathy. Three incisional biopsies were performed within a one-month period, but only diagnoses of chronic inflammation or inflammatory pseudotumor were reported. The patient was discharged under impression of inflammatory pseudotumor and advised to have follow-up. However, while the largest nodule remained stable, the smaller satellite nodules progressively enlarged within four months. The patient received wide excision with latissimus dorsi myocutaneous island flap reconstruction. Five months after the wide excision, follow-up physical examination revealed no evidence of recurrence or lymphadenopathy.
Laboratory analysis revealed positive antinuclear antigen of homogenous type, increased T suppressor cells (48%, normal :20-36%) with decreased T helper and T suppressor ratio ( T4/T8 ratio: 0.8; normal: 1.5-2). CD 19 (B lymphocyte) percentage was within normal limit (7%; normal: 5-15%). There was increased immunoglobulin G (IgG: 1920 mg/ dL; normal: 766-1844 mg/dL) and immunoelectrophoresis revealed polyclonal gammopathy. The remaining hemogram, biochemical profile, lgM, lgA, and complements were within normal value. Urinalysis was also normal.
A piece of skin and subcutis tissue of 8 x 7cm was excised along with multiple nodules (Figure 1). The largest nodule measured 5x5x2cm. The overlying skin appeared tensely stretched and intensely erythematous without ulceration. The cut surface revealed separate, well-defined, yellowish tumors in the dermis and subcutis.
Microscopy revealed a diffuse inflammatory infiltrate occupying dermis and subcutis with obliteration of normal structures. Mammary glands were not involved. The infiltrate was composed of a large amount of mature plasma cells, histiocytes and small lymphocytes. Eosinophils and polymorphonuclear cells were absent. The histiocytes had abundant pale or eosinophilic cytoplasm with irregular indistinct cell border and vesicular nuclei. Cells with multiple nuclei, multilobulated nucleus and atypical hyperchromatic nucleus were occasionally seen. Mitotic figures were absent despite extensive search. Many of the histiocytes showed lymphophagocytosis with the number of intracytoplasmic lymphocytes varying from 1 to 55 (Figure 2). Phagocytosis of plasma cells was also frequently seen, while only very rare phagocytosis of red blood cells and polymorphonuclear cells were observed. Occasionally lymphocytes, plasma cells and red blood cells were observed within one histiocyte. The cells within the cytoplasm of the histiocytes appeared intact and were surrounded by a clear halo. The number of histiocytes with lymphophagocytosis varied from rare to numerous in different areas of the tumor. Sometimes, clusters of lymphophagocytotic histiocytes were observed in dilated lymphatic-like space (Figure 3). The stroma revealed focal fibrosis and slight vascular proliferation. Necrosis and hemorrhage were absent. Periodic acid Schiff reaction and acid-fast stain for microorganisms were negative.
Immunohistochemically, most of the histiocytes were positive for S100 protein (Figure 4). Some of the histiocytes also stained with T cell marker-UCHL1, as well as kappa and lambda light chains. The plasma cells expressed polyclonal kappa and lambda light chains. The lymphocytes expressed an approximately equal number of T cells and B cells by UCHL1 and L26 stain, respectively.
Electromicroscopic study revealed the presence of lymphocytes within cytoplasm of the histiocytes (Figure 5). However, the preservation was so poor that it was not possible to determine whether the lymphocytes were truly involved in emperipolesis, or whether they were in phagocytic vacuoles and were being destroyed. Extensive search failed to detect Birbeck granules. Indeterminate dendritic cells as described by Perrin et al [5] were absent.
Review of previous biopsy slides showed few histiocytes with lymphophagocytosis admixed in the heavy plasma cell infiltrate. The histiocytes also expressed S100 protein. The phenomenon of lymphophagocytosis was more apparent after S100 stain.
