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  • SCImago Journal Rank (SJR):0,11
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Rev Esp Patol 2018;51:23-6 - DOI: 10.1016/j.patol.2017.01.001
Brief report
Histiocytic sarcoma with bladder involvement: Case report and literature review
Sarcoma histiocítico con afectación vesical: notificación de un caso y revisión de la bibliografía
Mª Jesús Fernández-Aceñero, , Pablo Pérez Alonso, Cristina Díaz del Arco
Department of Surgical Pathology, Hospital Clínico Universitario San Carlos, Madrid, Spain
Recibido 29 noviembre 2016, Aceptado 23 enero 2017

We report an unusual case of histiocytic sarcoma with bladder involvement. An 80 year-old man with a previous history of diffuse large B-cell malignant lymphoma presented with hematuria and back pain. Serial urine cytologies revealed no urothelial malignant cells, but cystoscopy showed a large intravesical mass. The patient underwent transurethral resection (TUR) of the tumor. The bladder TUR specimen showed a widely infiltrating epithelioid neoplasm, with intense immunohistochemical positivity for CD45 and histiocytic markers (CD68, lysozime and fascin). Histopathological diagnosis was histiocytic sarcoma. As the patient's condition was progressively deteriorating, only palliative care was indicated and he died one month after TUR. Although histiocytic sarcoma can often be widespread at the time of diagnosis, to our knowledge, this is the first report of a case presenting with urinary symptoms. Histiocytic sarcoma can mimic many other malignant lesions, and only immunohistochemistry can define the tumor cells, allowing correct therapy. We discuss the differential diagnosis and possible associations.


Presentamos un caso infrecuente de sarcoma histiocítico con afectación vesical. Varón de 80 años con historia previa de linfoma maligno difuso de células B grandes que presenta hematuria y dolor de espalda. Citologías seriadas de orina no mostraron células uroteliales malignas, pero una citoscopia reveló una gran masa intravesical. Se practicó una resección transuretral del tumor. La resección transuretral de la vejiga mostró una neoplasia tipo epitelioide con fuerte expresión de CD45 y de marcadores histiocíticos tales como CD68 lisozima y fascina con diagnóstico de sarcoma histiocítico. Tras el estudio, el paciente se deterioró progresivamente indicándose solo cuidados paliativos, con exitus al mes de la cirugía. Aunque el sarcoma histiocítico suele estar en estadio avanzado en el momento del diagnóstico, creemos que este caso es el primero en comenzar con síntomas urinarios. El sarcoma histiocítico puede simular diversas lesiones neoplásicas, siendo la inmunohistoquímica necesaria para un diagnóstico correcto. Discutimos diagnósticos diferenciales y posibles asociaciones.

Malignant lymphoma, Histiocytic neoplasms, Sarcoma, Bladder tumors
Palabras clave
Linfoma maligno, Neoplasia histiocítica, Sarcoma, Tumores vesicales

Neoplasms originating from histiocytic and dendritic cells are very uncommon, representing less than 1% of all hematolymphoid neoplasms.1 The most recent 2008 classification of hematolymphoid tumors has established clear-cut criteria for the diagnosis of these neoplasms.2 Within this category we find Langerhans cell histiocytosis (LCH), histiocytic sarcoma (HC), follicular dendritic cell sarcoma (FDCS), interdigitating cell sarcoma (ICS), indeterminate dendritic cell sarcoma (IDCS) and fibroblastic reticular cell tumor (FRCT), with presumed different embryological origins. Although the old term histiocytic tumors persists, in fact most of them are not truly macrophagic, but originate rather from stem cell CD34+ precursors. Diagnosis of these tumors relies on immunohistochemistry (IHC), for they share morphological features with many other malignant tumors. Due to their infrequency, therapeutical experience is limited; in the literature there are isolated case reports or short case series. Interestingly, our literature review revealed many veterinary cases; this kind of tumor would appear to be much more frequent in animals, especially in dogs and cats.3,4 We report a case of histiocytic sarcoma that presented with urinary symptoms and discuss the differential diagnoses and possible associations.

Case report

An 80-year-old Caucasian man presented with hematuria and back pain. He had a past history of diffuse large B cell lymphoma in 2006 with node and spleen involvement, for which he had been splenectomized and treated with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) and rituximab with a favorable response. Follow-ups at the Hematology Unit of Hospital Clínico San Carlos showed no recurrences. In February 2016 he presented with acute hematuria and back pain. Serial urine cytological samples showed no malignant urothelial cells and no further action was taken. Eight months later during a routine follow-up consultation he complained of weight loss and malaise. Computed tomography (CT) showed enlarged retroperitoneal lymph nodes. Positron emission tomography–computed tomography (PET-TC) did not show any increased glucose uptake in nodes, but revealed a suspicious lesion in the bladder. Cystoscopy revealed a large infiltrating ulcerative mass involving the bladder wall. Transurethral resection (TUR) of the mass obtained a fairly large amount of tumor tissue.

