A 71-year-old African American man with a history of prostatic adenocarcinoma presents to his oncologist with low back pain. He was diagnosed with non-resectable prostatic adenocarcinoma 4 years ago. He has undergone radiation therapy and chemotherapy. Over the past 3 months, he has developed constant mild non-radiating low back pain that occasionally wakes him up from sleep. He denies any recent falls or trauma. His past medical history is notable for hypertension, diabetes mellitus, coronary artery disease, and gout. He also has a history of thyroid cancer and underwent thyroidectomy 5 years ago. He takes lisinopril, metoprolol, aspirin, metformin, and allopurinol. He has a 40-pack-year smoking history and drinks alcohol socially. His temperature is 99.2°F (37.3°C), blood pressure is 150/85 mmHg, pulse is 84/min, and respirations are 18/min. On exam, he is well-appearing and in no acute distress. He is mildly tender to palpation along the lumbar vertebral spinous processes. A computerized tomography (CT) scan of the lumbar spine demonstrates a blastic and sclerotic lesion in the L5 vertebral body. Which of the following findings would most likely be seen on a serum study of this patient?
Q242
A 13-year-old boy is brought to his pediatrician for evaluation of leg pain. Specifically, he has been having pain around his right knee that has gotten progressively worse over the last several months. On presentation, he has swelling and tenderness over his right distal femur. Radiographs are obtained and the results are shown in figure A. His family history is significant in that several family members also had this disorder and others had pathology in the eye near birth. The patient is referred for a genetic consult, and a mutation is found on a certain chromosome. The chromosome that is most likely affected also contains a gene that is associated with which of the following pathologies?
Q243
A 32-year-old woman visits her primary care provider with the results of a recent colonoscopy, which was ordered after 3 episodes of rectal bleeding in the last month. Her grandmother, mother, and sister all have been diagnosed with nonpolyposis colorectal cancer, at ages 65, 50, and 40 years, respectively. Colonoscopy for this patient revealed a large, flat, right-sided adenoma. Histopathological examination of the lesion showed villous histology and high-grade dysplasia. Which of the following helps explain the condition of this patient?
Q244
A 58-year-old male undergoes a surveillance colonoscopy in which a 2 cm adenoma is identified and removed. Had this adenoma not been excised, the patient would have been at risk of progression to carcinoma. Which of the following is the final mutational step in the progression from adenoma to carcinoma?
Q245
A 16-year-old male presents to the emergency department complaining of episodes of pounding headache, chest fluttering, and excessive sweating. He has a past history of kidney stones that are composed of calcium oxalate. He does not smoke or drink alcohol. Family history reveals that his mother died of thyroid cancer. Vital signs reveal a temperature of 37.1°C (98.7°F), blood pressure of 200/110 mm Hg and pulse of 120/min. His 24-hour urine calcium, serum metanephrines, and serum normetanephrines levels are all elevated. Mutation of which of the following genes is responsible for this patient's condition?
Q246
A 38-year-old man presents to his primary care practitioner for 2 months of rectal bleeding. He also reports occasional diarrhea and abdominal pain. His family history is relevant for his father and uncle, who died from complications of colorectal cancer. Colonoscopy shows more than 10 colorectal adenomas. Which of the following genes is most likely affected in this patient?
Q247
A 72-year-old man presents to the emergency department with a complaint of rectal bleeding. He describes blood mixed in with the stool, which is associated with a change in his normal bowel habit such that he is going more frequently than normal. He also has some crampy left-sided abdominal pain and weight loss. His symptoms started 2 months ago, but he thought they are due to lack of dietary fiber intake and excess consumption of red meat. He has had type 2 diabetes mellitus for 35 years for which he takes metformin. He also uses daily low-dose aspirin for cardioprotection and occasional naproxen for knee pain. His family history is irrelevant. On examination, his abdomen and digital rectal examination are normal. Colonoscopy shows an ulcerating mucosal lesion with a narrow bowel lumen and biopsy shows a moderately differentiated adenocarcinoma. Which of the following is the greatest risk factor for colorectal cancer in this patient?
