MALIGNANT CAUSES

OF FEVER-
PATHOPHYSIOLOGY
AND MANIFESTATIONS

DR. SYED HASAN AMIR

ASSISTANT PROFESSOR
GEN MEDICINE
JNMCH, AMU
Fever: An Intricate
Temperature Phenomenon

Fever is an elevation of body temperature

that exceeds the normal daily variation and
occurs in conjunction with an increase in
the hypothalamic set point (e.g., from 37°C
to 39°C).
Normal Body Temperature
Control Center Measurement Methods

The hypothalamus, acting as the control center, Temperature can be measured orally, rectally
regulates body temperature by receiving signals (generally slightly higher), or using tympanic
from peripheral nerves and maintaining a normal membrane thermometers. Each method has its own
temperature range despite external variations. accuracy and variations.

Menstruation Effect Baseline Temperature

Women experience a slight decline in morning A 0.15°C increase in baseline temperature is

temperature during the pre-ovulation phase, associated with a 0.52% increase in 1-year
followed by a rise of approximately 0.6°C (1°F) mortality, highlighting the significance of
during ovulation and throughout the luteal phase. temperature as a vital sign.
Fever: The Hypothalamic Response

1 Raising the Set Point

Fever occurs when the hypothalamic set point elevates, akin to raising
the thermostat in a room. This set point shift activates neurons in the
vasomotor center, initiating vasoconstriction, particularly in the
peripheral areas.

2 Feeling Cold
Vasoconstriction and blood flow redistribution lead to decreased heat
loss from the skin, resulting in the sensation of coldness. A person
experiencing fever may feel a chill and might engage in behavioral
adjustments like adding more clothing or bedding.

3 With the initial drop in skin temperature, the body begins to activate
shivering to increase heat production from muscles. Non-shivering heat
production from the liver also contributes to raising the core temperature.

4 Fever Maintenance
Once the hypothalamic set point is reached and body temperature
stabilizes at the febrile level, the hypothalamus maintains this elevated
temperature.
 Fever vs. Hyperthermia

1 Fever 2 Hyperpyrexia 3 Hypothalamic Fever

Fever involves the elevation of Hyperpyrexia refers to an extremely In some cases, fever occurs due to
body temperature beyond the high fever, often exceeding 41.5°C abnormal hypothalamic function resulting
normal daily variation, resulting (106.7°F). It is commonly seen in from trauma, hemorrhage, tumor, or
from the hypothalamic set point severe infections or CNS hemorrhages, malfunction. Most patients with
being raised. It is accompanied likely mediated by neuropeptides hypothalamic damage tend to have
by various physiological acting as central antipyretics. subnormal temperatures.
responses, including
vasoconstriction, shivering, non-
shivering thermogenesis, and
behavioral adjustments to raise
body temperature.

4 Hyperthermia (Heat Stroke)

Hyperthermia, often referred to as heat stroke, is characterized by an uncontrolled

increase in body temperature beyond the body's ability to dissipate heat. It is not related
to pyrogenic molecules and can be caused by excessive heat exposure or production.
Unlike fever, hyperthermia may not respond to antipyretics.
Heat Balance and Thermoregulation
1 Heat Loss vs. Production
The human body maintains heat balance through
intricate thermoregulatory mechanisms. These
mechanisms include adjusting heat loss and heat
production to ensure normal body temperature
despite variations in the environment.
3 Heat Production
The body generates heat through various
metabolic processes, including cellular
respiration and muscular activity. This internal
production helps maintain body temperature
within the physiological range.
2 Heat Loss Mechanisms
The body manages heat loss through radiation,
conduction, convection, and evaporation. The
interplay between these mechanisms helps
dissipate heat and maintain thermal equilibrium.
4 Feedback Loop
The thermoregulatory feedback loop, involving
the hypothalamus and peripheral sensors,
continuously monitors and adjusts heat balance
to keep the body in a state of homeostasis.
PATHOPHYSIOLOGY OF FEVER
 MALIGNANT CAUSES OF FEVER - Neoplasms

 Hematologic malignancies  lymphomatoid granulomatosis

 Amyloidosis
 angioimmunoblastic
lymphoma
 Castleman’s disease
 Hodgkin’s disease
 hypereosinophilic syndrome
 Leukemia
 malignant histiocytosis
 multiple myeloma
 myelodysplastic syndrome
 Myelofibrosis
 non-Hodgkin’s lymphoma
 Plasmacytoma
 systemic mastocytosis
 Solid tumors :
Most solid tumors and metastases can cause fever.
• Breast, colon, hepatocellular, lung, pancreatic, and renal cell
carcinomas.

