Transcript Fieleke

MOC Self-Assessment
David Fieleke, MD
A 27 year-old male was recently diagnosed with his seventh basal cell
carcinoma. A photograph of his palm and panoramic radiograph of the
upper and lower jaw are shown below. A germline mutation in which
gene is the primary cause of his syndrome?
A. TYR
B. XPA-XPG
C. BLM / RECQL3
D. CDKN2A
E. PTCH1
A 27 year-old male was recently diagnosed with his seventh basal cell
carcinoma. A photograph of his palm and panoramic radiograph of the
upper and lower jaw are shown below. A germline mutation in which
gene is the primary cause of his syndrome?
A. TYR
B. XPA-XPG
C. BLM / RECQL3
D. CDKN2A
E. PTCH1
A 27 year-old male was recently diagnosed with his seventh basal cell
carcinoma. A photograph of his palm and panoramic radiograph of the
upper and lower jaw are shown below. A germline mutation in which
gene is the primary cause of his syndrome?
A. TYR
B. XPA-XPG
C. BLM / RECQL3
D. CDKN2A
E. PTCH1
E. PTCH1
This patient has basal cell nevus syndrome, an autosomal dominant
disorder caused by a germline mutation in PTCH1 (or less
commonly PTCH2 or SUFU) which is part of the sonic hedgehog
signaling pathway.
Patients with basal cell nevus syndrome develop numerous basal
cell carcinomas, usually beginning at a young age (median age of
onset is 20).
Associated developmental defects can include palmar and plantar
pits, macrocephaly, dysgenesis of the corpus callosum, falx cerebri
calcification, coarse facies, cleft palate, bifid ribs, and spina bifida
occulta).
Basal cell nevus syndrome patients are also predisposed to multiple
other neoplasms including, medulloblastomas, meningiomas,
odontogenic keratocysts, rhabdomyosarcomas, fibrosarcomas,
cardiac fibromas, and ovarian fibromas.
Schematic of the sonic hedgehog (SHH) pathway in a
representative keratinocyte. Normally, hedgehog ligand activates
the pathway by binding to and inhibiting PTCH1, allowing
depression of smoothened (SMO), activation of suppressor of
fused gene (SUFU), and the downstream upregulation of
GLI1 transcription factors that are involved in cell growth and
proliferation.
Distractors
Each answer choice is a gene which when
defective leads to a disorder or syndrome
with an increased risk of skin cancer.
Distractors
TYR encodes for the enzyme tyrosinase which is mutated in
Oculocutaneous albinism type 1.
These patients have white hair, white or pink skin with the inability to
tan, and translucent eyes. All types of skin malignancies occur with
an increased frequency in OCA type 1, with squamous cell
carcinoma being the most prevalent.
Distractors
XPA-XPG encode for proteins involved in DNA repair, mutations of
which lead to the various phenotypes of xeroderma pigmentosum.
These defects in DNA repair lead to hypersensitivity to the
damaging effects of ultraviolet radiation. There is a 1000-fold
increase in skin cancers in these patients.
Distractors
BLM / RECQL3 is defective in Bloom syndrome.
The gene products are helicases involved in DNA synthesis, and
when defective the result is telomere dysfunction and genomic
instability.
Patients with Bloom syndrome have a high-pitched voice,
characteristic facial features, photosensitivity, and a significantly
increased risk of cutaneous squamous cell carcinoma.
Distractors
CDKN2A encodes two proteins (p16INK4A and p14ARF) which are
tumor suppressors important for cell cycle inhibition.
The loss of these cell cycle suppressors leads to a heritable
increased cutaneous melanoma risk.
Patients are also at increased risk for pancreatic cancer as well as
certain central nervous system tumors.
Citations
Ranshoff KJ, Jaju PD, Tang JY, et al. Familial skin cancer
syndromes: Increased melanoma risk. J Am Acad Dermatol. 74,3:
423-434.
Jaju PD, Ranshoff KJ, Tang JY et al. Familial skin cancer
syndromes: Increased nonmelanotic skin cancers and
extracutaneous tumors.J Am Acad Dermatol. 74,3: 437-451.
