Lymphoreticular Pathology Flashcards
Site for production of lymphocytes
What could this be
Primary lymphocytes
Are sites where lymphocytes encounter Ags and undergo Ag-driven proliferation and differentiation – lymph nodes, spleen, Peyer’s patches
Where could this be
Secondary lymphocytes
What is another name for secondary lymphocytes
Peripheral lymphocytes
What are tertiary lymphocytes
Tertiary lymphoid organs are acquired lymphoid tissues in the stomach, skin, respiratory and reproductive tracts in response to infection
The paracortex is mainly populated by
The paracortex is mainly populated by T-cells responsible for Cellular Mediated Immunity (CMI). Expansion of the paracortex is an indication of CMI response
The cortex is populated by
The cortex is organised into follicles and is populated by B-cells, which participate in humoral immune response
What do activates T cells express
Activated T-cells express HLA-DR and IL-2R (CD25), and differentiate into TH-1 or TH-2 cells, depending on the nature of the Ag.
70% of T-cells are CD4+ helper cells, intermingled with relatively sparse CD8+ T-cells.
True or false
True
What does the medulla contain
The medulla, close to the hilum consists of cords and sinuses. Medullary cords contain transformed lymphoid cells and plasma cells.
How do lymphocytes enter into circulation
Lymphocytes from the circulation enter into the node thru specialised vessels – high endothelial venules in the paracortex.
Follicles in the newborn have germinal centres – 1o follicles, consisting mainly of mature, naïve B-cells.
True or false
False
Follicles in the newborn have germinal centers
How are secondary follicles formed
Secondary follicles are formed as a result of antigenic stimulation, and are characterised by the presence of germinal centres.
What do germinal centers of follicles consist of
The germinal centres consist of B-cells (Follicular centre cells)
- centroblasts (large non-cleaved cells)
- centrocytes (small cleaved cells)
- large cleaved
- small non-cleaved cells
- tingible body macrophages
- follicular dendritic cells
Most often is secondary to bacterial infection. Common in axillary, inguinal nodes from infections in extremities.
●Cervical nodes may be enlarged in infections of the teeth and tonsils.
●Bacteraemia and viral infections may lead to acute generalised LAP.
●Grossly LN is enlarged, oedematous and reddish. Rarely poses a diagnostic problem.
●Micro-enlargement of follicles and germinal centre, suppuration, neutrophil infiltration.
What condition could this be
Acute lymphadenitis
What are some characteristics of lymph nodes in chronic reactions
Usually they are non tender because node enlargement occur over time
NB
Chronic immune reaction can promote the appearance of organized immune cells in nonlymphoid tissue
- H Pylori gastritis, aggregate mucosa lymphocytes simulates payers patches
- Rheumatoid arthritis, B cell follicles appear in the inflamed Synovium
Seen in TB.
●Suppurative granulomatous LAP is seen in LGV and cat scratch disease.
●LGV = STD caused by Chlamydia trachomatis (L1, L2 and L3).
●Characterised by stellate abscesses, buboes and +ve Frei test.
What condition could this be
Granulomatous lymphadenitis
What is follicular hyperplasia
Follicular enlargement due to widening of the GC –seen in Rheumathoid arthritis, toxoplasmosis, measles, AIDS.
What causes paracortical expansion
Increased stimulation by T-cells. Seen in viral infections, pertusis, infectious mononucleosis.
What are some reactive states of
Sinus histiocytosis/hyperplasia
Dermatopathic lymphadenopathy
Lipomelanic reticulosis
What is sinus histiocytosis/hyperplasia
Distension of medullary sinuses by histiocytes. In nodes draining areas of inflammation and neoplasia e.g axilla LN in breast cancer.
Where are dermatopathic lymphadenopathy seen in
Seen in nodes draining areas of chronic dermatitis, Seen in psoriasis, mycosis fungoides, etc
Sometimes it may be seen in the absence of dermatitis.
Histology shows infiltrate of lymphocytes containing melanin and neutral fats
What could this be
Lipomelanic reticulosis
a febrile illness first described in Japanese children and now seen in other places.
●Characterised by fever, conjunctivitis, skin rash, pharyngitis and cervical LAP. 40% of patients also have arthritis.
What could this be
Kawasaki disease
What are some drugs which could induce LAPs
Anticonvulsants-dipheny-hydantoin and carbamazepin (Tegretol). Characterized by fever, rash, eosinophilia, splenomegaly, follicular hyperplasia.
