Stefano A. Pileri. Chair of Pathology Haematopathology Unit Department L. and A. Seràgnoli. Bologna University Anatomic Theatre
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1 Histiocytic and dendritic cell tumours Stefano A. Pileri Chair of Pathology Haematopathology Unit Department L. and A. Seràgnoli gnoli Bologna University Anatomic Theatre
2 Ilya Ilyich Mechnikov CD163+ Macrophage phagocytosing Treponema pallidum Phagocytosis in innate immunity against infection Nobel Prize in Physiology or Medicine 1908 Some pathological processes and neoplasms derived from true histiocytes of relevance in diagnostic haematopathology Haemophagocytic Syndromes Rosai-Dorfman Disease Xanthogranuloma family Cutaneous and/or systemic (including Erdheim-Chester disease) Histiocytic Sarcoma
3 In addition to mononuclear phagocytes, granulocytes, and lymphocytes, we noticed a large stellate cell with distinct properties from the former cell types. The term dendritic cell would thus be appropriate for this particular cells type. J Exp Med 1973;137: Paul Langerhans Nobel Prize in Physiology or Medicine
4 Dendritic Cells Dendritic cells (DC) are a sparsely distributed, migratory group of elements specialized for the uptake, transport, processing and presentation of antigens to T and B cells (adaptative immunity). Shortman K and Liu Y-J. Nat Rev Immunol 2002; 2:151
5 Dendritic Cells IN VITRO (EX VIVO) Myeloid DC (MDC) Monocyte-derived DC (Mo- DC) Plasmacytoid DC (PDC) IN VIVO Langerhans cells Interdigitating DC Interstitial DC One cell with many names
6
7 Langerhans Cells Epithelia (skin, lung, mucosa) Interstitial DC Interstitium (dermis, heart, kidney, ) Zaba LC, et al. J Clin Invest 2007; 117; Ochoa MT, et al. J Invest Dermatol 2008; 128; Langerhans DC Langerin CD1a Langerin/CD207 S100 E-cadherin CD163 F-XIIIa CD11c CD68 MMR/CD206 DCSIGN/CD209 FXIII-a Macrophage CD1a Interstitial DC (CD1a) CD1c CD11c CD68 MMR/CD206 DCSIGN/CD209
8 Secondary Lymphoid Organs Lymph maturation and migration Interstitial DC Langerhans DC Cytokines,CD40L DNA, RNA, LPS Peripheral Tissues
9 Interdigitating Dendritic Cells CD1a S-100 CD1a S-100 RECENTLY IMMIGRATED LONG STANDING Langerin Langerin
10 Langerhans DC: DCLAMP - IDC: DCLAMP +
11 DC-SIGN+ in Lymph node parenchyma Interstitial-like DC Steady-state migration B T
12
13 FDC CB FDC FDC
14 Other DC-like cells Mesenchymal Stem cells Follicular Dendritic Cells FDC CD21+35 Primary and secondary B follicles Long-living, antigen-carrying cells, involved in GC physiology DRC-1, CD21, CD23, CD35 Clusterin, Podoplanin CXCL13 (S100) KiM4p, NGFR Fascin CD23
15 Other DC-like cells Mesenchymal Stem cells Fibroblastic Reticulum Cells FRC Traffic area of the lymph node Delimitate conduits for immune cell migration and contacts Actins, Desmin, Fascin CD68 VCAM-1 SM ACTIN CK8/18 (subset)
16
17 Composite nodule HEV Lennert & Remmele, 1958 Interfollicular lymphoblasts Lennert, 1978 T-associated plasma cells
18 Nature Med 1999; 5: Anti-IFNa
19 PDC/IPC in peripheral blood and tissues 0.01~0.05% CD3, CD19, CD20, CD11c, CD13, CD14, CD33, CD16, CD56, CD4, CD36, CD68, CD123, BDCA2, ILT3, TCL1, Neg (Lin - ) Pos PARAFFIN CD68 CD123 (IL3Ra) CLA/Heca452 BCL11a TCL1 CD2AP Granzyme B Cella M, et al. Nat Med 1999; 5:919 CD2AP CD123 BDCA-2 CD123 FROZEN CD303/BDCA2 CD123 (IL3Ra) Chem-R23
20 GM-CSF IL-4 CD34+ GM-CSF TNF-a GM-CSF IL-4 TGF-b CD14- CD11c+ CD1a+CLA+ FLT3L TPO PDC CD14+ CD11c+ CD1a-CLAmonocyte CD14- CD11c- CD1a- BDCA2+ CD123+ Progenitors Blood Precursors Interstitial DC Langerhans DC Plasmacytoid DC IL3 CD40L Bacteria Viruses Immature DC Mature DC
21
22
23 W Burgdorf JKC Chan G Delsol F Facchetti CDM Fletcher TM Grogan KL Grogg ES Jaffe RJ Jaffe DM Jones SA Pileri LM Weiss
24
25 Histiocytic sarcoma Median age: 42.4 years (6 months - 75 years) M/F = 2.6/1 Presentation: nodal (27%) extranodal (55%) (skin, intestine, bone) systemic (18%) [malignant histiocytosis] Stage III-IV (78%) Hepato/splenomegaly (22%) Pancytopenia (18%) Possible association with other tumors (18%)
26 Large cells (>20μm) with round-oval eccentric nuclei (indented or convoluted). Finely-moderately dispersed chromatin. One or more small but distinct nucleoli. Abundant cytoplasm mitotic figures/10 HPF. More often, moderate degree of pleomorphism.
