Multiple Choice Questions – Northwestern University 11/20/2017

1. Which of the following proteins is typically also upregulated in tumors with a β-catenin mutation?

A. c-KITB. FOXL2C. Cyclin D1D. p53E. BAP1

Correct answer: C

Explanation: Cyclin D1 is a major regulator of the progression of cells into the proliferative stage of the cell cycle. It has been shown to be a direct target for activation by the β-catenin pathway through the LEF-1 binding site on the cyclin D1 promoter. Upregulation of β-catenin, leads to overexpression of cyclin D1 as a result.

Reference:

Shtutman, M. et al. “The cyclin D1 gene is a target of the β-catenin/LEF-1 pathway.” PNAS 1999; 96(10): 5522-5527

2. A patient is found to have a polypoid mass in the left nasal cavity involving the maxillary sinus. The mass is removed surgically, and histological sections reveal a herringbone spindle cell proliferation. Hemangiopericytic vessels are appreciated, as well as areas of proliferation of the surface glandular epithelium. IHC studies show diffuse positivity for S100 and desmin. What is the diagnosis?

A. Synovial sarcomaB. Biphenotypic sinonasal sarcoma

C. Malignant peripheral nerve sheath tumorD. Spindle cell rhabdomyosarcomaE. Inverted papilloma

Correct answer: B

Explanation: Biphenotypic synovial sarcomas are low-grade spindle cell lesions in the nasal cavity. They can have hemangiopericytic vasculature and will often have hyperplasia of the overlying epithelium, imparting an appearance similar to an inverted papilloma. These tumors have combined expression of both neural and myogenic markers, separating them from synovial sarcomas, MPNST’s, and rhabdoid tumors. The diagnosis can be confirmed with FISH or rtPRC for the PAX3-MAML3 fusion protein.

References:

Lewis, JT et al. “Low-grade sinonasal sarcoma with neural and myogenic features: a clinicopathologic analysis of 28 cases.” Am J Surg Pathol. 2012 Apr;36(4):517-25

Wang, X. et al. “Recurrent PAX3-MAML3 Fusion in Biphenotypic Sinonasal Sarcoma.” Nat Genet. 2014 Jul; 46(7): 666–668.

3. Which of the following salivary gland tumors is more commonly found in minor salivary glands?

A. Acinic Cell CarcinomaB. Mammary Analog Secretory CarcinomaC. Mucoepidermoid CarcinomaD. CystadenomaE. Oncocytoma

Correct Answer: D

Explanation: Cystadenomas are more common in minor salivary glands. The other four tumors are more commonly seen in major salivary glands.

Reference:

S. Budnick, R.H.W. Simpson, Cystadenoma, in: A.K. El-Naggar, J.K.C. Chan, J.R. Grandis, T. Takata, P.J. Slootweg (Eds.), World Health Organization Classification of Head and Neck Tumours, IARC Press, Lyon, 2017, p.191.

4. What gene rearrangement FISH can be performed to definitively rule out a mucoepidermoid carcinoma in salivary gland tumors with mucinous differentiation?

A. ETV6B. PLAGC. NTRK3D. CRTC1E. MAML2

Correct Answer: E

Explanation: MAML2 fusions are found in a majority of mucoepidermoid carcinomas. 70% of tumors show the gene partner to be CRTC1.

Reference:

Fujimaki, M et al. “Oncocytic mucoepidermoid carcinoma of the parotid gland with CRTC1-MAML2 fusion transcript: report of a case with review of the literature”. Human Pathology. 2011; 42, 2052-2055.

5. Which of the following is true regarding cervical ectopic pregnancy?

A. Cervical ectopic pregnancies account for 5% of all ectopic pregnancies.B. Hysterectomy is required for the treatment of all patients with cervical ectopic pregnancy.C. There is not a risk of significant hemorrhage with cervical ectopic pregnancy.D. Endometrial damage, leiomyomas, and in vitro fertilization are potential predisposing factors for

cervical ectopic pregnancy.E. None of the above.

