October 2020 — Head and Neck & Surgical

A 12 year old boy was diagnosed with a cystic lesion of the mandible associated with an impacted tooth. The cyst was curetted and submitted for histopathologic evaluation.

CLICK IMAGE TO SEE: Virtual Microscopy

Which of the following genes harbors oncogenic driver mutations in this lesion?

  • CTNNB1
  • BRAF
  • KRAS
  • PTCH1

The correct answer is...

The correct answer is KRAS.

Adenomatoid odontogenic tumor is a rare benign epithelial odontogenic neoplasm, which most frequently arises in the anterior mandible of young patients and is commonly associated with an impacted tooth 1. Microscopic examination shows a nodular pattern of growth with spindle-shaped or basaloid neoplastic cells and scattered ductular structures2. Driver mutations in KRAS codon 12 (c.35G>T or c.34G>C) can be identified in approximately 70% of those tumors3.

Because of its prospensity for arising in the mandible of young patients and its variable morphologic features, adenomatoid odontogenic tumor has to be differentiated from ameloblastoma, which frequently has driver mutations in BRAF (most commonly BRAF V600E) or CTNNB14.

PTCH1 alterations have been reported to have a role in the pathogenesis of odontogenic keratocyst, a much more common mandibular cystic lesion featuring squamous lining with a characteristic cuboidal basal cell layer.5


References
1. Philipsen HP, Reichart PA. Adenomatoid odontogenic tumour: facts and figures. Oral Oncol. 1999;35:12531.
2. Wright JM, Kusama K. Adenomatoid odontogenic tumour. In: El-Naggar A, Chan JKC, Grandis JR, Takata T, Slootweg PJ, editors. WHO Classification of Head and Neck Tumours. 4th edn. Lyon, France: IARC; 2017. p. 2212.
3. Coura BP, Bernardes VF, de Sousa SF, et al. KRAS mutations drive adenomatoid odontogenic tumor and are independent of clinicopathological features. Mod Pathol. 2019;32(6):799-806.
4. Brown NA, Rolland D, McHugh JB, et al. Activating FGFR2-RAS-BRAF mutations in ameloblastoma. Clin Cancer Res. 2014;20(21):5517-5526.
5. Diniz MG, Borges ER, Guimarães AL, et al. PTCH1 isoforms in odontogenic keratocysts. Oral Oncol. 2009;45(3):291-295. doi:10.1016/j.oraloncology.2008.05.020.

Photo of Kyriakos Chatzopoulos, M.D. Kyriakos Chatzopoulos, M.D.
Resident, Anatomic and Clinical Pathology
Mayo Clinic
Photo of Michael Rivera, M.D. Michael Rivera, M.D.
Consultant, Anatomic Pathology
Mayo Clinic
Assistant Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science

October 2020 — Laboratory Genetics and Genomics

Multiplex ligation-dependent probe amplification (MLPA) testing on a female for Prader Willi/ Angelman syndrome indicates a copy number state double the norm for the critical region with methylation specific probes at a copy number state of approximatly 3 (Figs A and B). There is no clinical phenotype information from the ordering provider.

Click on image to view larger.

What is the best explanation for this unusual pattern?

  • 47,XX,+psu idic(15)(q13.3)mat
  • 47,XX,+ 15/46,XX (mosaic trisomy 15, extra copy is paternal in origen)
  • 47,XX,+psu idic(15)(q13.3)pat
  • 46,XX dup(15)(q11.2-q11.3) (duplication in critical region on maternal allele)

The correct answer is...

The correct answer is 47,XX,+psu idic(15)(q13.3)mat.

Since the copy state at this genomic locus is 4, there must be two additional copies of this region. Since the methylated probe copy state is falling at three, we can infer that three of these copies are methylated and therefore maternally derived.

The MLPA test for Prader Willi / Angeman Synrome only includes probes located in the critical region. However, the best explanation for such an unusual pattern is a pseudoisodicentric 15q arm of maternal origin.