Rosai-Dorfman disease limited strictly to the skin is rare [3]. It is even more rare with the lesion confined exclusively to the skin of the breast and presenting as an apparent breast tumor [4]. Several cases with subcutaneous Rosai-Dorfman disease over the breast were briefly mentioned in reference 2; however, detailed information about their clinical presentation was not available. Literature review of cutaneous Rosai-Dorfman disease presenting as a breast tumor is shown in Table 1. In addition, three cases of intraparenchymal breast lesion had been reported [2,6] (Table 2).
Despite similar histopathological features in both nodal and extranodal sites, a diagnosis of extranodal lesion is often overlooked in the absence of lymphadenopathy. Focal areas of tumor with rare or very few typical histiocytes also increase the possibility of misdiagnosis in this case. It is apparent that a high index of suspicion is required to recognize this rare breast tumor-mimicking cutaneous Rosai-Dorfman disease.
Differential diagnosis of the lesion included plasma cell mastitis, granulomatous mastitis, extramedullary plasmacytoma, granulomatous infection, plasma cell granuloma, sarcoidosis, Langerhans cell histiocytosis, and non-Langerhans cell histiocytosis including xanthogra-nulomas, dermatofibroma, reticulohistiocytoma cutis, hemophagocytic syndrome and malignant histiocytosis. The lack of mammary gland involvement excluded the possibility of plasma cell or granulomatous mastitis. The polyclonal and mature appearance of plasma cells ruled out a diagnosis of plasmacytoma. The possibility of infection with granulomatous reaction was excluded by lack of necrosis and microorganism by special stains. A diagnosis of plasma cell granuloma was unlikely in the presence of S100-positive histiocytes and lymphophago-cytosis. Sarcoidosis is rare in this country, and histiocytes in this condition are S100 negative. The histiocytes in Langerhans cell histiocytosis also express S100 protein; however, they exhibit characteristic renal-shaped nuclei and eosinophilic infiltrate without lymphophagocytosis. The lack of Birbeck granule also excluded the possibility of Langerhans cell histiocytosis. The histiocytes of most other non-Langerhans cell histiocytosis lack S100 expression. Although S100 staining and leukophagocytosis have been reported in reticulohistiocytoma cutis [7,8], ground-glass histiocytes and infrequent plasma cells are features of reticulohistiocytoma cutis. Significant nuclear pleomorphism and mitoses are required for diagnosis of malignant histiocytosis.
It is evident from this case that there may be recurrence two and a half years after complete excision. Although skin involvement does not adversely affect prognosis [2], it has been shown that extranodal disease may herald widespread lymphadenopathy [2,7].
The risk of recurrence or widespread lympha-denopathy cannot be predicted by either clinical or histopathological features [2]. Therefore, a diagnosis of Rosai-Dorfman disease limited to a single organ should prompt investigation of lesions elsewhere. This case have experienced a total course of approximately six years of exclusively cutaneous lesion limited to the breast without lymphadenopathy.
It is presumed that Rosai-Dorfman disease is immune-mediated; polyclonal gammopathy and reversed T4/T8 ratio are common in patients with the lesion [2]. This case also had the same phenomenon of polyclonal gammopathy and reversed T4/T8 ratio.
The characteristic cells in Rosai-Dorfman disease express features of both Langerhans type dendrite cell and non-Langerhans phagocytic cell by their expression of S100 protein and phagocytotic activity, respectively. The common expression of cathepsin D and E also suggests some phenotype overlap between Langerhans cells and typical cells in Rosai-Dorfman disease [9]. The same phenomenon of positive staining for UCHL1, kappa and lambda light chains of the histiocytes as in this case had been previously reported [10].
In summary, a case of Rosai-Dorfman disease is reported limited exclusively to the skin and manifestating as recurrent breast tumor. The diagnosis is often overlooked in the absence of lymphadenopathy. Therefore, a high index of suspicion is required to recognize this rare cutaneous Rosai-Dorfman disease.
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Copyright: 1997, Chinese Medical Association (Taipei)