27 Degree of pleomorphism more pronounced in some cases, with frequent spindle and/or multinucleated cells. Growth pattern: diffuse and cohesive.
28 Erythrophagocytosis: absent or inconspicuous. Lymphophagocytosis: exceptional. Foamy/xanthomatous appearance: occasional.
29 Phenotype: CD68 + (KP1 = PG-M1) 100% CD % Lysozyme + 90% CD % S % CD4 + 50% CD68/KP1 CD68/PG-M1
30
31 Phenotype: Ki % (mean: 18.8%) Negativity for CD1a, CD21, CD35, CNA.42, CD34, MPO, B- and T-cell markers, and CD30 (with minor exceptions), as well as for EBER at ISH. Lysozyme MIB-1/Ki-67
32 Electron microscopy Lysosomes + RER + mitochondria Birbeck granules - Junctions - Desmosomes - Projections -
33 Molecular biology Lineage promiscuity? Dual genotype? Cross-contamination? Small clonal-like lymphoid populations?
34 Behaviour Aggressive tumour. 50% of the patients die of progressive disease. 30% of the patients achieve CR, but relapse. Only 20% patients alive and in CR.
35 Blood. 2008; 112: ALK CD163 1/3: TPM3/ALK
36 Disseminated Juvenile Xanthogranuloma Proliferation of histiocytes similar to those of the dermal JXG with a foamy (xanthomatous) component and Touton-type giant cells. Occurring by age 10 years (50% within the 1 st year) with the exception of Erdheim-Chester disease. Association with NF1 (and JMML and LCH). Skin, mucosa, CNS, eye, liver, lymph node, lung and BM. Positivities for CD14, CD68, CD163, Stabilin-1, Factor XIIIa and fascin (dermal /interstitial DC). S-100 in 20% of cases. CD1a and Langerin negative. Benign though CNS lesions can cause local consequences and even death.
37 Langerhans cell tumours Langerhans cell histiocytosis Langerhans cell sarcoma
38 Langerhans cell Histiocytosis Clonal proliferation of Langerhans cells Single or multiorgan disorder Indolent aggressive disease (stage-dependent) Willman CL, et al. Langerhans'cell histiocytosis (histiocytosis X): a clonal proliferative disease. N Engl J Med 1994;331:154-60
39 LCs predominant and admixed with varying amounts of eosinophils, histiocytes, neutrophils and lymphocytes. Large size. Benign-looking grooved nuclei with inconspicuous nucleoli. Wide rim of acidophilic cytoplasm mitotic figures/10 HPF.
40 At times, a certain degree of atypia is observed. These cases show more prominent nucleoli, a higher pleomorphism and a lower content of eosinophils mitotic figures/10 HPF. Such finding is, however, irrelevant on prognostic grounds.
41 Phenotype: CD1a + S Langerin + CD68 +/- Lys +/- CD45 -/+ CD1a Ki-67: 2-25% (10%) S-100 Langerin Negativity for CD21, CD35*, CD30, B and T-cell markers, MPO, CD34, and EBER by ISH.
42 Electron microscopy Lysosomes -/+ Birbeck granules + Junctions - Desmosomes - Projections -
43 CD1a
44 Association of LCH with other neoplasms The two diseases are totally independent LCH is clonal The LCH is a focal reaction to the malignant neoplasm
45 Willman CL, et al. Langerhans'cell histiocytosis (histiocytosis X): a clonal proliferative disease. N Engl J Med 1994;331: Clonal (9/10 cases) Yousem SA, et al. Pulmonary Langerhans' cell histiocytosis: molecular analysis of clonality. Am J Surg Pathol 2001;25:630-6 Twenty-four nodules in 13 female patients 7 (29%) clonal, 17 (71%) nonclonal Six cases with multiple discrete nodules, three (50%) showed a nonclonal LCH cell population In contrast to systemic LCH, pulmonary LCH appears to be primarily a reactive process in which non-lethal, nonmalignant clonal evolution of LCH cells may arise in the setting of non-clonal LCH cell hyperplasia.
