Pathways Case Studies: February 2023

A 45-year-old Caucasian man with no family history of colon cancer or risk factors just underwent screening colonoscopy. During that colonoscopy, three polyps (endoscopist noted A: 3 mm loop; B: 4 mm loop; C: 9 mm loop) were taken from the right/ascending colon. Pathology found that A was a tubular adenoma with low-grade dysplasia, B was a tubular adenoma with low-grade dysplasia, and C was a tubulovillous adenoma characterized with low-grade dysplasia. 

Figure 1: Colonoscopy Diagram

Using the guideline decision tree, what should be the patient’s follow-up?

  • 7-year colonoscopy
  • 3-year colonoscopy
  • 1-year colonoscopy
  • 6-month colonoscopy

The correct answer is ...

3-year colonoscopy.

As you follow the diagram, you will be led on a path to adenoma type. If you look at the report above, all polyps were removed via loop excision without piecemeal noting. Next, you note that one of the polyps was noted to be tubulovillous, so you progress down. Then you note that there were not greater than 10 polyps on exam, so branch out to the right and you arrive at 3-year follow-up colonoscopy.1 

Another item to note is the documentation of partial polyps and fragmentation of the polyps, which are important in the reporting and patient outcomes. In addition, decision trees similar to the one presented in this case are immensely powerful tools in medicine. They distill knowledge into an easy-to-view format that even non-medical patients can follow. They have been utilized in publications of guidelines for years. They can also be distilled for informaticians, analysts, and engineers into clinical decision support logic for use in an EMR very easily by supplementing the branches into "if/else" logic functions. Some software has even utilized this format for knowledge, automation, and treatment recommendation (Epic and Trisotec).2,3,4


  1. Gupta S, Lieberman D, Anderson JC, et al. Recommendations for follow-up after colonoscopy and polypectomy: a consensus update by the US Multi-Society Task Force on Colorectal Cancer. Gastrointest Endosc. 2020 Mar;91(3):463-485.e5. doi:10.1016/j.gie.2020.01.014
  2. Greenes, R. A. (Ed.). (2014). Clinical decision support: the road to broad adoption. Academic Press.
  3. Epic. (n.d.). Retrieved April 15, 2022, from
  4. Trisotech. (2022, April 11). Retrieved April 15, 2022, from

Jason Greenwood, M.D., M.S.

Fellow, Clinical Informatics
Mayo Clinic Scholar
Mayo Clinic

Justin Juskewitch, M.D., Ph.D.

Senior Associate Consultant, Transfusion Medicine
Mayo Clinic
Assistant Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science

A 63-year-old woman presented with a high WBC count and splenomegaly, but no lymphadenopathy. A bone marrow biopsy showed a subset of the neoplastic cells appear positive for SOX11, focal positive for CD5, negative for cyclin D1 and LEF1 and flow was negative for CD200. The overall clinical, morphologic, and immunophenotypic findings are atypical for either CLL or MCL (Figure 1A, 1B, and 1C). FISH was normal for the CLL panel and the CCND1 and IGH gene regions (Figure 1C). 

Figure 1

What test should be performed next to clarify the diagnosis? 

  • Reperform cyclin D1 stain, as there was likely an error.
  • Chromosome analysis to determine if there is hyperdiploidy.
  • CCND2 FISH probe to rule in a possible cyclin D1-negative MCL.
  • Chromosomal microarray to identify any copy number variants and rule out CLL.

The correct answer is ...

CCND2 FISH probe to rule in a possible cyclin D1-negative MCL.

It is reported that CCND2 rearrangements are the most frequent genetic events in cyclin D1-negative MCL. Therefore, FISH for CCDN2 would be the next best step to clarify the diagnosis.


  1. Salaverria I, Royo C, Carvajal-Cuenca A, et al. CCND2 rearrangements are the most frequent genetic events in cyclin D1(-) mantle cell lymphoma. Blood. 2013 Feb 21;121(8):1394-1402. doi:10.1182/blood-2012-08-452284

Alaa Koleilat, Ph.D.

Fellow, Laboratory Genetics & Genomics
Mayo Clinic

Xinjie Xu, Ph.D.

Consultant, Laboratory Genetics & Genomics
Mayo Clinic
Assistant Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science

A 62-year-old man presented with dysphonia and was found to have a 6 cm right-sided thyroid mass, extending between the trachea and the esophagus, with involvement of the right recurrent laryngeal nerve and esophageal musculature.