The 59 year-old male depicted below was evaluated in clinic and a
biopsy was performed, confirming the suspected diagnosis. Due to the
size and location of the tumor, the Mohs surgeon considered
attempting to shrink the tumor medically prior to surgical excision. Side
effects that were reviewed with the patient included muscle spasms,
hair loss, and taste disturbance. Which of the following medications
was discussed?
A. Vemurafenib
B. Pembrolizumab
C. Vismodegib
D. Imatinib
E. Alemtuzumab
The 59 year-old male depicted below was evaluated in clinic and a
biopsy was performed, confirming the suspected diagnosis. Due to the
size and location of the tumor, the Mohs surgeon considered
attempting to shrink the tumor medically prior to surgical excision. Side
effects that were reviewed with the patient included muscle spasms,
hair loss, and taste disturbance. Which of the following medications
was discussed?
A. Vemurafenib
B. Pembrolizumab
C. Vismodegib
D. Imatinib
E. Alemtuzumab
The 59 year-old male depicted below was evaluated in clinic and a
biopsy was performed, confirming the suspected diagnosis. Due to the
size and location of the tumor, the Mohs surgeon considered
attempting to shrink the tumor medically prior to surgical excision. Side
effects that were reviewed with the patient included muscle spasms,
hair loss, and taste disturbance. Which of the following medications
was discussed?
A. Vemurafenib
B. Pembrolizumab
C. Vismodegib
D. Imatinib
E. Alemtuzumab
C. Vismodegib
The diagnosis is basal cell carcinoma, which is extensively involving
the lower eyelid and medial canthus.
The gold standard for treatment is surgical excision, preferably Mohs
surgery due to its high cure rate and tissue sparing abilities.
However, because of the possible functional impairment and
cosmetic disfigurement that surgery may present in this case,
treatment with Vismodegib could be considered.
C. Vismodegib
Aberrant Hedgehog pathway signaling due to genetic alterations
play a vital role in the pathogenesis and progression of basal cell
carcinoma.
Vismodegib is a small-molecule inhibitor of the Hedgehog pathway.
It has been approved by the FDA for treatment of adults with
metastatic BCC or locally advanced BCC that recurred after surgical
treatment or for patients who are not candidates for surgery or
radiation.
The most common side effects of vismodegib therapy are muscle
spasms, dysgeusia, and alopecia. Some patients also experience
weight loss, nausea, fatigue, decreased appetite, or diarrhea.
Neoadjuvant vismodegib has been shown to reduce basal cell
carcinoma surgical defect area by 31% if used for at least 3 months.
Therefore, neoadjuvant vismodegib could be considered for large
basal cell carcinomas in functionally and cosmetically sensitive
locations.
Distractors
Each of the other answer choices is a targeted therapy that is
utilized in cutaneous oncology:
Distractors
Vemurafenib
– Used in metastatic melanoma harboring the BRAF V600E
mutation, seen in approximately 50% of all melanomas.
– Selectively inhibits the mutated BRAF V600E kinase. This
reduces signaling through the aberrant mitogen-activated protein
kinase (MAP kinase) pathway.
Distractors
Pembrolizumab
– Highly selective monoclonal antibody against programmed cell
death protein 1 (PD-1).
– PD-1 and its ligands play a major role in regulating immune
response through various mechanisms. When abnormally
expressed by tumor cells and lymphocytes in the
microenvironment, immune evasion by cancer cells can occur.
– Blockade of the abnormal pathway results in tumor growth
suppression and decreased metastasis.
– Pembrolizumab has been effective in treating advanced
melanoma.
Distractors
Imatinib mesylate
– Protein-tyrosine kinase inhibitor that inhibits the BCR-ABL
tyrosine kinase.
– Also has affect against platelet-derived growth factor (PDGF)
and stem cell factor (SCF), c-kit, and inhibits PDGF- and SCFmediated cellular events.
– It can be used in cutaneous oncology for the treatment of
dermatofibrosarcoma protuberans (DFSP) which is
characterized by specific chromosomal abnormalities involving
the platelet derived growth factor B locus (amplified t(17; 22)
translocation or a linear unbalanced t(17; 22) containing the
COL1A1 –PDGFB fusion gene is present).