This abnormality is rare but has been reported in the literature in connection with dysmorphic features, intellectual disability, growth deficiency, triangular facies, and brachydactyly [1]. Patients with idic (15) of paternal origin seem to have normal development.


References
1. Szabo A, Czako M, Hadzsiev K, Duga B, Komlosi K, Melegh B. Partial tetrasomy of the proximal long arm of chromosome 15 in two patients: the significance of the gene dosage in terms of phenotype. Mol Cytogenet. 2015;8:41.

Photo of Jaime Lopes, Ph.D. Jaime Lopes, Ph.D.
Resident, Laboratory Genetics and Genomics
Mayo Clinic
Photo of Linda Hasadsri, M.D., Ph.D Linda Hasadsri, M.D., Ph.D.
Consultant, Laboratory Genetics and Genomicsy
Mayo Clinic
Assistant Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science

October 2020 — Hematopathology

A 50-year-old man comes to the office due to progressive lower limb weakness. His past medical history includes diabetes mellitus and erectile dysfunction. On examination, he has hepatosplenomegaly and lower limb edema. Laboratory evaluation shows thrombocytosis. Imaging studies reveal multiple bone sclerotic lesions and moderate pericardial effusion. Bone marrow flow cytometry and immunohistochemistry (CD138) show <5 % lambda-restricted plasma cells. Bone marrow biopsy and aspirate are shown below.

What is the most likely diagnosis?

  • Myeloproliferative neoplasm
  • Waldenström macroglobulinemia
  • Plasma cell myeloma
  • POEMS syndrome

The correct answer is...

The correct answer is POEMS syndrome.

POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein, Skin changes) diagnosis requires the presence of both mandatory criteria (polyneuropathy plus monoclonal plasma cell disorder), plus at least one major criterion (osteosclerotic bone lesion[s], Castleman disease, or elevated serum or plasma vascular endothelial growth factor levels), in addition to at least one minor criterion (endocrine abnormalities, skin changes, organomegaly, extravascular volume overload, thrombocytosis/polycythemia, and papilledema). The patient in the above vignette presented clinically with lower leg weakness (polyneuropathy), monoclonal plasma cells by flow cytometry, osteosclerotic lesions, diabetes mellitus and erectile dysfunction (endocrine abnormalities), hepatosplenomegaly (organomegaly), lower limb edema and pericardial effusion (volume overload), and thrombocytosis - thus fulfilling the diagnostic criteria of POEMS syndrome. On bone marrow (BM) biopsy and aspirate, most POEMS patients with thrombocytosis present with megakaryocytic hyperplasia that may demonstrate megakaryocytic clustering and cytologic atypia as shown above. Other BM findings that, if present with megakaryocytic hyperplasia, may be present in POEMS syndrome is plasma cell rimming around reactive lymphoid aggregates (not shown above).

Myeloproliferative Neoplasm (MPN) is a clonal hematopoietic stem cell disorder characterized by proliferation of one or more of the myeloid cell lines (erythroid, granulocytic, megakaryocytic). Patients usually have a hypercellular bone marrow with megakaryocytic hyperplasia forming clusters, increased peripheral blood counts (thrombocytosis and/or erythrocytosis) and splenomegaly - a presentation similar to the above case vignette. However, the constellation of clinical symptoms that define POEMS syndrome is absent and the presence of the monoclonal gammopathy and clonal plasma cell population are not seen in MPNs. Molecular testing for mutations associated with MPNs (JAK2, CALR, MPL) will be negative in POEMS syndrome in spite of the BM morphology.

Plasma cell myeloma patients usually present with renal insufficiency, hypercalcemia, osteolytic bone lesions (not sclerotic changes), anemia, pathologic fractures, and a >10% plasma cells in the bone marrow along with a monoclonal protein in the serum and/or urine. Megakaryocytic hyperplasia and clustering is not a feature seen on bone marrow biopsy in standard myeloma patients.