Answer: D

Explanation: Cervical ectopic pregnancies account for <1% of all ectopic pregnancies. In the past, due to the association of cervical ectopic pregnancy with significant hemorrhage, it was treated presumptively with hysterectomy. However, improved ultrasound resolution and earlier detection have led to the development of more conservative management. The five treatment categories for cervical ectopic pregnancy include intra-amniotic feticide, systemic chemotherapy with methotrexate, surgical excision by curettage or hysterectomy, tamponade, and reduction of blood supply. Predisposing factors including endometrial damage, leiomyoma, intrauterine devices, in vitro fertilization, and primary embryo anomaly have been implicated in the pathogenesis of cervical ectopic pregnancy. However, the rarity of the condition has prevented retrospective studies, and the association with these factors remains weak.

Reference:

Singh S. Diagnosis and management of cervical ectopic pregnancy. Journal of Human Reproductive Sciences. 2013;6(4):273-276.

6. Which of the following is true regarding placental site trophoblastic tumor (PSTT)?

A. PSTT is thought to develop from neoplastic transformation of cytotrophoblast with differentiation into chorionic-type intermediate trophoblast.

B. Tumor cells invade and replace the muscular wall of blood vesselsC. The immunohistochemical staining pattern shows positivity for p63.D. The Ki-67 proliferation index is <1%.E. None of the above.

Answer: B

Explanation: PSTT is thought to occur due to neoplastic transformation of cytotrophoblast that differentiate into implantation site intermediate trophoblast. In comparison, epithelioid trophoblastic tumor (ETT) demonstrates chorionic-type intermediate trophoblast differentiation. Histology of PSTT shows invasion and replacement of the muscular wall of blood vessels by intermediate trophoblast with fibrinoid material deposition (“transformed” blood vessels). Immunohistochemical staining shows positivity for hPL, a Ki-67 proliferation index of >10%, and negativity for p63. In contrast, immunohistochemical staining of ETT shows positivity for p63 with only focal staining for hPL.

Reference:

Kurman RJ, Hedrick Ellenson L, Ronnett BM. Blaustein's Pathology of the Female Genital Tract. 6th ed. New York, NY: Springer; 2011.

7. Which of the following are features of adenocarcinoma with enteroblastic differentiation?

A. Mucin productionB. Cribriform architectural patternC. Resembles fetal lungD. Contains supranuclear and infranuclear vacuolesE. PAS-D positive

Correct Answer: D

Explanation: Adenocarcinoma with enteroblastic differentiation typically shows columnar cells with prominent clear cytoplasm growing tubular, papillary, and solid patterns. The morphology resembles fetal gut, and the clear cytoplasm is caused by supranuclear and infranuclear vacuoles containing glycogen.

Reference:

Mitsuma, Koko et al. “A case of adenocarcinoma with enteroblastic differentiation of the ampulla of Vater.” Pathology International 2016; 66: 230-235.

8. What stains are used to characterize enteroblastic differentiation?

A. AFP, GPC3, SALL4B. SALL4, AFP, CDX2C. PAS, PAS-D, AFPD. GPC3, CK20, DOG1E. CDX2, PAS, AFP

Correct Answer: A

Explanation: The enteroblastic lineage markers are AFP, GPC3 (both fetal oncoproteins) and SALL4 (embryonic stem cell marker representing fetal gut-like differentiation). PAS and PAS-D can determine if a clear cell contains mucin or glycogen, but this is not enough to determine enteroblastic differentiation. CDX2 stains nuclei of intestinal epithelial cells, so is helpful for determining cellular phenotype. The other stains listed were not used in this case.

Reference:

Murakami, Takashi et al. “Clinicopathologic and immunohistochemical characteristics of gastric adenocarcinoma with enteroblastic differentiation: a study of 29 cases.” Gastric Cancer 19 (2016): 503-505.