Benign tumors :
• Angiomyolipoma, cavernous hemangioma of the liver,
craniopharyngioma, necrosis of dermoid tumor in Gardner’s
syndrome.
Hematological Malignancies

Leukemia Hodgkin's Lymphoma

Non-Hodgkin's Lymphoma
Lymphoid Malignancies

1 Multiple Myeloma

Chronic Lymphocytic Leukemia 2

.

3 Acute Lymphoblastic Leukemia

Burkitt Lymphoma 4
Lymphoproliferative Disorders

Mantle Cell Lymphoma Follicular Lymphoma

Mantle cell lymphoma is a type of non-Hodgkin's Follicular lymphoma is a slow-growing type of non-
lymphoma that usually arises from B lymphocytes and Hodgkin's lymphoma that affects the B lymphocytes
typically involves lymph nodes, spleen, and bone and usually involves lymph nodes, bone marrow, and
marrow. other organs.

Diffuse Large B-Cell Lymphoma Cutaneous T-Cell Lymphoma

 CHRONIC LEUKEMIAS

 Myeloid lineage lymphoid lineage

 chronic myeloid chronic lymphocytic
leukemia
leukemia

 chronic neutrophilic leukemia

 chronic eosinophilic leukemia
 chronic myelomonocytic leukemia
 juvenile myelomonocytic leukemia
Chronic myeloid leukemia-BCR-
ABL -positive

 CML is a myeloproliferative neoplasm arising from neoplastic

transformation of pluripotent BM stem cells .

 CML is distinguished from other MPDs by the presence of a chimeric

BCR-ABL gene derived from portions of the BCR (breakpoint cluster)
gene on chromosome 22 and the ABL (abelson) gene on chromosome
9.

 More than 90% of cases, BCR-ABL is created by a reciprocal (9;22)

(q34;q11.21) translocation (the so-called Philadelphia chromosome [Ph]).

 In the remaining cases the BCR-ABL fusion gene is formed by

cytogenetically complex or cryptic rearrangments .
Etiology
 ionizing radiation
 alkylating agents, and exposure to other biologically
active chemicals.
There does not appear to be an inherited predisposition.

EPIDEMIOLOGY
 worldwide annual incidence of 1-2 cases per 1 lakh
population
Primarily affects adults 25-60 years old, with a peak at 40-
59
 Slight male predominance
 CLINICAL FEATURES
Majority asymptomatic, insidious
onset

SYMPTOMS SIGNS
 fatigue • splenomegaly
 weight loss • Sternal tenderness
 abdominal fullness • Lymphadenopathy
 left upper quadrant pain • Hepatomegaly
 easy bruising or bleeding • Purpura
 anorexia • Retinal hemorrhage
 fever
 CHRONIC LYMPHOCYTIC LEUKAEMIA
• CHRONIC LYMPHOCYTIC LEUKEMIA is a monoclonal proliferation of mature B lymphocytes defined by
an absolute number of malignant cells in the blood ( 5×10⁹/L ).
• CLL is primarily a disease of older adults , median age at diagnosis is 71 .
• Male : Female – 2: 1 .
• Familial associated malignancy , 8.5 fold elevated risk in first degree relatives .
• SMALL LYMPHOCYTIC LYMPHOMA – B lymphocytes ≤5×10⁹/L
Presence of lymphadenopathy or /and splenomegaly .
• MONOCLONAL B CELL LYMPHOCYTOSIS –B lymphocytes < 5×10⁹/L.
-Absence of lymphadenopathy , organomegaly ,

anaemia , thrombocytopenia , constitutional symptoms.

