Cancer-5 Notes Page 1 of 10

University of Ottawa
Molecular Mechanisms of Disease (HSS 2305)
Fall 2022

Gene-5: Problem-Based Learning (PBL) in

molecular oncology
November 14-16, 2022
Figure 1. A 3-year-old girl with retinoblastoma.1 An eye examination performed while the patient was under anesthesia
showed leukocoria (Panel A), as well as iris neovascularization and a white, nodular mass in the posterior chamber.

LEARNING OUTCOMES
After studying this module on “PBL in molecular oncology” you will master the following learning objectives:
8 LO1: Examine cases studies in molecular oncology.

1. BACKGROUND READING AND ONLINE RESOURCES

Readings
o Turnpenny, P. D., Ellard, S., & Cleaver, R. (2021). Emery’s Elements of Medical Genetics & Genomics (16th ed.). Elsevier.
§ Chapter 14: The genetics of cancer… and cancer genetics. pp. 184 – 209
o Fowler, S., Roush, R., & Wise, J. (2016). Concepts of Biology. Houston, TX: OpenStax.
§ Chapter 6.3: Cancer & the Cell Cycle.2 Pages 143 – 144 (PDF book)
o Croce, C. M. (2008). Oncogenes and Cancer. N Engl J Med, 358(5), 502–511.
https://doi.org/10.1056/nejmra072367

Online Resources
o Cancer (Genetic Science Learning Center) à https://learn.genetics.utah.edu/content/history/cancer/
o Cancer à https://ib.bioninja.com.au/standard-level/topic-1-cell-biology/16-cell-division/cancer-development.html
o National Human Genome Research Institute (NHGRI) à https://www.genome.gov/genetics-glossary/Sex-Linked
o Retinoblastomaà https://www.mskcc.org/sites/default/files/node/1211/documents/retinoblastoma_english_0.pdf
o Genetics Home Reference (GHR) à https://ghr.nlm.nih.gov/
§ Retinoblastoma à https://medlineplus.gov/genetics/condition/retinoblastoma/
§ Neuroblastoma à https://medlineplus.gov/genetics/condition/neuroblastoma/
§ Non-hodgkin’s Lymphoma in children à https://medlineplus.gov/ency/article/007686.htm

Videos
o YouTube #1: Neuroblastoma (Osmosis) à https://youtu.be/ej_2OOBmtPc
o YouTube #2: Retinoblastoma à https://youtu.be/SOsPWg9IQLI
o YouTube #3: Breast Cancer (Osmosis) à https://youtu.be/auF4tT0ETM4
o YouTube #4: Cervial Cancer (Osmosis) à https://youtu.be/NgO9kdWeg1k
o YouTube #4: Oncogenetics - Mechanism of Cancer (Armando Hasudungan) à https://youtu.be/1mo80kTZgW4
o TEDEd video: Leukemia à https://ed.ted.com/lessons/what-is-leukemia-danilo-allegra-and-dania-puggioni

1 Peeler, C., & Gonzalez, E. (2022). Retinoblastoma. N Engl J Med, 386(25), 2412–2412. https://doi.org/10.1056/nejmicm2118356
2 Fowler, S., Roush, R., & Wise, J. (2016). Concepts of Biology. Houston, TX: OpenStax. Retrieved November 14, 2022, from
https://openstax.org/books/concepts-biology/pages/6-3-cancer-and-the-cell-cycle
Molecular Mechanisms of Disease (HSS 2305) Darnel, A.D. © Fall 2022
 Cancer-5 Notes Page 2 of 10
2. SOMATIC VS GERMLINE MUTATIONS
In multicellular organisms, mutations can be classed as
either somatic or germline:
① Somatic mutations – occur in a single body
cell and cannot be inherited (only tissues
derived from mutated cell are affected).
② Germline mutations – occur in gametes and
can be passed onto offspring (every cell in the
entire organism will be affected).

Figure 2. Somatic vs Germline Mutations3

8 LO1: Examine cases studies in molecular oncology.

3. NEUROBLASTOMA
o Neuroblastoma = most common and most deadly solid tumour that occurs in children outside of the brain.4
o Most common tumour diagnosed in the first year of life.
o Approximately 50-70 new cases of neuroblastoma are diagnosed every year in Canada à about 50-70% of these
cases the disease has already metastasized at the time it is found.
o This is the highest rate of metastasis for all paediatric cancers.

