August 2020 — Genitourinary

A 44-year-old female presented with left flank pain and gross hematuria and was found to have an 11.5 cm mass in the left kidney. Radical nephrectomy was performed and H&E, cytokeratin 7, CD117 immunostains, and chromosomal microarray results are provided.

What is your diagnosis?

  • Low-grade oncocytic tumor (LOT)
  • Chromophobe renal cell carcinoma
  • Oncocytoma
  • Well-differentiated neuroendocrine tumor (carcinoid) of the kidney

The correct answer is...

The correct answer is Chromophobe renal cell carcinoma.

Chromophobe renal cell carcinoma (ChRCC) is the 3rd most common type of renal cell carcinomas, characterized by tumor cells with wrinkled (“koilocytic”) nuclei and distinct cell borders. The eosinophilic variant shows similar nuclear features, often accompanied by perinuclear halos. More than 85% of ChRCC show losses of chromosomes 1, 2, 6, 10, 13, 17, 21 and Y.

This tumor shows nested architecture with peripheral palisading of cells, somewhat resembling the organoid pattern that is often seen in carcinoid tumors. However, no immunohistochemical expression of chromogranin and synaptophysin was identified, excluding this possibility. Tumor morphology as well as strong positivity for both cytokeratin 7 and CD117 (C-KIT) excluded the diagnoses of oncocytoma, that is generally CK7 negative, and CD117 positive. Similarly, recently described low-grade oncocytic tumors of the kidney, that are CK7 positive/ CD117 negative were excluded. However, lack of definitive nuclear features as well as a peculiar peripheral palisading of the tumor cells made the definitive diagnosis of ChRCC challenging.

Chromosomal microarray (CMA) was performed and showed losses of chromosomes 1, 2, 6, 10, 13, 17, 21 and Y thereby supporting the diagnosis of ChRCC.

1. Amin MB et al: Chromophobe renal cell carcinoma: histomorphologic characteristics and evaluation of conventional pathologic prognostic parameters in 145 cases. Am J Surg Pathol. 32(12):1822-34, 2008.
2. Davis CF, Ricketts CJ, Wang M, et al. The somatic genomic landscape of chromophobe renal cell carcinoma. Cancer Cell. 2014;26(3):319-330.
3. Andeen NK, Qu X, Antic T, Tykodi SS, Fang M, Tretiakova MS. Clinical utility of chromosome genomic array testing for unclassified and advanced-stage renal cell carcinomas. Arch Pathol Lab Med. 2019;143(4):494-504.
4. Trpkov, K., Williamson, S. R., Gao, Y., Martinek, P., Cheng, L., Sangoi, A. R., Hes, O. (2019). Low-grade oncocytic tumour of kidney (CD117-negative, cytokeratin 7-positive): a distinct entity? Histopathology, 75(2), 174-184.

Photo of Oleksandr Kravtsov, M.D. Oleksandr Kravtsov, M.D.
Fellow, Surgical Pathology
Mayo Clinic
Photo of Sounak Gupta, M.B.B.S., Ph.D. Sounak Gupta, M.B.B.S., Ph.D.
Senior Associate Consultant, Anatomic Pathology
Mayo Clinic
Assistant Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science

August 2020 — Gynecological

One consulting slide from a 46 year old female with hysterectomy. The outside pathology diagnosis is inactive endometrium, adenomyosis and leiomyomata. But they send in one slide only to ask question about the adenomyosis.

What is your diagnosis?

  • Direct endometroid adenocarcinoma invasion
  • Endometroid adenocarcinoma arising from adenomyosis
  • Complex adenomyosis
  • Classical adenomyosis

The correct answer is...

The correct answer is Endometroid adenocarcinoma arising from adenomyosis

This fits the invasion by "Microcystic, elongated, and fragmented (MELF) glands​" pattern. Because there is no endometroid adenocarcinoma in the endometrium, this case belongs to the endometroid adenocarcinoma arising from adenomyosis.

