Pathways Case Studies: September 2023

This case is that of a 60-year-old woman with a medical history significant for progressively worsening ventricular function (ejection fraction of 26%), complete heart block, sick sinus rhythm with syncopal episodes, and status post-intracardiac defibrillator placement two years ago. Unfortunately, she was found deceased in bed by her partner, who states she was feeling well and had no acute complaints in the preceding days. The following photos show what was found at autopsy.

Figure 1: Gross image of a short-axis cross section of the left and right ventricles at mid level.
Figure 2: Histologic section of the anterior wall of the left ventricle (Hematoxylin & eosin, 10x original magnification). 
Figure 3: Histologic section of the anterior wall of the left ventricle (Hematoxylin & eosin, 160x original magnification). 

What is the most appropriate diagnosis based on the clinical history and pathologic evaluation? 

  • Cardiac sarcoidosis
  • Arrhythmogenic cardiomyopathy
  • Giant cell myocarditis
  • Acute myocardial infarction

The correct answer is ...

Cardiac sarcoidosis.

This patient’s gross evaluation shows a short axis cross-section of the left and right ventricles. There is near-circumferential and well-demarcated tan-white fibrosis of the left ventricle and interventricular septum that predominately involves the epicardium and extends to involve the mid-myocardium. There is relative sparing of the endomyocardium, although focal areas show transmural involvement. Upon histologic evaluation, there is extensive involvement by non-necrotizing granulomas with prominent lymphohistiocytic inflammation. These findings, along with the clinical history of arrhythmia and progressively worsening cardiac function, are consistent with a diagnosis of cardiac sarcoidosis (CS).

CS is a challenging diagnostic entity, as it may be asymptomatic in a large portion of the affected population. When symptomatic, the presentation may include arrhythmias, conduction system abnormalities, palpitations, chest pain, dyspnea, syncope, heart failure, or sudden death. Clinicians must have a low threshold for considering and evaluating for CS, as imaging can be nonspecific and endomyocardial biopsy can have a low sensitivity given the patchy nature of myocardial involvement. When there is suspicion for CS at the time of explantation or autopsy, especially in the setting of a sudden death, it is important to sample the conduction system well. CS has a predilection for the atrioventricular node and right and left bundle branches, which accounts for the development of conduction system abnormalities and arrhythmias.

The sparing of the endomyocardium lessens the likelihood that this disease process occurred as the result of an ischemic event (i.e., myocardial infarct), which first affect the endomyocardial surface as a watershed area and extend outward. Furthermore, the distribution of the fibrosis does not follow a pattern one would expect after an ischemic event in one of the three major coronary arteries, as there are patchy affected areas even within the distribution of the individual coronary arteries.

While giant cell myocarditis (GCM) is in the differential for an individual with giant cell inflammation in the myocardium, there are several features that decrease the likelihood of the diagnosis in this case. Clinically, it would be uncommon for GCM to occur in someone who was asymptomatic or had slowly progressive cardiac dysfunction over a several year period. The clinical progression for someone with GCM is profoundly rapid and the prognosis is poor. The histologic presentation tends to have an abundance of eosinophils, which are thought to be the main etiology of the widespread myocardial injury and subsequent cardiac dysfunction. While there are some eosinophils in the inflammatory infiltrate in this case, they make up a small percentage of the overall inflammation. 

Lastly, given the clinical history of arrhythmia and the presentation with sudden death, arrhythmogenic cardiomyopathy (AC) is also a reasonable differential diagnosis. The gross and histologic findings for AC, however, differ from CS in that one will typically expect to find a dilated right ventricle with fibrofatty replacement of the ventricular wall. The fibrofatty replacement may be patchy or diffuse, and left ventricular involvement is subepicardial. The interventricular septum is typically spared. Of note, while this was previously referred to as arrhythmogenic right ventricular cardiomyopathy, newer data shows that the involvement often is equally represented between both ventricles or may involve the left ventricle alone.


  1. Burke A, Aubry MC, Maleszewski J, Alexiev B, Tavora F. (2017). Practical thoracic pathology: diseases of the lung, heart, and thymus. Wolters Kluwer. 
Square photo of Philip Hurst

Philip Hurst, M.D.

Fellow, Anatomic & Clinical Pathology
Mayo Clinic

Melanie Bois, M.D.

