wbc disorders affecting systemically and orally

1. Pathology Of White
Blood Cells
Cells
Prepared by: Dr. Shaimaa
P.G student
Dept. of oral pathology

2. WHITE CELL DISORDERS
Non-Neoplastic Disorders of White Cells
Leukopenia
neutropenia-Agranulocytosis
Reactive Leukocytosis
infectious mononucleosis
Reactive Lymphadenitis
Acute non-specific lymphadenitis
chronic non-specific lymphadenitis
cat scratch disease

3. WHITE CELL DISORDERS
Disorders of white cells include deficiencies (leukopenias) and
proliferations, which may be reactive or neoplastic.
Reactive proliferation in response to a primary, often
microbial, disease is common.
Neoplastic disorders, though less common, are more ominous
They cause approximately 9% of all cancer deaths in adults and a
staggering 40% in children younger than 15 years of age.

4. Leukopenia
Leukopenia results most commonly from a decrease in granulocytes,
the most numerous circulating white cells.
Lymphopenia is much less common; it is associated with rare congenital
immunodeficiency diseases, advanced human immunodeficiency virus
(HIV) infection, and treatment with high doses of corticosteroids.

5. Neutropenia/Agranulocytosis
A reduction in the number of granulocytes in blood is known as
neutropenia or, when severe, agranulocytosis.Neutropenic persons are
susceptible to bacterial and fungal
infections, in whom they can be fatal. The risk of infection rises sharply
as the neutrophil count falls below 500 cells/µL.

6. PATHOGENESIS
The mechanisms underlying neutropenia can be divided into two broad
categories:
• Decreased granulocyte production.Clinically important reductions in
granulopoiesis are most often caused by marrow failure (as occurs in
aplastic anemia), extensive
replacement of the marrow by tumor (such as in leukemias), or cancer
chemotherapy. Alternatively, some neutropenias are isolated, with only
the differentiation of committed granulocytic precursors being
affected. The forms of neutropenia are most often caused by certain
drugs or, less commonly, by neoplastic proliferations of cytotoxic T
cells and natural killer (NK) cells.

7. • Increased granulocyte destruction. This can be encountered with
immune-mediated injury (triggered in some cases by drugs) or in
overwhelming bacterial, fungal, or rickettsial infections due to increased
peripheral utilization. Splenomegaly also can lead to the sequestration
and accelerated removal of neutrophils.

8. MORPHOLOGY
•The alterations in the bone marrow depend on the underlying cause of
the neutropenia.
•Marrow hypercellularityis seen when there is excessive neutrophil
destruction or ineffective granulopoiesis, such as occurs in megaloblastic
anemia.
•agents such as drugs that cause neutropenia do so by suppressing
granulocytopoiesis,
thus decreasing the numbers of granulocytic precursors.
•Erythropoiesis and megakaryopoiesis can be normal if the
responsible agent specifically affects granulocytes, but most
myelotoxic drugs reduce marrow elements from all
lineages.

9. Clinical Features.
•Agranulocytosis can occur at any age, but is somewhat more common in
adults, particularly women.
•The initial symptoms often are malaise, chills, and fever,
with subsequent marked weakness and fatigability. Infections constitute
the major problem.
•Regional lymphadenitis accompanies the infection in any of these
locations. If treatment is not promptly instituted, the infection progresses
to generalized sepsis, which may be life threatening.

10. Oral manifestation.
•necrotizing ulcerations of the oral mucosa, tonsils and pharynx.
•Particularly involved are the gingiva and palate.
•The lesions appear as ragged necrotic ulcers covered by a gray or even
black membrane
•Usually no purulent discharge is noticed. Significantly, there is little or
no apparent inflammatory cell infiltration around the periphery of the
lesions, although hemorrhage does occur, especially from the gingiva.
•the patients often manifest excessive salivation.
•It is obvious that all oral surgical procedures, particularly
tooth extraction, are contraindicated in cases of agranulocytosis.

11. Histologic Features.
•the essential fault is the lack of development of normal granular
leukocytes, the ulcerated areas exhibit no polymorphonuclear reaction to
the bacteria in the tissues, and rampant necrosis ensues.
•the microscopic appearance of the jaws in agranulocytosis and reported
necrosis of the gingiva, beginning adjacent to the sulcus and spreading
into the free gingiva, periodontal ligament and even alveolar bone.
•Rapid destruction of the supporting tissues of the teeth follows.

12. Laboratory Findings.
•The white blood cell count in agranulocytosis is often below 2000 cells
per cubic millimeter with an almost complete absence of granulocytes or
polymorphonuclear cells. The red blood cell count and platelet count are
usually normal, although occasionally anemia is present.
•The bone marrow is relatively normal except for the absence of
granulocytes, metamyelocytes and myelocytes.
•Promyelocytes and myeloblasts are usually present in near normal
numbers; however, and for this reason it appears that the basic defect is
an arrest in cell maturation.