9. Which of these is speculated to cause the lymphoid hyperplasia in Micronodular thymoma with lymphoid hyperplasia?

A. Langerhans cellsB. Dendritic cells C. Host response to tumor antigens D. All of the above

Correct Answer: D

Explanation: It has been speculated that the lymphoid hyperplasia present is either a host response to tumor antigens or tissue response to unrelated intrathymic antigens. Zhu et. al. found CD1a+, S100+, langerin positive Langerhans cells (LCs) reside mainly within the epithelial component and progressively mature to dendritic cells (DCs). As they migrate towards the stroma, they form clusters with mature T lymphocytes, thus activating them resulting in lymphoid follicle formation. Ishikawa et. al. compared numbers of LCs and DCs between micronodular thymomas and Type A and Type AB thymomas using antibodies specific to each cell. The results showed that the number of LCs in the tumor epithelium and the number of mature DCs in the tumor stroma were significantly higher in micronodular thymoma than in Type A and Type AB thymomas.

Reference:

Zhu, Pengcheng et al. Langerhans cells proliferation in ectopic micronodular thymoma with lymphoid stroma: a case report. Int J Exp Pathology 2014; 7(10); 7262-7267

10. All of the following are true about micronodular thymic carcinoma with lymphoid hyperplasia except:

A. The epithelial cells are arranged in a nodular patternB. The lymphoid hyperplasia is composed of a mixed population of both T and B lymphocytes C. The epithelial cells within the nodules are bland with no cytologic atypia or mitotic activityD. Patient’s rarely have a history of myasthenia gravis or other autoimmune disorders

Correct Answer: C

Explanation: Micronodular thymic carcinomas with lymphoid hyperplasia patients rarely have a history of myasthenia gravis or any other autoimmune disorders. Microscopically, there are micronodules of epithelial cells set within a lymphoid background with germinal centers and mixed B and T cell lineage. The epithelial cells in the nodules are large, round to oval, with vesicular nuclei and

conspicuous nucleoli. These cells have frankly malignant features consisting of atypia, increased mitosis, and necrosis.

Reference:

Weissferdt, Annikka and Moran, Cesar A. Micronodular thymic carcinoma with lymphoid hyperplasia: a clinicopathological and immunohistochemical study of five cases. Modern Pathology (2012) 25, 993-999.

11. After how long of a lanthanum carbonate therapy course would a dialysis patient expect to see the histologic changes above in the gastric mucosa?

A. DaysB. WeeksC. Months to YearsD. DecadesE. Unable to be determined

Correct Answer: E

Explanation: The amount of lanthanum carbonate deposition in histiocytes of the gastrointestinal tract have not been found to be related to duration or amount of therapy.

Reference:

Shitomi, Y., Nishida, H., Kusaba, T., Daa, T., Yano, S., Arakane, M., Kondo, Y., Nagai, T., Abe, T., Gamachi, A., Murakami, K., Etoh, T., Shiraishi, N., Inomata, M. and Yokoyama, S. (2017), Gastric lanthanosis (lanthanum deposition) in dialysis patients treated with lanthanum carbonate. Pathol Int, 67: 389–397. doi:10.1111/pin.12558

12. What anatomical site is most often involved by lanthanosis?

A. Lymph nodesB. StomachC. Small intestineD. LiverE. Esophagus

Correct Answer: B

Explanation: It is thought that lanthanum carbonate absorption in the gastrointestinal tract is enhanced by its dissolution in an acidic environment. Therefore, since the stomach is most acidic, lanthanum carbonate most easily dissolves here, and re-precipitates in the more alkaline mucosal tissue. The small intestine and colon have more alkaline secretions, making lanthanum deposition there rarer.

Reference:

Shitomi, Y., Nishida, H., Kusaba, T., Daa, T., Yano, S., Arakane, M., Kondo, Y., Nagai, T., Abe, T., Gamachi, A., Murakami, K., Etoh, T., Shiraishi, N., Inomata, M. and Yokoyama, S. (2017), Gastric lanthanosis (lanthanum deposition) in dialysis patients treated with lanthanum carbonate. Pathol Int, 67: 389–397. doi:10.1111/pin.12558