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

A 55-year-old man was referred for pancytopenia with several months of increasing fatigue and increased frequency in infections. FISH studies, chromosomal analysis, and flow cytometry are shown in Figure 1, Figure 2, and Figure 3, respectively. Histopathologic findings on peripheral blood demonstrated atypical promyelocytes with kidney shaped nuclei, purple cytoplasm, and Auer rods. On banded analysis, of 20 metaphases, 12 demonstrated the abnormality highlighted by arrows in Figure 2. T-cell gene rearrangement and eosinophil panel were both negative. 

Figure 1: FISH studies
Figure 2: Chromosomal analysis
Figure 3: Flow cytometry

Based on histopathologic evaluation and supplementary studies, what is the most likely diagnosis?

  • Acute lymphoblastic leukemia
  • Acute myeloid leukemia with monocytic differentiation
  • Acute promyelocytic leukemia
  • Acute basophilic leukemia

The correct answer is ...

Acute promyelocytic leukemia.

Flow cytometry (images above) identified blasts that express CD34 (dim), CD45 (dim), CD13, CD15 (dim), CD33, CD117, signifying a myeloid differentiation. The FISH studies and chromosomal analysis (images above) both demonstrate a translocation between chromosomes 15 and 17, more specifically t(15;17)(q24.1;q21.2)​. These in combination with the histomorphology features are diagnostic of acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML) that has abnormal maturation of promyelocytes. It is defined by its fusion of the PML gene and the RARA gene mostly by t(15;17)(q24.1;q21.2)​. APL typically occurs in the age range of 20-59 and represent about 5%-8% of AML in younger patients.(2,4) Histologic features show bilobed or kidney-shaped nuclei and Auer rods. Cytoplasm can be bright pink, red, or purple. Patients with this diagnosis have a 10%-20% risk of relapse. 

APL can have a variety of clinical manifestations including weakness, fatigue, infection, or pancytopenia. It is important for APL to be diagnosed and treated quickly, as one of the most important complications to be aware of is the risk of coagulopathy and disseminated intravascular coagulation, which can lead to death if untreated.


  1. Acute promyelocytic leukaemia (APL) side effects. Blood Cancer UK. Accessed May 23, 2023. ​
  2. Amoth H, Perry AM. APL with PML::RARA. website. Accessed May 19, 2023.​
  3. Jimenez JJ, Chale RS, Abad AC, Schally AV. Acute promyelocytic leukemia (APL): a review of the literature. Oncotarget. 2020;11(11):992-1003. Published 2020 Mar 17. doi:10.18632/oncotarget.27513.​
  4. Platzbecker U, Khoury J, Akkari Y, et al. Myeloid proliferation and neoplasms. In: WHO Classification of Tumours Editorial Board. Haematolymphoid tumours [Internet; beta version ahead of print]. Lyon (France): International Agency for Research on Cancer; 2022 [cited 2023 05 16]. (WHO classification of tumours series, 5th ed.; vol. 11). Available from:​

Nadarra Stokes, M.D.

Resident, Anatomic & Clinical Pathology
Mayo Clinic

Xinjie Xu, Ph.D.

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

A 4 cm well-circumscribed intramuscular mass was incidentally identified within the right psoas muscle of a 68-year-old man who was undergoing workup for elevated PSA. This fusiform mass demonstrated a globular enhancement pattern and showed no obvious intralesional fat on T1 images. The patient denied any weakness or pain with flexion of the right hip. Orthopedic oncology was consulted, and targeted right psoas muscle mass biopsy (combined FNA/core biopsy) was performed.

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Figure 7

What is the best diagnosis based upon combined cytomorphology, core histomorphology, clinical setting and imaging findings? 

  • Metastatic mucinous adenocarcinoma of gastric origin
  • Intramuscular myxoma
  • Myxoid chondrosarcoma
  • Myxoid liposarcoma

The correct answer is ...

Intramuscular myxoma.

Papanicolaou-stained direct smears showed a paucicellular spindle cell proliferation with myxoid and finely fibrillar background material. The lesional cells showed low nuclear/cytoplasmic ratios and were cytologically bland with small, elongated nuclei and bipolar cytoplasmic processes. No significant pleomorphism, cellular atypia, or necrosis was evident. Hematoxylin and eosin-stained core biopsy histology slides showed findings identical to the smears, confirming a hypocellular and hypovascular lesion comprised of bland spindle cells lacking atypia and dispersed in variably fibrillar to myxoid backgrounds. Entrapped skeletal muscle fibers were focally noted. As in the cytology, characteristic long and slender cytoplasmic processes were noted. The combined clinical setting, imaging findings, cytomorphology, and core histomorphology were those of an intramuscular myxoma.

