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| Web: | mayocliniclabs.com |
|---|---|
| Email: | mcl@mayo.edu |
| Telephone: | 800-533-1710 |
| International: | +1 855-379-3115 |
| Values are valid only on day of printing | |
A 62-year-old woman has been diagnosed with hyperlipidemia for six years. She has a strong family history of high cholesterol, a lipid profile suggestive of familial hypercholesterolemia, but is negative on genetic testing. Patient has no prior history of hypertension or diabetes, is an active smoker, and her estimated 10-year risk for atherosclerotic cardiovascular disease (ASCVD) was 8.6% [Statin Choice Decision AID - Site (mayoclinic.org)]. Previous trials of lipid lowering medications were unsuccessful due to statin-induced myalgias.
Patient had an emergency department visit for chest pain. An electrocardiogram and troponin panel ruled out myocardial infarction. Plasma ceramides, CT imaging, and cardio-stress test were ordered in follow-up.
The correct answer is ...
Patient at high risk; may benefit from aggressive treatment and lifestyle changes.
Ceramides are bioactive lipids produced in all cells and tissues. They act as secondary messengers for cell signaling and are involved in apoptosis, inflammation, obesity, and insulin resistance. Testing circulating plasma ceramides can be clinically useful in many ways, including: a) identifying patient with high-risk coronary heart disease, who might benefit from more intense medical intervention; b) assessing risk of patients with intermediate cardiovascular risk based on conventional lipids; c) assessing treatment response and motivating patient compliance to therapy and lifestyle changes.1-3
How are ceramides associated with coronary heart disease?
Ceramides are independent risk markers for predicting negative cardiovascular outcomes.4 Certain ceramide species have a strong association with atherosclerotic cardiovascular disease (ASCVD), elevated ceramides associated with increased risk, and poor clinical outcomes (such as fatal myocardial infarction and cardiovascular mortality). These have been supported by numerous case-control, large-scale population studies, and randomized clinical trials.2,3,5 Ceramides including N-palmitory-sphingosine (Cer16:0), N stearoyl-sphingosine (Cer18:0), and N nervonoyl-sphingosine (Cer24:1) are linked with cardiovascular mortality. Hazard ratios for Cer16:0, Cer18:0, Cer24:1, and ASCVD outcomes from different studies ranged from 1.1 (95%CI, 1.02, 1.21) to 4.49 (95% CI, 2.24 -8.99), and multivariate analysis shows lack of association with LDL-cholesterol concentration and other traditional risk factors.2 These indicate ceramides provide independent risk stratification for cardiovascular disease beyond LDL-cholesterol.
Ceramide risk score: what is it?
Individual ceramide species have specific physiological functions. Furthermore, individual ceramide species vary widely in their relative serum concentrations between individuals. This complexity hinders direct clinical interpretation for a given ceramide in isolation.3 The MI-Heart Ceramide risk score measures four ceramides and weighs their contribution to ASCVD risk to provide a simple and readily communicated result.4,6 This approach has been validated in a large-scale, population-based study of more than 8,000 healthy individuals7 and a Mayo Clinic study in an >1,000 angiography cohort,3 which showed that a patient at high-risk category has a 1.5- to 4.2-fold increased risk for major adverse cardiovascular events (MACE) and MACE death compared with a low-risk group.3,7
Follow-up
Ceramides suggested the patient was high-risk for ASCVD despite the intermediate risk calculated. Imaging studies confirmed mild coronary blockage with high-risk of ASCVD events. The patient elected to begin aggressive lipid lowering treatment (PCSK9-inhibitor) and lifestyle changes (smoking cessation, Mediterranean diet, and increased exercise). Ceramides and traditional lipids normalized over 18 months.
Qian Wang, Ph.D.
Fellow, Clinical Chemistry
Mayo Clinic
Jeff Meeusen, Ph.D.
Consultant, Clinical Chemistry
Mayo Clinic
Assistant Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science
A 75-year-old man with a history of Crohn’s disease, status post decades remote proctocolectomy, presented with firmness around his anal opening. Imaging studies demonstrated a complex cystic mass lesion in the presacral proctocolectomy bed. By imaging, areas of papillary projections were noted in the cystic mass. The mass abutted both the seminal vesicles and the prostate, without evidence of direct invasion. This cyst was initially identified on imaging decades prior, and follow-up studies confirmed progressive increase in size over time.
The correct answer is ...
Tailgut cyst.
The histological sections demonstrate strips of fibrous tissue (up to 10 mm) with a single layer of mucinous glandular epithelium at one tip. The epithelial cells are positive for CK20, CDX2, and SATB2. The findings are in keeping with a lower gastrointestinal/colonic epithelial phenotype. The appearance is compatible with a tailgut cyst.