Histopathology showed a diffuse neoplasm, composed of medium sized cells with abundant clear cytoplasm and irregular and slightly pleomorphic nuclei (Fig. 1). Most cells had prominent nucleoli, but no melanin pigment was found. The overall picture was concordant with a clear cell carcinoma. The tumor cells widely infiltrated the muscular layer with vascular invasion. Immunohistochemistry for cytokeratin (wide spectrum AE1-AE3) was negative, as it was for GATA3 and epithelial membrane antigen (EMA). P63 was positive in 30% of the tumor cells. Subsequently we performed a much wider immunohistochemical panel, including melanocytic, lymphoid and muscular specific markers (namely, HMB45, Melan A, S100 protein, CD20, CD79a, BCL2, BCL6, CD10, CD3, desmin and actin) with negative results. The lack of specific IHC staining led us to review the H&E stained slides and we noted that some tumor cell nuclei showed a clear indentation (Fig. 2). For this reason we added immunohistochemical markers of hystiocytic differentiation, namely CD68 (EBM clone 11, Dako Denmark), which was intensely positive (Fig. 3). We then performed CD45, fascin, CD23, CD21, CD1a and lysozime to discard dendritic follicular cells or Langerhans cells origin. Only lysozime and fascin were positive and we could establish a definite diagnosis of histiocytic sarcoma. PCR was performed and confirmed rearrangement of IgH in the tumor.

Figure 1.

Low power view of the tumor cells showing clear cytoplasms and slightly pleomorphic nuclei (H-E 100×).

Figure 2.

Indentation of the tumor cells nuclei, suggesting histiocytic origin (H-E, 400×).

Figure 3.

CD68 intense expression in the tumor cells (IHC for CD68, 200×).

Due to the advanced age of the patient and the clear and fast decline in his overall condition, no adjuvant therapy was given; he received palliative care only. He died one month after diagnosis.


Histiocytic tumors are very rare neoplasms, comprising less than 1% of all hematological malignancies.1,2 Histologically, these lesions are hard to diagnose, for they share morphological similarities with many other malignant neoplasms, including carcinoma, epitheloid sarcomas and melanomas. The advent of IHC staining has made diagnosis easier, for these lesions are shown to express common markers of histiocytic lineage, such as CD68 or lysozime. The 2008 WHO classification of lymphoid neoplasms recognizes six different entities within the histiocytic malignant tumors, which can reliably be distinguished with IHC markers.2 Emile et al. proposed a new classification of histiocytic tumors into 4 groups: Langerhans group, malignant histiocytosis group, R group (Rosai-Dorfman disease and non-cutaneous non-Langerhans cell histiocytosis) and H group (hemophagocytic lymphohistiocytosis and macrophage activation syndrome).5 In the most recent WHO classification and for the first time, the presence of B and/or T cell rearrangement does not preclude diagnosis of histiocytic lineage, for it has been clearly shown that some bona-fide histiocytic tumors have this kind of molecular abnormality, common to other lymphoid malignant neoplasms.6 The new WHO classification is very similar to the previous one, except for the order of the entities and the addition of Erdheim-Chester disease. Moreover, BRAFV600E mutation has been observed in Langerhans cell histiocytosis, histiocytic sarcoma, follicular dendritic cell sarcoma, disseminated juvenile xanthogranuloma and Erdheim-Chester disease.7

The most frequent histiocytic neoplasm is Lagerhans cell histiocytosis (LCH) and all the other entities seem to be rather infrequent. A recent retrospective 25 year-review from a single center found 32 cases of histiocytic malignant tumors, 62% of which were LCH.8 Histiocytic sarcoma was second in frequency with 6 cases in the series.

HS usually affects middle-aged adults (median age 46–55 years), although there have been some reports in children9 or adolescents.10 Both sexes are equally affected, although some reports suggest a slight male preponderance. Prognosis is intermediate with a median survival of 52 months, with a wide variation according to stage and location.8 Disease is usually localized at the time of diagnosis, but it can also present with widespread disease. It most frequently involves nodes, bone marrow, intestine, brain and skin.11 However, there are exceptional reports of cases involving the uterine cervix,12 the choroid13 or the liver.14 To the best of our knowledge there are no previous reports of bladder involvement by HS.