Q248
A 62-year-old man seeks evaluation at an outpatient clinic for a single, red, crusty lesion on the shaft of his penis and a similar lesion on the middle finger of his left hand. He recently immigrated to the US from Africa. The lesions are painless and the physicians in his country treated him for syphilis and eczema, with no improvement. He lives with his 4th wife. He smokes 2 packs of cigarette per day and has been doing so for the last 30 years. He is not aware of any family members with malignancies or hereditary diseases. The physical examination is remarkable for an erythematous plaque, with areas of crusting, oozing, and irregular borders on the dorsal surface of the penile shaft and a similar lesion on his left middle finger (shown in the picture). The regional lymph nodes are not affected. A biopsy is obtained and the pathologic evaluation reveals cells with nuclear hyperchromasia, multinucleation, and increased mitotic figures within the epidermis. What is the most likely diagnosis?
Q249
A 35-year-old woman, gravida 2, para 2, comes to the physician with intermenstrual bleeding and heavy menses for the past 4 months. She does not take any medications. Her father died of colon cancer at the age of 42 years. A curettage sample shows dysplastic tall, columnar, cells in the endometrium without intervening stroma. Germline sequencing shows a mutation in the MLH1 gene. Which of the following is the most likely underlying cause of neoplasia in this patient?
Q250
A 45-year-old woman presents with heavy menstrual bleeding between her periods. The patient also complains of experiencing an irregular menstrual cycle, weight loss, bloating, and constipation. She has had 3 uncomplicated pregnancies, all of which ended with normal vaginal deliveries at term. She has never taken oral contraception, and she does not take any medication at the time of presentation. She has no family history of any gynecological malignancy; however, her grandfather and mother had colon cancer that was diagnosed before they turned 50. On physical examination, the patient appears pale. Gynecological examination reveals a bloody cervical discharge and slight uterine enlargement. Endometrial biopsy reveals endometrial adenocarcinoma. Colonoscopy reveals several polyps located in the ascending colon, which are shown to be adenocarcinomas on histological evaluation. Which of the following mechanisms of DNA repair is likely to be disrupted in this patient?
Neoplasia US Medical PG Practice Questions and MCQs
Question 241: A 71-year-old African American man with a history of prostatic adenocarcinoma presents to his oncologist with low back pain. He was diagnosed with non-resectable prostatic adenocarcinoma 4 years ago. He has undergone radiation therapy and chemotherapy. Over the past 3 months, he has developed constant mild non-radiating low back pain that occasionally wakes him up from sleep. He denies any recent falls or trauma. His past medical history is notable for hypertension, diabetes mellitus, coronary artery disease, and gout. He also has a history of thyroid cancer and underwent thyroidectomy 5 years ago. He takes lisinopril, metoprolol, aspirin, metformin, and allopurinol. He has a 40-pack-year smoking history and drinks alcohol socially. His temperature is 99.2°F (37.3°C), blood pressure is 150/85 mmHg, pulse is 84/min, and respirations are 18/min. On exam, he is well-appearing and in no acute distress. He is mildly tender to palpation along the lumbar vertebral spinous processes. A computerized tomography (CT) scan of the lumbar spine demonstrates a blastic and sclerotic lesion in the L5 vertebral body. Which of the following findings would most likely be seen on a serum study of this patient?
A. Increased calcium, decreased phosphate, increased alkaline phosphatase, and increased parathyroid hormone
B. Decreased calcium, decreased phosphate, increased alkaline phosphatase, and increased parathyroid hormone
C. Normal calcium, normal phosphate, increased alkaline phosphatase, and normal parathyroid hormone (Correct Answer)
D. Decreased calcium, increased phosphate, increased alkaline phosphatase, and increased parathyroid hormone
E. Normal calcium, normal phosphate, normal alkaline phosphatase, and normal parathyroid hormone
Explanation: ***Normal calcium, normal phosphate, increased alkaline phosphatase, and normal parathyroid hormone***
- This pattern is characteristic of **osteoblastic metastases** from prostate cancer, where bone formation is increased due to cancerous deposits. The body attempts to compensate by increasing *ALP* (marker of bone turnover) while maintaining normal calcium and phosphate levels through homeostatic mechanisms.
