Intrapelvic Bulky Tumor as an Unusual Presentation of Erdheim-Chester Disease
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1 CASE REPORT Intrapelvic Bulky Tumor as an Unusual Presentation of Erdheim-Chester Disease Satoru Taguchi 1,2, Yukiko Kishida 3, Koichi Tamura 3, Yorito Nose 2, Toshikazu Sato 1,2, Akira Ishikawa 1,2, Yukio Homma 1 and Mitsunori Yamakawa 4 Abstract Erdheim-Chester disease (ECD) is a rare form of non-langerhans cell histiocytosis, which is known to affect various organs; however, there have been no reports of its intrapelvic involvement. We herein describe the case of 69-year-old man who died of a rapidly-growing intrapelvic tumor, which was finally diagnosed as ECD at autopsy. Immunohistochemically, the tumor cells were positive for CD68 and BRAF V600E, and negative for CD1a. Since BRAF V600E has recently been reported to be specific to ECD, it can be a useful biomarker for diagnosis, especially in atypical cases. Key words: BRAF V600E, Erdheim-Chester disease, histiocytosis, intrapelvic tumor, non-langerhans cell histiocytosis, pelvic tumor (Intern Med 54: , 2015) () Introduction Erdheim-Chester disease (ECD) is a rare form of non- Langerhans cell histiocytosis of unknown etiology that was first described by William Chester in 1930 (1). Because of the better recognition of this condition, the number of reported cases has increased over the past 10 years, and as of now, approximately 500 cases of ECD have so far been reported in the literature (2). ECD is characterized by xanthomatous or xanthogranulomatous infiltration of various tissues with a wide range of manifestations (3). The most common symptom of ECD is bone and joint pain resulting from bilateral osteosclerosis of the long bones, but it can also affect skin, lung, heart, kidney, retroperitoneal space, orbit, and the central nervous system (CNS) (3). In general, the diagnosis of ECD is difficult, because of its rarity and due to the variety of clinical manifestations. Some authors have reported that Technetium-99 m bone scintigraphy may be helpful in the early detection of ECD (4); however, the clinical pathway to diagnosis is often a tortuous conundrum when a patient with ECD presents with extraskeletal manifestations (5). The intrapelvic involvement of ECD is extremely unusual. Retroperitoneal involvement (so-called pseudo retroperitoneal fibrosis ) is seen in approximately 30% of ECD cases and sometimes causes hydronephrosis, however, a distinguishing characteristic of ECD is that the pelvic ureters are always spared (2). We herein report an extremely rare case of ECD which formed an intrapelvic bulky tumor without typical skeletal involvement. Clinical summary Case Report A 69-year-old man who had undergone 20 years of hemodialysis for end-stage renal disease due to hypertensive nephrosclerosis presented to our hospital with severe constipation and abdominal distension. Computed tomography (CT) demonstrated a large mass of 700 ( ) cm 3, which was suspected of originating in the prostate. The mass occupied the pelvic cavity and compressed the rectum (Fig. 1a). Technetium-99 m bone scintigraphy indicated me- Department of Urology, Graduate School of Medicine, The University of Tokyo, Japan, Department of Urology, Tokyo Teishin Hospital, Japan, Department of Pathology, Tokyo Teishin Hospital, Japan and Department of Pathological Diagnostics, Yamagata University Faculty of Medicine, Japan Received for publication January 15, 2015; Accepted for publication June 8, 2015 Correspondence to Dr. Satoru Taguchi, satorutaguchi33@gmail.com 3241
2 Figure 1. Computed tomography (CT) demonstrated a large mass of 700 ( ) cm 3, suspected of having originated in the prostate. The mass occupied the pelvic cavity and was compressing the rectum (a). Technetium-99m bone scintigraphy indicated metastases in the pelvic bone and lumbar spine, whereas it did not reveal osteosclerosis of the long bones which is a typical manifestation of ECD (b). The postmortem CT imaging revealed that the tumor finally grew to 3,000 ( ) cm 3 in size (c). the disease could not be controlled and the patient s general condition worsened. He died six weeks after his first visit. Postmortem CT revealed that the pelvic tumor grew to a final size of 3,000 ( ) cm 3 in size (Fig. 1c), while the bone lesions remained nearly unchanged. No new lesions were detected in the whole body, including the