13. Cyclic Neutropenia
(Periodic neutropenia, cyclic agranulocytic angina, periodic
agranulocytosis)
Cyclic neutropenia is an unusual form of agranulocytosis characterized
by a periodic or cyclic diminution in circulating polymorphonuclear
neutrophilic leukocytes as a result of bone marrow maturation arrest,
accompanied by mild clinical manifestations, which spontaneously
regresses only to recur subsequently in a rhythmic pattern. The etiology
of this diseaseis unknown.

14. Clinical features
headache, arthritis, cutaneous infection and conjunctivitis.
In contrast to other types of primary agranulocytosis, rampant bacterial
infection is not a significant feature, presumably because the neutrophil
count is low for such a short time.

15. Oral Manifestations.
Patients with this disease typicallyexhibit a severe gingivitis, sometimes
a stomatitis with ulceration, which corresponds to the period of the
neutropenia and is due to bacterial invasion, chiefly from the gingival
sulcus, in the absence of a defense mechanism.
With return of the neutrophil count to normal, the gingiva assumes a
nearly normal clinical appearance. In children, the repeated insult of
infection often leads to considerable
loss of supporting bone around the teeth. The
widespread severe ulceration usually seen in agranulocytosis

16. Radiographic Features.
The intraoral radiographs typically exhibit mild to severe loss of
superficial alveolar bone, even in children, as a result of the repeated
cyclic gingivitis, advancing to periodontitis.
In children, this loss of bone around multiple teeth has sometimes been
termed ‘prepubertal periodontitis’, and it is frequently indicative of a
serious systemic disease.

17. Reactive Leukocytosis
•An increase in the number of white cells in the blood is common
in a variety of inflammatory states caused by microbial and
nonmicrobial stimuli.
•Leukocytoses are relatively nonspecific and are classified according to
the particular white cell series that is affected
in some cases reactive leukocytosis may mimic leukemia.
•Such “leukemoid” reactionsmust be distinguished from true white
cell malignancies.
•Infectious mononucleosis merits separate consideration because it
gives rise to a distinctive syndrome associated with
lymphocytosis.

18. Infectious Mononucleosis
Infectious mononucleosis is an acute, self-limited disease of
adolescents and young adults that is caused by EpsteinBarr virus (EBV),
a member of the herpesvirus family.
The infection is characterized by
(1)fever, sore throat, and generalized lymphadenitis and
(2) a lymphocytosis of activated, CD8+ T cells.

20. •Infection of EBV takes place in childhood but symptomatic disease is
uncommon, and even though infected hosts mount an immune
response, more than half continue to shed virus.

21. PATHOGENESIS
Transmission to a seronegative “kissing cousin” usually involves
direct oral contact. It is hypothesized that the virus initially infects
oropharyngeal epithelial cells and then spreads to underlying lymphoid
tissue (tonsils and adenoids), where mature B cells are infected.
The infection of B cells takes one of two forms.
In a minority of cells, the infection is lytic, leading to viral
replication and eventual cell lysis accompanied by the release of virions.
In most cells, however, the infection is nonproductive, and the virus
persists in latent form as an extrachromosomal episome.

22. B cells that are latently infected with EBV undergo polyclonal activation
and proliferation,as a result of the action of several EBV proteins.
These cells disseminate in the circulation and secrete antibodies with
several specificities, including the well-known heterophil antisheep red
cell antibodies that are detected in diagnostic tests for mononucleosis.

23. Early in the course of the infection, IgM antibodies are formed against
viral capsid antigens. Later the serologic response shifts to IgG
antibodies, which persist for life.
cytotoxic CD8+T cells and NK cells.
Virus specific CD8+T cells appear in the circulation as atypical
lymphocytes, a finding that is characteristic of mononucleosis.In
otherwise healthy persons, the fully developed humoral and cellular
responses to EBV act as brakes on viral shedding.
In most cases, a small number of latently infected EBV-positive B cells
escape the immune response and persist for the life of the patient.

24. MORPHOLOGY
The major alterations involve the blood, lymph nodes, spleen, liver,
central nervous system, and occasionally other organs.
There is peripheral blood leukocytosis; the white cell count is usually
between 12,000 and 18,000 cells/µL.
Typically more than half of these cells are large atypical
lymphocytes,12 to 16 µm in diameter, with an oval, indented, or folded
nucleus and abundant cytoplasm with a few azurophilic granules

25. •Lymphadenopathy is common a few cells resembling Reed-Sternberg
cells, the hallmark of Hodgkin lymphoma, often are seen.
•splenomegaly
Clinical features:
•classically manifests with fever, sore throat, lymphadenitis,

26. Oral manifestation:
acute gingivitis and stomatitis, the appearance of a white or gray membrane in
various areas, palatal petechiae and occasional oral ulcers.
Edema of the soft palate and uvula
petechial hemorrhages of the soft palate near the junction with the hard palate as an
early manifestation
The lesions persisted for 3–11 days and then gradually
faded. They must be differentiated from areas of increased
vascularity and pigmented areas.