- The **blastic and sclerotic lesion** on CT confirms increased bone formation, which elevates **alkaline phosphatase** (ALP), a marker of osteoblastic activity, while the general calcium and phosphate regulation remains within normal limits.
*Increased calcium, decreased phosphate, increased alkaline phosphatase, and increased parathyroid hormone*
- This profile suggests **primary hyperparathyroidism**, which is typically associated with bone resorption and hypercalcemia, not the blastic lesions seen here.
- While *ALP* can be increased in severe hyperparathyroidism due to increased bone turnover, the combination of **hypercalcemia** and **hypophosphatemia** points away from metastatic prostate cancer.
*Decreased calcium, decreased phosphate, increased alkaline phosphatase, and increased parathyroid hormone*
- This pattern is indicative of **osteomalacia** or **rickets**, where poor mineralization leads to low calcium and phosphate, triggering secondary hyperparathyroidism.
- This is inconsistent with the **sclerotic (blastic)** bone lesions observed in the patient.
*Decreased calcium, increased phosphate, increased alkaline phosphatase, and increased parathyroid hormone*
- This combination points towards **chronic kidney disease** with secondary hyperparathyroidism, where impaired phosphate excretion leads to hyperphosphatemia, causing hypocalcemia and a rise in PTH.
- While *ALP* can be elevated in renal osteodystrophy, the primary bone lesion is typically osteitis fibrosa cystica rather than blastic metastases.
*Normal calcium, normal phosphate, normal alkaline phosphatase, and normal parathyroid hormone*
- This would suggest a **normal bone metabolism** with no significant bone disease or metastatic involvement.
- This contradicts the presence of a **blastic lesion** on CT and the patient's symptoms of low back pain due to metastatic prostate cancer.
Question 242: A 13-year-old boy is brought to his pediatrician for evaluation of leg pain. Specifically, he has been having pain around his right knee that has gotten progressively worse over the last several months. On presentation, he has swelling and tenderness over his right distal femur. Radiographs are obtained and the results are shown in figure A. His family history is significant in that several family members also had this disorder and others had pathology in the eye near birth. The patient is referred for a genetic consult, and a mutation is found on a certain chromosome. The chromosome that is most likely affected also contains a gene that is associated with which of the following pathologies?
A. Pancreatic cancers
B. Colorectal cancer
C. Soft tissue sarcomas
D. Neurofibromas
E. Breast cancer (Correct Answer)
Explanation: ***Breast cancer***
- This clinical scenario describes hereditary retinoblastoma, characterized by **osteosarcoma** (leg pain, distal femur swelling, and tenderness in a young boy), **retinoblastoma** (eye pathology near birth), and a family history.
- The gene mutated in hereditary retinoblastoma is the **RB1 gene**, located on **chromosome 13**. This chromosome also contains the **BRCA2 gene**, which is associated with an increased risk of **breast cancer**.
*Pancreatic cancers*
- While certain genetic mutations can increase the risk of pancreatic cancer (e.g., **BRCA1/2**, PALB2, ATM), the specific gene and chromosome linked to the described primary condition (hereditary retinoblastoma/osteosarcoma) do not directly point to pancreatic cancer as the most strongly associated co-pathology on that same chromosome in the context of the given options.
- The RB1 gene is on chromosome 13, and while BRCA2 (also on chromosome 13) can be associated with pancreatic cancer, breast cancer is a more prominent association for BRCA2.
*Colorectal cancer*
- Colorectal cancer is often associated with mutations in genes like **APC** (familial adenomatous polyposis) on chromosome 5 or **MLH1**, **MSH2** (Lynch syndrome) on other chromosomes, not primarily chromosome 13 in the context of retinoblastoma.
- There is no direct strong link between the RB1 gene/chromosome 13 and colorectal cancer that would make it the most likely answer among the choices.
*Soft tissue sarcomas*
- While retinoblastoma patients have an increased risk of subsequent cancers, including soft tissue sarcomas, the question asks about a pathology associated with a gene on the **same chromosome** as RB1.
- No major gene causing soft tissue sarcomas is primarily located on chromosome 13 and as prominently linked as BRCA2 to breast cancer.