Pathogenesis of Neuroblastoma
o Neuroblastoma is a cancer that develops from immature nerve cells found in several areas of the body.
o Neuroblastoma most commonly arises in and around the adrenal glands, which have similar origins to nerve cells.
o Neuroblastoma can also develop in other areas of the abdomen and in the chest, neck and near the spine.
o Neuroblastoma most commonly affects children age 5 or younger, though it may rarely occur in older children.
o Some forms of neuroblastoma go away on their own, while others may require multiple treatments.
o The cause of neuroblastoma is not well understood.
§ The great majority of cases are sporadic and nonfamilial.
§ About 1–2% of cases run in families and have been linked to specific gene mutations.
§ Familial neuroblastoma in some cases is caused by rare germline mutations:
Ø anaplastic lymphoma kinase (ALK) gene.
Ø PHOX2B gene
Ø KIF1B gene

o YouTube #1: Neuroblastoma (Osmosis) à https://youtu.be/ej_2OOBmtPc

Figure 3. This is a coronal post-gadolinium T1-weighted MPRAGE* MRI of a 2-year-old

female with known neuroblastoma.5 There are orbital and skull vault metastases, with
associated enhancing soft-tissue masses. The skull lesions are extradural masses which
deform the underlying brain. The right orbital lesion forms a superior extraconal mass,
depressing the right globe. Neuroblastoma not uncommonly metastasizes to the skull.
The metastases are generally osteolytic, enlarge the bone, strip the dura from it, and
produce intracranial mass effect. Other skull metastases include osteogenic sarcoma
(usually osteoblastic lesions); leukaemia; Wilm’s tumour; Ewing’s tumour; and
hepatoblastoma.

3 Cornell, B. (2016). Somatic vs Germline Mutations [Digital image]. Retrieved November 14, 2022, from
https://ib.bioninja.com.au/standard-level/topic-3-genetics/33-meiosis/somatic-vs-germline-mutatio.html
4 Neuroblastoma Canada (2018). http://neuroblastoma.ca/neuroblastoma/statistics/
5 Dawes, L. (2008, February 25). Neuroblastoma mets. Radiopaedia. https://commons.wikimedia.org/wiki/File:Neuroblastoma_mets.JPG
Molecular Mechanisms of Disease (HSS 2305) Darnel, A.D. © Fall 2022
 Cancer-5 Notes Page 3 of 10
Case Study 1: Recent Advances in Neuroblastoma6
Neuroblastoma is an embryonal tumor of the
autonomic nervous system, meaning that the cell of
origin is thought to be a developing and incompletely
committed precursor cell derived from neural-crest
tissues. As may be expected with a disease of
developing tissues, neuroblastomas generally occur in
very young children; the median age at diagnosis is
17 months. The tumors arise in tissues of the
sympathetic nervous system, typically in the adrenal
medulla or paraspinal ganglia, and thus can present
as mass lesions in the neck, chest, abdomen, or pelvis.
The clinical presentation is highly variable, ranging
from a mass that causes no symptoms to a primary
tumor that causes critical illness as a result of local
invasion, widely disseminated disease, or both. The
incidence of neuroblastoma is 10.2 cases per million
children under 15 years of age; it is the most common
cancer diagnosed during the first year of life.

Figure 4. Neuroblastoma is a childhood cancer that is diagnosed at a median age of about 17 months. Tumors
can arise anywhere along the sympathetic nervous system, with the majority occurring in the adrenal medulla. Primary
tumors in the neck or upper chest can cause Horner's syndrome (ptosis, miosis, and anhidrosis). Tumors along the spinal
column can expand through the intraforaminal spaces and cause cord compression, with resulting paralysis. Although
many lower-stage neuroblastomas are encapsulated and can be surgically excised with little chance of complications,
higher-stage tumors often infiltrate local organ structures, surround critical nerves and vessels such as the celiac axis,
and are largely unresectable at the time of diagnosis. Neuroblastomas typically metastasize to regional lymph nodes
and to the bone marrow by means of the hematopoietic system. Tumor cells metastatic to marrow can infiltrate
cortical bone. Neuroblastomas also can metastasize to the liver, most notably in patients with stage 4S tumors, in
whom involvement can be extensive; however, transient and complete regression often occurs with no intervention
other than supportive care.