Waldenström macroglobulinemia (WM) is lymphoplasmacytic lymphoma with the presence of an IgM monoclonal gammopathy. Patients may have signs and symptoms related to the high IgM levels including hyperviscosity syndrome (blurring or loss of vision, headache, vertigo, etc.), neuropathy, cryoglobulinemia and renal insufficiency. In contrast, patients with POEMS syndrome present with polyneuropathy, monoclonal plasma cell disorder, and other constellation of clinical symptoms (see major and minor criteria in A). Bone marrow and/or lymph node biopsies in WM usually have abnormal lymphoplasmacytic infiltrates. These abnormal cellular infiltrates, along with absence of other the clinical criterion for POEMS syndrome distinguishes both entities.

Solitary plasmacytoma of bone (SPB) patients have a single osteolytic bone lesion, whereas patients with POEMS syndrome usually have multiple osteosclerotic lesions. In addition, the presence of other clinical criterion in POEMS syndrome should help distinguish between these two entities.


References
1. Dao LN, Hanson CA, Dispenzieri A, Morice WG, Kurtin PJ, Hoyer JD. Bone marrow histopathology in POEMS syndrome: a distinctive combination of plasma cell, lymphoid, and myeloid findings in 87 patients. Blood. 2011;117(24):6438-6444. doi:10.1182/blood-2010-11-316935
2. Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15(12):e538-e548. doi:10.1016/S1470-2045(14)70442-5
3. Rajkumar SV. POEMS syndrome. UpToDate. Retrieved July 22 2020 from https://www.uptodate.com/contents/poems-syndrome
4. Tefferi A, Pardanani A. Myeloproliferative Neoplasms: A Contemporary Review. JAMA Oncol. 2015;1(1):97-105. doi:10.1001/jamaoncol.2015.89
5. Soutar R, Lucraft H, Jackson G, et al. Guidelines on the diagnosis and management of solitary plasmacytoma of bone and solitary extramedullary plasmacytoma. Br J Haematol 2004; 124:717.
6. Dimopoulos MA, Panayiotidis P, Moulopoulos LA, Sfikakis P, Dalakas M. Waldenström's macroglobulinemia: clinical features, complications, and management. J Clin Oncol. 2000;18(1):214-226. doi:10.1200/JCO.2000.18.1.214

Photo of Jaime Lopes, Ph.D. Mazen Osman, M.B.,B.Ch.
Resident, Anatomic and Clinical Pathology
Mayo Clinic
Photo of Jaime Lopes, Ph.D. Rebecca King, M.D.
Consultant, Hematopathology
Mayo Clinic
Associate Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science

October 2020 — Gynecological

A 43-year-old woman presented to her primary care provider with irregular vaginal bleeding.

Based on the photomicrographs above, what is the best diagnosis?

  • Normal products of conception
  • Complete hydatidiform mole
  • Partial hydatidiform mole
  • Hydropic abortus

The correct answer is...

The correct answer is complete hydatidiform mole.

A complete hydatidiform mole (CHM) typically presents as heavy vaginal bleeding, β-hCG level out of proportion to normal, and significantly enlarged uterus when compared with gestational age. Histologic examination will demonstrate uniformly large, hydropic villi with central cisterns and karyorrhectic debris within the villous stroma. Additionally, the abnormal villi will have trophoblastic hyperplasia in a concentric distribution, rather than in a polar distribution as would be seen in normal villi.

Partial hydatidiform moles, in contrast to CHM, should have two populations of villi. One population would appear normal and the other would appear large and atypical with syncytiotrophoblastic hyperplasia. Villous blood vessels may have evidence of fetal development with the presence of nucleated red blood cells in circulation1.

Hydropic abortions are typically distinguishable from molar pregnancies from morphologic features, however, due to earlier imaging detection of a molar pregnancy, this distinction may be challenging as the characteristic features of a hydatidiform mole are seen beginning in the second trimester2.

Except in very rare occasions, CHM are known to be a result of diandry (paternal fertilization of an empty egg; monospermic or dispermic), thus lacking maternal genetic material. When the morphologic features are not diagnostic of a CHM, this genetic variation can be helpful in making a definitive diagnosis. CDKN1C/P57 gene is maternally expressed and paternally imprinted (due to methylation), therefore, immunohistochemical stain for p57 will be immunoreactive in maternally derived proteins. In a CHM, p57 reactivity will be lost in the villous stroma and cytotrophoblastic nuclei. Decidua and extravillous intermediate trophoblast will always have nuclear immunoreactivity for p57 and can serve as an internal control1.