*Neurofibromas*
- Neurofibromas are characteristic of **neurofibromatosis type 1 (NF1)**, caused by a mutation in the **NF1 gene** located on chromosome 17.
- This is a different chromosome and gene entirely from the RB1 gene on chromosome 13.
Question 243: A 32-year-old woman visits her primary care provider with the results of a recent colonoscopy, which was ordered after 3 episodes of rectal bleeding in the last month. Her grandmother, mother, and sister all have been diagnosed with nonpolyposis colorectal cancer, at ages 65, 50, and 40 years, respectively. Colonoscopy for this patient revealed a large, flat, right-sided adenoma. Histopathological examination of the lesion showed villous histology and high-grade dysplasia. Which of the following helps explain the condition of this patient?
A. Chromosomal instability
B. Chemical carcinogenicity
C. DNA hypermethylation
D. Environmental carcinogenicity
E. Microsatellite instability (Correct Answer)
Explanation: ***Microsatellite instability***
- The patient's **family history** of early-onset, **nonpolyposis colorectal cancer** in three first-degree relatives across three generations strongly suggests a **hereditary syndrome**, specifically **Lynch syndrome (HNPCC)**, which is characterized by **microsatellite instability**.
- **Lynch syndrome** results from germline mutations in **DNA mismatch repair genes** (e.g., MLH1, MSH2, MSH6, PMS2), leading to accumulation of mutations in microsatellite regions and increased cancer risk. The patient's large, flat, right-sided adenoma with villous histology and high-grade dysplasia is also typical of Lynch syndrome-associated lesions.
*Chromosomal instability*
- **Chromosomal instability** (CIN) is characteristic of the **adenoma-carcinoma sequence** seen in sporadic colorectal cancer, involving large-scale chromosomal alterations (aneuploidy, translocations, deletions).
- While CIN is common in sporadic colorectal cancers, the strong family history and early onset in this patient point away from the typical CIN pathway as the primary cause.
*Chemical carcinogenicity*
- **Chemical carcinogenicity** refers to cancer development due to exposure to specific chemicals, which is generally associated with sporadic cancers and lacks the clear hereditary pattern seen here.
- While environmental factors can influence cancer risk, the striking familial presentation in this case makes a solely chemical cause unlikely.
*DNA hypermethylation*
- **DNA hypermethylation** of promoter regions leading to gene silencing, particularly the **CpG island methylator phenotype (CIMP)**, is found in both sporadic colorectal cancers and some Lynch syndrome cases (especially those with MLH1 promoter methylation).
- However, **microsatellite instability** is the direct consequence of germline mutations in mismatch repair genes, which is the fundamental defect in Lynch syndrome suggested by the patient's family history.
*Environmental carcinogenicity*
- **Environmental carcinogenicity** broadly refers to cancer caused by external factors such as diet, smoking, or radiation.
- While environmental factors can play a role in all cancers, the strong autosomal dominant inheritance pattern and early onset of nonpolyposis colorectal cancer in this patient's family point towards a specific genetic predisposition rather than solely environmental causes.
Question 244: A 58-year-old male undergoes a surveillance colonoscopy in which a 2 cm adenoma is identified and removed. Had this adenoma not been excised, the patient would have been at risk of progression to carcinoma. Which of the following is the final mutational step in the progression from adenoma to carcinoma?
A. p53 inactivation (Correct Answer)
B. APC mutation
C. COX-2 overexpression
D. SMAD 2/4 loss
E. K-ras mutation
Explanation: ***p53 inactivation***
- **p53 loss of function** is typically the final genetic event in the **adenoma-to-carcinoma sequence**, facilitating unrestricted cell growth and preventing apoptosis in dysplastic cells.
- The **p53 tumor suppressor gene** normally checkpoints cell division and induces programmed cell death, making its inactivation critical for malignant transformation.
*APC mutation*
- **APC (adenomatous polyposis coli) mutation** is often the **initiating event** in colorectal adenoma formation, leading to aberrant crypt foci and polyp formation.
- While critical for early tumor genesis, it does not represent the final step in progression to invasive carcinoma.
