Heart 

This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2022, Case 05, and is hypertrophic cardiomyopathy of the heart. The information provided in this case was accurate and correct at the time of publication in 2022. Any changes in terminology since the time of publication may not be reflected in this case. 

Histologic examination shows myocytes with abundant cytoplasm and enlarged, box-shaped nuclei. There are regions of disorganized bundles of myocytes intersecting at perpendicular and oblique angles. Foci of interstitial fibrosis are present on some sections. In combination with the gross examination and clinical history, the findings are supportive of the diagnosis of hypertrophic cardiomyopathy.  

Hypertrophic cardiomyopathy (HCM) is an inherited cardiac disease associated with mutations in one of several sarcomeric protein genes with approximately 70% involving the beta-myosin heavy chain gene (MYH7) or the myosin binding protein C gene (MYBPC3). More than 1,400 disease-causing mutations have been identified. At least 50% of cases are familial with an autosomal dominant pattern of inheritance and age-related penetrance. Sporadic cases are associated with de novo mutations.  

HCM is characterized by left ventricular hypertrophy (LVH) in the absence of another cardiac or systemic disease capable of producing hypertrophic changes (eg, aortic valve stenosis, systemic hypertension). Typically present by early adulthood, LVH is often asymmetric with prominent septal hypertrophy. Outflow tract obstruction is present in up to two-thirds of cases. Some patients remain asymptomatic, while others experience angina, dyspnea, or episodes of syncope. Sudden cardiac death is infrequent (occurring in 1% to 2% of patients) but may be the first manifestation of HCM. The risk is highest during adolescence and young adulthood and is the leading cause of death in young athletes.  

Macroscopically, the heart typically shows asymmetric LVH with a septal thickness measuring >1.3 times the thickness of the posterior left ventricular free wall. Symmetric hypertrophy is present in a minority of patients, and right ventricular involvement has been reported. LVH is variable but is usually ≥15 mm in an adult. In children, hypertrophy is defined by a wall thickness ≥2 standard deviations above the mean based on age, sex, and body size. Additionally, the mitral valve leaflets are often enlarged or elongated, and a fibrous imprint from the septal leaflet may be present on the opposing endocardium. The coronary arteries may show myocardial bridging, identified as short segments of the coronary branches embedded within the myocardium. Due to age-related penetrance, a normal heart in young patients does not exclude a diagnosis of HCM.  

Microscopically, there is myocyte hypertrophy, myofiber disarray, and variable interstitial fibrosis. Myofiber disarray is the histologic hallmark of HCM and is characterized by loss of the normal parallel arrangement of myocytes. Intertwined cells are arranged at perpendicular and oblique angles with increased Y-shaped branching and areas with a whorled appearance. This finding is present in nearly all patients with HCM and may be seen in regions with normal or only mildly increased wall thickness. Although it can be focally present in other forms of cardiovascular disease, diffuse myofiber disarray is highly specific for HCM. Additionally, the coronary arteries are often abnormal and show luminal narrowing and medial hypertrophy.

Multimodality imaging (echocardiogram or cardiac magnetic resonance imaging) and genetic testing have diminished the role of endomyocardial biopsy (EMB) in diagnosis. EMB can be helpful to exclude other cardiomyopathies with a hypertrophic phenotype, including infiltrative or storage diseases. Comprehensive genetic testing panels using DNA-based methods can provide an unequivocal diagnosis of HCM in the presence of a known disease-causing mutation. However, these mutations are detected in fewer than 50% of patients, and genetic testing is primarily used to identify at-risk family members without ventricular hypertrophy.

Important factors to consider in the differential diagnosis of LVH include family history, age of onset, clinical presentation, pattern of hypertrophy (symmetric vs. asymmetric), and histopathology.

Cardiac amyloidosis is an acquired or inherited disorder of extracellular amyloid fibril deposition and is more common in middle to late adulthood. Infiltration leads to hypertrophy of the ventricular walls, and asymmetric septal hypertrophy may be seen in some types of amyloidosis. Histologically, the interstitium is expanded by pale pink material surrounding myocytes or within vascular walls. The presence of amyloid can be confirmed with a Congo red stain, and fibrils are seen on electron microscopy.

