This term and disease was relatively common prior to age of immunohistochemistry and sophisticated molecular biology techniques which pathologists helped to pioneer. Cases which have previiously been reported as histiocytic lymphoma almost all represent lymphomas of T or B lineage, especially anaplastic large cell lymphoma. The commonest sites of involvement by true histiocytic lymphomas are lymph node, gastrointestinal tract, skin, and soft tissue. Regardless of site, this tumor has an aggressive behavior and most often presents with a high stage of disease. The pathologist must rely upon a combination of the morphologic features of histiocytes an appropriate immunohistochemical markers. Although not specific, CD68 and lysozyme have been used. This positivity is combined with lack of markers for T and B cell malignancies, myeloid markers, CD30, and Langherhans cells.
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Special Stains/Immunohistochemistry/Electron Microscopy
Prognosis and Treatment
Commonly Used Terms
EPIDEMIOLOGY CHARACTERIZATION SYNONYMS Malignant histiocytosis
AGE Mean 44 years, wide age range INCIDENCE
Histiocytic sarcomas and monoblastic leukemias. A clinical, histologic, and immunophenotypical study.
Lauritzen AF, Delsol G, Hansen NE, Horn T, Ersboll J, Hou-Jensen K, Ralfkiaer E.
Department of Pathology, Herlev Hospital, University of Copenhagen, Denmark.
Am J Clin Pathol 1994 Jul;102(1):45-54 Abstract quote
Eight histiocytic sarcomas, identified by examination of more than 2000 malignant lymphomas, are described.
For comparison, tumor infiltrates from five monoblastic leukemias were also analyzed. The histiocytic sarcomas were all high-grade malignancies consisting of markedly pleomorphic large cells with many mitotic figures. At presentation, six of the patients had systemic symptoms (fever, fatigue, loss of weight), skin infiltrates, and lymphadenopathy. Despite aggressive chemotherapy, clinical remissions were short, and six patients died of disease .5-48 months (mean, 6.5 months) after diagnosis. The remaining two patients are alive and in partial or complete remission 7 and 12 months after diagnosis. Immunotypic examination showed that all the histiocytic sarcomas were positive for macrophage-related antigens and negative for antigens on B cells, T cells, myeloid cells, epithelial cells, and melanocytes. T-cell receptor and immunoglobulin genes were studied in three cases and were present in a germline configuration. One of the histiocytic sarcomas resembled Langerhans' cells in phenotype and morphology; it was classified as a Langerhans' cell sarcoma. The remaining histiocytic sarcomas did not express accessory cell-associated antigens, but more closely resembled "ordinary" tissue macrophages; they were positive for lysozyme and/or CD68, followed in frequency by CD11c, CD4, CD11b, CDw32, peanut agglutinin receptor, and CD13. Similar features were seen in the monoblastic leukemias. These conditions could only be distinguished from histiocytic sarcoma by clinical and morphologic, rather than immunophenotypic, criteria. Expression of oncoprotein p53 was studied in nine cases and was positive in six of six histiocytic sarcomas and one of three monoblastic leukemias. Rare malignancies show features consistent with the derivation from macrophages. Two entities may be distinguished: those that resemble antigen-presenting accessory cells and those that more closely resemble ordinary tissue macrophages.
Recognition of these tumors is important clinically and requires assessment of clinical, morphologic, and immunophenotypic features, supplemented by analysis of T-cell receptor and immunoglobulin genes. Whether (or how) p53 gene mutations are implicated in their pathogenesis will be an important topic for future investigation.
DISEASE ASSOCIATIONS CHARACTERIZATION
True histiocytic lymphoma following B-acute lymphoblastic leukaemia: case report with evidence for a common clonal origin in both neoplasms.
Bouabdallah R, Abena P, Chetaille B, Aurran-Schleinitz T, Sainty D, Dubus P, Arnoulet C, Coso D, Xerri L, Gastaut JA.
Department of Haematology, Cancer Centre Institut Paoli-Calmettes, Universite de la Mediterranee, Marseille, France.
