Pathways Case Studies: March 2021

Cardiovascular Pathology
Pulmonary Pathology
Hematopathology Case 1
Hematopathology Case 2
Hematopathology and Laboratory Genetics and Genomics
By MCL Education • March 12, 2021

The patient is a 28-year-old woman from East Africa who presents to the Emergency Department with a three-week history of intermittent chest pain. Work-up reveals a severe ascending aortic aneurysm for which she undergoes a segmental resection with aortic root repair. As a child she had juvenile glaucoma, which was treated surgically. Her father has hyperlipidemia and severe coronary artery disease. Her mother has a history of an aortic aneurysm with aortic root repair.

Figure 1: Area 1 H&E 10x
Figure 2: Area 1 VVG 10x
Figure 3: Area 2 H&E 10x
Figure 4: Area 2 VVG 10x
Figure 5: Area 3 H&E 10x
Figure 6: Area 3 VVG 10x

Given the history and histopathologic findings, what is the most likely underlying etiology of this patient’s aneurysm? 

  • Mutation in fibrillin-1 (FBN1)
  • Spirochetal infection
  • Mutation in transforming growth factor beta-2 (TGFB2)
  • Systemic hypertension

The correct answer is ...

The diagnosis in this case is: Mutation in fibrillin-1 (FBN1).

This patient is most likely to have an aortic aneurysm as a result of Marfan syndrome — a condition caused by a mutation in fibrillin-1, an extracellular matrix protein. Marfan has an incidence of approximately 2-3 per 10,000 individuals and occurs in both familial and sporadic forms. Clinically, patients may exhibit a wide constellation of findings including long limbs, scoliosis, pectus excavatum or carinatum, joint laxity, lens subluxation, and prolapse of the atrioventricular valves. As in this case, patients have a higher incidence of glaucoma and are at an increased risk of developing aortic aneurysms.1 Histologically, aortic resections show medial degeneration and laminar medial necrosis. Historically, this was referred to as a “cystic medial degeneration” — a term that is now out of favor. Normal aortic specimens show three layers of the aortic wall (intima, media, adventia), with the medial layer organized into stacked lamellar units running in parallel. The laminae are composed of elastic tissue, extracellular matrix, smooth muscle cells, and mucopolysaccharides. Medial degeneration is characterized by mucoid extracellular matrix accumulation (MEMA) with elastic fiber thinning and fragmentation.  Laminar medial necrosis is characterized by loss of smooth muscle nuclei, and collapse of elastic fibers.  In Marfan syndrome, the pattern of medial degeneration and laminar medial necrosis can be incredibly severe, with almost complete loss of elastic fibers as is seen in this case (Areas 1 and 2). However, not all of the aortic wall is affected and some non-anuerysmal areas are spared of elastic fiber fragmentation and have normal appearing histomorphology (Area 3). 

MEMA can be subclassified as either translamellar (MEMA-T) or intrlamellar (MEMA-I). In MEMA-T, the extracellular matrix appears as pools or lakes that have expanded and distorted the layers between lamellar units (Area 2). In MEMA-I there is an increase in extracellular matrix without significantly distorting the layered arrangement of lamellar units. While not specific, MEMA-T is observed in several syndromic conditions associated with aortic aneurysms, including Marfan, Ehlers-Danlos, and Turner syndrome. Loeys-Dietz syndrome is a similar connective tissue disorder that is associated with aortic aneurysms and is characterized by mutations of transforming growth factor related proteins (TGFB2, TGFBR1, TGFBR2). While MEMA-T can be seen in Loeys-Dietz patients, the MEMA-I pattern is more closely associated with the syndrome.2

Inflammatory lesions of the aorta can result in aneurysmal changes with a wide variety of inflammatory histologic patterns depending on the underlying etiology (infectious, autoimmune, etc.). Syphillitc aortitis classically shows “tree bark” gross pathology with a characteristic endarteritis obliterans seen histologically. The vessels of the adventia and vasa vasorum are particularly targeted by the inflammatory reaction, leading to ischemic injury to the aorta. Clinically the patients typically present with congestive heart failure and severe cardiomegaly (cor bovinum).3

While systemic hypertension is probably the most common cause of aortic root dilatation and ascending aorta aneurysms, the extent of medial degeneration and laminar medial necrosis is much more attenuated compared to the severe degenerative histopathologic findings in this case.