27. Laboratory tests:
•The normal titer of agglutinins and hemolysins in human blood
against sheep red blood cells does not exceed 1 : 8. In infectious
mononucleosis; however, the titer may rise to 1 : 4096.
•This is referred to as a positive Paul-Bunnell test and is both
characteristic and pathognomonic of the disease. Agglutination of horse
RBCs on exposure to EB virus heterophile antibodies (Monospot test) is
a highly specific test.

28. Reactive Lymphadenitis
Infections and nonmicrobial inflammatory stimuli often activate
immune cells residing in lymph nodes, which act as defensive barriers.
Any immune response against foreign antigens can lead to lymph node
enlargement (lymphadenopathy). The infections causing lymphadenitis
are varied and numerous, and may be acute or chronic.

29. Acute Nonspecific Lymphadenitis
This form of lymphadenitis may be isolated to a group of nodes draining a local infection, or
be generalized, as in systemic infectious and inflammatory conditions.

30. MORPHOLOGY
•Inflamed nodes in acute nonspecific lymphadenitis are swollen,
gray-red, and engorged.
•Histologically, there are large germinal centers containing numerous
mitotic figures. When the cause is a pyogenic organism, a neutrophilic
infiltrate is seen around the follicles and within the lymphoid sinuses.
•With severe infections, the centers of follicles can undergo necrosis,
leading to the formation of an abscess.
•Affected nodes are tender and may become fluctuant if abscess
formation is extensive. The overlying skin is frequently red and may
develop draining sinuses. With control of the infection the lymph
nodes may revert to a normal “resting” appearance or if damaged
undergo scarring.

31. Chronic Nonspecific Lymphadenitis
Depending on the causative agent, chronic nonspecificlymphadenitis
can assume one of three patterns:
follicular hyperplasia, paracortical hyperplasia, or sinus histiocytosis.

32. MORPHOLOGY
Follicular Hyperplasia. This pattern occurs with infections or
inflammatory processes that activate B cells, which migrate into B cell
follicles and create the follicular (or germinal center) reaction.
The reactive follicles contain numerous activated B cells, scattered T
cells, and phagocytic macrophages containing nuclear debris (tingible
body macrophages), and a meshwork of antigen-presenting follicular
dendritic cells.
Causes of follicular hyperplasia include rheumatoid arthritis,
toxoplasmosis, and early HIV infection.

33. Findings that favor follicular hyperplasia are
(1) the preservation of the lymph node architecture;
(2) variation in the shape and size of the germinal centers;
(3) the presence of a mixture of germinal center lymphocytes of
varying shape and size;
(4) prominent phagocytic and mitotic activity in germinal
centers.

34. Paracortical Hyperplasia.
This pattern is caused by immune reactions involving the T cell
regionsof the lymph node. When activated, parafollicular T cells
transform into large proliferating immunoblasts that can efface the
B cell follicles. Paracortical hyperplasia is encountered in viral
infections(such as EBV), after certain vaccinations(e.g.smallpox), and in
immune reactions induced by drugs(especially phenytoin).
Sinus Histiocytosis. This reactive pattern is characterized
by distention and prominence of the lymphatic sinusoids,
owing to a marked hypertrophy of lining endothelial
cellsand an infiltrate of macrophages (histiocytes).It
often is encountered in lymph nodes draining cancers and
may represent an immune response to the tumor or its
products.

35. Cat-Scratch Disease
Cat-scratch disease is a self-limited lymphadenitis caused by the
bacterium Bartonella henselae.It is primarily a disease of childhood; 90%
of the patients are younger than 18 years
of age. It manifests with regional lymphadenopathy, most frequently in
the axilla and the neck. The nodal enlargement appears
approximately 2 weeks after a feline scratch
or, less commonly, after a splinter or thorn injury. An inflammatory
nodule, vesicle, or eschar is sometimes visible at the site of the
skin injury. In most patients the lymph node enlargement regresses
over a period of 2 to 4 months. Encephalitis, osteomyelitis, or
thrombocytopenia may develop in rare patients.

36. MORPHOLOGY
•The nodal changes in cat-scratch disease are quite characteristic.
Initially sarcoid-like granulomas form, but these then undergo central
necrosis associated with an infiltrate of neutrophils.
•These irregular stellate necrotizing granulomas are similar in
appearance to those seen in a limited number of other infections,
such as lymphogranuloma venereum.
•The microbe is extracellular and can be visualized with silver stains.
•The diagnosis is based on a history of exposure to cats, the characteristic
clinical findings, a positive result on serologic testing for antibodies to
Bartonella,and the distinctive morphologic changes in the lymph nodes

37. NEOPLASTIC PROLIFERATIONS OF WHITE CELLS
Tumors are the most important disorders of white cells.
They can be divided into three broad categories based on the origin of
the tumor cells:
1. Lymphoid neoplasms, which include non-Hodgkin lymphomas
(NHLs), Hodgkin lymphomas, lymphocytic leukemias, and plasma
cell neoplasms and related disorders. some normal stage of
lymphocyte differentiation, a feature that serves as one of the bases
for their classification.
2. Myeloid neoplasms arise from progenitor cells that give rise to
the formed elements of the blood: granulocytes, red cells, and
platelets.

