Flashcards in Week 5 Deck (34):
Describe the DNA damage that occurs from UV radiation and explain how this damage can lead to cancer.
-UV kills cells because of the accumulation of DNA damage
-Ultraviolet light is absorbed by a double bond in pyrimidine bases (such as thymine and cytosine in DNA), opening the bond and allowing it to react with neighboring molecules. If it is next to a second pyrimidine base, the UV-modified base forms direct covalent bonds with it. The most common reaction forms two new bonds between the neighboring bases, forming a tight four-membered ring. Other times, a single bond forms between two carbon atoms on the rings, forming a “6-4 photoproduct.”
How is UV damage fixed?
Our cells use a process known as “nucleotide excision repair” to identify and remove ultraviolet damage. Dozens of proteins work together to seek out corrupted bases, unwind the local DNA double helix and clip out a segment of about 30 bases around the damage. The normal DNA replication machinery then fills the gap, restoring the DNA to its proper form. Nucleotide excision repair is our sole defense against ultraviolet damage
normal cellular pathways of DNA repair after damage due to irradiation
Nucleotide excision repair: damaged nucleotide(s) are removed along with a surrounding patch of DNA. In this process, a helicase (DNA-opening enzyme) cranks open the DNA to form a bubble, and DNA-cutting enzymes chop out the damaged part of the bubble. A DNA polymerase replaces the missing DNA, and a DNA ligase seals the gap in the backbone of the strand
mechanisms of photoprotection
clinical presentation for cutaneous melanoma
• A new or changing mole or blemish is the most common warning sign for melanoma.
• Variation in color and/or an increase in diameter, height, or asymmetry of borders of a pigmented lesion
• Symptoms such as bleeding, itching, ulceration, and pain in a pigmented lesion are less common
• Note: the majority of cutaneous melanoma arises de novo (ie, on normal-appearing skin and not in association with a precursor nevus aka existing mole/birthmark)
risk factors for cutaneous melanoma
• a persistently changed or changing mole
• irregular varieties of pigmented lesions (including dysplastic moles and lentigo maligna)
• a congenital mole
• Caucasian race
• a previous cutaneous melanoma
• family history of cutaneous melanoma
• sun sensitivity
-excessive sun exposure
Asymmetry, borders, color, diameter, evolving
general guidelines for excisional biopsy
, 1-3 mm of normal skin surrounding the pigmented lesion should be removed to provide accurate diagnosis and histologic microstaging
Wider margins (>1 cm) could theoretically disrupt afferent cutaneous lymphatic flow and affect the ability to identify the sentinel node(s) accurately
Sentinel lymph node biopsy
generally indicated for pathologic staging of the regional nodal basin(s) for primary tumors greater than 1 mm depth and when certain adverse histologic features (eg, ulceration, high mitotic rate, lymphovascular invasion) are present in thinner melanomas.
histopathology of cutaneous melanoma
-melanomas progress through two phases;
- radial (horizontal) growth phase (RGP), characterized by centrifugal spread of neoplastic melanocytes within the epidermis and infiltration of the papillary dermis by single cells or small nests
-second, vertical growth phase (VGP), is characterized by the presence of dermal nests/nodules of atypical melanocytes that are larger than and/or cytologically distinct from their intraepidermal counterparts
significance of genetic profiling in treatment of cutaneous melanoma
important to know where the mutation/problem originates. Whether it's BRAF, RAS, or C-KIT gives you an indication of how it's specifically causing melanoma and a better idea of how to treat it
rationale for lymphadenectomy
-patients who present with palpable lymphadenopathy, it is appropriate to confirm diagnosis with fine needle aspiration, core needle, or open biopsy of the clinically enlarged lymph node(s).
-absence of radiological evidence of distant metastases, wide excision of the primary site and complete dissection of the involved lymph node basin is indicated.
-staging purposes, the number of positive nodes, the total number of nodes examined and the presence or absence of extranodal tumor extension must be recorded.
use of 18FDG-PET/CT scanning in the evaluation and staging of cutaneous melanoma
Positron emision tomography (PET) with 2-deoxy-2-fluorine-18-fluoro-D-glucose (18FDG), an analogue of glucose, provides valuable functional information based on the increased glucose uptake and glycolysis of cancer cells
use of tyrosinekinase in immunoperoxidase staining method
-tyrosinekinase is made in melanocytes, it is used in staining of lymph to check for melanocytes in lymph which is indicative of met to the metastasis
use of tyrosinekinase in immunoperoxidase staining method
-tyrosinekinase is made in melanocytes, it is used in staining of lymph to check for melanocytes in lymph which is indicative of met
BRAF in development of cutaneous melanoma
-BRAF is a serine/threonine protein kinase that sits at the top of a cascade of other serine/threonine kinases of the MAPK family. Activating mutations in BRAF stimulate each of these downstream kinases and ultimately activate transcription factors.