Br J Haematol 2001 Jun;113(4):1047-50 Abstract quote
True histiocytic lymphoma (THL) is a very rare type of non-Hodgkin's lymphoma (NHL) in which neoplastic cells exhibit markers of histiocytic differentiation. Some cases of THL have been reported in patients with previous acute lymphoblastic leukaemia (ALL), especially in children and young adults, in whom the acute leukaemia was of T-cell origin. The relationship between the initial lymphoid tumour and the secondary THL remains unclear, as a common monoclonal origin shared by both neoplasms has never been definitively demonstrated.
We report a patient with B-ALL who developed a nodal and extranodal tumour with histological and immunohistochemical features of THL 4 years after the initial diagnosis. Genotypic study showed that both neoplasms contained the same immunoglobulin heavy gene rearrangement, which has not been reported previously.
CHARACTERIZATION GENERAL VARIANTS
True histiocytic lymphoma (monocytic sarcoma)
Soria C, Orradre JL, Garcia-Almagro D, Martinez B, Algara P, Piris MA.
Department of Dermatology, Virgen de la Salud Hospital, Toledo, Spain.
Am J Dermatopathol 1992 Dec;14(6):511-7 Abstract quote
The clinical, histological, immunophenotypic, and genotypic characteristics of two cases of cutaneous genuine histiocytic lymphoma are described.
Both cases presented as cutaneous lesions. Both patients remain alive and free of disease at 26 and 10 months after the diagnosis and after having been treated with polychemotherapy. Neither peripheral blood nor bone marrow infiltration was detected in either case. Histological and immunophenotypic examination showed dense, diffuse dermic infiltrates of mononuclear cells with positive macrophage-associated markers (CD11c, CD68), and negative T- or B-cell-associated antigens. A germline configuration of both T-cell receptor and immunoglobulin genes was observed in gene rearrangement studies. Although most of the cases that have been diagnosed as histiocytic lymphoma or malignant histiocytosis in the past turned out to be B- or T-large-cell lymphomas, a small number of cases (two in our consecutive series of 350 cases) show characteristics of monocyte-macrophage tumors.
We stress the importance of the CD68 marker in the diagnosis of true histiocytic lymphoma, suggest a therapeutic approach based on similarities with monocytic leukemia, and propose the use of the term monocytic sarcoma for this clinicopathological presentation.
True histiocytic lymphoma of small intestine. Analysis of two S-100 protein-positive cases with features of interdigitating reticulum cell sarcoma.
Miettinen M, Fletcher CD, Lasota J.
Department of Pathology and Cell Biology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
Am J Clin Pathol 1993 Sep;100(3):285-92 Abstract quote
Two cases of true histiocytic lymphoma of the small intestine occurred in middle-aged patients, manifesting as tumors causing intestinal obstruction.
One of the patients died of uncontrollable local and metastatic disease, 16 months after surgery and polychemotherapy, and the other patient is alive 12 months after surgery and chemotherapy.
The histologic characteristics of the tumor cells, namely complex nuclear outlines and abundant variably eosinophilic cytoplasm, suggested histiocytic differentiation. Both cases had negative results for B-cell and T-cell markers but stained for the histiocytic markers lysozyme, CD68, and HLA-DR and had positive results for S-100 protein and vimentin. Acetone-fixed frozen sections of one case showed positive results for several histiocytic markers, including CD11c, CD14, CD33, CD68, and BerMac3 (unclustered monoclonal antibody). CD4, a T-cell antigen present in a subset of histiomonocytic cells, had positive results in the cytoplasm. The tumor cells had negative results for CD1a, CD15, and CD30. Immunoglobulin and T-cell receptor gene probes showed germline configuration in one case studied.
These results indicate the tumors are true histiocytic lymphomas, which have immunophenotypic features of both ordinary histiocytes and interdigitating reticulum cells.
Histiocytic sarcoma of the spleen associated with hypoalbuminemia, hypo gamma-globulinemia and thrombocytopenia as a possibly unique clinical entity--report of three cases.
Kimura H, Nasu K, Sakai C, Shiga Y, Miyamoto E, Shintaku M, Wakatsuki S, Tominaga K, Abe M, Maruyama Y. I
nternal Medicine, Hobara Central Hospital, Fukushima, Japan.
Leuk Lymphoma 1998 Sep;31(1-2):217-24 Abstract quote
We report three patients with histiocytic sarcoma of the spleen associated with severe hypoalbuminemia, hypo gamma-globulinemia and thrombocytopenia.