head. Autopsy, excluding the CNS, was performed in order to examine the tumor tissue pathologically. Pathological findings Figure 2. A macroscopic image of the removed pelvic tumor: it almost occupied the pelvic cavity and extended to surrounding tissues. tastases to the pelvic bone and lumbar spine (Fig. 1b). Although serum prostate-specific antigen (PSA) was within the normal limits (2.2 ng/ml), a transrectal ultrasound-guided needle biopsy of the prostate was performed to obtain a definite diagnosis. The pathological findings showed that a small amount of prostate cancer tissue (four of 12 cores, Gleason score 4+4=8) coexisted with the infiltration of a large number of foamy histiocytes. The patient was started on androgen deprivation therapy and underwent colostomy to treat the rectal obstruction. However, the progression of A macroscopic examination showed that a bulky fibrotic tumor occupied the pelvic cavity almost completely and extended to the surrounding tissues such as the urinary bladder and colon (Fig. 2). A microscopic examination demonstrated the diffuse proliferation of foamy histiocytes (i.e. xanthoma cells) within the involved tissues (Fig. 3a). Touton and multinucleated giant cells were occasionally seen (Fig. 3b). An immunohistochemical analysis revealed that the cells were diffusely positive for CD68, CD163, CD10, fascin, vimentin and BRAF V600E; focally positive for S-100 protein and HMB45; and negative for dendritic cell markers (CD1a, langerin, DC- SIGN, and DEC205) (Table). Microscopic images of the immunohistochemical staining of CD68 and BRAF V600E are shown in Fig. 3c and d, respectively. Combining these findings with the aggressive clinical course, the main tumor was finally diagnosed as ECD. Prostate cancer tissue was detected in small discrete spots within the main ECD lesion (Fig. 4), but osteosclerotic lesions in 3242
3 a b c d Figure 3. The microscopic findings at autopsy demonstrated the diffuse proliferation of foamy histiocytes within the involved tissues [a: Hematoxylin and Eosin (H&E) staining]. Multinucleate giant cells were occasionally found in the tumor cell population (b: arrows, H&E staining). Immunohistochemical staining showed that the tumor cells were diffusely positive for both CD68 (c) and BRAF V600E (d). Table. The Results of the Immunohistochemical Analysis in the Present Case. Antibody Tumor cells (foamy histiocytes) CD68 (MGP1) CD68 (KP1) CD163 (+, diffuse) Fascin Vimentin CD10 BRAF V600E S-100 protein (+, focal) HMB45 (+, focal) Factor XIIIa (-) HO-1 (-) DC-SIGN (-) DEC205 (-) CD1a (-) Langerin (-) ALK (-) Ki-67 labeling index: 15 30% (-): negative, (+): weakly to moderately positive, (++): strongly positive the lumbosacral region were found to be prostate cancer metastases. The case was externally reviewed by a pathologist specializing in lymphoreticular and soft tissue tumors (Pf. Mitsunori Yamakawa) to reach the final diagnosis. Discussion The present case was an extremely rare manifestation of ECD in the following two respects: first, the patient presented with an intrapelvic tumor derived from ECD, although the retroperitoneal involvement of ECD does not usually affect the pelvic organs (2). To the best of our knowledge, this is the first reported case of the intrapelvic involvement of ECD. Second, this case lacked skeletal involvement, which is seen in up to 96% of ECD patients, most typically as bilateral osteosclerosis (2). According to the previously-reported diagnostic criteria, ECD is mostly diagnosed by its characteristic histological findings, which include foamy histiocyte infiltration of polymorphic granuloma and fibrosis or xanthogranulomatosis, with CD68-positive and CD1a-negative immunostaining. These characteristic histiocytes may be found in almost any tissue in cases of ECD (2, 6). As stated in the Results, the present case met all of these requirements. Furthermore, the tumor cells of this case were diffusely positive for BRAF V600E, which has recently been reported to be specific for ECD among the non-langerhans cell histiocytoses (7). Histiocytic sarcoma should be considered in the differential di- 3243