References

  1. Judge, D. P., & Dietz, H. C. (2005). Marfan’s syndrome. Lancet (London, England), 366(9501), 1965–1976. https://doi.org/10.1016/S0140-6736(05)67789-6
  2. Halushka, M. K., Angelini, A., et al. (2016). Consensus statement on surgical pathology of the aorta from the Society for Cardiovascular Pathology and the Association For European Cardiovascular Pathology: II. Noninflammatory degenerative diseases - nomenclature and diagnostic criteria. Cardiovascular Pathology, 25(3), 247–257. https://doi.org/10.1016/j.carpath.2016.03.002
  3. Stone, J. R., Bruneval, P., et al. (2015). Consensus statement on surgical pathology of the aorta from the Society for Cardiovascular Pathology and the Association for European Cardiovascular Pathology: I. Inflammatory diseases. Cardiovascular Pathology, 24(5), 267-278. https://doi.org/10.1016/j.carpath.2015.05.001
Andrew Layman portrait square

Andrew Layman, M.D.
Fellow, Cardiovascular Pathology
Mayo Clinic

Melanie Bois, M.D.
Senior Associate Consultant, Anatomic Pathology
Mayo Clinic
Assistant Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science

A middle-aged woman underwent a left lung surgical wedge biopsy. 

Figure 1: H&E
Figure 2: High Power VVG

What is the likely diagnosis? 

  • Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) 
  • Constrictive bronchiolitis
  • Organizing pneumonia (OP) 
  • Respiratory bronchiolitis (RB)

The correct answer is ...

The diagnosis in this case is: Constrictive bronchiolitis.

This is a case of constrictive bronchiolitis, which is an uncommon fibrosing small airway disease with a poor prognosis. Patients usually present with an insidious onset of dyspnea and cough over weeks to months. A combination of a pulmonary function test and imaging findings can be helpful in making a diagnosis. A pulmonary function test (PFT) maybe normal or show an obstructive pattern with hyperinflation, which cannot be reversed with bronchodilators. Plain chest radiograph are usually normal. The most consistent imaging abnormality is bronchial wall thickening and expiratory air trapping (mosaic attenuation) seen on inspiratory and expiratory high-resolution computed tomography (HRCT). The etiology of constrictive bronchiolitis varies and includes infection, toxic fumes, drug toxicity, ingestion of Sauropus androgynous juice (used for weight loss), collagen vascular disease and idiopathic.  

At a cursory glance the histological findings of constrictive bronchiolitis may not be readily observed. The defining feature is bronchial wall thickening by subepithelial concentric fibrosis leading to narrowing of the bronchial lumen and in some instances the fibrosis progresses to complete obliteration of the bronchioles. The fibrosis ranges from immature loose collagen mixed with a fibroblastic proliferation or more mature dense acellular collagen. A bronchial and the accompanying pulmonary artery should be similar in size and noticing a significantly smaller bronchial can be a clue to the diagnosis. A Verhoeff-Van Gieson (VVG) stain, pictured above, can highlight expansion between the bronchial lumen and the smooth muscle and in late stage disease highlight the elastic fiber remnants in a completely obliterated bronchial. 

OP is a nonspecific pattern of acute lung injury that can be identified on low power by the characteristic mucopolysaccharide-rich intraluminal fibroblastic plugs within intact alveolar and distal bronchioles. Unlike constrictive bronchiolitis, OP is often associated with accumulation of microvesicle foamy macrophages in the alveolar sacs. OP can be the result of many etiologies that are often inferred based on the clinical setting.

DIPNECH is a clinical diagnosis and the presenting symptoms are similar to constrictive bronchiolitis. The widespread neuroendocrine hyperplasia and carcinoid tumorlets associated with DIPNECH can lead to fibrotic destruction of the bronchioles. Fibrotic stroma with nests of uniform neuroendocrine cells in most cases is easily identified upon microscopic examination. RB is usually an incidental finding present in most current smokers. RB has also been reported in individuals with a remote history of smoking and non-smokers with exposure to second hand smoke. Scattered pigmented macrophages within respiratory bronchioles and the adjacent alveolar parenchyma associated with minimal chronic inflammation and fibrosis is the histologic hallmark of RB.

References

  1. Churg, Andrew and Muller, Nestor. (2020) Atlas of Interstitial Lung Disease Pathology (2nd ed.) Philadelphia, PA: Wolters Kluwer.
  2. Katzenstein, Anna-Luise. (2016) Diagnostic Atlas of Non-Neoplastic Lung Disease. New York, NY: Sringer Publishing Company. 