After the clinical diagnosis of splenic tumor of unknown origin was made, all three patients underwent splenectomy. The histiocytic origin of the tumor was confirmed histopathologically and immunohistochemically using a panel of antibodies. In contrast to malignant histiocytosis (MH), which typically reveals severe generalized clinical manifestations and a rapidly fatal course caused by the disseminated proliferation of neoplastic histiocytes, these patients were asymptomatic or showed only mild clinical symptoms for a long period of time until the recurrence was detected by which time the tumor cells had already spread to other organs. All three cases were characteristically associated with hypoalbuminemia, hypo gamma-globulinemia and thrombocytopenia, which returned to normal after splenectomy.
Splenic histiocytic sarcoma with the features described here may represent a unique clinical entity, distinct from MH.
Primary Histiocytic Lymphoma of the Central Nervous System A Neoplasm Frequently Overshadowed by a Prominent Inflammatory Component
Wah Cheuk, M.B.B.S. ; Norman Walford, M.B. , F.R.C.Path. ; June Lou, M.B.B.S. ; Arthur K. C. Lee, M.B.B.S. ; C. F. Fung, M.B.B.S. ; K. H. Au, M.B.B.S. ; L. S. Mak, B.Sc. ; John K. C. Chan, M.B.B.S.
From the Department of Pathology (W.C., L.S.M., J.K.C.C.) and the Department of Oncology and Radiotherapy (K.H.A.), Queen Elizabeth Hospital; and the Departments of Pathology (N.W.) and Pediatric Oncology (J.L.), Kadang Kerbau Women's and Children's Hospital, Singapore; and St. Paul's Hospital, Hong Kong (A.K.C.L., C.F.F.).
Am J Surg Pathol 2001;25:1372-1379 Abstract quote
True histiocytic lymphoma, as defined by strict criteria, is a very rare neoplasm.
We describe three cases occurring as primary tumors in the central nervous system. The patients, two females and one male, ranged in age from 11 to 69 years. The tumors involved the brain in two cases and spinal cord in one, with a size ranging from 7 to 17 mm. Two patients died at 4 months and 8 months, respectively, and one was alive with disease at 5 months. Pathologically, the tumors comprised groups and sheets of noncohesive large cells with pleomorphic vesicular nuclei, distinct nucleoli, and abundant eosinophilic cytoplasm. A dense inflammatory infiltrate consisting of neutrophils, lymphocytes, plasma cells, and histiocytes was present, with multiple foci of necrosis and abscess formation.
All three cases demonstrated an identical immunophenotype: positive for CD68 and lysozyme; focally positive for S-100 protein, CD45RB, and CD4; and negative for CD3, CD20, CD21/CD35, CD1a, CD30, ALK1, myeloperoxidase, glial fibrillary acidic protein, and cytokeratin. The proliferative index ranged from 20% to 35%.
Ultrastructural examination further confirmed the histiocytic nature of the tumor cells, characterized by irregularly folded or multisegmented nuclei and abundant cytoplasm containing lysosomes; Birbeck granules, interdigitating cell processes, and cell junctions were not found.
Although the presence of abundant inflammatory cells could obscure the neoplastic histiocytes, making the distinction from inflammatory conditions difficult, awareness of this unusual histologic feature and the invariable finding of pleomorphic cells in some areas of the lesion permit the correct diagnosis to be made.
HISTOLOGICAL TYPES CHARACTERIZATION GENERAL Key is a pink staining cytoplasm-lymphomas usually have an amphophilic cytoplasm
Malignant lymphoma of true histiocytic origin: histiocytic sarcoma. A morphological, ultrastructural, immunological, cytochemical and clinical study of 10 cases.
van der Valk P, te Velde J, Jansen J, Ruiter DJ, Spaander PJ, Cornelisse CJ, Meijer CJ
Virchows Arch A Pathol Anat Histol 1981;391(3):249-65 Abstract quote
Ten tumors of true histiocytic origin (Histiocytic Sarcoma) are presented.