A febrile disease of children and young adults.
●There is bilateral cervical LAP, Some patients have immune deficiency
What could this be
Sinus histiocytosis with massive lymphadenopathy (SHML) (Rosai-Dorfman syndrome)
A necrotising histiocytic lymphadenitis
Self-limited, SLE-like disease affecting cervical LN of young individuals.
What condition could this be
Kikuchi’s disease
What are some characteristics of an AIDs-related LAP
Persistent generalised LAP is seen in 60% of HIV / AIDS patients. Lymph nodes in HIV show a spectrum of changes:
- Severe follicular hyperplasia
- Regressive follicular hyperplasia
- Follicular involution, progressing to
lymphocyte depletion. Helper T-cells are reduced and suppressor T-cells are increased in the germinal centres.
The changes correspond to clinical progression from early asymptomatic HIV infection to AIDS.
●LNs may also show malignant lesions such as Kaposi sarcoma, HL, NHL.
●Progressively transformed germinal centre (PTGC) – Most often affects the cervical LN of young males. Very few cases evolve into NLPHL.
What are lymphomas
Lymphomas are tumours of the immune system and majority are of B-cell origin.
●Lymphomas constitute a major cause of lymphadenopathy, morbidity + mortality; they may be nodal or extranodal.
●Based on the presence or absence of the Reed-Sternberg cell, lymphomas are classified into Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL)
What are the classification of lymphomas based on the presence and absence of Reed-Sternberg cell
Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL)
●First described by Thomas Hodgkin in 1832 while serving as a curator at Guy’s hospital.
● HL is mainly a nodal disease.
●It has a predetermined mode of spread.
●It arises from a lymph node or a chain of nodes and spreads to anatomically contiguous chain.
●Years of controversy on the nature of HL.
●Majority of cells in HL are non neoplastic inflammatory cells within which are R-S cells and variants.
What condition could this be
Hodgkin lymphoma
Who proved that RS cells are clonally related malignant lymphoid B-cell
Kuppers et al (1994) proved beyond doubt that Hodgkin and R-S cells are clonally-related malignant lymphoid B-cell. The name therefore changed from HD to HL
First described by Sternberg and Dorothy Reed is a tumour giant cell 20-30mm in diam. It has two nuclei or a bilobed nucleus, each measuring 12-18mm in diam. Each nucleus has a nucleolus, which is typically eosinophilic, with a clear zone around it, giving an owl eye appearance.
What cell is this
The classical Reed-Sternberg cell
What are other cells associated with classical Reed-Sternberg cell
Other cells : Lacunar cell, Lymphocytic and Histiocytic (popcorn) cell, Hodgkin cell
What is Hodgkin’s lymphoma
HL is a tumour of germinal centre B-cell with non-productive Ig gene rearrangements, representing failed attempts at B-cell Ab production. Under normal circumstances, such cells undergo apoptosis in the germinal centre, and the mechanisms by which H-RS cell escape cell death have been unravelled
What is the characteristic giant cell in HL and NLPHL respectively
The characteristic giant cell in HL is H-RS cell and in NLPHL L and H cell.
H-RS cells express proteins found in other cell lines but not CD20 and ………
CD79a
What do L and H cells express
L and H cells express CD20 and Bcl-6 typical of GC B-cells.
At what stage does NLPHL arise
NLPHL arises at GC stage of B-cell maturation.
What are other factors which could cause Hogkin’s lymphoma
Environmental (viral infection) and genetic factors are also important.
The risk of concordance for HL in monozygotic twins is 100, compared to dizygotic twins with no increased risk.
What is the role of HBV in HL
EBV contributes to oncogenesis in HL.
●The risk of developing HL is 3x higher in those with history of IM.
●~ 50% HL in developed world is EBV +ve.
●Transforming ability of EBV mainly through LMPs
LMP1 mimics constitutively active CD40R, a signaling pathway leading to NFKB activation in Ag-activated B-cell.
LMP2 shuts down BCR expression, prevents activation but also mimics BCR
Both LMP1 and LMP2 may activate NFKB with upregulation of anti-apoptotic genes
Upregulation inhibits Fas signaling pathway enabling pre-apoptotic H-RS cells to survive negative selection.
●However, only ~ 50% of CHL are EBV +ve.
●There must be additional transforming events in EBV –ve cases
Most common subtype of HL in Europeans
●Common in young women below the age of 40, and has a predilection for mediastinal lymph nodes.