Distractors
Alemtuzumab
– Humanized monoclonal antibody against the CD52 surface
antigen on multiple immune cells, including T and B
lymphocytes.
– Its use results in the cells harboring the antigen to be depleted
from the blood via antibody dependent cellular cytotoxicity.
– Initially approved for chronic lymphocytic leukemia (CLL) but is
also often effective in erythrodermic mycosis fungoides / Sezary
Syndrome due to depletion of central memory T cells that
predominate in Sezary Syndrome.
Citations
Sekulic A, Migden MR, Lewis K, et al. Pivotal ERIVANCE basal cell carcinoma (BCC)
study: 12-month update of efficacy and safety of vismodegib in advanced BCC. J Am
Acad Dermatol. 72,6: 1021–1026.
Ally MS, Aasi S, Wysong A, et al. An investigator open-label clinical trial of
vismodegib as a neoadjuvant to surgery for high-risk basal cell carcinoma. 71,5: 904–
911.
Sharma A, Shah SR, Illum H, et al. Vemurafenib: targeted inhibition of mutated BRAF
for treatment of advanced melanoma and its potential in other malignancies. Drugs.
3;72(17):2207-22.
McDermott J, Jimeno A. Pembrolizumab: PD-1 ihibition as a therapeutic strategy in
cancer. Drugs Today. 51;1: 7-20.
Labropoulos SF, Razis ED. Imatinib in the treatment of dermatofibrosarcoma
protuberans. Biologics. 1;4: 347-353.
Jawed SI, Myskowski PL, Horwitz S, et al. Primary cutaneous T-cell lymphoma
(mycosis fungoides and Sezary syndrome). Par II. Prognosis, management, and
future directions. J Am Acad Dermatol. 70;2: 223.e1–223.e17.
A 72-year-old male is seen with the following lesion on his left superior
forehead. A saucerization biopsy is performed which confirms in situ
disease. A staged excision is planned. After an initial excision with
5 mm margins, you receive word from the dermatopathologist that the
specimen was positive for in situ disease at the medial margin. Which
of the following histopathological features best describe what the
dermatopathologist has identified?
A. Clusters and single cells within the epidermis with nuclear enlargement with atypia,
prominent nucleoli and well-defined ample cytoplasm. Pagetoid scatter is prominent.
Immunohistochemistry: CK7+ and CAM 5.2+.
B. Poorly circumscribed proliferation of atypical cells with pagetoid scatter. Predominance of
individual melanocytes (over nests) which extend along adnexal epithelium, but do not invade
into the underlying dermis. Immunohistochemistry: S100+, HMB45+, MART-1+.
C. Poorly circumscribed proliferation of atypical cells with pagetoid scatter. Asymmetric nests
of cells with large nuclei and occasional mitoses lack maturation as they descend into the
dermis. Immunohistochemistry: S100+, HMB45+, MART-1+.
D. Full-thickness atypia without maturation in the epidermis that extends along adnexal
structures but does not invade into the dermis. Acanthosis, parakeratosis, mitotic figures, and
occasional pagetoid scatter are present. Immunohistochemistry: pankeratin+, p53+, MART-1-.
E. Epidermal pagetoid scatter overlying lobules of atypical basaloid cell with sebaceous
differentiation. The lobules have infiltrative borders, central necrosis, and frequent mitotic
figures. Immunohistochemistry: EMA+, adipophilin+.
A 72-year-old male is seen with the following lesion on his left superior
forehead. A saucerization biopsy is performed which confirms in situ
disease. A staged excision is planned. After an initial excision with
5 mm margins, you receive word from the dermatopathologist that the
specimen was positive for in situ disease at the medial margin. Which
of the following histopathological features best describe what the
dermatopathologist has identified?
A. Clusters and single cells within the epidermis with nuclear enlargement with atypia,
prominent nucleoli and well-defined ample cytoplasm. Pagetoid scatter is prominent.
Immunohistochemistry: CK7+ and CAM 5.2+.