Figure 5. Model of Genetic Susceptibility to

Neuroblastoma. The y axis indicates the theoretical
relative risk of neuroblastoma, and the x axis
indicates the number of known and theoretical
susceptibility alleles. A genetic threshold for the
development of disease has been postulated, and
malignant transformation is probably modified by
interactions related to environmental exposure. A
mutation in the ALK or PHOX2B gene results in a
single, highly penetrant risk allele that allows
developing neuroblastic tissue to meet or exceed this
threshold for malignant transformation. These types of
mutations are powerful enough to permit
neuroblastoma to occur within families as a mendelian
trait. On the other hand, there are multiple common
DNA variations (polymorphisms) in a large number of genes that cooperate to reach this threshold in patients without
ALK or PHOX2B mutations. For these sporadic cases of neuroblastoma, an excessive inheritance of “risk” variants has
been postulated that increases susceptibility to the disease. Discovered susceptibility genes include FLJ22536,
BARD1, and NBPF23. The total number of susceptibility loci is not currently known, nor is it known whether these
polymorphisms act in an additive or synergistic (epistatic) fashion.

6 Maris, J. M. (2010). Recent Advances in Neuroblastoma. N Engl J Med, 362(23), 2202–2211. https://doi.org/10.1056/nejmra0804577
Molecular Mechanisms of Disease (HSS 2305) Darnel, A.D. © Fall 2022
 Cancer-5 Notes Page 4 of 10
4. RETINOBLASTOMA
o Retinoblastoma occurs in 1/15,000 live births (in Canada) 7 and represents about 2% of childhood cancers.
o Usually diagnosed in children < 2 years of age; < 5% of cases are diagnosed in those > 5 years of age.
o The cancer may be hereditaryà inheritance is mainly autosomal dominant but with incomplete penetrance.8
o Approx. 25% of patients have bilateral disease, which is always heritable.
o Approx.15% of patients have heritable unilateral disease
o The remaining 60% of patients have nonhereditary unilateral disease.

Pathogenesis of Retinoblastoma inheritance

o Involves mutational deactivation of both alleles of a retinoblastoma suppressor gene (RB1)
o RB1 is located on chromosome 13q14.
o In the hereditary form, a germline mutation alters one allele in all cells
o In a somatic (nonhereditary) mutation, both alleles in the retinal cells (the 2nd hit in this 2-hit model) are altered,
resulting in the cancer.
o YouTube #2: Retinoblastoma à https://youtu.be/SOsPWg9IQLI

Case Study 2: Retinoblastoma9

A 3-year-old girl was brought to the emergency department with a 2-month history of a white pupil and a 1-day
history of redness and pain in the right eye. An eye examination performed while the patient was under anesthesia
showed leukocoria (Panel A), as well as iris neovascularization and a white, nodular mass in the posterior chamber.
The left eye was normal. B-scan ultrasonography showed tumor calcification and vitreous seeding in the affected
eye. A diagnosis of retinoblastoma was made. Magnetic resonance imaging of the head showed retinal and
choroidal invasion without extraocular extension (Panel B). Given the high-risk clinical features, the eye was
enucleated the next day. Histopathological examination confirmed the diagnosis. Genetic testing did not show a
germline mutation in the tumor suppressor gene RB1, and therefore the tumor was attributed to a somatic,
nonheritable mutation. Leukocoria requires urgent evaluation by an ophthalmologist in order to quickly identify
life-threatening causes. When detected early, retinoblastoma can be treated with focal therapy that can salvage
vision and the eye. When diagnosis is delayed, however, the condition is often treated with enucleation and systemic
chemotherapy to prevent life-threatening metastasis. After enucleation, the patient underwent six cycles of
chemotherapy. There was no evidence of recurrent disease on subsequent examinations.

Figure 6. A 3-year-old girl with retinoblastoma. An eye examination performed while the patient was under
anesthesia showed leukocoria (Panel A), as well as iris neovascularization and a white, nodular mass in the posterior
chamber. The left eye was normal. B-scan ultrasonography showed tumor calcification and vitreous seeding in the
affected eye. A diagnosis of retinoblastoma was made. Magnetic resonance imaging of the head showed retinal
and choroidal invasion without extraocular extension (Panel B).