The tumor cells were identified as histiocytes by immunological, cytochemical and ultrastructural criteria (cytoplasmic lysozyme activity, presence of C3 and Fc gamma receptor, strong acid phosphatase and alpha-naphthyl acetate esterase activity, presence of lysosomes, absence of cell junctions and evidence of phagocytosis). The tumors identified in this way showed the following histological characteristics: diffuse proliferation of large tumor cells with ample cytoplasm, containing granular or occasionally diffuse diastase resistant PAS positive material, erythrophagocytosis, and haemosiderin pigment. The large or enormous nuclei were irregular, with occasional deep indentations, sharply defined nuclear membrane, coarse chromatin and conspicuous nucleoli. Despite the uniformity of these criteria differences in presence of alpha 1-antitrypsin, alpha 1-antichymotrypsin and 5 Nucleotidase activity and the number of lysosomes in the cytoplasm were found. The findings are suggestive of a spectrum of cytological in these Histiocytic Sarcomas. The clinical picture ranged from monolocalization in a lymphoid organ to that of a diffuse Malignant Histiocytosis.
The relationship between good response to therapy and complete remission and the absence of alpha 1-antitrypsin and a high number of lysosomes is discussed.
Malignant histiocytosis and related tumors. A clinicopathologic study of 42 cases using cytological, histochemical and ultrastructural parameters.
van Heerde P, Feltkamp CA, Hart AA, Somers R, van Unnik JA, Vroom TM.
Hematol Oncol 1984 Jan-Mar;2(1):13-32 Abstract quote
Light and electron microscopical, immunohistochemical and clinical characteristics in 42 cases of malignant neoplasms, arising from true histiocytes, are described.
These were separated in a lymphoma-like subtype, called true histiocytic lymphoma (29 patients) and a disseminated variant, called malignant histiocytosis (9 patients). In addition 4 related histiocytic tumors are discussed, including 2 tumors arising from interdigitating cells. Sinus pattern and cytologic features, especially 'window' nuclei, are emphasized as diagnostic criteria. Erythrophagocytosis was not a constant finding. Electron microscopic features, presence of acid phosphatase, acid alpha-naphthylacetate esterase, lysozyme, alpha 1-antitrypsin, alpha 1-antichymotrypsin, Ia-antigen and absence of B- and T-cell markers, were important in establishing the histiocytic nature or excluding a non-histiocytic tumor. A distinct male predominance existed (male:female = 2.5:1) with a higher relapse free period in females (p = 0.032). A high number of mitotic figures appeared to be a favourable sign, p = 0.020 and 0.019, for remission rate and relapse free period respectively. The degree of cell differentiation and the immunohistochemical pattern did not show a correlation with remission and relapse free period.
Extranodal involvement and the presence of short profiles of endoplasmic reticulum were prognostically unfavourable signs. True histiocytic lymphomas showed a higher remission rate (p = 0.041) and relapse-free period (p = 0.017) than malignant histiocytosis.
Malignant lymphomas of true histiocytic origin. A clinical, histological, immunophenotypic and genotypic study.
Ralfkiaer E, Delsol G, O'Connor NT, Brandtzaeg P, Brousset P, Vejlsgaard GL, Mason DY.
Department of Pathology, Rigshospitalet, University of Copenhagen, Denmark.
J Pathol 1990 Jan;160(1):9-17 Abstract quote
The clinical, histological, immunophenotypic and genotypic properties of four cases of lymphoma of true histiocytic origin are described.
The cases were identified by typing 925 non-Hodgkin's lymphomas by immunophenotypic and/or genotypic techniques, and they all presented with skin lesions. The histological and immunophenotypic examination showed dense, diffuse infiltrates of markedly pleomorphic mononuclear cells that were positive for macrophage-associated markers, and negative for B-cell, T-cell and myeloid cell-associated antigens. Staining for Ki-1 and epithelial membrane antigen was also negative. Gene rearrangements studies were performed in three cases, and all of these showed germline configuration of both T-cell receptor and immunoglobulin genes. In all cases, the clinical course was aggressive with rapid and widespread dissemination to internal organs, poor response to conventional chemotherapy, and short survival times (0.5 to 14 months).
This suggests that although true histiocytic tumours are very rare, their recognition may be important for clinical and/or prognostic reasons.
CHARACTERIZATION SPECIAL STAINS IMMUNOPEROXIDASE CD68 is not specific
Must confirm histiocytic nature of neoplasm by excluding other lymphomas with markers such as CD45, CD4, CD43
NOTE: Some histiocytic lymphomas may express S-100
True histiocytic lymphoma: histopathologic, immunophenotypic and genotypic analysis.