B. Poorly circumscribed proliferation of atypical cells with pagetoid scatter. Predominance of
individual melanocytes (over nests) which extend along adnexal epithelium, but do not invade
into the underlying dermis. Immunohistochemistry: S100+, HMB45+, MART-1+.
C. Poorly circumscribed proliferation of atypical cells with pagetoid scatter. Asymmetric nests
of cells with large nuclei and occasional mitoses lack maturation as they descend into the
dermis. Immunohistochemistry: S100+, HMB45+, MART-1+.
D. Full-thickness atypia without maturation in the epidermis that extends along adnexal
structures but does not invade into the dermis. Acanthosis, parakeratosis, mitotic figures, and
occasional pagetoid scatter are present. Immunohistochemistry: pankeratin+, p53+, MART-1-.
E. Epidermal pagetoid scatter overlying lobules of atypical basaloid cell with sebaceous
differentiation. The lobules have infiltrative borders, central necrosis, and frequent mitotic
figures. Immunohistochemistry: EMA+, adipophilin+.
A 72-year-old male is seen with the following lesion on his left superior
forehead. A saucerization biopsy is performed which confirms in situ
disease. A staged excision is planned. After an initial excision with
5 mm margins, you receive word from the dermatopathologist that the
specimen was positive for in situ disease at the medial margin. Which
of the following histopathological features best describe what the
dermatopathologist has identified?
A. Clusters and single cells within the epidermis with nuclear enlargement with atypia,
prominent nucleoli and well-defined ample cytoplasm. Pagetoid scatter is prominent.
Immunohistochemistry: CK7+ and CAM 5.2+.
B. Poorly circumscribed proliferation of atypical cells with pagetoid scatter. Predominance of
individual melanocytes (over nests) which extend along adnexal epithelium, but do not invade
into the underlying dermis. Immunohistochemistry: S100+, HMB45+, MART-1+.
C. Poorly circumscribed proliferation of atypical cells with pagetoid scatter. Asymmetric nests
of cells with large nuclei and occasional mitoses lack maturation as they descend into the
dermis. Immunohistochemistry: S100+, HMB45+, MART-1+.
D. Full-thickness atypia without maturation in the epidermis that extends along adnexal
structures but does not invade into the dermis. Acanthosis, parakeratosis, mitotic figures, and
occasional pagetoid scatter are present. Immunohistochemistry: pankeratin+, p53+, MART-1-.
E. Epidermal pagetoid scatter overlying lobules of atypical basaloid cell with sebaceous
differentiation. The lobules have infiltrative borders, central necrosis, and frequent mitotic
figures. Immunohistochemistry: EMA+, adipophilin+.
Correct Answer: B
The image and associated description depict melanoma in situ.
The histopathology of melanoma in situ reveals a poorly
circumscribed proliferation of atypical cells with pagetoid scatter.
There is a predominance of individual melanocytes (over nests)
which extend along adnexal epithelium, but do not invade into the
underlying dermis. Immunohistochemistry: S100+, HMB45+,
MART-1+.
Distractors
All other answer choices describe the
histopathology of other tumors that can
have pagetoid spread in the epidermis.
Distractors
Answer choice A describes Paget’s Disease / Extramammary
Paget’s Disease
– Clusters and single cells within the epidermis with nuclear enlargement with
atypia, prominent nucleoli and well-defined ample cytoplasm. Pagetoid scatter is
prominent. Immunohistochemistry: CK7+ and CAM 5.2+.
Distractors
Answer choice C describes invasive melanoma
– Poorly circumscribed proliferation of atypical cells with pagetoid scatter.
Asymmetric nests of cells with large nuclei and occasional mitoses lack
maturation as they descend into the dermis. Immunohistochemistry: S100+,
HMB45+, MART-1+.
Distractors
Answer choice D describes squamous cell carcinoma in situ
(Bowen’s Disease)
– Full-thickness atypia without maturation in the epidermis that extends along
adnexal structures but does not invade into the dermis. Acanthosis,
parakeratosis, mitotic figures, and occasional pagetoid scatter are present.
Immunohistochemistry: pankeratin+, p53+, MART-1-.