Lacey Schrader MD portrait square

Lacey Schrader, M.D.
Fellow, Pulmonary Pathology
Mayo Clinic

Joanne Yi, M.D.
Consultant, Anatomic Pathology
Mayo Clinic
Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science

A 74-year-old man is being evaluated for a 2.5 cm well-circumscribed right parotid mass with accompanying regional lymphadenopathy. He has a history of an unspecified immune deficiency disorder, chronic lymphocytic leukemia (diagnosed five years prior), and recurrent MSSA abscesses and cellulitis in the chin, scalp, and chest regions.

Figure 1
Figure 2

Based on morphology from an excisional biopsy of the right parotid gland, what is the most likely diagnosis?

  • Castleman disease
  • Kimura disease
  • Angiolymphoid hyperplasia with eosinophilia (ALHE)
  • Hodgkin disease, mixed cellularity type

The correct answer is ...

The diagnosis in this case is: Kimura disease.

Correct answer: Kimura disease

Kimura disease is a chronic inflammatory disorder that involves subcutaneous tissues and lymph nodes predominantly in the head and neck region and is characterized by angiolymphoid proliferation and eosinophilia. Diffuse eosinophilia, eosinophilic microabscesses, and infiltration of germinal centers, sometimes resulting in folliculolysis, are part of the process. Vascular hyperplasia may be pronounced. Described in 1948, the disease is endemic in Asia an sporadic in the West. Kimura disease is suggestive of an infectious origin, but no pathogen has been demonstrated.

Incorrect: Hodgkin disease, mixed cellularity type

Has in common with Kimura disease eosinophils, plasma cells, and sclerosis, but lacks the hyperplastic germinal centers and deposits of IgE. The presence of Reed-Sternberg cells determines a positive diagnosis.

Incorrect: Angiolymphoid hyperplasia with eosinophilia (ALHE)

Owing to histologic similarities, ALHE has been confused with or mistaken for an early stage of Kimura disease. In contrast with Kimura disease, which is common in Asians, predominantly males, and seated deep in subcutaneous tissues, ALHE is seen in Caucasians, more often in females, involves the superficial skin forming clusters of papules, and is characterized by hypertrophic endothelial cells protruding into or occluding the vascular lumina. More important, the lymphadenopathy is an essential part of Kimura disease and is not present in ALHE.

Incorrect: Castleman disease

This entity includes vascular hyperplasia but lacks eosinophilia and has involuted hyalinized rather than hyperplastic germinal centers.

References

  • Chen, Hong, et al. "Kimura disease: a clinicopathologic study of 21 cases." The American journal of surgical pathology 28.4 (2004): 505-513.
  • Hui PK, Chan JK, Ng CS, Kung IT, Gwi E. Lymphadenopathy of Kimura's disease. The American journal of surgical pathology. 1989 Mar 1;13(3):177-86.
  • Googe, P. B., N. L. Harris, and M. C. Mihm Jr. "Kimura's disease and angiolymphoid hyperplasia with eosinophilia: two distinct histopathological entities." Journal of cutaneous pathology 14.5 (1987): 263-271.
Mazen Atiq MBBS portrait square

Mazen Atiq, M.B.B.S.
Resident, Clinical Pathology
Mayo Clinic

Ellen McPhail, M.D.
Consultant, Hematopathology
Mayo Clinic
Associate Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science

A 47-year-old presented with a right arm lesion that was gradually increasing in size. There is no significant past medical history. Punch biopsy of the lesion was performed. Representative images are shown in Figures 1 and 2.

Figure 1: HE
Figure 2: OCT2

What is your diagnosis?

  • Reactive fibrohistiocytic infiltrate 
  • Rosai-Dorfman disease
  • IgG4 disease
  • Erdheim-Chester disease

The correct answer is ...

The diagnosis in this case is: Rosai-Dorfman disease.