 SIGNS AND SYMPTOMS
• Unspecific: night sweats, fever, weakness (many patients have
fatigue, reduced exercises tolerance or malaise, weight loss)
• Recurrent infections (bacterial, viral – herpes zoster, fungal) – they
are the most common
cause of death
• Bleeding and symptoms of anemia and thrombocytopenia
• Lymphadenopathy (lymph node enlargement)– at diagnosis -
nontender in 80% of patients
later - may become very large
• Splenomegaly - mild to moderate in 50% of patients
• Hepatomegaly
HAEMATOLOGIC AND MARROW
FINDINGS
CBC –
• lymphocytosis ≥5×10 ⁹/L
• Anaemia
• Thrombocytopenia
PERIPHERAL BLOOD SMEAR –
• Small mature lymphocytes with rounded nuclei , clumped chromatin ,
scanty cytoplasm .
• smudge cells .
BONE MARROW –
• Diffuse infiltration of small mature appearing lymphocytes .
ACUTE LYMPHOBLASTIC LEUKEMIA
• Acute lymphoblastic leukemia is a malignant disease of marrow in
which early lymphoid precursors proliferate and replace normal
hematopoietic cells.
• Commonest malignancy of childhood
• Majority 2-10 years and peak incidence is between 4-5 yrs of age.
• 85% are B cell
• 15% are T cell
MULTIPLE MYELOMA

• Multiple myeloma (MM) is a plasma cell malignancy in which

monoclonal plasma cells proliferate in bone marrow, resulting in
an overabundance of monoclonal paraprotein (M protein),
destruction of bone, and displacement of other hematopoietic
cell lines.
• First described in 1848, MM is part of a spectrum of diseases
ranging from monoclonal gammopathy of unknown significance
(MGUS) to plasma cell leukemia.
• Signs and symptoms

• MM can range from asymptomatic to severely symptomatic with

complications requiring emergent treatment. Presenting signs and symptoms
of MM include the following:
• Fever
• Bone pain
• Pathologic fractures
• Spinal cord compression (from pathologic fracture)
• Weakness, malaise
• Bleeding, anemia
• Infection (often pneumococcal)
• Hypercalcemia
• Kidney failure
• Neuropathies
Bone marrow aspirate demonstrating plasma cells of multiple myeloma. Note the blue cytoplasm, eccentric nucleus, and perinuclear pale zone (or halo).
HODGKIN LYMPHOMA
• Hodgkin lymphoma is a potentially curable lymphoma.
• The World Health Organization classifies Hodgkin lymphoma into the
following types :
• Nodular sclerosing
• Mixed cellularity (see the image below)
• Lymphocyte depleted
• Lymphocyte rich
• Nodular lymphocyte predominant
Signs and symptoms

• Asymptomatic lymphadenopathy
• Unexplained weight loss, unexplained fever, night sweats
• Chest pain, cough, shortness of breath
• Pruritus
• Pain at sites of nodal disease
• Back or bone pain
• Nodular sclerosis Hodgkin lymphoma (NSHL) has a strong genetic component and has often
previously been diagnosed in the family
• Palpable, painless lymphadenopathy in the cervical area, axilla, or inguinal area
• Involvement of the Waldeyer ring (back of the throat, including the tonsils) or occipital (lower
rear of the head) or epitrochlear (inside the upper arm near the elbow) area
• Splenomegaly and/or hepatomegaly
• Superior vena cava syndrome may develop in patients with massive mediastinal
lymphadenopathy
• Central nervous system symptoms or signs may be due to paraneoplastic syndromes,
including cerebellar degeneration, neuropathy, Guillain-Barre syndrome or multifocal
leukoencephalopathy
Mixed cellularity Hodgkin lymphoma showing both
mononucleate and binucleate Reed-Sternberg cells in a
background of inflammatory cells
NON HODGKIN LYMPHOMA
• Non-Hodgkin lymphomas (NHLs) are tumors originating from
lymphoid tissues, mainly of lymph nodes.
• These tumors may result from chromosomal translocations,
infections, environmental factors, immunodeficiency states, and
chronic inflammation.
• TYPES-
low-grade lymphomas
Intermediate Lymphomas
high-grade lymphomas
Clinical features

• Adenopathy: Most patients

• Extranodal involvement: More than one third of patients; most
common sites are GI/GU tracts (including Waldeyer ring), skin, bone
marrow, sinuses, thyroid, CNS.
• B symptoms: Temperature >38°C, night sweats, weight loss >10%
from baseline within 6 months; in approximately 30-40% of patients