Distractors
Answer choice E describes sebaceous carcinoma
– Epidermal pagetoid scatter overlying lobules of atypical basaloid cell with
sebaceous differentiation. The lobules have infiltrative borders, central necrosis,
and frequent mitotic figures. Immunohistochemistry: EMA+, adipophilin+.
Citations
Higgins HW, Lee KC, Galan A, et al. Melanoma in situ: Part I.
Epidemiology, screening, and clinical features. J Am Acad Dermatol.
73,2:181-190.
Higgins HW, Lee KC, Galan A, et al. Melanoma in situ: Part 2.
Histopathology, treatment, and clinical management . J Am Acad
Dermatol. 73,2:193-203.
Cassarino DS, DeRienzo DP, Barr RJ. Cutaneous squamous cell
carcinoma: a comprehensive clinicopathologic classification – part
one. J Cutaneous Pathology. 33,3:191-206.
Lopes LL, Lopes IM, Lopes LR, et al. Mammary and extramammary
Paget’s disease. An Bras Dermatol. 90,2:225-231.
Ansai S, Hashimoto H, Aoki T, et al. A histochemical and
immunohistochemical study of extra-ocular sebaceous carcinoma.
Histopathology. 22,2: 127-134.
http://idsblinck.blogspot.co.uk/2009_11_01_archive.html
A 62 year-old male presented with the tumor shown below on the right
lower lip. A biopsy confirmed squamous cell carcinoma. Which of the
following characteristics is not considered a high risk tumor feature that
affects staging of cutaneous SCC according to the most recent
American Joint Committee on Cancer Staging Manual (Seventh
Edition)?
A. History of kidney transplant
B. Perineural invasion
C. Location on lip
D. Depth of invasion > 2mm
E. Poorly differentiated histology
A 62 year-old male presented with the tumor shown below on the right
lower lip. A biopsy confirmed squamous cell carcinoma. Which of the
following characteristics is not considered a high risk tumor feature that
affects staging of cutaneous SCC according to the most recent
American Joint Committee on Cancer Staging Manual (Seventh
Edition)?
A. History of kidney transplant
B. Perineural invasion
C. Location on lip
D. Depth of invasion > 2mm
E. Poorly differentiated histology
A 62 year-old male presented with the tumor shown below on the right
lower lip. A biopsy confirmed squamous cell carcinoma. Which of the
following characteristics is not considered a high risk tumor feature that
affects staging of cutaneous SCC according to the most recent
American Joint Committee on Cancer Staging Manual (Seventh
Edition)?
A. History of kidney transplant
B. Perineural invasion
C. Location on lip
D. Depth of invasion > 2mm
E. Poorly differentiated histology
A. History of kidney transplant
Cutaneous squamous cell carcinoma can be locally invasive, but
also has the potential to metastasize to regional lymph nodes or
distant organs.
It is the leading cause of death among skin cancer, which is often a
result of uncontrolled regional disease.
A. History of kidney transplant
Various staging schemes for cutaneous SCC have been developed.
The most recent proposed by the American Joint Committee on
Cancer (Cancer Staging Manual, 7th edition) identifies the following
characteristics of the tumor as high risk features:
– depth/invasion > 2mm thickness
– Clark level ≥ IV
– perineural invasion
– anatomic location (primary site ear, primary site lip)
– differentiation (poorly differentiated or undifferentiated).
A. History of kidney transplant
Immunosuppression (such as solid organ transplantation and history
of CLL) was acknowledged as being associated with worse
outcome, but it does not alter the staging scheme as presented by
the AJCC.
This was done because strict TNM criteria preclude inclusion of
extra-tumoral clinical risk factors in the staging system.
Tumor recurrence is another factor associated with an increased risk
of nodal metastasis but was not included in the AJCC-7.
The National Comprehensive Cancer Network (NCCN Clinical Practice
Guidelines in Oncology) has recently identified a more extensive list of high
risk features that should be considered when evaluating and treating
potentially high-risk cutaneous squamous cell carcinoma.