References
1. Horii Mariko, Kindelberger David, Quade Bradley, Boyd Theona, Crum Christopher, Parast Mana. (2018).‘Trophoblast Neoplasia’, in Crum, C.P. (ed.) Diagnostic Gynecologic and Obstretic Pathology. Philadelphia: Elsevier. pp. 1103-1136.
2. Rita L. Romaguera, Maria M. Rodriguez, Jocelyn H. Bruce, Tania Zuluaga, Ana Viciana, Manuel A. Penalver* & Mehrdad Nadji (2004) MOLAR GESTATIONS AND HYDROPIC ABORTIONS DIFFERENTIATED BY p57 IMMUNOSTAINING, Fetal and Pediatric Pathology, 23:2-3, 181-190, DOI: 10.1080/15227950490890351

Photo of Elise Venable, M.B.B.S., formerly Elise Roche Elise Venable, M.B.B.S.
Resident, Anatomic and Clinical Pathology
Mayo Clinic
@VenableMBBS
Photo of Maryam Shahi, M.D. Maryam Shahi, M.D.
Senior Associate Consultant, Laboratory Medicine and Pathology
Mayo Clinic

October 2020 — Gastroenterology

A 30 year old woman with history of endometriosis presents to the emergency department with a sudden onset of acute abdominal pain. CT imaging demonstrates a large 20 cm fluid density mass originating in the upper left quadrant of the abdomen.

Figure 1: Gross - Distal pancreas, spleen, and adjacent mass
Figure 2: H&E, 100x
Figure 3: Select immunostains, 100x

What is your diagnosis?

  • Hemangioma
  • Angiomyolipoma
  • Lymphangioma
  • Lymphangiomyoma

The correct answer is...

The correct answer is Lymphangioma.

This lesion consists of variably sized vascular spaces lined by a single layer of endothelial cells which form anastamosing spaces occupied by eosinophilic proteinaceous debris, lymphocytes, and erythrocytes. Also present is an interstitial stroma with fibrosis and lymphoid infiltrate. Rare blood vessels are identified throughout the lesion. The endothelial lining is highlighted by vascular/lymphocytic markers and are HMB45, MelanA, and PAX-8 negative (not shown). These morphologic and immunophenotypic features are consistent with a lymphangioma. A hemangioma would likely contain more abundant smaller vascular spaces; they are also generally better circumscribed. While morphologically consistent with a lymphangiomyoma or angiomyolipoma, these lesions are generally both HMB45 positive.

Lymphangiomas often occur in young children, and the exact pathogenesis is not yet fully determined. They are traditionally classified into four separate categories (capillary, cavernous, cystic, and mixed). Frequently found in more superficial locations, they do rarely occur within the GI tract, most commonly within the small intestine, large intestine, and esophagus. A lymphangioma arising from the pancreas, such as with this lesion, is extremely rare.


References
1. Wiegand, S., Eivazi, B., Barth, P.J., Von Rautenfeld, D.B., Folz, B.J., Mandic, R., Werner, J.A., 2008. Pathogenesis of lymphangiomas. Virchows Archiv.. doi:10.1007/s00428-008-0611-z
2. Karajgikar, J., Deshmukh, S., 2019. Pancreatic Lymphangioma. Journal of Computer Assisted Tomography.. doi:10.1097/rct.0000000000000818
3. Fujii, M., Saito, H., Yoshioka, M., Shiode, J., 2018. Rare Case of Pancreatic Cystic Lymphangioma. Internal Medicine.. doi:10.2169/internalmedicine.9445-17
4. WHO Classification of Tumours of the Digestive System. International Agency for Research on Cancer, 2019.

Photo of Matthew Woge, M.D. Matthew Woge, M.D.
Resident, Surgical 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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