7 Canadian Association of Optometrists (2022). https://opto.ca/eye-health-library/retinoblastoma

8 “Penetrance refers to the proportion of people with a particular genetic variant (or gene mutation) who exhibit signs and symptoms of a genetic
disorder. If some people with the variant do not develop features of the disorder, the condition is said to have reduced (or incomplete) penetrance.”
Definition obtained from: What are reduced penetrance and variable expressivity?: MedlinePlus Genetics. (21 April 2021).
https://medlineplus.gov/genetics/understanding/inheritance/penetranceexpressivity/
9 Peeler, C., & Gonzalez, E. (2022). Retinoblastoma. N Engl J Med, 386(25), 2412–2412. https://doi.org/10.1056/nejmicm2118356
Molecular Mechanisms of Disease (HSS 2305) Darnel, A.D. © Fall 2022
 Cancer-5 Notes Page 5 of 10
Case Study 3: Retinoblastoma10
Retinoblastoma is an aggressive eye cancer of infancy and childhood. Survival and the chance of saving vision
depend on severity of disease at presentation. Retinoblastoma was the first tumour to draw attention to the
genetic aetiology of cancer. Despite good understanding of its aetiology, mortality from retinoblastoma is about
70% in countries of low and middle income, where most affected children live. Poor public and medical awareness,
and an absence of rigorous clinical trials to assess innovative treatments impede progress. Worldwide, most of the
estimated 9000 newly diagnosed patients every year will die. However, global digital communications present
opportunities to optimise standards of care for children and families affected by this rare and often devastating
cancer. Parents are now leading the effort for widespread awareness of the danger of leucocoria. Genome-level
technologies could make genetic testing a reality for every family affected by retinoblastoma. Best-practice
guidelines, online sharing of pathological images, point-of-care data entry, multidisciplinary research, and clinical
trials can reduce mortality. Most importantly, active participation of survivors and families will ensure that the whole
wellbeing of the child is prioritised in any treatment plan.

Figure 7. Progression of retinoblastoma (A) from small intraretinal tumours that can be cured by laser treatment
and cryotherapy (TNM T1a, IIRC A) to massive orbital retinoblastoma probably extending into the brain (TNM T4a-
b). A difference in age at diagnosis recorded between Canada and Kenya could be the difference between possible
cure and certain death (B). The Canadian child with leucocoria was diagnosed because of the left-hand image, which
was taken by his sister with his mother's mobile phone. TNM=Tumor Node Metastasis Cancer Staging.11 IIRC=the
International Intraocular Retinoblastoma Classification.12

10 Dimaras, H., Kimani, K., Dimba, E. A., Gronsdahl, P., White, A., Chan, H. S., & Gallie, B. L. (2012). Retinoblastoma. The Lancet, 379(9824), 1436–
1446. https://doi.org/10.1016/s0140-6736(11)61137-9
11 Finger P Harbour J Murphree A et al. (2010). Chapter 52: retinoblastoma. in: Edge SB Byrd DR Compton CC Fritz AG Greene FL Trotti A AJCC
Cancer Staging Manual, 7th ed. Springer Science and Business Media, Berlin: 561-568.
12 Linn Murphree, A. (2005). Intraocular Retinoblastoma: the Case for a New Group Classification. Ophthalmology Clinics of North America, 18(1),
41–53. https://doi.org/10.1016/j.ohc.2004.11.003
Molecular Mechanisms of Disease (HSS 2305) Darnel, A.D. © Fall 2022
 Cancer-5 Notes Page 6 of 10
5. MEDULLOBLASTOMA (MB)13
Medulloblastoma is the most common embryonal tumor in children. The current standard of care comprises surgical resection,
radiation and chemotherapy. Patients are stratified into standard and high risk based on the degree of resection, presence
of metastatic disease and histopathology. Cure rates dramatically improved during the past decades reaching 70–80%
(high and average risk, respectively). Infant medulloblastoma has a worse outcome as the use of radiation therapy is very
limited, a group of patients still has dismal outcome despite appropriate therapy, and the unacceptable long-term therapy
side effects in survivors. Advanced molecular techniques have allowed scientists to discover four distinct molecular subgroups
and correlate them with multiple factors such as histopathology, clinical behavior and possible therapeutic targets.