  • Rosai-Dorfman disease (RDD) is a non-Langerhans cell histiocytosis also known as sinus histiocytosis with massive lymphadenopathy. The classic sporadic RDD typically involves the lymph nodes, however, extranodal sites have been reported including skin, bone, nasal cavity, and soft tissue.1 Morphologically, RDD is characterized by emperipolesis (engulfment of lymphocytes by large histiocytes) with expression of CD68, CD163, S100, and negative for CD1a and langerin. Recently, we described a new marker, OCT2, which is a transcription factor that  is expressed in the lesional histiocytes of RDD in >95% of cases (Figure 2, inset shows lesional RDD histiocytes).2 OCT2 expression is usually negative in other histiocytic neoplasms (e.g. Erdheim Chester disease, Langerhans cell histiocytosis).2
  • Erdheim-Chester disease is a non-Langerhans cell histiocytosis and a clonal systemic process with multiorgan involvement and variable clinical outcomes.1 Typical clinical presentation of ECD includes central diabetes insipidus, perinephric fibrosis, and sclerotic bone lesions. The lesional histiocytes strongly express CD68, CD163, Factor 13A. BRAF V600E is positive in a subset of cases.
  • IgG4 disease: The diagnosis of IgG4-related disease rests on the combined presence of the characteristic histopathological appearance, including dense lymphoplasmacytic infiltrate, a storiform pattern of fibrosis, and obliterative phlebitis and increased numbers of IgG4+ plasma cells (varies among affected organs, ranging from 10 to 200 cells/HPF).3
  • Reactive fibrohistiocytic infiltrate: A reactive fibrosis with mixed inflammatory infiltrate, although in the differential, the presence of emperiopolesis and strong OCT2 expression rules out this possibility. The reactive histiocytes are negative for OCT2.2

References

  1. Emile JF, Abla O, Fraitag S, et al. Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages. Blood 2016 Jun 2; 127(22): 2672-2681.
  2. Ravindran A, Goyal G, Go RS and Rech, KL. Rosai-Dorfman Disease Displays a Unique Monocyte-Macrophage Phenotype Characterized by Expression of OCT2. Am J Surg Pathol. 2021 Jan;45(1):35-44
  3. Deshpande V, Zen Y, Chan JK, et al. Consensus statement on the pathology of IgG4-related disease. Mod Pathol. 2012;25(9):1181-1192.
Photo of Aishwarya Ravindran, M.B.B.S.

Aishwarya Ravindran, M.B.B.S.
Resident, Anatomic and Clinical Pathology
Mayo Clinic
@aravindranmd

Photo of Karen Rech, M.D.

Karen Rech, M.D.
Consultant, Hematopathology
Mayo Clinic
Associate Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science
@KarenRechMD

A bone marrow aspirate from a 69-year-old woman with a suspected diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) was received for CLL FISH panel, flow cytometry and immunohistochemistry (IHC) studies. IHC performed on the core biopsy showed CD20+ B cells with co-expression of CD5 and cyclin D1. Flow cytometry demonstrated a kappa light-chain restricted B-cell population, which was positive for CD20 (bright), CD5, and CD45, and negative for CD23 and CD200. A Dual Color Dual Fusion Probe FISH for CCND1/IGH and Break Apart FISH for CCND1 showed signals as presented in the figure. 

Figure 1
Figure 2

What is the most likely interpretation of these results?

  • Evidence of a CCND1/IGH rearrangement and disruption of the CCND1 gene; confirms a mantle cell lymphoma (MCL) diagnosis
  • Evidence of a CCND1/IGH rearrangement and disruption of the CCND1 gene; excludes a a CLL/SLL diagnosis
  • No evidence of a CCND1/IGH rearrangement or disruption of the CCND1 gene region; does not exclude a mantle cell lymphoma (MCL) diagnosis
  • No evidence of a CCND1/IGH rearrangement or disruption of the CCND1 gene region; confirms a CLL/SLL diagnosis

The correct answer is ...

The diagnosis in this case is: No evidence of a CCND1/IGH rearrangement or disruption of the CCND1 gene region; does not exclude a mantle cell lymphoma (MCL) diagnosis.

Mantle cell lymphoma (MCL) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) are mature CD5-positive B-cell neoplasms which may have a similar clinical presentation but different prognosis. MCL generally follows a moderately to highly aggressive clinical course, which portends a poor prognosis for most patients, and requires a different therapeutic approach. Therefore, it is critical to distinguish between MCL and CLL/SLL [1,2].

Several features aid in the distinction of MCL from CLL/SLL, such as flow cytometric immunophenotyping and cytogenetic findings. MCL expresses CD5, bright CD20 and normal/bright (restricted) surface immunoglobulin light chains, but not CD23 and CD200, which are typically positive in CLL/SLL [1]. Furthermore, MCL is associated with upregulation of CCND1 due to a t(11;14)(q13;q32) (CCND1/IGH) translocation present in nearly 95% of cases, and therefore the detection of a CCND1/IGH rearrangement is useful in supporting a diagnosis of MCL in the differential diagnosis of CD5-positive, mature B-cell neoplasms [3].