*COX-2 overexpression*
- **Cyclooxygenase-2 (COX-2) overexpression** leads to increased prostaglandin production, which can promote cell proliferation, angiogenesis, and inhibit apoptosis.
- It is an important factor in tumor growth and progression but occurs earlier in the sequence and is not the terminal mutational step for carcinoma.
*SMAD 2/4 loss*
- **SMAD 2/4 loss of function** disrupts the **TGF-β signaling pathway**, which normally inhibits cell growth and promotes differentiation.
- This event typically occurs in the late adenoma stage, contributing to dysplasia, but **p53 inactivation** is considered the final critical step for full malignant transformation.
*K-ras mutation*
- **K-ras mutation** is a well-known event in the **adenoma-to-carcinoma sequence**, occurring earlier than p53 inactivation, usually in intermediate-sized adenomas.
- It leads to constitutive activation of the RAS/MAPK pathway, promoting cell growth and survival, but generally before full malignant transformation.
Question 245: A 16-year-old male presents to the emergency department complaining of episodes of pounding headache, chest fluttering, and excessive sweating. He has a past history of kidney stones that are composed of calcium oxalate. He does not smoke or drink alcohol. Family history reveals that his mother died of thyroid cancer. Vital signs reveal a temperature of 37.1°C (98.7°F), blood pressure of 200/110 mm Hg and pulse of 120/min. His 24-hour urine calcium, serum metanephrines, and serum normetanephrines levels are all elevated. Mutation of which of the following genes is responsible for this patient's condition?
A. RET proto-oncogene (Correct Answer)
B. BCL2
C. BRAF
D. BCR-ABL
E. HER-2/neu (C-erbB2)
Explanation: ***RET proto-oncogene***
- The patient's symptoms (pounding headache, chest fluttering, sweating, hypertension, tachycardia), elevated metanephrines, and a history of kidney stones (suggesting **hyperparathyroidism**) combined with a family history of **thyroid cancer** are classic for **Multiple Endocrine Neoplasia type 2A (MEN2A)**.
- **MEN2A** is caused by a germline mutation in the **RET proto-oncogene** and typically involves **medullary thyroid carcinoma**, **pheochromocytoma** (explaining the adrenal symptoms), and **primary hyperparathyroidism**.
*BCL2*
- The **BCL2 gene** is an **anti-apoptotic gene** primarily associated with lymphomas, particularly **follicular lymphoma**, where its overexpression promotes cell survival.
- Mutations or translocations involving BCL2 are not linked to endocrine disorders like MEN2A or the specific combination of symptoms seen in this patient.
*BRAF*
- The **BRAF gene** encodes a protein involved in cell growth signaling and is commonly mutated in various cancers, most notably **melanoma** and **papillary thyroid carcinoma**.
- While associated with thyroid cancer, a BRAF mutation does not explain the pheochromocytoma, hyperparathyroidism, or the specific family history indicative of MEN2A.
*BCR-ABL*
- The **BCR-ABL fusion gene** results from the **Philadelphia chromosome translocation (t(9;22))** and is the hallmark of **chronic myeloid leukemia (CML)** and some cases of acute lymphoblastic leukemia.
- This gene is a potent oncogene in hematopoietic malignancies and has no association with the endocrine tumors or symptoms described in the patient.
*HER-2/neu (C-erbB2)*
- **HER-2/neu (C-erbB2)** is an oncogene that encodes a receptor tyrosine kinase and is primarily associated with **breast cancer** and some **gastric cancers**, where its overexpression indicates a more aggressive tumor and guides targeted therapy.
- This gene is not implicated in the pathogenesis of MEN2A or the constellation of symptoms observed in this patient.
Question 246: A 38-year-old man presents to his primary care practitioner for 2 months of rectal bleeding. He also reports occasional diarrhea and abdominal pain. His family history is relevant for his father and uncle, who died from complications of colorectal cancer. Colonoscopy shows more than 10 colorectal adenomas. Which of the following genes is most likely affected in this patient?