38. The myeloid neoplasms fall into three fairly distinct subcategories:
•acute myeloid leukemias,in which immature progenitor cells
accumulate in the bone marrow;
•myeloproliferative disorders,in which an inappropriate increase in
the production of formed blood elements leads to elevated blood
cell counts; and
•myelodysplastic syndromes, which are characteristically associated
with ineffective hematopoiesis and cytopenias.
3. Histiocytic neoplasms include proliferative lesions of macrophages
and dendritic cells. Of special interest is a spectrum of proliferations
of Langerhans cells (Langerhans cell histiocytoses).

40. Lymphoid Neoplasms
•characteristically manifest as leukemias, with involvement of the bone
marrow and the peripheral blood. Others tend to manifest as
lymphomas, tumors that produce masses in lymph nodes or other
tissues.
plasma cell tumors usually arise within the bones and manifest as
discrete masses, causing systemic symptoms related to the production
of a complete or partial monoclonal immunoglobulin.

41. •lymphoid neoplasms have the potential to spread to lymph nodes and
various tissues throughout the body, especially the liver, spleen, bone
marrow, and peripheral blood.
•Because of their overlapping clinical behavior, the various lymphoid
neoplasms can be distinguished with certainty only by the morphologic
and molecular characteristics of the tumor cells.

44. The WHO classification of lymphoid neoplasms considers the
morphology, cell of origin (determined by immunophenotyping), clinical
features, and genotype (e.g., karyotype, presence of viral genomes) of
each entity. It encompasses all lymphoid neoplasms, including leukemias
and multiple myeloma, and
separates them on the basis of origin into three major categories: (1)
tumors of B cells, (2) tumors of T cells and NK cells, and (3) Hodgkin
lymphoma.

46. Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma
Acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma
are aggressive tumors, composed of immature lymphocytes
(lymphoblasts), that occur predominantly in children and young adults.
The various lymphoblastic tumors are morphologically
indistinguishable, often cause similar signs and symptoms, and are
treated similarly

47. PATHOGENESIS
•The principal pathogenic defect in acute leukemia and lymphoblastic
lymphoma is a block in differentiation.
•This “maturation arrest” stems from acquired mutations in specific
transcription factors that regulate the differentiation of immature
lymphoid or myeloid progenitors.
•Normal B cell, T cell, and myeloid differentiation are regulated by
different lineage-specific transcription factors; accordingly, the mutated
transcription factor genes found in acute leukemias derived from each of
these lineages also are distinct.
•The most commonly mutated transcription factor genes are TEL1,
AML1, E2A, PAX5,and EBFin ALLs of B cell origin (B-ALLs) and
TAL1 and NOTCH1 in T cell ALLs (T-ALLs).

48. In tumors manifesting as “leukemias,” blasts accumulating in the
marrow suppress the growth of normal hematopoietic cells by physical
displacement and by other, poorly understood mechanisms. Eventually
this suppression produces bone marrow failure, which accounts for the
major clinical manifestations. The therapeutic goal, therefore, is to
reduce the leukemic clone sufficiently to allow normal hematopoiesis
to resume.

49. Clinical Features of Acute Leukemias
Acute leukemias have the following characteristics:
• Abrupt, stormy onset.Most patients present for medical attention
within 3 months of the onset of symptoms.
• Clinical signs and symptoms related to suppressed marrow
function,including fatigue (due to anemia), fever (reflecting infections
resulting from neutropenia), and bleeding (petechiae, ecchymoses,
epistaxis, gum bleeding) secondary to thrombocytopenia
• Bone pain and tenderness, resulting from marrow expansion and
infiltration of the subperiosteum
• Generalized lymphadenopathy, splenomegaly, and
hepatomegaly due to dissemination of the leukemic cells.These are
more pronounced in ALL than in AML.
• Central nervous system manifestations, including headache,
vomiting, and nerve palsies resulting from meningeal spread. These are
more common in children than in adults and in ALL than in AML.

50. Laboratory Findings in Acute Leukemias
•The diagnosis of acute leukemia rests on the identification of blasts.
The peripheral blood sometimes contains no blasts (aleukemic
leukemia); in such cases the diagnosis can be established only by
marrow examination.
•The white cell count is variable; it may be greater than 100,000 cells/µL
but in about half of the patients is less than 10,000 cells/µL. Anemia is
almost always present, and the platelet count usually is below
100,000/µL. Neutropenia is another common finding.

51. Lymphoblasts also often contain cytoplasmic glycogen granules that are periodic acid–
Schiff–positive, whereas myeloblasts are often peroxidase-positive

52. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
•Chronic lymphocytic leukemia (CLL) and small lymphocytic
lymphoma (SLL) are essentially identical, differing only in the extent
of peripheral blood involvement.
•if the peripheral blood lymphocyte count exceeds 4000 cells/µL, the
patient is diagnosed with CLL;
•if it does not, a diagnosis of SLL is made. Most patients with
lymphoid neoplasms fit the diagnostic criteria for CLL, which is the
most common leukemia of adults in the Western world.