Most patients have no previous history of disease (so-called primary HS), although some HS have affected people with kidney transplantation.15 A rather common association of these lesions is with lymphoid neoplasms, that can arise both prior or subsequent to diagnosis of HS. Old classifications discarded HS diagnosis when B and/or T cell rearrangements were found and considered these cases as dedifferentiation of a previous lymphoma, but the 2008 WHO classification allows diagnosis of HS even in the presence of these rearrangements for HS is considered a transdifferentiation or a dual differentiation within lymphoid neoplasms. Malignant lymphoma can precede HS, even for decades,16–18 but it can also be synchronous with or even present after HS diagnosis.19 In our patient diffuse large B cell lymphoma had been diagnosed and treated 10 years before with good results. The present neoplasm did not show any marker of lymphoid lineage (it was negative for CD20, CD79a, CD10, MUM1, BCL2 and BCL6), although it preserved the clonal rearrangement of IgH, as already described in the literature. This fact has been interpreted either as transdifferentiation or divergent differentiation from a similar stem cell.

Diagnosis is based on histopathological features and IHC studies. These neoplasms do not show any specific growth pattern and are usually diffuse proliferations of medium to large cells with clear and even xanthomized cytoplasm. Differential diagnosis of these tumors is extensive and includes neoplasms of almost any lineage. However, careful inspection usually reveals histopathological features of histiocytic differentiation, such as nuclear indentation or small multiple nucleoli. Keratins, melanocytic markers and lymphoid markers should, by definition, be negative in HS, as should muscle cell and neural ones. Definitive diagnosis relies on the expression of histiocytic markers, like CD68, lysozime or fascin, coupled with the lack of expression of markers of specific lineage, like CD1a and langerin (LCH) or CD23 and CD21 (FDCS).8

Therapy is not well standardized, for most cases are sporadic and series are rather short. However, there seems to be agreement that surgical resection is the mainstay of therapy, followed in disseminated cases by chemotherapy and/or radiation therapy to control local recurrence after surgery. Recent studies have analyzed the molecular abnormalities in HS by next generation sequencing, to find that most HS carry somatic mutations in BRAF, mainly G464V and N581S.20 In the evolving era of personalized medicine and targeted therapy these new insights into the molecular features of tumors could lead to the development of targeted strategies of therapy that could improve prognosis.21 In this respect a recent report by Coutermarsh-Ott et al.22 has proposed NF-kB signaling inhibition as a means to control disease.

Ethical disclosuresProtection of human and animal subjects

The authors declare that no experiments were performed on humans or animals for this study.

Confidentiality of data

The authors declare that they have followed the protocols of their work center on the publication of patient data.

Right to privacy and informed consent

The authors declare that no patient data appear in this article.


The authors acknowledge no funding for the elaboration of the present study.

Conflicts of interest

The authors declare no conflicts of interest.