1. Mayo Clin Proc 1995 Dec;70(12):1137-41. Accuracy of frozen section diagnosis in surgical pathology: review of a 1-year experience with 24,880 cases at Mayo Clinic Rochester. Ferreiro JA, Myers JL, Bostwick DG
2. Virchows Arch. 2019 Nov;475(5):537-549. Recent advances in invasive adenocarcinoma of the cervix. Stolnicu S, Hoang L, Soslow RA.
3. Curr Gastroenterol Rep. 2019 Feb 28;21(4):10. Inflammation and Neoplasia of the Pouch in Inflammatory Bowel Disease. Khan F, Shen B.
4. Rom J Morphol Embryol. 2018;59(1):13-22. Clinicopathological significance and prognostic value of myoinvasive patterns in endometrial endometrioid carcinoma. Amălinei C, Aignătoaei AM, Balan RA, Giuşcă SE, Lozneanu L, Avădănei ER, Căruntu ID.
5. Mod pathol. 2016 Jan;29 Suppl 1:S59-77. Practical issues related to uterine pathology: staging, frozen section, artifacts, and Lynch syndrome. Soslow RA​

Photo of Yilan Li, M.D. Ph.D., M.D. Yilan Li, M.D., Ph.D.
Resident, Anatomic Pathology (2019-2020)
Mayo Clinic
Photo of Amy Clayton. M.D. Amy Clayton, M.D.
Division Chair, Anatomic Pathology
Mayo Clinic
Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science

August 2020 — Molecular

A 4 month-old Caucasian boy with an unremarkable family history was hospitalized for new-onset pancytopenia and was diagnosed with anaplastic anemia of unknown etiology. Additionally, the patient had developmental delays with hypotonia, pancreatic insufficiency and failure to thrive. At age 25 months he was hospitalized for “septic” appearance. Lab values were remarkable for elevated liver function enzymes, blood ammonia levels, and lactic acidemia. A rare inherited condition was suspected and a muscle biopsy was sent for molecular testing (Fig.1).

Which of the following syndromes/diseases best fits the clinical presentation and molecular testing of this patient?

  • Diamond-Blackfan anemia
  • Evans syndrome
  • Pearson syndrome
  • Fanconi anemia

The correct answer is...

The correct answer is Pearson syndrome.

Pearson syndrome is a rare inherited disorder, which is caused by deletion in mitochondrial DNA. Heteroplasmy and extent to which different tissues are affected lead to variable clinical presentation and disease onset. Most common symptoms include transfusion dependent refractory anemia, bone marrow biopsy showing cytoplasmic vacuoles in erythroid precursors, lactic acidosis and pancreatic insufficiency. Molecular studies showing large deletion in mitochondrial DNA are important for diagnosis.

Diamond–Blackfan anemia is a rare syndrome, which is not related to mitochondrial DNA but it is a disease of ribosomal biogenesis and function. Clinical presentation includes short stature, red cell aplasia and increased risk of malignancy.

Fanconi anemia is a rare autosomal recessive bone marrow failure syndrome, which is due to mutations in proteins involved in DNA repair. Major complications are aplastic anemia and high probability for developing of malignancies. Deletion in mitochondrial DNA does not play a role in the pathogenesis.

Evans syndrome is an autoimmune condition that presents with cytopenias, commonly includes autoimmune hemolytic anemia and immune thrombocytopenia. Deletion in mitochondrial DNA does not play a role in the pathogenesis.

1. Jyothi Muni Reddy, Joe Jose, Anand Prakash, Shanthala Devi, Pearson Syndrome: A Rare Inborn Error of Metabolism With Bone Marrow Morphology Providing a Clue to Diagnosis, Sudan J Paediatr. 2019;19(2):161-164
2. Wild KT, Goldstein AC, Muraresku C, Ganetzky RD, Broadening the phenotypic spectrum of Pearson syndrome: Five new cases and a review of the literature. Am J Med Genet A. 2020 Feb;182(2):365-373
3. Sarah Ball, Diamond Blackfan Anemia, Hematology Am Soc Hematol Educ Program 2011;2011:487-91
4. Alter BP, Fanconi anemia and the development of leukemia. Best Pract Res Clin Haematol. 2014 Sep-Dec;27(3-4):214-21
5. Rivalta B et al, Evans Syndrome in Childhood: Long Term Follow-Up and the Evolution in Primary Immunodeficiency or Rheumatological Disease. Front Pediatr. 2019 Jul 23;7:304