53. PATHOGE NESIS
•CLL/SLL is an indolent, slowly growing tumor, suggesting that
increased tumor cell survival is more important than tumor cell
proliferation in this disease.
•the tumor cells contain high levels of BCL2,a protein that inhibits
apoptosis
•immune dysregulation.Through unclear mechanisms, the accumulation
of CLL/SLL cells suppresses normal B cell function, often resulting in
hypogammaglobulinemia. approximately 15% of patients have
autoantibodies against their own red cells or platelets. When present, the
autoantibodies are made by nonmalignant bystander B cells,
indicating that the tumor cells somehow impair immune tolerance. As
time passes the tumor cells tend to displace the normal marrow
elements, leading to anemia, neutropenia, and eventual
thrombocytopenia.

54. Clinical Features
•When first detected, CLL/SLL is often asymptomatic.
•fatigability, weight loss, and anorexia.
•Generalized lymphadenopathy and hepatosplenomegaly The leukocyte
•count may be increased only slightly (in SLL) or may exceed 200,000
cells/µL.
•Hypogammaglobulinemia, leads to an increased susceptibility to
bacterial infections.
•Less commonly autoimmune hemolytic anemia and thrombocytopenia
are seen.
•Many patients live more than 10 years after diagnosis and die of
unrelated causes. The median survival is 4 to 6 years, however, and as
time passes, CLL/SLL tends to transform to more aggressive tumors
that resemble either prolymphocytic leukemia or diffuse large B cell
lymphoma. Once transformation occurs, the median survival is less
than 1 year.

55. Oral manifestation:
•gingivitis, gingival hyperplasia, hemorrhage, petechiae and ulceration of
the mucosa.
• In severe cases the teeth may be almost completely hidden. The
gingivae are boggy, edematous and deep red. They bleed easily. The
gingival swelling is due to the leukemic infiltration in areas of mild
chronic irritation. Purpuric lesions of the oral mucosa analogous to the
cutaneous ecchymoses may also be seen.

57. •The gingival hemorrhage which commonly occurs is due to ulceration
of the sulcus epithelium and necrosis of underlying tissue. Since the
normal white blood cells distribution is
greatly disturbed, a normal inflammatory response to even a mild
infection is impossible.
•Rapid loosening of the teeth due to necrosis of the periodontal ligament
has been reported, and destruction of alveolar bone also occurs in some
cases.

58. MORPHOLOGY
•In SLL/CLL, sheets of small lymphocytes and scattered illdefined
foci of larger, actively dividing cells diffusely efface involved lymph
nodes.
•The predominant cells are small, resting lymphocytes with dark, round
nuclei, and scanty cytoplasm.The foci of mitotically active cells are
called proliferation centers,which are pathognomonic for CLL/SLL.
•In addition to the lymph nodes, the bone marrow, spleen, and liver are
involved in almost all cases.
•In most patients there is an absolute lymphocytosisfeaturing small,
mature-looking lymphocytes. The circulating tumor cells are fragile
and during the preparation of smears frequently are disrupted,
producing characteristic smudge cells.
•Variable numbers of larger activated lymphocytes are also usually
present in the blood smear.

62. MALIGNANT LYMPHOMA
•NON-HODGKIN’S LYMPHOMA
•AFRICAN JAW LYMPHOMA(BURKITT’S LYMPHOMA)
•HODGKIN’S DISEASE
•SOLITARY PLASMA CELL MYELOMA

63. Malignant Lymphoma
“Malignant lymphoma is a neoplastic proliferative process of
the lymphopoietic portion of the reticuloendothelial system
that involves cells of either the lymphocytic or histiocytic
series in varying degrees of differentiation and occurs in an
essentially homogeneous population of a single cell type. The
character of histologic involvement is either diffuse (uniform)
or nodular and the distribution of involvement may be regional
or systemic (generalized); however, the process is basically
multicentric in character. Lymphomas and leukaemias of
lymphocytes and histiocytes are identical, and the variation in
the frequency of cells appearing in the peripheral blood
appears to be related to differences in distribution and is
dependent usually upon the occurrence of bone marrow
involvement.”

64. Non-Hodgkin’s Lymphoma
The non-Hodgkin’s lymphomas are a heterogeneous group of
lymphoproliferative malignancies which can involve both lymph nodes
and lymphoid organs as well as extranodal organs and tissues.
Etiology. Genetic abnormalities
The most common chromosomal abnormality associated with NHL is
the t(14;18)(q32;q21)
Environmental factors -pesticides and
herbicides (e.g. organophosphates, chlorophenols), solvents and
organic chemicals (e.g. benzene, carbon tetrachloride), and wood
preservatives. Thus certain workers like pesticide applicators, workers
in the petroleum, rubber, plastics, and synthetic industries have a
slightly increased risk of NHL.
Patients who receive cancer chemotherapy and/or radiation
therapy are at increased risk of developing NHL.