A. RAS
B. TP53
C. hMLH1
D. PPAR
E. APC (Correct Answer)
Explanation: ***APC***
- This patient's presentation with **numerous colorectal adenomas** (over 10), early-onset symptoms (38 years old), and a strong **family history of colorectal cancer** (father and uncle) is highly characteristic of **Familial Adenomatous Polyposis (FAP)**.
- FAP is an **autosomal dominant** condition caused by a germline mutation in the **APC tumor suppressor gene**, leading to the development of hundreds to thousands of adenomatous polyps in the colon, which inevitably progress to colorectal cancer if untreated.
*RAS*
- **RAS mutations** are commonly found in sporadic colorectal cancers and play a role in tumor growth and progression, but they are not typically associated with the **hereditary syndrome of multiple adenomas** seen in this patient.
- RAS activation leads to an increase in **cell proliferation** and can contribute to the development of many cancers, but not as the primary genetic defect in a polyposis syndrome.
*TP53*
- **TP53** is a well-known tumor suppressor gene, and mutations are involved in various cancers, including colorectal cancer (often in its later stages). However, germline mutations in TP53 are associated with **Li-Fraumeni syndrome**, which involves a broad spectrum of early-onset cancers and is not primarily characterized by numerous colonic adenomas.
- TP53 mutations are generally hallmarks of **genomic instability** and are more often seen in the progression of sporadic cancers rather than initiating a polyposis syndrome.
*hMLH1*
- **hMLH1** is a gene involved in **DNA mismatch repair**. Germline mutations in this gene, along with other mismatch repair genes (e.g., MSH2, MSH6, PMS2), are responsible for **Lynch syndrome (hereditary non-polyposis colorectal cancer - HNPCC)**.
- While Lynch syndrome is an important cause of hereditary colorectal cancer, it is characterized by fewer polyps (typically <10) that progress rapidly to cancer, and an increased risk of other cancers (e.g., endometrial), which differs from the presentation of **hundreds of adenomas** seen in FAP.
*PPAR*
- **PPARs (Peroxisome Proliferator-Activated Receptors)** are a group of nuclear receptor proteins that play roles in metabolism, cell differentiation, and inflammation.
- While PPAR pathways have been investigated for their potential role in cancer development and as therapeutic targets, **mutations in PPAR genes are not directly linked** to a common hereditary colorectal cancer syndrome characterized by numerous adenomas like FAP.
Question 247: A 72-year-old man presents to the emergency department with a complaint of rectal bleeding. He describes blood mixed in with the stool, which is associated with a change in his normal bowel habit such that he is going more frequently than normal. He also has some crampy left-sided abdominal pain and weight loss. His symptoms started 2 months ago, but he thought they are due to lack of dietary fiber intake and excess consumption of red meat. He has had type 2 diabetes mellitus for 35 years for which he takes metformin. He also uses daily low-dose aspirin for cardioprotection and occasional naproxen for knee pain. His family history is irrelevant. On examination, his abdomen and digital rectal examination are normal. Colonoscopy shows an ulcerating mucosal lesion with a narrow bowel lumen and biopsy shows a moderately differentiated adenocarcinoma. Which of the following is the greatest risk factor for colorectal cancer in this patient?
A. Lack of dietary fiber intake
B. Low-dose aspirin use
C. Naproxen use
D. Increasing age (Correct Answer)
E. Metformin use
Explanation: ***Increasing age***
- **Age** is the most significant **non-modifiable risk factor** for colorectal cancer, with incidence rising sharply after age 50.
- The patient's age of **72 years** places him in a high-risk category for developing colorectal cancer.
*Lack of dietary fiber intake*
- While a **low-fiber diet** is considered a risk factor for colorectal cancer, its impact is generally less significant compared to age.
- This is a **modifiable risk factor**, and its absence doesn't outweigh the inherent risk associated with advanced age.
*Low-dose aspirin use*
- **Low-dose aspirin** is known to have a **protective effect** against colorectal cancer, particularly with long-term use.
- Therefore, it would *decrease*, rather than increase, the risk in this patient.
*Naproxen use*
- **Naproxen**, an NSAID, is also associated with a **reduced risk** of colorectal cancer.
- Similar to aspirin, its use would generally be considered protective, not a risk factor.