●Characterised by presence of lacunar cells.
●Has a nodular pattern with fibrous bands separating nodules.
●Diffuse areas, areas of necrosis may also be seen.
Lacunar cells are many, H-RS cells are very few.
●Background shows inflammatory cells, palisaded histiocytes resembling granulomas.
●Graded (Grades 1 and 2) based on the number and atypia of R-S cells.
Grade 2 tumours show increased rate of relapse, shorter survival, worse response to initial therapy and worse prognosis than NS-1.
What could this be
Nodular sclerosis
Occurs at a younger age group in underdeveloped countries compared with those in industrialised nations. Among Caucasians it is more common in older males.
●The stroma shows plasma cells, eosinophils and histiocytes.
●Tumour cells are EBV+ in over 60% of cases.
What condition could this be
Mixed cellularity
Entity has undergone attrition with the use of IHC.
●Cases previously diagnosed as LD were actually anaplastic carcinomas or high grade NHLs.
●LD occurs in older patients, in HIV +ve individuals and in developing countries.
●It is aggressive but probably curable.
What could this be
Lymphocyte depletion
hese are cases of classical HD with a background infiltrate of predominantly lymphocytes, rare or no eosinophils. Generally not common, and is uncommon before 40 years. EBV negative.
What could this be
Lymphocyte-rich CHL
Has a nodular growth pattern. It differs in so many respects (morphology, immunophenotype, clinically) from classical HL.
●However, it resembles HL more than it resembles NHL.
What condition could this be
NLPHL
The neoplastic R-S cells are v. scarce.
●An indolent disease with a tendency to be localized, also responds to local Rx.
●Immunophenotype: CD45+. EMA +, CD15 and CD 30 –ve; +ve for B-cell- associated Ags - CD20, BCL6.
●Some cases may evolve from progressively transformed germinal centers.
What condition could this be
NLPHD
How is Hodgkin lymphoma staged
I – A single lymph node or a single extralymphatic organ
●II- 2 or more groups of lymph nodes on the same side of diaphragm or localized involvement of an extralymphatics organ or site(IIE)
●III- Lymph nodes on different side of diaphragm without or with involvement of an extralymphatic organ or site (IIIE)
●IV- Diffuse involvement of 1 or more extralymphatic organs or sites with or without lymphatic involvement
What are some differences between HL and NHL
Unlike HL:
It has a haphazard mode of spread.
It commonly involves extranodal sites.
It has a leukaemic phase.
What is NHL
Driving this continual reclassification are:
●New data on the biology of lymphomas.
●Uncertainty as to what is important in the accurate classification of lymphomas (is it morphology, immunophenotype, genotype, clinical behaviour, something else?).
●NHL may be nodular or diffuse. Nodular NHLs are more common in adults and they have a better prognosis than diffuse type.
●In children NHLs are commonly extra nodal, diffuse and high grade
NHL may be low, interm. or high grade.
●Low grade NHLs e.g SLL (CLL in bone marrow) are indolent, but incurable. Leukaemic phase is common with low grade NHL than with high grade.
●Some intermediate grade lymphoma have aggressive rate of growth but are potentially curable using CHOP chemoRx.(cyclophosphamide, hydroxydau-norubicin, oncovin and prednisolone)
High grade NHLs (Burkitt lymphoblastic lymphoma) are the most common types in children. Prognosis in adults is unfavorable; in children a cure rate of 80-90% could be achieved.
●NHL is more common in males. The incidence and mortality is increasing from HIV-infected population.
What is the etiology of NHL
The search for the etiology of NHL is partially successful.
●Congenital and acquired immune deficiency states are the best recognized risk factors for developing NHL.
●The association between gastric marginal zone lymphoma and H. pylori infection is well known.
●EBV and adult T-cell leukaemia/lymphoma virus are recognised causes of some types of NHL.
However, the etiology of the majority of NHL remains unknown.
●Excessive exposure to sunlight and electromagnetic fields are thought to play a role. Attention is also being focused on the role of: herbicides, pesticides, contamination of ground and surface water by nitrites from fertilisers, hepatitis C virus infection as well as occupational exposure to some solvents used in hairdressing. Exposure to petrochemicals is a risk factor for developing NHL.