Intramuscular myxomas are most often diagnosed in middle-aged to older individuals (40–70 years) and are more common in females (M:F ratio: ~0.3:1). Most lesions are sporadic, but a minority are associated with fibrous dysplasia, which is most often polyostotic (Mazabraud syndrome). Clinical features are only occasionally sufficient to distinguish benign from malignant tumors of soft tissue. Most soft tissue sarcomas of the extremities and trunk present as a large, painless, incidentally noted mass that patients sometimes associate with an episode of injury. Conversely, some patients present with rapidly growing tumors that are occasionally painful, leading to a rapid medical opinion. The seemingly innocent presentation and the rarity of sarcomas often leads to their initial misinterpretation as benign conditions. All superficial soft tissue lesions measuring >5 cm, and all deep-seated lesions, are statistically likely to be sarcomas. Intramuscular myxoma is an exception to this rule. It is a benign but deep-seated soft tissue lesion. Classic intramuscular myxoma is typically a nonrecurrent tumor, whereas the cellular subtype has a small risk for local nondestructive recurrence. Malignant transformation does not occur.

The differential diagnosis of intramuscular myxoma is subdivided into three categories, including nonneoplastic conditions, benign neoplasms, and malignancies. Relevant nonneoplastic differentials include intramuscular ganglion cyst and focal mucinosis. Potential benign neoplastic conditions in the differential diagnosis include myxoid nerve sheath tumors, myxoid leiomyomata, and angiomyxomas. Malignant differential diagnostic entities include diseases such as malignant peripheral nerve sheath tumor, low-grade fibromyxoid sarcoma, myxoid chondrosarcoma, myxoid liposarcoma, and metastatic mucinous carcinomas.

The current case lacks the branching capillary vasculature and lipoblasts expected in myxoid liposarcoma. The myxoid backgrounds in this case should not be mistaken for epithelial mucin, and no floating neoplastic epithelial cells or cell groups are present, making the diagnosis of a metastatic mucinous carcinoma unlikely. Myxoid chondrosarcomas arising in extraskeletal locations would typically show polygonal or oval lesional cells arranged in clusters and cords and dispersed in myxoid backgrounds. The majority of intramuscular myxomas are associated with GNAS1 mutations, while different molecular/genetic findings would be expected in the various entities in the differential diagnosis.


  1. Enzinger FM. Intranmuscular myxoma; a review and follow-up study of 34 cases. Am J Clin Pathol. 1965; 43:104-113. doi:10.1093/ajcp/43.2.104
  2. Ireland DC, Soule EH, Ivins JC. Myxoma of somatic soft tissues. A report of 58 patients, 3 with multiple tumors and fibrous dysplasia of bone. Mayo Clin Proc. 1973;48(6):401-410.
  3. Nielsen GP, O'Connell JX, Rosenberg AE. Intramuscular myxoma: a clinicopathologic study of 51 cases with emphasis on hypercellular and hypervascular variants. Am J Surg Pathol. 1998;22(10):1222-1227. doi:10.1097/00000478-199810000-00007
  4. Van Roggen JF, McMenamin ME, Fletcher CD. Cellular myxoma of soft tissue: a clinicopathological study of 38 cases confirming indolent clinical behavior. Histopathology. 2001;39(3):287-297. doi:10.1046/j.1365-2559.2001.01209.x
  5. Majoor BCJ, van de Sande MAJ, Appelman-Dijkstra NM, et al. Prevalence and Cclinical features of Mazabraud syndrome: a multicenter European study. J Bone Joint Surg Am. 2019;101(2):160-168. doi:10.2106/JBJS.18.00062
  6. Casali PG, Blay JY; ESMO/CONTICANET/EUROBONET Consensus Panel of experts. Soft tissue sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up [published correction appears in Ann Oncol. 2010 Aug;21(8):1736] [published correction appears in Ann Oncol. 2010 Aug;21(8):1736]. Ann Oncol. 2010;21 Suppl 5:v198-v203. doi:10.1093/annonc/mdq209
  7. Margaret von Mehren M, Randall RL, Benjamin RS, et al. Soft Tissue Sarcoma, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2018;16(5):536-563. doi:10.6004/jnccn.2018.0025
  8. Layfield LJ, Dodd L, Klijanienko J. Myxoid neoplasms of bone and soft tissue: a pattern-based approach. J Am Soc Cytopathol. 2021;10(3):278-292. doi:10.1016/j.jasc.2020.09.009
  9. Wakely PE Jr, Jin M. Myxoid liposarcoma: Fine-needle aspiration cytopathology in the molecular era. A report of 24 cases, J Am Soc Cytopathol. Volume 5, Issue 3, 2016, Pages 162-169, ISSN 2213-2945,
  10. Satturwar S, Wakely PE Jr, Pantanowitz L. Approach to FNA of Myxoid Soft Tissue Tumors. Adv Anat Pathol. 2022 Nov 1;29(6):380-388. doi:10.1097/PAP.0000000000000354. 
  11. WHO Classification of Tumors: Soft Tissue and Bone Tumours (5th ed.)