S.A. Pileri,T.M. Grogan,N.L. Harris,P. Banks,E. Campo,J.K. Chan
Tumours of histiocytes and accessory dendritic cells: an immunohistochemical approach to classification from the international lymphoma study group based on 61 cases
Histopathology, 41 (2002), pp. 1-29
Histiocytic and dencritic cell neoplasms
WHO classification of tumours of haematopoietic and lymphoid tissues,
P.F. Moore
A review of histiocytic diseases of dogs and cats
Vet Pathol, 51 (2014), pp. 167-184 http://dx.doi.org/10.1177/0300985813510413
N.G. Dervisis,M. Kiupel,Q. Qin,L. Cesario
Clinical prognostic factors in canine histiocytic sarcoma
Vet Comp Oncol, (2016), http://dx.doi.org/10.1111/vco.12252
[in press]
J.F. Emile,O. Abla,S. Fraitag,A. Horne,J. Haroche,J. Donadieu
Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages
W. Huang,T. Qiu,L. Zeng,B. Zheng,J. Ying,X. Feng
High frequency of clonal IG and T-cell receptor gene rearrangements in histiocytic and dendritic cell neoplasms
[in press]
S.H. Swerdlow,E. Campo,S.A. Pileri,N.L. Harris,H. Stein,R. Sibert
The 2016 revision of the World Health Organization classification of lymphoid neoplasms
S. Dalia,M. Jaglal,P. Chervenick,H. Cualing,L. Sokol
Clinicopathologic characteristics and outcomes of histiocytic and dendritic cell neoplasms: the moffitt cancer center experience over the last twenty five years
Cancers, 6 (2014), pp. 2275-2295 http://dx.doi.org/10.3390/cancers6042275
N. Mittal,V. Aakalu,S. Mehendele,P. Setabutr,E. Michals,M.L. Schmidt
Primary orbital histiocytic sarcoma in a child successfully treated with multiagent chemotherapy
J Pediatr Hematol Oncol, 38 (2016), pp. 653-657 http://dx.doi.org/10.1097/MPH.0000000000000649
H.R. Haynes,Z. Melegh,S. Vanjani,M. Cieka,S. Beavers,N. Rooney
Sudden unexpected death from an undiagnosed histiocytic sarcoma in an adolescent female
Forensic Sci Med Pathol, 12 (2016), pp. 486-490 http://dx.doi.org/10.1007/s12024-016-9800-2
T. Ueno,H. Nishijima,H. Kurotaki,A. Kurose,M. Tomiyama
An unusual case of chronic meningitis due to histiocytic sarcoma of the central nervous system with meningeal dissemination
Neurol Sci, 37 (2016), pp. 1875-1877 http://dx.doi.org/10.1007/s10072-016-2636-4
F. Binesh,M.K. Zarchi,M.R. Vahidfar,Z.K. Hadgiabadi
Primary histiocytic sarcoma of the uterine cervix: an extremely rare entity
[in press]
Y. Krishna,I. Araujo,S. Warrier,H. Heimann,S.E. Coupland
Diffuse histiocytic sarcoma involving the choroid
JAMA Ophthalmol, 134 (2016), pp. 1198-1200 http://dx.doi.org/10.1001/jamaophthalmol.2016.2867
T. Kubo,S. Kiryu,H. Akai
Hepatic involvement of histiocytic sarcoma: CT and MRI findings
Korean J Radiol, 17 (2016), pp. 758-762 http://dx.doi.org/10.3348/kjr.2016.17.5.758
M. Pollen,S. El Jamal,J. Lewin,V. Manucha
Histiocytic sarcoma in a kidney transplant patient: a case report and review of the literature
Case Rep Pathol, 2016 (2016), pp. 3591050 http://dx.doi.org/10.1155/2016/3591050
E. Wang,C.B. Hutchinson,Q. Huang,S. Sebastian,C. Rehder,A. Kanaly
Histiocytic sarcoma arising in indolent small B-cell lymphoma: report of two cases with molecular/genetic evidence suggestive of a ‘transdifferentiation’ during the clonal evolution
Leuk Lymphoma, 51 (2010), pp. 802-812 http://dx.doi.org/10.3109/10428191003699845
E. Wang,J. Papalas,C.B. Hutchinson,E. Kulbacki,Q. Huang,S. Sebastian
Sequential development of histiocytic sarcoma and diffuse large B-cell lymphoma in a patient with a remote history of follicular lymphoma with genotypic evidence of a clonal relationship: a divergent (bilineal) neoplastic transformation of an indolent B-cell lymphoma in a single individual
Am J Surg Pathol, 35 (2011), pp. 457-463 http://dx.doi.org/10.1097/PAS.0b013e3182098799
J. Ansari,A.R. Naqash,R. Munker,H. El-Osta,S. Master,J.D. Cotelingam
Histiocytic sarcoma as a secondary malignancy: pathobiology, diagnosis, and treatment
Eur J Haematol, 97 (2016), pp. 9-16 http://dx.doi.org/10.1111/ejh.12755
S. Fernandez-Pol,C.D. Bangs,A. Cherry,D.A. Arber,D. Gratzinger
Two cases of histiocytic sarcoma with BCL2 translocations and occult or subsequent follicular lymphoma
Q. Liu,K. Tomaszewicz,L. Hutchinson,J.L. Hornick,B. Woda,H. Yu
Somatic mutations in histiocytic sarcoma identified by next generation sequencing
Virchows Arch, 469 (2016), pp. 233-241 http://dx.doi.org/10.1007/s00428-016-1965-2
B.H. Durham,E.L. Diamond,O. Abdel-Wahab
Histiocytic neoplasms in the era of personalized genomic medicine
Curr Opin Hematol, 23 (2016), pp. 416-425 http://dx.doi.org/10.1097/MOH.0000000000000256
S. Coutermarsh-Ott,A. Simmons,V. Capria,T. LeRoith,J.E. Wilson,B. Heid
NLRX1 suppresses tumorigenesis and attenuates histiocytic sarcoma through the negative regulation of NF-κB signaling
Oncotarget, 7 (2016), pp. 33096-33110 http://dx.doi.org/10.18632/oncotarget.8861
Corresponding author. (Mª Jesús Fernández-Aceñero mgg10167@gmail.com)
Copyright © 2017. Sociedad Española de Anatomía Patológica