Medulloblastoma
o Most common type of malignant brain
tumor in childhood.
o Aggressive solid tumor malignancy that
develops in the posterior fossa, which
contains the brain stem and cerebellum.
o Boys are affected more frequently than
girls, with cases usually occurring
between 5 and 9 years of age.
o MB is classified into four molecular
subgroups:
① Wingless [WNT]
② Sonic Hedgehog [SHH]
③ group 3 [G3]
④ group 4 [G4])
Figure 8. Medulloblastoma pathophysiology.14
Signs & Symptoms
§ Related to cerebellar dysfunction and á intracranial pressure (ICP) due to blockage of the fourth ventricle.
§ Patients present with headache, nausea, vomiting, imbalance, and visual disturbances.
§ Nerve compression may cause truncal ataxia,15 seizures and sensory deficits.

Case Study 4: Paediatric Medulloblastoma16

A 4-year-old boy presented to the emergency department with a sudden hearing loss, vertigo17 and gait ataxia
and a two-week history of neck pain, morning vomiting and headaches. He was GCS 15 and had papilloedema. CT
and then MRI revealed a solitary 4th ventricular lesion with diffuse
leptomeningeal18 enhancement and early obstructive
hydrocephalus. Three days after presentation, he underwent
posterior fossa craniotomy for gross total resection of the intra-
axial component of the tumour. Histopathological features were
consistent with large cell anaplastic (LCA) medulloblastoma, WHO
grade IV. CSF cytology revealed medulloblastoma cells.

Figure 9. Sagittal and axial T1 contrast-enhanced MRI showing

medulloblastoma in the posterior wall of the fourth ventricle.

13 Doussouki, M. E., Gajjar, A., & Chamdine, O. (2019). Molecular genetics of medulloblastoma in children: diagnostic, therapeutic and prognostic
implications. Future Neurology, 14(1), FNL8. https://doi.org/10.2217/fnl-2018-0030
14 Muniz, J. (2017). Medulloblastoma. Retrieved Nov. 14, 2022, from https://twitter.com/medcomic/status/1486716380233670668/photo/1
15 Ataxia: the loss of full control of bodily movements.
16 Raghu, A.L.B., et al. (2017). Delayed diffuse cerebellar swelling after resection of medulloblastoma: case report and review of literature. Childs
Nerv Syst. 33(11):2047-2049. doi: 10.1007/s00381-017-3496-9
17 Vertigo: a sensation of whirling and loss of balance caused by disease affecting the inner ear or associated cranial nerve.
18 Leptomeningeal: having to do with the leptomeninges, the two innermost layers of tissues that cover the brain and spinal cord.
Molecular Mechanisms of Disease (HSS 2305) Darnel, A.D. © Fall 2022
 Cancer-5 Notes Page 7 of 10
6. BREAST CANCER19
Germline mutations in BRCA1 and BRCA2 predispose to common human malignancies, most notably tumors of the breast
and ovaries. The proteins encoded by these genes have been implicated in a plethora of biochemical interactions and
biological functions, confounding attempts to coherently explain how their inactivation promotes carcinogenesis. Here, I
argue that tumor suppression by BRCA1 and BRCA2 originates from their fundamental role in controlling the assembly
and activity of macromolecular complexes that monitor chromosome duplication, maintenance, and segregation across
the cell cycle. A tumor-suppressive role for the BRCA proteins as "chromosome custodians" helps to explain the clinical
features of cancer susceptibility after their inactivation, provides foundations for the rational therapy of BRCA-deficient
cancers, and offers general insights into the mechanisms opposing early steps in human carcinogenesis.

Figure 10. Cancer predisposition and cellular defects associated with BRCA1/2 mutation.20 (A) Inherited BRCA1/2
mutations confer predisposition to a range of cancers, predominantly breast and ovarian cancer. (B) Genome
maintenance functions of BRCA1/2. Beyond their canonical role in homologous recombination repair, BRCA1 and BRCA2
are involved in the protection of stalled replication forks and repair by the Fanconi anemia pathway. (C) BRCA1/2
inactivation leads to defective DNA repair and consequent usage of error-prone DNA repair pathways, collapse
of stalled forks, and defective completion of crosslink repair. Abbreviations: AltEJ, alternative end-joining; NHEJ, non-
homologous end-joining; SSA, single-strand annealing.