*Metformin use*
- Studies suggest that **metformin**, used for type 2 diabetes, may have a **protective effect** against colorectal cancer.
- This medication is unlikely to be a risk factor and might even contribute to a lower risk.
Question 248: A 62-year-old man seeks evaluation at an outpatient clinic for a single, red, crusty lesion on the shaft of his penis and a similar lesion on the middle finger of his left hand. He recently immigrated to the US from Africa. The lesions are painless and the physicians in his country treated him for syphilis and eczema, with no improvement. He lives with his 4th wife. He smokes 2 packs of cigarette per day and has been doing so for the last 30 years. He is not aware of any family members with malignancies or hereditary diseases. The physical examination is remarkable for an erythematous plaque, with areas of crusting, oozing, and irregular borders on the dorsal surface of the penile shaft and a similar lesion on his left middle finger (shown in the picture). The regional lymph nodes are not affected. A biopsy is obtained and the pathologic evaluation reveals cells with nuclear hyperchromasia, multinucleation, and increased mitotic figures within the epidermis. What is the most likely diagnosis?
A. Bowen's disease (Correct Answer)
B. Bowenoid papulosis
C. Erythroplasia of Queyrat
D. Lichen sclerosus
E. Condyloma acuminata
Explanation: ***Bowen's disease***
- The patient presents with **solitary, erythematous, crusty lesions on the penile shaft and finger**, which are characteristic of Bowen's disease, an in situ squamous cell carcinoma. The histological findings of **nuclear hyperchromasia, multinucleation, and increased mitotic figures within the epidermis** further confirm this diagnosis.
- The **lack of improvement with syphilis and eczema treatments** and the patient's **smoking history** (a risk factor for SCC) support this diagnosis over benign conditions.
*Bowenoid papulosis*
- This condition typically presents as **multiple, small, reddish-brown to violaceous papules**, often in the genital area of younger individuals.
- Unlike Bowen's disease, it is generally considered a **benign or low-grade intraepithelial neoplasia** with a lower risk of progression to invasive cancer.
*Erythroplasia of Queyrat*
- This is a form of **squamous cell carcinoma in situ** that specifically affects the **glans penis or prepuce**, presenting as a well-demarcated, velvety, erythematous patch.
- While histologically similar to Bowen's disease, the patient's lesion is on the **penile shaft and finger**, making Bowen's disease a more encompassing diagnosis for both sites.
*Lichen sclerosus*
- This is a **chronic inflammatory skin condition** characterized by **atrophic, white, sclerotic plaques**, often on the genitals.
- It does not present with the **crusting, oozing, and irregular borders** described, nor the specific histological features of squamous cell carcinoma in situ.
*Condyloma acuminata*
- These are **genital warts caused by HPV**, appearing as soft, flesh-colored, verrucous papules or plaques.
- They typically lack the **crusting, oozing, and histological features of severe atypia and increased mitotic figures** seen in this patient's biopsy.
Question 249: A 35-year-old woman, gravida 2, para 2, comes to the physician with intermenstrual bleeding and heavy menses for the past 4 months. She does not take any medications. Her father died of colon cancer at the age of 42 years. A curettage sample shows dysplastic tall, columnar, cells in the endometrium without intervening stroma. Germline sequencing shows a mutation in the MLH1 gene. Which of the following is the most likely underlying cause of neoplasia in this patient?
A. Inability to excise bulky DNA adducts
B. Defective checkpoint control transitions
C. Impaired repair of deaminated DNA bases
D. Accumulation of double-stranded DNA breaks
E. Instability of short tandem DNA repeats (Correct Answer)
Explanation: ***Instability of short tandem DNA repeats***
- The presence of a **germline mutation in the MLH1 gene**, combined with a family history of early-onset colon cancer (father died at 42), is highly indicative of **Lynch syndrome (hereditary nonpolyposis colorectal cancer or HNPCC)**.
- Lynch syndrome is caused by defects in **DNA mismatch repair (MMR) genes**, such as MLH1, which leads to microsatellite instability (MSI) where **short tandem DNA repeats** accumulate mutations due to inefficient repair.