Histologic sections showed diffuse involvement of the entire right thyroid lobe by multiple tumor foci (Figures 1-4). Mitotic count was up to 10 mitosis per 2 mm2 and both lymphatic invasion and angioinvasion was present.

Figure 1
Figure 2
Figure 3
Figure 4

What is the most likely diagnosis?

  • Poorly differentiated thyroid carcinoma.
  • Widely invasive follicular thyroid carcinoma.
  • Infiltrative follicular variant papillary thyroid carcinoma.
  • Differentiated high-grade follicular thyroid carcinoma.

The correct answer is ...

Differentiated high-grade follicular thyroid carcinoma.

Differentiated high-grade thyroid carcinoma (DHGTC) belongs to the category of high-grade follicular cell-derived thyroid carcinomas, which was first introduced in the 2022 version of the World Health Organization Classification of Tumours. This category encompasses both DHGTC and poorly differentiated thyroid carcinoma (PDTC). Both of these tumors exhibit high-grade features but do not have anaplastic differentiation. By definition, DHGTC retains the architectural pattern of lower-grade follicular cell-derived carcinomas (papillary, follicular, or solid pattern), but the mitotic count is ≥5 mitosis per 2 mmand/or tumor necrosis is present. On the other hand, diagnosis of PDTC is based on the Turin consensus criteria, which in addition to increased mitotic count and/or tumor necrosis, includes the presence of a solid/trabecular/insular growth pattern as well as the absence of conventional nuclear features of papillary thyroid carcinoma (PTC).

DHGTCs are subclassified according to their histologic features into DHGTC, papillary type or, rarely, DHGTC, follicular type. In our case the overall architectural and cytologic features were those of DHGTC, follicular type, given the follicular growth pattern, absence of cytologic features of PTC, and increased mitotic activity present. The tumor was also widely invasive, which is commonly observed with DHGTC, follicular type.

DHGTCs are aggressive tumors with survival rates in between lower-grade follicular cell-derived carcinomas and anaplastic thyroid carcinoma. The 5-year overall survival of DHGTCs is 50%-70%. Additionally, these tumors have a high frequency of extrathyroidal extension as well as lymph node and distant metastases.

Molecular studies have indicated that DHGTCs develop from lower-grade follicular cell-derived carcinomas. This is supported by the fact that DHGTCs retain mutations that are frequently found in lower-grade carcinomas, such as RAS and BRAFV600E, but they usually acquire additional mutations associated with aggressive behavior, such as TERT promotor mutations. The tumor mutational burden of DHGTCs is also intermediate, between that of lower-grade carcinomas and anaplastic thyroid carcinoma.


  1. WHO Classification of Tumours Editorial Board. Endocrine and neuroendocrine tumours [Internet]. Lyon (France): International Agency for Research on Cancer; 2022 [cited 2022 December 7]. (WHO classification of tumours series, 5th ed.; vol. 10). Available from:
  2. Wong KS, Dong F, Telatar M, Lorch JH, Alexander EK, Marqusee E, Cho NL, Nehs MA, Doherty GM, Afkhami M, Barletta JA. Papillary thyroid carcinoma with high-grade features versus poorly differentiated thyroid carcinoma: an analysis of clinicopathologic and molecular teatures and outcome. Thyroid. 2021 Jun;31(6):933-940. doi:10.1089/thy.2020.0668. Epub 2021 Jan 19. PMID: 33143568.
  3. Xu B, David J, Dogan S, Landa I, Katabi N, Saliba M, Khimraj A, Sherman EJ, Tuttle RM, Tallini G, Ganly I, Fagin JA, Ghossein RA. Primary high-grade non-anaplastic thyroid carcinoma: a retrospective study of 364 cases. Histopathology. 2022 Jan;80(2):322-337. doi:10.1111/his.14550. Epub 2021 Oct 7. PMID: 34449926; PMCID: PMC9425734.
  4. Hiltzik D, Carlson DL, Tuttle RM, Chuai S, Ishill N, Shaha A, Shah JP, Singh B, Ghossein RA. Poorly differentiated thyroid carcinomas defined on the basis of mitosis and necrosis: a clinicopathologic study of 58 patients. Cancer. 2006 Mar 15;106(6):1286-95. doi:10.1002/cncr.21739. PMID: 16470605.

Haukur Einarsson, M.D.

Resident, Anatomic and Clinical Pathology 
Mayo Clinic

Michael Rivera, M.D.