-Melanomas with BRAF mutations also often show loss of the PTEN tumor sup- pressor, leading to heightened activation of the PI3K/ AKT pathway.
RAS in development of cutaneous melanoma
-RAS is a small sized plasma membrane-associated GTP binding protein. These proteins primarily regulate growth and, as a molecular switch, they connect signals from cell surface receptors to transcription factors and cell cycle regulating proteins in the nucleus. RAS proteins exist either in GTP-bound state (active) or GDP-bound (inactive) state. In normal cells, following binding of a ligand to its cognate receptor tyrosine kinase (RTK) RAS becomes activated. Once activated, RAS recruits and stimulates a number of signaling pathways including mitogen-activated protein kinas (MAPK) pathway and the phosphoinositide 3-kinase/AKT (PI3K/AKT) pathway.
- mutation of KRAS gene is the most common type of RAS mutation in human malignant disease, in melanoma, a point mutation of NRAS is most frequent and was the first oncogene to be identified
C-KIT in development of cutaneous melanoma
-encodes the KIT protein, KIT (also known as CD117), a receptor tyrosine kinase, plays a critical role in melanocyte development, proliferation, differentiation, migration, and survival. KIT activation leads to activation of downstream targets, including the MAPK, PI3K, and signal transducer and activator of transcription (STAT) signaling pathways and microphthalmia-associated transcription factor (MITF)
selectively inhibits some mutated forms of the protein kinase B-raf (BRAF). BRAF V600 mutations result in constitutive activation of the BRAF pathway; through BRAF inhibition, dabrafenib inhibits tumor cell growth. The combination of dabrafenib and trametinib allows for greater inhibition of the MAPK pathway, resulting in BRAF V600 melanoma cell death
Trametinib reversibly and selectively inhibits mitogen-activated extracellular kinase (MEK) 1 and 2 activation and kinase activity. MEK is a downstream effector of the protein kinase B-raf (BRAF); BRAF V600 mutations result in constitutive activation of the BRAF pathway (including MEK1 and MEK2). Through inhibition of MEK 1 and 2 kinase activity, trametinib causes decreased cellular proliferation, cell cycle arrest, and increased apoptosis.
Role of TP53 in tumor biology
-tumor suppressor gene
-involved in G2 checkpoint and checks for cell size and correct DNA replication before mitosis
Role of RB1 in tumor biology
-tumor suppressor gene
-involved in G1 checkpoint; responsible for checking cell size, nutrients, growth factors and DNA damage before replication
clinical presentation of osteosarcoma
- pain, swelling, decreased ROM, lymphadenopathy, fever/night sweats
growing pains vs. pain from osteosarcoma
-growing pains do not cause tenderness, guarding, or reduced ROM and patient will have normal CBC and ESR
-pain from osteosarcoma will cause tenderness, guarding, or reduced ROM and patient will have abnormal CBC and ESR
features of sclerotic infiltration of bone on x-ray
-sun burst appearance or condmans triangle
purpose of MRI in evaluating suspected bone tumors
○better identifies the edema (high water content) in and around the reactive zone of the pseudocapsule illuminating the potential surgical margin.
-shown to be superior to CT in displaying the medullary canal extent of the tumor, suspected “skip” lesions, soft-tissue extension, and overall anatomic location of an extremity tumor.
purpose and mechanism of whole-body PET-CT in the workup of osteosarcoma
(1) selecting the region of a tumor most likely to yield diagnostic information for biopsy,
(2) staging known malignancies,
(3) monitoring the effect of therapy,
(4) to establish the cause of suspected recurrence seen on other imaging modalities. It differentiates between fibrosis and recurrent tumor
(5) detecting tumor recurrence, especially in the presence of elevated levels of tumor markers,
(6) differentiating benign from malignant lesions,
(7) searching for an unknown primary tumor with metastasis of unknown origin,
(8) guiding radiation therapy planning.
Percutaneous core needle biopsy
- better, safe and accurate method for diagnosing of bone tumors
-performed through a small stab using the Jamshidi needle and taking multiple cores from the representative part of the tumor
common patho findings of osteosarcoma
-in metaphysis of long bone
-large tumor with destruction of inner cortex
-will be osteoblastic, fibroblastic, or chondroblastic
-abundant mitotic figures
use of neoadjuvant chemotherapy
-given pre-operatively for regression of primary tumor (trying to save limb); decreases spread of tumor
-given 3-4 weeks before surgery
forms complexes with DNA by intercalation between base pairs, and it inhibits topoisomerase II activity by stabilizing the DNA-topoisomerase II complex, preventing the religation portion of the ligation-religation reaction that topoisomerase II catalyzes
Benefits and risks of surgery in managing osteosarcoma
-pros: enhanced allograft union, bio effect on OS cell differentiation
-cons: increased risk of met, increased risk of malignancy, failure to augment allograft union, unintended systemic consequences