●B cell acute lymphoblastic leukaemia/lymphoma
●T Cell acute lymphoblastic Leukaemia/lymphoma
What condition could this be
Lymphoid leukemia
What are some examples of NHL from a matured B cell origin
Burkitt lymphoma
2.Diffuse large B cell lymphoma
3.Extranodal marginal B cell lymphoma
4.Follicular lymphoma
5.Hairy cell leukaemia
6.Multiple myeloma/solitary plasmacytoma
7.Small lymphocytic lymphoma/ chronic lymphocytic leukaemia
What are some examples of NHL from a mature T cell origin
Adult T cell leukaemia/lymphoma
2.Peripheral T cell lymphoma
3.Anaplastic large cell lymphoma
4.Extra nodal NK/T Cell lymphoma
5.Mycosis fungoides/Sazary syndrome
6.Large granular lymphocytic leukaemia
First described by Dennis Burkitt, a surgeon in Uganda in 1958.
●The most common malignant tumour in children in most of tropical Africa and the fastest-growing tumour known.
●Usually extra nodal, highly aggressive with a possibility of cure.
●Endemic form, which occurs in Africa involves the jaw or abdominal organs.
●Sporadic form, seen in older children and adults present with intra-abdominal mass.
What condition could this be
Burkitt lymphoma
What is the epidemiology of Burkitt lymphoma
The geographic distribution of BL in high incidence areas is governed by two parameters: temperature and humidity.
●BL is common in tropical areas where the mean monthly temperature is over 60oF (15.5oC) and the relative humidity is high.
●The BL belt is within lat. 10-15o N and S of the equator.
●Rare in highland areas >1550m above sea level; unknown in dry arid areas with rainfall <50 cm per year
It is unknown in cold areas with diurnal temperatures <16oC.
●It is rare < 2 years and > 15 years; the peak incidence is 5-9 years.
●Boys are affected twice as often as girls.
●It is rare among the higher socio-economic group of Africans in endemic areas
What is the etiology of BL
Circumstantial evidence links EBV with BL. EBV is transmitted by saliva. It infects B-cells, nasopharyngeal epithelium and is ubiquitous, worldwide.
●In 100% of cases of endemic BL, tumour cells carry EBV genome and express EBV-encoded antigens.
●EBV infects B-cells by binding to complement receptor type 2 (CR2, CD21). The spectrum of sequelae to EBV infection is wide and viral replication is controlled by humoral and T-cell immune reaction in most cases.
T-cell immunity is required for the control of EBV infection.
●Individuals with deficiency in T-cell mediated immunity are susceptible to uncontrolled, widely-disseminated and lethal acute EBV infection.
●Malaria infection is known to cause T-cell immunodeficiency, and this association may be the link between EBV infection and BL.
●Only 20% of sporadic BL, seen in other parts of the world carry the EBV genome.
oth endemic and sporadic BL have translocation of c-myc oncogene from chr 8 to chr 14 in the Ig Heavy chain; in a minority of cases Ig λ, chr 8 to chr 22 or Ig к chr 2 to chr 8. This leads to deregulation of c-myc, causing proliferation without differentiation.
●The M:F ratio for sporadic BL is 5:1.
●Peripheral LAP is very rare in endemic BL, whereas it is seen in 10% of cases of sporadic BL.
What are the clinical presentations of Burkitts lymphoma
Jaw mass in 75% of cases; the maxilla is more often affected than the mandible.
●Abdominal mass in 60% of cases; ascites is frequent.
●CNS disease (30% of cases) manifests as paraplegia, multiple cranial nerve paralysis or malignant pleiocytosis.
●Other organs: thyroid, testes, breast, ovaries.
What are the histological findings of Burkitt lymphoma
Histology shows monomorphic sheets of lymphoblasts within which are scattered macrophages with phagocytosed debris, giving the classical “starry sky” appearance.
How is Burkitt lymphoma treated
Chemotherapy CHOP
●Lasix given to ensure urine output of 100-150ml/hour
●Xanthine oxydase inhibitor (Allopirinol) started at least 24 hours before chemoRx to offset anticipated hyperuricaemia.
Relapse: 2 patterns:
Early relapse within 3 months of chemoRx, at original site.
Late relapse > 3 months of chemoRx, at new sites, frequent CNS involvement.
What is the staging for Burkitt lymphoma
Stage A – Single extra-abdominal mass.
●Stage B – Multiple extra-abdominal Mass.
●Stage C – Abdominal mass with or
without facial tumour.
Stage D – Abdominal mass with sites of tumour other than facial or bone marrow.
Stage AR – Abdominal mass with > 90% of tumour resected.