Mariana Usatii, M.D., C.M., M.S.

Fellow, Cytopathology 
Mayo Clinic

Charles Sturgis, M.D.

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

Chromosomal microarray analysis was performed on amniotic fluid from a 32-year-old woman at 14 weeks gestation. A 6.2 megabase deletion from 15q11.2 to 15q13.1 was identified, consistent with results from a cell-free DNA prenatal screen. This heterozygous deletion was confirmed by fluorescent in situ hybridization.

Figure 1

Based upon these results, what is the most appropriate interpretation and next step?

  • This data confirms the presence of a pathogenic heterozygous deletion on chromosome 15q that is incompatible with life. No further testing is recommended.
  • This data confirms the presence of a pathogenic heterozygous deletion on chromosome 15q in the fetal DNA that is associated with two disparate genetic diseases (Prader-Willi syndrome and Angelman syndrome). Methylation testing is recommended to determine which disease is affecting the fetus.
  • This data confirms the presence of a pathogenic heterozygous deletion on chromosome 15q in the fetal DNA that is associated with two disparate genetic diseases (Prader-Willi syndrome and Angelman syndrome). Uniparental disomy testing is recommended to distinguish which disease is affecting the fetus.
  • This data confirms the presence of a benign heterozygous deletion on chromosome 15q in the fetal DNA. This deletion will bear no phenotypic consequences, therefore no further testing is recommended.

The correct answer is ...

This data confirms the presence of a pathogenic heterozygous deletion on chromosome 15q in the fetal DNA that is associated with two disparate genetic diseases (Prader-Willi syndrome and Angelman syndrome). Methylation testing is recommended to determine which disease is affecting the fetus.

The recurrent deletion that impacts chromosome 15q11.2 to 15q13.1 has been well established as pathogenic for either Prader-Willi syndrome (PWS) or Angelman syndrome (AS). The explanation for how a deletion of the same region can be associated with two disparate genetic disorders lies in an epigenetic phenomenon known as imprinting. Imprinting is the selective silencing of genes depending on their parental origin and can be achieved by methylation of the DNA in the vicinity of the gene. Genes in this region of chromosome 15q are known to be biallelic (expressed on both alleles); only paternally expressed (maternally imprinted); or only maternally expressed (paternally imprinted). If the paternal allele is deleted, the paternally expressed genes will not be activated and the resulting phenotype is PWS. If the maternal allele is deleted, the maternally expressed genes will not be activated and the resulting phenotype is AS.

Deletion of this region is typically sporadic in the affected individual and is the mechanism that underlies 70% of individuals with PWS (deletion of paternal allele) and 70% of individuals with AS (deletion of the maternal allele). Once a deletion of this region has been detected, the parent-of-origin can be determined by looking at known methylation sites to determine levels of methylation in the patient as compared to what would be expected if both the maternal and paternal allele are present. This will allow for the dissection of the phenotype, and in this case, could lead to in utero diagnosis of the fetus with either PWS or AS. 


  1. Fermin Gutierrez MA, Mendez MD. Prader-Willi Syndrome. 2023 Jan 31. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. PMID: 31985954.
  2. Costa RA, Ferreira IR, Cintra HA, Ferreira Gomes LH, Cunha Guida, L. Genotype-phenotype relationships and endocrine findings in Prader-Willi syndrome. Front Endocrinol. 2019; 10:864. PMID:31920975. 

Jeanne Theis, Ph.D. 

Fellow, Laboratory Genetics and Genomics
Mayo Clinic

Nicole Lynn Hoppman, Ph.D.

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

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