46 Langerhans cell tumours Langerhans cell histiocytosis Langerhans cell sarcoma
47 Frankly malignant cytology. Nuclei with prominent nucleoli and rare grooves. Occasional eosinophils. > 50 mitotic figures/10 HPF.
48 Marked distension of the sinuses: frequent.
49 The same phenotypic profile as LCH, with a few exceptions: the higher MIB-1/Ki-67 marking (10-60%; mean = 22.5%) and occasional EBER and/or focal CD35 positivity. S-100 CD68 Ki-67
50 Behaviour Aggressive tumour. 50% of the patients died of progressive disease. 40% of the patients achieved CR, but some relapsed. Only a few patients alive and in complete remission. Occasional association with mediastinal germ cell tumour, shizophrenia or fibromyalgia.
51 Follicular dendritic cell and interdigitating dendritic cell sarcomas
52 Common morphologic features. Clear-cut distinction possible by IHC and EM. Large cells (>20μm) with a fusiform or ovoid shape. Oval central nucleus with delicate nuclear membrane, finely dispersed chromatin and a small, but distinct nucleolus. Abundant cytoplasm acidophilic on HE and grey on Giemsa. Indistinct cell borders.
53 Small amount of lymphocytes intermingled. Rare mitotic figures (1-5/ 10HPF). Whorled, fascicular or storiform pattern, at time reminiscent of the 360 pattern of meningioma. In rare cases, paracortical location (IDC sarcoma). In a few cases, residual HV Castleman disease.
54 In some cases, numerous bizarre, often atypical multinucleated cells, with higher mitotic activity and coagulative necrosis.
55 from follicular dendritic cells sarcomas from interdigitating dendritic cells
56 CD23 Podoplanin FDC sarcoma immunophenotype EGFR EGFR / Chr. 7 CD21, 23, 35, CNA.42 KiM4p, NGFR, EGFR Clusterin, Podoplanin, Claudin 4 + (use more than 1!) EGFR / Chr. 7 CD68 +/- CD1a - S100 -/+ CD117 - CD45RB, CK, CD20 exceptionally +
57 CD35 CD21
58
59 Electron microscopy Lysosomes e Birbeck granules - Junctions + Desmosomes + Projections +
60 Age: median 58.6 years (40-90 years). M/F = 1/1. Localised presentation (stage I): nodal (50%) or extra-nodal (mesentery, skin, liver, spleen, pharynx, oral cavity, etc.). Widespread presentation (stage IV): rare. Association with HV Castleman disease and schizophrenia in some cases. Occasional previous history of malignant tumour. Indolent tumour (P% of deaths for disease: 10%). Local recurrences in 40% of cases. Adverse prognostic factors: intra-abdominal disease larger than 6 cm, cytological atypia, necrosis, and high mitotic rate.
61 HV Castleman s disease HV Castleman Genetic alterations FDC dysplasia/overgrowth Further genetic alterations? FDC sarcoma (From: Chan JKC, Adv Anat Pathol 1997)
62 Inflammatory pseudotumour-like FDC sarcoma
63 from follicular dendritic cells sarcomas from interdigitating dendritic cells
64 S-100 Phenotype: S CD68 + or Lys + CD45 -/+ IDCS Negativity for CD1a, CD21, CD35, CNA.42, CD3, CD20, CD30, CD79a, MPO, CD34, and EBER by ISH. Ki-67: 10-15% CD68
65 Electron microscopy Lysosomes -/+ Birbeck granules - Junctions + Desmosomes - Projections +
66 Age: median 72 years (60-83 years). M/F = 1/1. Presentation: nodal (75%) or extra-nodal (skin). Stage: I (75%) IV (25%). Collection of more numerous cases needed in order to draw any conclusions on the behaviour of the disease.
67 Rare dendritic cell tumours - Indeterminate dendritic cell tumour - Fibroblastic reticular cell tumour - Dendritic cell tumour, NOS
68 CD1a S-100
69 Andriko et al. Am J Surg Pathol 1998, 2:1048 (SMA +, des + ) Ylagan et al. Diagn Cytopathol 2003, 28:278 (ker + ) Schuerfeld et al. Histopathology 2003, 43:491 (ker + ) S-100 Ker
70 PP Piccaluga, E Sabattini, F Bacci, C Agostinelli, M Rossi, C Sagramoso, S Righi, A Gazzola,, T Sista, M Piccioli, MR Sapienza, C Mannu,, F Fuligni,, F Sandri,, P Artioli, G De Biase,, G Da Pozzo, C Tigrini,, M Monari and D Bignami
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