4 a b c d Figure 4. Prostate cancer tissue was detected in small discrete spots within the main ECD lesion (a: arrows, H&E staining). Some prostatic adenocarcinoma cells showed trabecular growth (b: H&E staining). Immunohistochemically, the adenocarcinoma cells exhibited positive staining for AMACR, and negative staining for 34βE12, while the foamy tumor cell stained negatively for both antibodies (c). The adenocarcinoma cells also exhibited positive staining for PSA (d). agnosis of ECD, but could be distinguished in the present case, because, xanthoma cells do not proliferate uniformly in histiocytic sarcoma, as they did in our case (8, 9). Other than the histological characteristics, the patient age at the onset of ECD is reported to be years and the sex ratio shows a strong male predominance with 73% of the patients being males (2, 10). Although our patient fit the common age and sex characteristics, he lacked the typical symptom of long bone pain, as well as the other common manifestations of the disease such as bulging eyes (due to retro-orbital infiltration) or xanthomatous skin lesions. Imaging studies revealed no pericardial, pulmonary, or CNS involvement. Bone scintigraphy did not reveal osteosclerosis of the long bones, but detected lesions in the pelvic bone and lumbar spine, all of which were proven to be metastases from the prostate cancer at autopsy. The clinical presentation suggests the main cause of death to be ECD. Prior to death, the patient s PSA value was 0.7 ng/ml, which suggests that the androgen deprivation therapy was at least partially effective against the prostate cancer. The significance of the coexistence of ECD with prostate cancer was unclear. For reference, a case of ECD which developed two years after radiotherapy for prostate cancer has been reported (4); however, we could not find any reports of ECD coexisting with prostate cancer within the same lesion. Lastly, ECD is usually a progressive disease, with death from cardiac, pulmonary, or renal involvement occurring in approximately 50% of cases. The mean survival period after diagnosis was reported to be 19.2 months (range: months) before the establishment of a standard treatment regimen (11). On the other hand, recent studies have demonstrated the efficacy of interferon alpha, which was reported to be a major independent predictor of survival among ECD patients (2, 12). Thus, early diagnosis has become increasingly important. Such novel biomarkers as BRAF V600E, which assisted in the diagnosis of this atypical case, are expected to lead to an increase of early diagnoses. The authors state that they have no Conflict of Interest (COI). References 1. Chester W. Über lipoidgranulomatose. Virchows Arch Pathol Anat Physiol 279: , Haroche J, Arnaud L, Cohen-Aubart F, et al. Erdheim-Chester disease. Curr Rheumatol Rep 16: 412, Veyssier-Belot C, Cacoub P, Caparros-Lefebvre D, et al. Erdheim- 3244
5 Chester disease: clinical and radiologic characteristics of 59 cases. Medicine (Baltimore) 75: , Balink H, Hemmelder MH, de Graaf W, Grond J. Scintigraphic diagnosis of Erdheim-Chester disease. J Clin Oncol 29: e470- e472, Mills JA, Gonzalez RG, Jaffe R. Case records of the Massachusetts General Hospital: Case A 43-year-old man with fatigue and lesions in the pituitary and cerebellum. N Engl J Med 359: , Mazor RD, Manevich-Mazor M, Shoenfeld Y. Erdheim-Chester Disease: a comprehensive review of the literature. Orphanet J Rare Dis 8: 137, Haroche J, Charlotte F, Arnaud L, et al. High prevalence of BRAF V600E mutations in Erdheim-Chester disease but not in other non-langerhans cell histiocytoses. Blood 120: , Chang KL, Weiss LM. Other histiocytic and dendritic cell neoplasms. In: Hematopathology. 1st ed. Jaffe ES, Harris NL, Vardiman JW, Campo E, Arber DA, Eds. Elsevier, Philadelphia, 2011: Grogan TM, Pileri SA, Chan JKC, Weiss LM, Fletcher CDM. Histiocytic sarcoma. In: World Health Organization Classification of Tumours, WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Swerdlow SH, Campo E, Harris NL, et al, Eds. International Agency for Research on Cancer (IARC), Lyon, 2008: Haroche J, Amoura Z, Dion E, et al. Cardiovascular involvement, an overlooked feature of Erdheim-Chester disease: report of 6 new cases and a literature review. Medicine (Baltimore) 83: , Haroche J, Arnaud L, Amoura Z. Erdheim-Chester disease. Curr Opin Rheumatol 24: 53-59, Arnaud L, Hervier B, Neel A, et al. CNS involvement and treatment with interferon-alpha are independent prognostic factors in Erdheim-Chester disease: a multicenter survival analysis of 53 patients. Blood 117: , The Japanese Society of Internal Medicine
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