Photo of Krasimira (Krasi) Rozenova, M.D., Ph.D Krasimira (Krasi) Rozenova, M.D., Ph.D.
Resident, Anatomic and Clinical Pathology (2019-2020)
Mayo Clinic
Photo of Linda Hasadsri, M.D., Ph.D. Linda Hasadsri, M.D., Ph.D.
Consultant, Laboratory Genetics and Genomics
Mayo Clinic
Assistant Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science

August 2020 — Bone and Soft Tissue, Surgical, Cytogenetics, & Molecular

22-year-old female, gravida 1, para 1, came to ED for evaluation of abdominal pain 7/10 and complaints of constipation for 3 weeks. She was a smoker with a family history of lung cancer. On exam, rectal and uterine adnexa was abnormal (nodularity posterior to uterus, fixed tender). CT scan of chest, abdomen, and pelvis showed multiple large confluent masses, measuring 2.5 cm - 9.3 cm. CT-guided multiple core pelvic biopsies with H&E is showed in the photomicrograph. Immunohistochemical stains were positive for Keratin AE1/AE3 (focally), keratin CAM 5.2 (focally), SALL4, NUTM1 and negative for CD99, SOX10, desmin, PAX8, TTF1, Synaptophysin and OCT4.

What is the diagnosis and gene rearrangement associated with the lesion?

  • Alveolar rhabdomyosarcoma { t(2;13)(q35;q14): PAX3-FOXO1}
  • Ewing sarcoma {t(11;22)(q24;q12) FLI1-EWSR1}
  • Desmoplastic small round cell tumor {t(11;22)(p13; q12) WT1-EWSR1}
  • NUT carcinoma {t(15;19)(q14;p13) NUTM1-BRD4}

The correct answer is...

The correct answer is NUT carcinoma {t(15;19)(q14;p13) NUTM1-BRD4}.

NUT stands for nuclear protein in testis. Formerly called NUT midline carcinoma due to tendency for midline sites, can occur anywhere in the body. ~35% involve the head and neck, most commonly in the sinonasal tract. Although originally described in children it can affect people of all ages. No sex or geographic predilection. Highly aggressive malignancy with median survival of < 1 year.

Highly infiltrative tumor frequently involving multiple anatomic subsites. Nonspecific white-tan cut surface commonly demonstrating prominent necrosis. Histologically defined by primitive monotonous round to oval nuclei with variably prominent nucleoli and areas of abrupt keratinization. Small to medium sized cells with minimal indistinct to clear cytoplasm. High mitotic rate with prominent tumor necrosis. Foci of abrupt squamous differentiation with clear to eosinophilic cytoplasm and keratin pearl formation.

IHC positive for NUT 1, pancytokeratin, EMA, P63/ P40, CD34, INI 1 retained. IHC negative for CD 99, S100, synaptophysin, chromogranin.

Defined by translocations involving the NUT gene on 15q14 with BRD4-NUT (19p13) fusion in 67% of cases. Other cases show BRD3-NUT or NSD3-NUT fusions. Fusions block epithelial differentiation and maintains proliferation in tumor cells. In clinical trials, some patients show rapid response to extra terminal bromodomain inhibitors although prognosis remains poor.

1. Rearrangement of the NUTM1 gene at 15q14 has been observed in NUT midline carcinoma (Bauer et al., Clin Cancer Res 18:5773-5779, 2012).

Photo of Vishnu Serla, M.B.B.S. Vishnu Serla, M.B.B.S.
Resident, Molecular Genetic Pathology
Mayo Clinic
Photo of Jorge Torres-Mora, M.D. Jorge Torres-Mora, M.D.
Consultant, Anatomic Pathology
Mayo Clinic
Assistant Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science

August 2020 — Liver

A 45 year-old male with a history of end stage liver disease and cirrhosis due to Hepatitis C is admitted to the hospital for liver transplant. Pre-transplant imaging did not reveal a mass lesion in the liver, but confirmed subcentimeter nodularity consistent with the patient’s long standing cirrhosis. Alpha-fetoprotein was 75 ng/ml (normal <10ng/ml). Grossly, the explanted liver revealed numerous nodules one centimeter or less in greatest dimension. Multiple nodules were sampled for histopathologic evaluation and are shown below.

Based on the history and photomicrographs, which one of the following diagnoses is correct?