*Inability to excise bulky DNA adducts*
- This mechanism is characteristic of defects in **nucleotide excision repair (NER)**, often seen in conditions like **xeroderma pigmentosum**, which is typically associated with skin cancers due to UV-induced DNA damage.
- The patient's presentation and MLH1 mutation point specifically to microsatellite instability, not bulky adduct repair.
*Defective checkpoint control transitions*
- Defects in cell cycle checkpoint control lead to uncontrolled cell proliferation and genomic instability, but this is a general mechanism in many cancers and not directly linked to MLH1 or microsatellite instability in the specific way that mismatch repair defects are.
- Mutations in genes like **p53** or **Rb** are classic examples of defective checkpoint controls, which is not the primary defect described by an MLH1 mutation.
*Impaired repair of deaminated DNA bases*
- This refers to defects in **base excision repair (BER)**, which is responsible for correcting small lesions like deaminated bases.
- While critical for DNA integrity, BER defects are not the primary mechanism behind Lynch syndrome and MLH1 mutations, which are specifically involved in correcting errors during DNA replication.
*Accumulation of double-stranded DNA breaks*
- This is typically associated with defects in **homologous recombination** or **non-homologous end-joining pathways**, often seen in conditions like **BRCA1/2 mutations** leading to breast and ovarian cancers.
- MLH1 mutations primarily affect mismatch repair and do not directly lead to an accumulation of double-stranded breaks.
Question 250: A 45-year-old woman presents with heavy menstrual bleeding between her periods. The patient also complains of experiencing an irregular menstrual cycle, weight loss, bloating, and constipation. She has had 3 uncomplicated pregnancies, all of which ended with normal vaginal deliveries at term. She has never taken oral contraception, and she does not take any medication at the time of presentation. She has no family history of any gynecological malignancy; however, her grandfather and mother had colon cancer that was diagnosed before they turned 50. On physical examination, the patient appears pale. Gynecological examination reveals a bloody cervical discharge and slight uterine enlargement. Endometrial biopsy reveals endometrial adenocarcinoma. Colonoscopy reveals several polyps located in the ascending colon, which are shown to be adenocarcinomas on histological evaluation. Which of the following mechanisms of DNA repair is likely to be disrupted in this patient?
A. Mismatch repair (Correct Answer)
B. Homologous recombination
C. Nucleotide-excision repair
D. Non-homologous end joining
E. Base-excision repair
Explanation: ***Mismatch repair***
- The patient's presentation with **endometrial adenocarcinoma** and **synchronous colon adenocarcinomas** (diagnosed before age 50 in multiple family members) is highly suggestive of **Lynch syndrome (hereditary nonpolyposis colorectal cancer or HNPCC)**.
- Lynch syndrome is caused by a germline mutation in one of the **DNA mismatch repair (MMR) genes** (e.g., MLH1, MSH2, MSH6, PMS2), leading to an inability to correct replication errors and resulting in microsatellite instability and cancer development.
*Homologous recombination*
- This pathway is crucial for repairing **double-strand DNA breaks** and is often deficient in cancers associated with **BRCA1/2 mutations**, leading to syndromes like hereditary breast and ovarian cancer.
- While homologous recombination defects can cause cancer, they are not typically linked to the specific constellation of endometrial and colon cancers seen in Lynch syndrome.
*Nucleotide-excision repair*
- This pathway is primarily responsible for repairing bulky DNA lesions, such as those caused by **UV radiation** or certain **chemotherapeutic agents**.
- Defects in nucleotide-excision repair are associated with conditions like **xeroderma pigmentosum**, characterized by extreme sensitivity to sunlight and skin cancers, which is not relevant to this patient's presentation.
*Non-homologous end joining*
- This is another major pathway for repairing **double-strand DNA breaks**, but it is generally considered more error-prone than homologous recombination.
- While defects in this pathway can lead to genomic instability and cancer, it is not the primary mechanism disrupted in Lynch syndrome.
*Base-excision repair*
- This pathway is responsible for removing damaged or modified bases from DNA, often initiated by **oxidative damage or alkylation**.
- While essential for maintaining genomic integrity, defects in base-excision repair are not the characteristic mechanism underlying the cancer predisposition seen in Lynch syndrome.