Several metabolic storage disorders affect the heart and are important to consider in children and adolescents. Fabry disease is an X-linked recessive lysosomal storage disorder. The disease often involves multiple organs but can be limited to the heart and present in adulthood. Concentric LVH is the most common pattern, but asymmetric septal hypertrophy may occur. Unlike HCM, Fabry disease is characterized histologically by prominent vacuolization of the myocytes as well as numerous concentric lamellar inclusions on electron microscopy.

Hypertensive heart disease is more common beyond adolescence and is associated with systemic hypertension and concentric LVH. Myocyte hypertrophy and variable interstitial fibrosis are features of hypertensive heart disease, but the myofiber disarray characteristic of HCM is not present.

Physiologic hypertrophy (athlete’s heart) represents a clinically benign form of ventricular hypertrophy resulting from long-term athletic training. Increased left ventricular wall thickness is symmetric and usually moderate but can be significant in some cases. Differentiating physiologic hypertrophy from HCM with mild LVH can be challenging. In addition to family history, asymmetric or unusual patterns of hypertrophy would favor HCM. Diffuse myocyte disarray is not a feature of physiologic hypertrophy.

1. Which of the following findings is most likely to be present in hypertrophic cardiomyopathy (HCM)? 
    
   1. Abnormal tricuspid valve
   2. Concentric right ventricular hypertrophy
   3. Diffuse myofiber disarray
   4. Myocytes with prominent vacuolization
   5. Normal coronary arteries pure seminomas from mixed germ cell tumors? 
      
       
2. Which of the following statements is true regarding HCM? 
    
   1. All disease-causing mutations have been identified in one sarcomeric protein gene.
   2. Endomyocardial biopsy is required for diagnosis.
   3. Familial cases show an autosomal recessive pattern of inheritance.
   4. Left ventricular outflow tract obstruction is present in all patients.
   5. Sudden cardiac death can be the first manifestation of HCM.
3. Which of the following features is most supportive of a diagnosis of physiologic hypertrophy (athlete’s heart)? 
    
   1. Clinical history of hypertension
   2. Concentric lamellar inclusions on electron microscopy
   3. Extracellular material highlighted by a Congo red stain
   4. Mutations in the beta myosin heavy chain gene (MYH7)
   5. Symmetric left ventricular hypertrophy 

1. d’Amati G, Giordano C. Cardiomyopathies in Buja LM, Butany J, Eds. In: Cardiovascular pathology. 4th Ed. Academic Press/Elsevier; 2016:(Ch 11)446-459,
2. Gersh BJ, Maron BJ, Bonow RO, et al. 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: Executive Summary. Circulation. 2011;124(24):2761-2796.
3. Hughes SE. The pathology of hypertrophic cardiomyopathy. Histopathology. 2004;44(5):412-427.
4. Kocovski L, Fernandes J. Sudden cardiac death: a modern pathology approach to hypertrophic cardiomyopathy. Arch Pathol Lab Med. 2015;139(3):413-416.
5. Marian AJ, Braunwald E. Hypertrophic cardiomyopathy: genetics, pathogenesis, clinical manifestations, diagnosis and therapy. Circ Res. 2017:121(7):749-770.
6. Maron BJ, Maron MS. Hypertrophic cardiomyopathy. Lancet. 2013;381(9862):242-255.
7. Mauer MS, Elliott P, Comenzo R, Semigran M, Rapezzi C. Addressing common questions encountered in the diagnosis and management of cardiac amyloidosis. Circulation. 2017;135(14):1357-1377.
8. Moskowitz IP, Koo S, Husain AN, Patterson K. The Cardiovascular System, In: Husain AN, Stocker JT, Dehner LP, Eds. Stocker and Dehner’s Pediatric Pathology. 4th Ed. Wolters Kluwer; 2016;(Ch.13)Pg 524-580.
9. O’Mahony C, Elliott P. Anderson-Fabry disease and the heart. Prog Cardiovasc Dis. 2010;52(4):326-335. 

1. C- Diffuse myofiber disarray   
2. E- Sudden cardiac death can be the first manifestation of HCM.
3. E-  Symmetric left ventricular hypertrophy