Hanson CA, Jaszcz W, Kersey JH, Astorga MG, Peterson BA, Gajl-Peczalska KJ, Frizzera G.
Department of Laboratory Medicine and Pathology, University of Minnesota Hospital and Clinic, Minneapolis 55455
Br J Haematol 1989 Oct;73(2):187-98 Abstract quote
Five cases of true histiocytic lymphoma (THL) were analysed by immunophenotyping and immunoglobulin/T-cell receptor genotyping.
These cases showed striking morphologic diversity but a strong degree of immunophenotypic homogeneity. The malignant cells reacted with multiple histiocytic markers including CD11c (Ki-M1, LeuM5), CD14, CD68 (Ki-M6) and Ki-M8; anti-HLA-DR and non-specific esterase staining was also found in all cases. The malignant cells did not express monoclonal immunoglobulin and did not react with the B- or T-cell monoclonal antibodies used except for those known to be cytoplasmically expressed in monocytes/histiocytes, such as CD4 and CD19; B- and T-cell staining was otherwise limited to background small lymphocytes. By genotypic analysis, three cases showed rearrangements: one with T beta, one with T beta and immunoglobulin heavy chain (JH) and one with both JH and light chain; the remaining two cases retained their immunoglobulin and T-cell receptor genes in germline configuration.
The results not only suggest that certain subsets of the histiocyte/reticulum cell system may be capable of rearranging immunoglobulin or T beta genes while simultaneously expressing multiple histiocytic surface antigens but also demonstrate the necessity of using multiple histiocytic-specific monoclonal antibodies and cytochemical staining in diagnosing THL. Gene rearrangement studies must be interpreted in conjunction with immunophenotyping and morphology in the determination of cell lineage.
Lymphomas of true histiocytic origin. Expression of different phenotypes in so-called true histiocytic lymphoma and malignant histiocytosis.
Hsu SM, Ho YS, Hsu PL.
Department of Pathology, University of Arkansas for Medical Science, Little Rock.
Am J Pathol 1991 Jun;138(6):1389-404 Abstract quote
The authors determined the phenotypes of neoplastic cells in true histiocytic lymphoma and malignant histiocytosis by using a large panel of monoclonal antibodies and enzyme histochemistry procedures.
Although the phenotypes overlapped slightly, the authors noted a distinct pattern in these tumors. The tumor cells of malignant histiocytosis generally expressed the monocyte markers CD11b, CD11c, CD14, and CD45, especially after induction with phorbol ester. In contrast, the tumor cells of true histiocytic lymphoma exhibited a marker expression very similar to that of Reed-Sternberg cells in Hodgkin's disease. These cells expressed markers CD30, 2H9, and 1A2, but rarely expressed CD11b, CD11c, CD14, or CD45. Regardless of their cytologic features, the tumor cells from both types of histiocytic lymphoma exhibited diffuse nonspecific esterase and acid phosphatase activities, and they expressed histiocyte markers CD15, CD68, LN5, 1E9, and M387 to varying degrees. The tumor cells from both lymphomas did not exhibit T- or B-cell markers, T-cell receptor or immunoglobulin gene rearrangements, or gene translation products, even when they were induced with phorbol ester. The phenotypic expression in these two histiocytic malignancies suggests that they are derived from different types of histiocytes, or from histiocytes in different stages of maturation or differentiation, or from histiocytes that have distinct mechanisms of tumorigenic transformation.
The expression of circulating monocyte markers in malignant histiocytosis suggests that this tumor originates in monocytes or free histiocytes, whereas the phenotype of true histiocytic lymphoma is compatible with an origin in fixed histiocytes, which generally are devoid of the monocyte markers CD11b and CD14.
KP1 (CD68)-positive large cell lymphomas: a histopathologic and immunophenotypic characterization of 12 cases.
Carbone A, Gloghini A, Volpe R, Pinto A.
Division of Pathology, Istituto Nazionale di Ricovero e Cura a Carattere Scientifico, Aviano, Italy.
Hum Pathol 1993 Aug;24(8):886-96 Abstract quote
CD68/KP1 antigen expression in a series of 298 non-Hodgkin's lymphoma (NHL) cases, including 41 cases of CD30/Ki-1-positive anaplastic large cell (Ki-1+ ALC) lymphomas, was examined.