Fluorescence in situ hybridization (FISH) is the current gold standard assay utilized to identify recurrent cytogenetic alterations in mature B-cell neoplasms. 

IGH/CCND1 rearrangements are typically detected by using a dual-color dual-fusion (D-FISH) strategy. D-FISH probes are used to identify specific translocations. The two genes involved in a translocation, in this case CCND1 and IGH, are labeled in different colors, and the detection of a classic 2-fusion signal confirms a rearrangement. 

In addition to the classic t(11;14), variant translocations involving CCND1 and IGK [t(2;11)] or IGL [t(11;22)] have also been reported [4,5]. In this case, a CCND1 break-apart probe set should be considered, to test whether the gene (or any other gene of interest) is involved in a rearrangement. Break-apart probes target two areas of a specific gene sequence. When the gene sequence is intact (not involved in a rearrangement), the green and red signals result in a fusion signal. Conversely, separation of the green and red signals constitutes evidence that the gene of interest is rearranged. 

When there is a strong suspicion of MCL, e.g. based on positive cyclin D1 IHC staining, but no evidence of CCND1 rearrangement by CCND1/IGH  D-FISH or CCND1 BAP FISH probes, a complex or cryptic rearrangement should be suspected [6]. Therefore, lack of evidence of a CCND1/IGH rearrangement or disruption of the CCND1 gene region does not rule out a diagnosis of MCL and may not necessarily confirm a CLL/SLL, especially in the context of clinical, immunophenotypic and immunohistochemical findings highly suggestive of MCL.

References

  1. Puente XS, Jares P, Campo E. Chronic lymphocytic leukemia and mantle cell lymphoma: crossroads of genetic and microenvironment interactions. Blood. 2018 May 24;131(21):2283-2296. 
  2. Jain P, Wang M. Mantle cell lymphoma: 2019 update on the diagnosis, pathogenesis, prognostication, and management. Am J Hematol. 2019 Jun;94(6):710-725.
  3. Pérez-Galán P, Dreyling M, Wiestner A. Mantle cell lymphoma: biology, pathogenesis, and the molecular basis of treatment in the genomic era. Blood. 2011 Jan 6;117(1):26-38. 
  4. Peterson JF, Meyer RG, Smoley SA, Webley M, Smadbeck JB, Vasmatzis G, Pearce K, Greipp PT, Ketterling RP, Craig FE, Stewart AK, Baughn LB. Whole Genome Mate-pair Sequencing of Plasma Cell Neoplasm as a Novel Diagnostic Strategy: A Case of Unrecognized t(2;11) Structural Variation. Clin Lymphoma Myeloma Leuk. 2019 Sep;19(9):598-602. 
  5. Fuster C, Martín-Garcia D, Balagué O, Navarro A, Nadeu F, Costa D, Prieto M, Salaverria I, Espinet B, Rivas-Delgado A, Terol MJ, Giné E, Forcada P, Ashton-Key M, Puente XS, Swerdlow SH, Beà S, Campo E. Cryptic insertions of the immunoglobulin light chain enhancer region near CCND1 in t(11;14)-negative mantle cell lymphoma. Haematologica. 2020 Aug;105(8):e408-e411. 
  6. Polonis K, Schultz MJ, Olteanu H, Smadbeck JB, Johnson SH, Vasmatzis G, Xu X, Greipp PT, Ketterling RP, Hoppman NL, Baughn LB, Peterson JF. Detection of cryptic CCND1 rearrangements in mantle cell lymphoma by next generation sequencing. Ann Diagn Pathol. 2020 Jun;46:151533. 
Photo of Kyriakos Chatzopoulos, M.D.

Katarzyna Thompson, Ph.D.
Resident, Laboratory Genetics and Genomics
Mayo Clinic

Jess Peterson MD portrait square

Jess Peterson, M.D.
Consultant, Hematopathology
Mayo Clinic
Associate Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science

Horatiu Olteanu, M.D., Ph.D.
Consultant, Hematopathology
Mayo Clinic
Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science
@HoratiuOlteanu

MCL Education

This post was developed by our Education and Technical Publications Team.

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