o YouTube #3: Breast Cancer (Osmosis) à https://youtu.be/auF4tT0ETM4

19 Venkitaraman, A. R. (2014). Cancer Suppression by the Chromosome Custodians, BRCA1 and BRCA2. Science, 343(6178), 1470–1475.
https://doi.org/10.1126/science.1252230
20 van Vugt, M. A., & Parkes, E. E. (2022). When breaks get hot: inflammatory signaling in BRCA1/2-mutant cancers. Trends in Cancer, 8(3), 174–
189. https://doi.org/10.1016/j.trecan.2021.12.003
Molecular Mechanisms of Disease (HSS 2305) Darnel, A.D. © Fall 2022
 Cancer-5 Notes Page 8 of 10
Case Study 5: The first case report of a large deletion of the BRCA1 gene in Croatia21

Rationale:
Breast cancer is one of the most common cancers in women, and it is the leading cause of cancer related deaths in
Croatia. BRCA1 and BRCA2 gene mutations are the most common cause of hereditary breast cancer.

Patient concerns:
In this report we describe a Croatian patient with no apparent family history of cancer, who developed breast cancer
first at 29, and again at 33.

Diagnosis:
Due to the early development of first breast cancer and triple negative status of the second, the attending physician
suspected a hereditary aspect.

Interventions:
Patient was sent to BRCA1 genetic testing. Subsequently, her mother and sister were sent to check for the mutation found
in the patient.

Outcomes:
BRCA1 exons 4-6 deletion was determined, and sequencing confirmed the deletion as
NG_005905.2:g.107648_117905del10257. Mother and sister were not affected, but since there were no available
family members on the fathers’ side, it was not possible to determine if this was a case of de novo mutation. Until now,
only in three reports with the similar mutation the exact mutation borders were determined. The mutation in this case
was not the same as previously reported and was more than twice in size.

Lessons:
All large deletions should be described at the nucleotide level, so that in cases with missing family data it would be
possible to deduce if the mutation is already known. If the mutation is already known, it is probably not a de novoevent,
since it is unlikely that the breakpoints would be exactly the same more than once.

7. LEUKEMIA
o Leukemia = a cancer found in the blood & bone marrow, caused by too many white blood cells in the body. The
WBCs don’t let the body fight disease and prevent the body from making red blood cells and platelets.
o These WBCs are not fully developed à called blasts or leukemia cells.
o TEDEd video: What is leukemia? by Danilo Allegra & Dania Puggioni à
https://ed.ted.com/lessons/what-is-leukemia-danilo-allegra-and-dania-puggioni

Leukemia symptoms
o Bone marrow failure to produce normally functioning blood cells:
§ Anemia features: weakness, shortness of breath and pallor.
§ Leukopenia features: infections (septicemia, pneumonitis).
§ Thrombocytopenia features: á hemorrhagic tendency

o Bone marrow hyperplasia, á accumulation, infiltration & proliferation of malignant cells results in:
§ Bone & Joint pain
§ Hepatosplenomegaly (spleen and/or liver enlargement)
§ Lymphadenopathy (enlarged lymph nodes)
§ Gingival hypertrophy (hyperplasia) and oral lesions

21 Musani, V., Sušac, I., Ozretić, P., Eljuga, D., & Levanat, S. (2017). The first case report of a large deletion of the BRCA1 gene in Croatia. Medicine,
96(48), e8667. https://doi.org/10.1097/md.0000000000008667
Molecular Mechanisms of Disease (HSS 2305) Darnel, A.D. © Fall 2022
 Cancer-5 Notes Page 9 of 10
(a) (b)

Figure 5. (a) Leukemia is categorized into four types

based on the onset (acute vs. chronic) and cell type
(lymphoblastic or myelogenous): ALL, AML, CLL and
CML. 22 (b) Common leukemia symptoms. 23

Table 1. Four major kinds of Leukemia Cell type

Cell Type Acute Chronic
Lymphocytic leukemia or
Acute lymphoblastic leukemia (ALL) Chronic lymphocytic leukemia (CLL)
"lymphoblastic"
Myelogenous leukemia or
Acute myelogenous leukemia (AML) Chronic myelogenous leukemia (CML)
"myeloid"

Chronic leukemia
o Characterized by the excessive buildup of relatively mature, but still abnormal, white blood cells.
o Typically taking months or years to progress à cells are produced at much higher rate than normal à abnormal
WBCs.
o Chronic leukemia mostly occurs in older people but can occur in any age group.

Acute leukemia
§ Characterized by a rapid á in the number of immature blood cells.
§ Crowding of immature cells in bone marrow makes this tissue unable to produce healthy blood cells.
§ Immediate treatment is required in acute leukemia because of the rapid progression & accumulation of malignant
cells, which spill over into the bloodstream & spread to other organs of the body.
§ Acute leukemias are the most common forms of leukemia in children.