Among the cases in this series, 12 large cell NHLs, including five centroblastic (G group according to the Working Formulation) NHLs, three immunoblastic (H group) NHLs, and four Ki-1+ ALC lymphomas, were found to express KP1. By extensive immunophenotypic analysis and in situ hybridization, KP1-positive large cell lymphomas of the G and H groups were assigned a B-cell phenotype. The pattern of KP1 staining usually consisted of localized small to medium-sized cytoplasmic dots; only two cases showed diffuse fine granular reactivity. In two of the four Ki-1+ ALC lymphomas tumor cells failed to express a B- or T-cell phenotype and stained positively for lysozyme, whereas in the other two cases they showed a hybrid T/histiocytic, phenotypic profile. KP1 staining of Ki-1+ ALC lymphoma cells was usually intense and showed a diffuse granular cytoplasmic pattern; tumor cells also expressed the CD13 antigen and showed strong reactivity with the anti-CD68 EBM11 antibody.
Our results suggest that certain subsets of large "blastic" B-cell lymphomas may simultaneously express the CD68/KP1 histiocyte-specific marker and other myeloid-associated antigens, indicating the necessity of using a multiparameter approach in the determination of cell lineage. Moreover, this study, which demonstrates that the expression of CD68/KP1 and CD30 antigens is not mutually exclusive, supports the view that a fraction of cases diagnosed as Ki-1+ ALC lymphomas (at least those with KP1 expression along with the lack of B- or T-antigen expression) represent true histiocytic lymphomas despite the Ki-1+ phenotype.
True histiocytic lymphoma with multiple skin nodules.
Osborne BM, Mackay B.
Department of Pathology, University of Texas M.D. Anderson Cancer Center, Houston 77030.
Ultrastruct Pathol 1994 Jan-Apr;18(1-2):241-6 Abstract quote
A 73-year-old white woman developed multiple cutaneous nodules that fluctuated in size and occasionally regressed. The tumor cells infiltrating the dermis were histiocytic by light microscopy, marker studies, and electron microscopy. Similar cells were present in a bone marrow biopsy specimen. A diagnosis of true histiocytic lymphoma was made.
The case illustrates some of the problems that may arise in evaluation of clinical and pathologic findings in a patient with a proliferative disorder of histiocytes and demonstrates the contribution that electron microscopy can provide in establishing the diagnosis.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES Anaplastic Large cell lymphoma-CD30 Graulocytic sarcoma Langerhan's cell histiocytosis Peripheral T cell lymphoma Large B-cell lymphoma
PROGNOSIS AND TREATMENT CHARACTERIZATION PROGNOSTIC FACTORS
Malignant histiocytosis (true histiocytic lymphoma) clinicopathological study of 25 cases.
Pileri S, Mazza P, Rivano MT, Martinelli G, Cavazzini G, Gobbi M, Taruscio D, Lauria F, Tura S.
Histopathology 1985 Sep;9(9):905-20 Abstract quote
Twenty-five cases originally diagnosed as malignant histiocytosis/true histiocytic lymphoma were reviewed according to both pathological and clinical criteria.
Microscopically, they were characterized by large, pleomorphic tumour cells showing variable degrees of atypia and phagocytic activity. The growth more often appeared as diffuse, being limited to the sinuses in only two cases. Cytochemistry on touch imprints showed tumour cells strongly positive for acid phosphatase and alpha-naphthyl-acetate esterase in all the samples tested. Immunohistochemistry on paraffin embedded sections using specific antisera showed tumour cell positivity for lysozyme in 12 of 25 cases, for alpha 1-antitrypsin in 24 of 25 cases and for alpha 1-antichymotrypsin in all 25 cases. Immunophenotyping on frozen-sections in three cases displayed a clear-cut reactivity of the neoplastic cells with the monoclonal antibody OKM1.
Clinically, the disease more often presented with B-symptoms, lymphadenopathy and mediastinal involvement. In the majority of the patients (18/25) it had a fatal and rapid course, despite therapy (median survival: 9 months; mean survival: 12 months). The presence of B-symptoms and bulky disease appeared as the only factors influencing the prognosis, both suggesting a more aggressive course of the tumour.
Sternberg S. Diagnostic Surgical Pathology. Third Edition. Lipincott Williams and Wilkins 1999.
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