65. viruses - Epstein-Barr virus in Burkitt’s lymphoma (especially in
endemic areas of Africa), sinonasal lymphoma in Asia and South
America, and lymphomas in immunocompromised patients; HTLV-1 in
adult T-cell lymphoma/leukaemia; and human herpes virus 8 (HHV 8) in
body cavity-based lymphomas in patients with HIV infection.
Immunodeficiency states -congenital immunodeficiency states (e.g.
ataxia telangiectasia, Wiskott–Aldrich syndrome, common variable
hypogammaglobulinemia, severe combined immunodeficiency (SCID)
as well as acquired immunodeficiency states (e.g. HIV infection,
iatrogenic immunosuppression for solid organ or bone marrow transplant
recipients).
Connective-tissue disorders, including Sjögren syndrome, rheumatoid
arthritis, chronic lymphocytic thyroiditis, and systemic lupus
erythematosus (SLE) are also associated with
increased risk of NHL.

66. CLINICAL FEATURES:
age: older than 50 years
Gender: male
High-grade lymphoblastic and small noncleaved cell lymphomas are
the only subtypes of B-cell NHL that are observed more commonly in
children and young adults.
Lymphadenopathy
fevers, night sweats, weight loss, and fatigue, pruritus are noticed.
shortness of breath, chest pain, cough, abdominal pain and distention, or
bone pain, may lead to identification of specific sites of involvement.
Neurological symptoms are important because CNS involvement
may occur with aggressive lymphomas.

67. Oral manifestations:
characterized by swellings which may grow rapidly and then ulcerate. In
some cases, these become large, fungating, necrotic, foul-smelling
masses.
Pain is a variable feature. When underlying bone is involved, tooth
mobility and pain may develop. A number of cases have been reported in
which paresthesia of the mental nerve developed.
lymphoproliferative disease of the hard palate, These lesions occurred
primarily in elderly men and women with an average age of 70 years.
They presented as soft, fluctuant swellings which were occasionally
bilateral. The swellings were ulcerated or discolored in some cases.
Although lymphoid lesions in the hard palate are very likely to be
lymphomas, follicular lymphoid hyperplasia can present in this anatomic
location and therefore careful histologic examination is of importance.

70. HISTOLOGIC FEATURES:
NODULAR FORM DIFFUSE FORM
•the neoplastic cells tend to aggregate in such a a monotonous distribution of cells, effacement
way that large clusters of cells are seen of lymphnode enitrely
•Adults children
•Favourable prognosis poor prognosis
The type of cells present are lymphocytes, reticulum cells and histiocytes.

73. Two principal cell types are observed in varying proportions: small cells
with irregular or cleaved nuclear contours and scant cytoplasm that are
referred to as centrocytes (small cleaved cells) and larger cells with
open nuclear chromatin, several nucleoli, and modest amounts of
cytoplasm that are referred to as centroblasts.

74. Peripheral blood involvement sufficient to produce lymphocytosis
(usually <20,000/dl) is observed in about 10% of patients. Bone marrow
involvement occurs in 65% of patients and characteristically takes the
form of paratrabecular lymphoid aggregates. Splenic white
pulp and hepatic portal triads are also frequently involve

77. •The common morphologic features that unite this group are the
relatively large cell size(usually four or five times that of a small
lymphocyte) and a diffuse pattern of growth.
•the tumor cells have a round or oval nucleus that appears vesicular
because of margination of chromatin at the nuclear membrane, but large
multilobed or cleaved nuclei predominate in some cases.
•Nucleoli may be two or three in number and located adjacent to the
nuclear membrane, or they may be single and centrally placed.
•Cytoplasm is usually present in moderate abundance and may be pale or
basophilic.

79. The NHLs can be divided into two prognostic groups: the indolent
lymphomas and the aggressive lymphomas.
Indolent type of NHL types have a relatively good prognosis, with
median survival as long as 10 years, but they usually are not curable in
advanced clinical stages. Early-stage (I and II) indolent NHL can be
effectively treated with radiation therapy alone. Most of the indolent
types are nodular (or follicular) in morphology.
aggressive type of NHL has a shorter natural history, but a significant
number of these patients can be cured with intensive combination chemo
therapy regimens. In general, with modern treatment of patients with
NHL, overall survival at five years is approximately 50–60%. 30–60% of
patients with aggressive NHL can be cured. The vast majority of relapses
occur in the first two years after therapy. The risk of late relapse is higher
in patients with a divergent histology of both indolent and aggressive
disease.

80. African Jaw Lymphoma
(Burkitt’s lymphoma)
A tumor peculiar to the children of tropical central Africa was reported
by Denis Parsons Burkitt (1958–59), which later became named after
him. Burkitt’s lymphoma (BL) occurs endemically in parts of Africa and
Papua, New Guinea and is restricted to areas with endemic malaria. BL
also occurs sporadically throughout the world.
It is a high-grade B-cell neoplasm and has two major forms: the endemic
(African) form and the nonendemic (sporadic) form. Burkitt’s lymphoma
is a childhood tumor but it is observed in adult patients too. Burkitt’s
lymphoma is one of the fastest growing malignancies in humans, with a
very high growth fraction.