  • Cirrhosis
  • Conventional Hepatocellular Carcinoma
  • Fibrolamellar hepatocellular Carcinoma
  • Cirrhosis-like hepatocellular carcinoma

The correct answer is...

The correct answer is Cirrhosis-like hepatocellular carcinoma.

Cirrhosis-like hepatocellular carcinoma (CL-HCC), also known as cirrhotomimetic hepatocellular carcinoma, is a rare variant of hepatocellular carcinoma occurring in cirrhotic livers. By definition CL-HCC is discovered after transplant during histologic evaluation of the liver explant. CL-HCC is unique in that it does not form a mass lesion unlike conventional hepatocellular carcinoma and instead forms numerous, 20 to >1000, subcentimeter nodules that are radiologically and macroscopically indistinguishable from regenerative nodules of cirrhosis.1-3 The numerous nodules are thought to be due to portal vein invasion leading to hepatic dissemination.4,5 Alpha-fetoprotein serum level is usually normal or only mildly elevated (<200ng/ml) and is equivocal for the diagnosis of hepatocellular carcinoma.

Histologically, CL-HCC demonstrates nodules of tumor cells surrounded by fibrotic bands similar to regenerative nodules in cirrhosis and are seen interspersed between non-neoplastic cirrhotic nodules. The tumor cells are typically well to moderately differentiated and often forming pseudoglandular and/or trabecular architecture. Clear cell change, cholestasis, steatosis, balloon cell change, and Mallory-Denk bodies can also be identified in the tumor cells. Frequent vascular invasion is also seen. The immunophentype of the tumor is similar to conventional hepatocellular carcinoma with positivity for HepPar-1, Arginase, and glypican-3.1,2 Of note, the molecular biology of CL-HCC has not been elucidated.

Treatment for hepatocellular carcinoma usually involves liver transplant for patient’s meeting the Milan criteria. In CL-HCC, patient’s are typically diagnosed after definitive treatment (liver transplant) in the setting of no known metastases. One study found the overall risk of recurrence is 57% with the 1 year and 3 year recurrence free rates being 67% and 50%, respectively. The same study also identified patients with CL-HCC involving <50% of the liver and clear cell change show a statistically better recurrence free survival.2

The differential diagnosis for CL-HCC includes conventional hepatocellular carcinoma, fibrolamellar carcinoma, and cirrhosis. Conventional hepatocellular carcinoma can be ruled out based on the absence of a dominate mass and the detection of the tumor histologically rather than on imaging or macroscopic evaluation. Fibrolamellar carcinoma also demonstrates fibrotic bands within the tumor; however, it also forms a dominate mass. Futhermore, fibrolamellar carcinoma usually occurs in young adults and does not occur in the background of cirrhosis. Finally, CL-HCC needs to be distinguished from cirrhosis based on histomorphology, evidence for lymphovascular invasion, and glypican-3 positivity.

1. Jakate S, Yabes A, Giusto D, et al. Diffuse cirrhosis-like hepatocellular carcinoma: a clinically and radiographically undetected variant mimicking cirrhosis. The American journal of surgical pathology. 2010;34(7):935-941.
2. Clayton EF, Malik S, Bonnel A, et al. Liver transplantation and cirrhotomimetic hepatocellular carcinoma: classification and outcomes. Liver transplantation: official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. 2014;20(7)> 3. Torbenson MS. Morphologic Subtypes of Hepatocellular Carcinoma. Gastroenterology clinics of North America. 2017;46(2):365-391.
4. Okuda K, Noguchi T, Kubo Y, Shimokawa Y, Kojiro M, Nakashima T. A clinical and pathological study of diffuse type hepatocellular carcinoma. Liver. 1981;1(4):280-289.
5. Kanematsu M, Semelka RC, Leonardou P, Mastropasqua M, Lee JK. Hepatocellular carcinoma of diffuse type: MR imaging findings and clinical manifestations. Journal of magnetic resonance imaging : JMRI. 2003;18(2):189-195.

Photo of Benjamin Van Treeck, M.D. Benjamin Van Treeck, M.D.
Resident, Anatomic and Clinical Pathology
Mayo Clinic
Photo of Rondell Graham, M.B.B.S. Rondell Graham, M.B.B.S.
Consultant, Anatomic Pathology
Mayo Clinic
Associate Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science
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