Acute Myelogenous Leukemia (AML) 24

§ Acute = progresses rapidly without
treatment
§ Myeloid = type of cell this leukemia
originates from.
§ Starts in the bone marrow, but quickly
moves into the blood.
§ Can sometimes spread to the lymph
nodes, liver, spleen, and CNS

Figure 11. AML is a cancer of the bone

marrow and the blood. 25

22 American Society of Hematology (2014) What is Leukemia? Retrieved November 14, 2022 from
http://blooddiseasedestination.com/2014/11/11/graphic-what-is-leukemia/
23 Häggström, M. (2008). Common symptoms of chronic or acute leukemia (Wikipedia) Retrieved November 14, 2022 from
https://en.wikipedia.org/wiki/Leukemia
24 Further details: http://www.llscanada.org/leukemia/acute-myeloid-leukemia
25 Muniz, J. (2016). AML. Retrieved November 14, 2022, from https://twitter.com/medcomic/status/701060113206013952/photo/1
Molecular Mechanisms of Disease (HSS 2305) Darnel, A.D. © Fall 2022
 Cancer-5 Notes Page 10 of 10
Acute Lymphoblastic Leukemia (ALL) 26
§ Acute = progresses rapidly without treatment;
§ Lymphoblastic = type of cell this leukemia originates from. See Figure 3.
§ Most common pediatric cancer.

ALL Pathophysiology
§ The DNA of a developing stem cell in the bone marrow is damaged à “acquired mutation.”
§ Stem cells that form WBCs start out as blast cells called lymphoblasts, which produce lymphocytes (a type of
white cell).
§ Three major types of lymphocytes (see also Figure 3):
1. B lymphocytes à produce antibodies to help combat infections
2. T lymphocytes à several functions including assisting B lymphocytes to make antibodies
3. Natural killer (NK) cells à attack virus-infected cells or tumor cells
§ Although ALL starts in a stem cell in the bone marrow, it can spread to other areas such as the CNS, and the lymph
nodes.

Figure 12. ALL is a cancer of the bone

marrow and the blood. ALL symptoms
include: aches in the arms, legs or
back, bruises for no clear reason,
enlarged lymph nodes
(lymphadenophathy), fever without an
obvious cause or a lasting, low-grade
fever, headaches, pale skin, pinhead-
size red spots under the skin (called
petechiae), prolonged bleeding from
minor cuts, shortness of breath during
normal physical activity, tiredness or
no energy, vomiting, and unexplained
weight loss.27

Case Study 5: Leukemia Cutis28

A 65-year-old man presented to the dermatology clinic with a 5-day history of a painful rash on his hands and elbows.
He had no other symptoms. Physical examination showed erythematous and purplish plaques on the dorsa of both hands
and elbows in a symmetric distribution. Laboratory examinations showed a white-cell count of 16,000 per cubic
millimeter (reference range, 4200 to 10,200) and a platelet count of 70,000 per cubic millimeter (reference range,
145,00 to 348,000). Skin biopsy of a lesion on the left
elbow revealed a perivascular lymphocytic infiltrate in
the dermis, with positive staining for myeloperoxidase,
CD123, Ki67, and CD68. A diagnosis of leukemia cutis
was made, and the patient was urgently referred to the
oncology clinic. A bone marrow biopsy revealed 15 to
20% blasts and molecular mutations in ASXL1, NRAS,
SRSF2, and TET2. The patient received a diagnosis of
chronic myelomonocytic leukemia and underwent stem-
cell transplantation. Two weeks after the transplantation,
the patient’s skin changes had resolved, and the cancer
has been in remission since.

Figure 13. Leukemia Cutis in a 65-year-old man.

26 Further details: http://www.llscanada.org/leukemia/acute-lymphoblastic-leukemia

27 Muniz, J. (2016). ALL. Retrieved November 14, 2022, from https://twitter.com/medcomic/status/703058359302426625/photo/1
28 Barry, D., & Schmieder, A. (2021b). Leukemia Cutis. N Engl J Med, 385(14), 1316–1316. https://doi.org/10.1056/nejmicm2103771
Molecular Mechanisms of Disease (HSS 2305) Darnel, A.D. © Fall 2022