81. Clinical Features.
African form most often involves themaxilla or mandible. The
involvement of abdominal organs, such as the kidneys, ovaries, or
retroperitoneal structures, is slightly
less common.
Sporadic form usually involves abdominal organs, with the most
common involvement of the distal ileum, cecum, or mesentery, and less
common involvement of other abdominal organs, pelvic organs, and
facial bones.

82. Eitiology:
immunosuppression caused by coexistent malaria or another infection,
the host is unable to generate an adequate T-lymphocyte response (i.e.
EBV-specific cytotoxic T cells) against B cells that are infected latently
with EBV. This subsequently results in excessive B cell proliferation
PATHOGE NESIS
Burkitt lymphoma is highly associated with translocations involving the MYCgene
on chromosome 8.

83. In the African form of Burkitt’s lymphoma, patients most often present
with swelling of the affected jaw or other facial bones, loosening of the
teeth, and swelling of the lymph nodes, which are nontender and rapidly
growing, in the neck or below the jaw. Abdominal presentation is slightly
less common.
Rare cases of Burkitt’s lymphoma can present as acute leukemia (L3-
ALL) with fever, anemia, bleeding, and adenopathy.
Major signs of Burkitt’s lymphoma include a soft tissue mass associated
with the involvement of the jaw or other facial bones, enlarged cervical
lymph nodes, abdominal masses, and ascites.

84. Histologic Features.
Burkitt’s lymphoma is a monoclonal proliferation of B lymphocytes
characterized by small noncleaved cells that are uniform in appearance
and that produce a diffuse pattern of tissue involvement.
Burkitt cells are homogeneous in size and shape, with round to oval
nuclei and slightly coarse chromatin, with multiple nucleoli, and with
intensely basophilic vacuolated cytoplasm that contains neutral fat.
Frequent mitotic figures usually are observed. A characteristic starry sky
appearance is imparted by scattered macrophages with an abundant clear
cytoplasm, often containing phagocytic cellular debris

87. Hodgkin’s Disease
(Hodgkin’s lymphoma, malignant lymphoma)
Hodgkin’s disease (HD) is considered as one of the two main types of
malignant lymphomas. Thomas Hodgkin first described Hodgkin’s
disease in 1832. it is a potentially curable
malignant lymphoma with distinct histology, biologic behavior, and
clinical characteristics.
The etiology of HD is unknown. Infectious agents, especially the
Epstein-Barr virus (EBV), may be involved in the pathogenesis. In as
many as 50% of HD cases, the tumor cells are EBV-positive. EBV
positivity is higher with mixed cellularity Hodgkin disease (60–70%)
than the nodular sclerosis Hodgkin disease (15–30%). Almost 100% of
HIV-associated HD cases are EBV-positive.

88. Clinical Features.
Age-specific incidence rates have a bimodal distribution in both genders,
peaking in young adults (aged 15–34 years) and older individuals (>55
years).
HD is more common in males than in females, with an age standardized
incidence of 1.8 cases per 100,000 population in males and 0.8 cases per
100,000 population in females.
This male predominance is particularly evident in children,

89. The first manifestation in the majority of cases is painless enlargement of
one or more cervical lymph nodes, not uncommon finding in other
lymphomas or in cases of simple upper respiratory tract or oral infection.
Palpable painless lymphadenopathy occurs in the cervical area (60–
80%), axilla (6–20%), and, less commonly, in the inguinal area (6–20%)
and Waldeyer ring or occipital nodes. The nodes
are usually firm and rubbery in consistency, and the overlying skin is
normal

90. unexplained weight loss, fever, night sweats are present in about 40% of
patients.
Chest pain, cough, and/or shortness of breath may be present due to a
large mediastinal mass or lung involvement. Rarely, hemoptysis is
observed. Alcohol-induced pain at sites of nodal disease is specific for
HD and occurs in less than 10% of patients. Patient may present with
pruritus or intermittent fever.
Back, abdomen or bone pain may occur rarely due to splenomegaly,
hepatomegaly, pressure from enlarged lymph nodes, involvement of bone
or vertebrae.

92. Histologic Features
1. Nodular sclerosis (NS) Hodgkin’s disease: 60–80% of all cases. The
morphology shows a nodular pattern. The broad bands of fibrosis divide the node
into ‘nodules’. The capsule is thickened. The characteristiccell is the lacunar-type
RS cell, which has a monolobated or multilobated nucleus and a small nucleolus
with abundant and pale cytoplasm. NS frequently is observed in adolescents and
young adults and usually involves the mediastinum and other supradiaphragmatic
sites.