Consultant, Anatomic Pathology
Mayo Clinic
Assistant Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science

A 72-year-old woman presented with progressively worsening right parotid swelling and right neck lymphadenopathy that occurred over a one-month timespan. Computer-tomography demonstrated multiple enlarged right intraparotid and cervical lymph nodes. A FNA of the cervical lymph nodes demonstrated polymorphous lymphocytes and scattered markedly atypical large cells with prominent nuclei. An excisional biopsy of a right neck lymph node, which was noted to be densely adherent to the surrounding soft tissue, was subsequently performed. 

The lymph node architecture was effaced by multifocal collections of large, atypical mononuclear cells (Figure 1). In addition to the stains performed in Figure 1, the large cells were positive for CD163 (weak), cyclin D1, OCT2 (weak in a subset), and showed an increased Ki-67 proliferation index. They were negative for PAX5, CD20, CD3, CD30, CD15, BRAF V600E, EBER, and BCL2. A subset of small residual germinal centers in the background demonstrated the suspicious immunophenotypic findings observed in Figure 2. 

Figure 1
Figure 2

Based on the main finding, what is the most likely diagnosis?

  • Langerhans cell sarcoma.
  • Interdigitating dendritic cell sarcoma.
  • Langerhans cell histiocytosis.
  • Follicular dendritic cell sarcoma.

The correct answer is ...

Langerhans cell sarcoma.

The correct answer is “Langerhans cell sarcoma,” which has also been recognized as malignant histiocytosis with Langerhans phenotype. Morphologically, the neoplasm effaces the lymph node architecture and consists of clusters of large, pleomorphic cells that demonstrate highly irregular nuclear contours, vesicular chromatin, prominent nucleoli, and abundant pale cytoplasm. The immunophenotypic features are those of a histiocytic neoplasm (expressing CD4, CD68, CD163) with a Langerhans cell phenotype, expressing CD1a, Langerin (rare single cells), S100, and ZBTB46 (Figure 1). Many cases of histiocytic and dendritic cell neoplasms show overlapping features due to shared progeny: They are believed to arise from a common myeloid stem cell differentiating towards histiocytic or dendritic cell types. Conversely, many of these neoplasms are associated with a preceding or concurrent lymphoproliferative disorder with which they share immunoglobulin or T-cell receptor rearrangements and chromosomal aberrations, constituting a transdifferentiation event.

In the case presented, the malignant histiocytic component demonstrated a BCL2 rearrangement. Although too minute for definitive FISH analysis, the small residual CD10 and BCL6-positive germinal centers that appear to show aberrant expression of BCL2 (Figure 2) are highly suggestive of in situ follicular neoplasia (ISFN). The suspicion for ISFN coupled with the BCL2 rearrangement (Figure 2) in the histiocytic neoplasm suggests a shared genetic background and that the histiocytic neoplasm is a secondary process resulting from transdifferentiation of a B-cell lymphoma.

Langerhans cell histiocytosis shares immunophenotypic features with our case but would show more bland cytology, including convoluted nuclei with thin nuclear membranes, longitudinal nuclear grooves, and eosinophilic cytoplasm in a background of eosinophils.

Follicular dendritic cell sarcoma cells are derived from mesenchymal stem cells and express CD21, CD23, and CD35 but lack expression of histiocytic and Langerhans cell markers. In addition, they frequently show a spindled cell appearance with interwoven cytoplasmic processes and plump nuclei with prominent nucleoli. Follicular dendritic cell sarcoma has not been shown to be related or consistently associated with other lymphoid neoplasms.

Interdigitating dendritic cell sarcoma is a neoplasm of spindled to ovoid cells with a characteristic phenotype with expression of S100 but lack of CD1a and Langerin. ZBTB46 is a marker that distinguishes dendritic cells from other immune cell lineages, including monocytes, and macrophages. This is especially useful in histiocytic/dendritic neoplasms arising in the context of other hematolymphoid malignancies, which often show ambiguous macrophage/dendritic cell marker expression, and in which ZBTB46 unambiguously establishes dendritic cell lineage.


  1. Medeiros, L.J., Ioachim’s Lymph Node Pathology (Wolters Kluwer Health, 2021) 
  2. Swerdlow et al., WHO classification of tumours of the haematopoietic and lymphoid tissues, IARC, 2017. 
  3. Satpathy AT, Brown RA, Gomulia E, Briseño CG, Mumbach MR, Pan Z, Murphy KM, Natkunam Y, Chang HY, Kim J. Expression of the transcription factor ZBTB46 distinguishes human histiocytic disorders of classical dendritic cell origin. Mod Pathol. 2018 Sep;31(9):1479-1486. doi:10.1038/s41379-018-0052-4. Epub 2018 May 9. PMID: 29743654; PMCID: PMC6138663.