Citations
Farasat S, Yu SS, Neel VA, et al. A new American Joint Committee
on Cancer staging system for cutaneous squamous cell carcinoma:
Creation and rationale for inclusion of tumor (T) characteristics. J
Am Acad Dermatol. 64;6: 1051-1059.
Navarrete-Dechent C, Vaness MJ, Droppelmann N, et al. High-risk
cutaneous squamous cell carcinoma and the emerging role of
sentinel lymph node biopsy: A literature review. J Am Acad
Dermatol. 73;1: 127–137.
Nuno-Gonzalez A, Vicente-Martin FJ, Pinedo-Moraleda F, et al.
Review: High Risk Squamous Cell Carcinoma. Actas Dermosifiliogr.
103;7: 567-578.
You are treating a 64 year-old female for the two large basal cell
carcinomas shown below. She weighs 68 kg. It has been challenging
to maintain adequate anesthesia and you have frequently had to inject
more 1% lidocaine with epinephrine (1:100,000) throughout the
procedures. You have injected a total of 48 mL of the local anesthetic
when the patient begins to complain of numbness around her mouth
and facial tingling. You suspect early signs of lidocaine toxicity. What
is the recommended safe maximum adult dose of lidocaine with
epinephrine in dermatologic surgery?
A. 2.0 mg/kg
B. 3.0 mg/kg
C. 4.5 mg/kg
D. 7 mg/kg
E. 55 mg/kg
You are treating a 64 year-old female for the two large basal cell
carcinomas shown below. She weighs 68 kg. It has been challenging
to maintain adequate anesthesia and you have frequently had to inject
more 1% lidocaine with epinephrine (1:100,000) throughout the
procedures. You have injected a total of 48 mL of the local anesthetic
when the patient begins to complain of numbness around her mouth
and facial tingling. You suspect early signs of lidocaine toxicity. What
is the recommended safe maximum adult dose of lidocaine with
epinephrine in dermatologic surgery?
A. 2.0 mg/kg
B. 3.0 mg/kg
C. 4.5 mg/kg
D. 7 mg/kg
E. 55 mg/kg
You are treating a 64 year-old female for the two large basal cell
carcinomas shown below. She weighs 68 kg. It has been challenging
to maintain adequate anesthesia and you have frequently had to inject
more 1% lidocaine with epinephrine (1:100,000) throughout the
procedures. You have injected a total of 48 mL of the local anesthetic
when the patient begins to complain of numbness around her mouth
and facial tingling. You suspect early signs of lidocaine toxicity. What
is the recommended safe maximum adult dose of lidocaine with
epinephrine in dermatologic surgery?
A. 2.0 mg/kg
B. 3.0 mg/kg
C. 4.5 mg/kg
D. 7 mg/kg
E. 55 mg/kg
D. 7 mg/kg
The manufacturer maximum recommended dose in adults is 7
mg/kg of lidocaine with epinephrine or 4.5 mg/kg of lidocaine without
epinephrine.
For children, the recommended maximum dose is 3.0-4.5 mg/kg of
lidocaine with epinephrine or 1.5-2.0 mg/kg of lidocaine without
epinephrine.
For tumescent local anesthesia as used for office-based liposuction,
a total lidocaine dose of 55 mg/kg has been shown to be safe.
D. 7 mg/kg
Local anesthetic systemic toxicity (LAST) is manifested by a
progression of central nervous system excitement.
– The first symtpoms a patient experiences are often circumoral
numbness and facial tingling.
– This can be followed by slurred speech, metallic taste, auditory
changes, and hallucinations.
– Hypertension and tachycardia may also be present.
– Severe toxicity can lead to seizures or central nervous system
depression, and the end-stage of a severe case is cardiac failure
or arrest.
Citations
Kouba DJ, LoPiccolo MC, Alam M, et al. Guidelines for the use of
local anesthesia in office-based dermatologic surgery. J Am Acad
Dermatol. 74;6: 1201–1219.
Alam M, Ricci D, Havey J, et al. Safety of peak serum lidocaine
concentration after Mohs micrographic surgery: A prospecrtive
cohort study. J Am Acad Dermatol. 63;1: 87–92.