94. 2.Mixed-cellularity Hodgkin’s disease 15–30%. Histologically, the infiltrate is usually
diffuse. RS cells are of the classic type (large, with bilobate, double or multiple
nuclei, and a large eosinophilic inclusion like nucleolus). It commonly affects the
abdominal lymph nodes and spleen. Patients with this histology typically have
advanced-stage disease with systemic symptoms and immunodeficiency.
3. Lymphocyte-depleted Hodgkin’s disease less than 1%. The infiltrate in lymphocyte-
depleted Hodgkin disease (LDHD) is diffuse and often appears hypocellular. Large
numbers of RS cells and bizarre sarcomatous variants are present. It is associated
with older age and HIV positivity. Patients usually present with advanced-stage
disease. EBV proteins are expressed in many of these tumors. Many cases of LDHD
diagnosed in the past actually were nonHodgkin’s lymphomas, often of the
anaplastic large-cell type.

95. Mixed cellularity type

97. 4.Lymphocyte-rich classic Hodgkin’s disease. 5%. In this type of HD,
RS cells of the classic or lacunar type are observed, with a background
infiltrate of lymphocytes. It requires immunohistochemical diagnosis.
Some cases may have a nodular pattern. Clinically, the presentation
and survival patterns are similar to those for mixedcellularity
Hodgkin’s disease.
5. Nodular lymphocyte-predominant Hodgkin’s disease5%. In contrast to
the other histological subtypes, the typical RS cells in nodular
lymphocytepredominant Hodgkin disease are not observed or appear
infrequently. Instead, a variant of RS cells, the lymphocytic and
histiocytic cells (L&H), or popcorn cells (their nuclei resemble an
exploded kernel of corn), are seen within a background of
inflammatory cells, predominantly benign lymphocytes. The L&H
cells are positive for B-cell antigens, such as CD19 and CD20, but
generally are negative for CD15 and CD30.

98. Lymphocyte predominance type

99. Characteristics of typical Reed–Sternberg cell
Characteristic malignant cells of Hodgkin’s diseases are large cells
known as Reed–Sternberg (RS) cells (typical and variant), 20–50
micrometers in diameter, abundant, ampho philic, finely
granular/homogeneous cytoplasm; two mirror-image nuclei (owl eyes)
each with an eosinophilic nucleolus and a thick nuclear membrane
(chromatin is distributed at the cell periphery). One or two percent of
these malignant cells are admixed within a reactive cell infiltrate
composed of variable proportions of lymphocytes, histiocytes,
eosinophils, and plasma cells. The Reed–Sternberg cells are identified as
large often binucleated cells with prominent nucleoli and an unusual
CD15+, CD30+ immunophenotype. In approximately 50% of cases, the
Reed–Sternberg cells are infected by the Epstein-Barr virus.
There are five recognized histologic types of Hodgkin’s
disease which form the basis for its classification

102. Solitary Plasma Cell Myeloma
(Plasmacytoma)
A plasmacytoma is a discrete, solitary mass of neoplastic monoclonal
plasma cells in either bone marrow or a soft tissue site. Solitary
plasmacytomas can be divided into two groups
according to location:
• Plasmacytoma of the skeletal system (solitary bone plasmacytoma).
• Soft tissue plasmacytoma (extramedullary plasmacytoma).

103. Clinical features:
Age: 50-60yrs
Gender prediliction: male
predisposition for the red marrow containing axial skeleton. thoracic vertebrae are most
commonly involved, followed by lumbar, sacral, and cervical vertebrae.
most common symptom is pain at the site of the skeletal lesion due to bone destruction
by the infiltrating plasma cells.
the patient presents with a painless swelling of the sternum, rib, or other bone.
Patients with vertebral involvement may also have evidence of spinal cord or nerve root
compression. A few patients present with symptoms and signs of demyelinating
polyneuropathy
Compression fractures of the thoracic and lumbar vertebral bodies usually result in
severe spasms and back pain.

104. Because of the usual presentation as submucosal lesions of the upper
aerodigestive tract, swelling, headache, nasal discharge, epistaxis, nasal
obstruction, sore throat, hoarseness, dysphonia, dysphagia, dyspnea,
epigastric pain, and hemoptysis are common symptoms.
Symptoms from plasmacytomas in other tissues are associated with the
site of the tumor, tumor size, and to compression and/or involvement of
the surrounding structures. The etiology is thought to be due to long-term
stimulation by inhaled irritants or viral infection.

105. Oral manifestation:
Extramedullary plasmacytoma may be situated on the gingiva, palate,
floor of the mouth, tongue, tonsils and pillars as well as the nasal cavity,
nasopharynx and paranasal sinuses.
The lesions are described as sessile or polypoid reddish masses in the
mucous membranes, which become lobulated as they enlarge, but do not
tend to ulcerate.

106. Radiographic Features. Radiographic examination of thebones in
solitary plasma cell myeloma reveals one of the two types of lesions.
One type is a purely destructive intra medullary
lesion suggestive of metastatic carcinoma. The other type of lesion is an
expansile one suggestive of a giant cell tumor.
Histologic Features. It has been stated previously that the histologic
features of the solitary and multiple myeloma are similar. In the well-
differentiated lesions of multiple myeloma it is impossible to distinguish
between the two.