Frido Bruehl, M.D.

Fellow, Hematopathology
Mayo Clinic

Adam Wood, D.O., M.S.

Consultant, Hematopathology
Mayo Clinic
Assistant Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science

The following are H&E and immunohistochemical stains for a tonsil from a 20-year-old man.

Figure 1
Figure 2
Figure 3

What is the most important ancillary study that you would include in your workup for a diagnosis?

  • CD45.
  • FISH analysis for BCL2, BCL6 and MYC rearrangements.
  • EBER in situ hybridization.
  • Immunoglobulin gene rearrangement study.

The correct answer is ...

EBER in situ hybridization.

The H&E sections of tonsil show prominent paracortical expansion by heterogeneous population of lymphocytes, histiocytes, plasma cells, and numerous large immunoblasts including occasional Hodgkin-like cells. A few benign follicles are present. The differential diagnosis based on morphology includes reactive lymphoid proliferation, large cell lymphoma, and classic Hodgkin lymphoma (CHL). These large lymphocytes are B-cells highlighted by CD20 and PAX5. They are also positive for CD30, but negative for CD15. Plasma cells and immunoblasts are polytypic by kappa and lambda light chain immunostaining.

In a setting of a young patient with tonsillar hypertrophy, an acute EBV infection (infectious mononucleosis) needs to be considered. EBER in-situ hybridization stains many small and large lymphocytes. When reviewing this patient’s history, he had a positive Monospot test. A diagnosis of EBV-positive lymphadenitis was rendered.

The phenotype of large lymphocytes does not support of a diagnosis of CHL. Hodgkin cells are typically positive for CD30, CD15 (subset of cases), MUM1, and PAX5 (weak), and are negative for CD20 and CD45. In contrast to EBER positivity in variably sized B-cells of EBV-positive lymphadenitis, EBER expression is limited in Hodgkin cells of CHL. 

It is challenging to differentiate EBV-positive lymphadenitis from EBV-positive diffuse large B-cell lymphoma (EBV+DLBCL) due to morphologic and phenotypic overlap, such as extensive immunoblast proliferation, necrosis, and nodal architecture effacement.1,2,3 Clonal evidence and clinical correlation are required for EBV+DLBCL. Clonal evidence includes immunoglobulin light chain restriction on large cells, evident immunoglobulin gene rearrangements, and cytogenetics and molecular alterations. When encountering a biopsy from a young patient with tonsil and lymphadenopathy in head and neck region with paracortical expansion by increased immunoblasts, an acute EBV infection needs to be investigated before a diagnosis of EBV+DLBCL. 

Acute infectious mononucleosis typically occurs in adolescence and patients may present with asymmetrical lymphadenopathy or tonsilitis. EBV replicates in B-cells, inducing B-cell activation and proliferation. Morphological features that hint to a reactive EBV process include a polymorphous infiltrate consisting of histocytes, lymphocytes, and plasma cells and retained nodal architecture.4 No clonal evidence by flow cytometry, molecular, and cytogenetics/FISH studies is helpful to rule out a neoplastic process. Monospot test, EBV-specific antibodies, and quantitative detection of EBV DNA should be performed clinically.


  1. Salvador AH, Harrison Jr EG, Kyle RA. Lymphadenopathy due to infectious mononucleosis: its confusion with malignant lymphoma. Cancer 1971;27:1029–1040.
  2. Kojima M, Nakamura S, Itoh H, et al Lymph node lesion in infectious mononucleosis showing geographic necrosis containing cytologically atypically B-cells. A case report. Pathol Res Pract 2004;200:53–57.
  3. Childs CC, Parham DM, Berard CW. Infectious mononucleosis. The spectrum of morphologic changes simulating lymphoma in lymph nodes and tonsils. Am J Surg Pathol 1987;11:122–132.
  4. Louissaint, A., Ferry, J., Soupir, C. et al. Infectious mononucleosis mimicking lymphoma: distinguishing morphological and immunophenotypic features. Mod Pathol 25, 1149–1159 (2012).
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Belinda Galeano, M.D., Ph.D.

Resident, Anatomic and Clinical Pathology
Mayo Clinic

Ji (Jane) Yuan, M.D., Ph.D.

Senior Associate Consultant, Hematopathology
Mayo Clinic
Associate Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science

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