Tailgut cysts are rare lesions. They are most often asymptomatic and identified incidentally. When symptomatic, patients usually present with fullness, constipation, dysuria, and pain during defecation. They are almost always located in the retrorectal space and are commonly multiloculated. Histological sections demonstrate columnar lining. In rare instances, transitional and squamous epithelium may also be seen. Rare cases (2% to 13%) may undergo malignant transformation. Surgical excision is recommended both for both symptomatic and asymptomatic lesions due to the possibility of malignant transformation.1
Cystic sacrococcygeal teratoma: Sacrococcygeal teratomas are the most common extragonadal germ cell tumors in young children. They are mostly benign but can rapidly grow to large size and cause heart failure and hydrops. They frequently present in utero or early infancy, may be asymptomatic or present with pain, paralysis, or symptoms related to bladder or rectal obstruction. The histological sections demonstrate more than two germ cell layers elements.2
Rectal duplication cyst: Duplication cysts are rare congenital cysts of unknown cause. They are usually symptomatic in the first couple of years. Prenatal imaging can diagnose this entity. An ultrasound finding showing a gut signature sign is pathognomic of duplication cyst. Cystic duplications are more common than tubular duplications. They can be associated with any part of gut, but ileum and esophagus are most common. When associated with rectum, duplication cysts present as uniloculated cysts in the prerectal space, and a continuity with the rectum can be appreciated. The histological sections demonstrate distinct mucosa, smooth muscle layers, and associated neural plexus.3
Neuroenteric cyst: Neuroenteric cyst are rare lesions of spinal axis composed of heterotopic endodermal tissue. During embryogenesis, the neuroenteric canal unites the yolk sac and amniotic cavity. Persistence of normally transient neuroenteric canal prevents appropriate separation of endoderm and notochord. This presents as congenital abnormality of spine, defined by mucus secreting epithelium reminiscent of GI tract. Such lesions account for 0.7%-1.3% of spinal cord tumors. Most neuroenteric cysts are located in the intradural/extramedullary compartment. Histological sections demonstrate mucin secreting columnar or cuboidal ciliated and nonciliated goblet cells surrounding a central cyst. Some lesions contain associated fat, cartilage, bone, or lymphatic tissues.4
Neeraja Yerrapotu, M.B.B.S.
Fellow, Surgical Pathology
Mayo Clinic
Charles Sturgis, M.D.
Consultant, Anatomic Pathology
Mayo Clinic
Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science
A 31-year-old G1P0 woman with oligohydramnios underwent emergent caesarean section at 36 weeks gestation for non-reassuring fetal heart tones. She delivered a liveborn, pale-appearing female infant. Gross examination of the placenta demonstrated multiple tan-yellow infarcts, including one with focal hemorrhage. Histologic sections of the parenchymal infarcts are represented in Figures 1 and 2.
The correct answer is ...
It can present as an incidental microscopic finding during placental examination.
The diagnosis is intraplacental choriocarcinoma. Choriocarcinoma is a biphasic malignant tumor composed of mononuclear trophoblast (i.e., cytotrophoblast, intermediate trophoblast) and multinucleated syncytiotrophoblast and can be gestational or non-gestational in origin. Gestational choriocarcinoma is frequently preceded by a complete hydatidiform mole, exhibiting an androgenetic (paternal only) genome, and is characterized pathologically by invasive sheets of biphasic trophoblast with marked cytologic atypia, increased mitotic activity, and large regions of hemorrhage and necrosis. The finding of chorionic villi is generally considered incompatible with a diagnosis of choriocarcinoma.
Intraplacental choriocarcinoma is a distinct type of gestational choriocarcinoma typically discovered in a third trimester placenta of a nonmolar (biparental diploid genome) gestation and contains chorionic villi displaying multiple layers of biphasic pleomorphic trophoblast extending into the intervillous space associated with villous infarcts and necrosis (Figures 1 and 2). Intraplacental choriocarcinoma is rare and likely underrecognized. It can present clinically as metastatic disease in the mother, fetomaternal hemorrhage, or stillbirth, or it may be detected as an incidental finding during placental examination. Grossly, intraplacental choriocarcinoma ranges from an identifiable mass lesion to resembling infarcts, thrombi, or fibrin deposition to appearing normal, and the diagnosis is determined microscopically.
Intraplacental choriocarcinoma confined to the placenta is associated with an excellent prognosis, and management by surveillance serum hCG levels has been proposed. Maternal metastatic disease is detected in approximately 50% of cases and has a relatively good prognosis following chemotherapy. Fetal metastasis occurs rarely and is associated with a poor outcome. It has been reported that approximately 60% of pregnancies complicated by intraplacental choriocarcinoma result in a liveborn infant with low neonatal mortality. Management by surveillance serum hCG levels has been proposed. Maternal metastatic disease is detected in approximately 50% of cases and has a relatively good prognosis following chemotherapy. Fetal metastasis occurs rarely and is associated with a poor outcome. It has been reported that approximately 60% of pregnancies complicated by intraplacental choriocarcinoma result in a liveborn infant with low neonatal mortality.
Luisa Ricaurte Archila, M.D.
Resident, Anatomic & Clinical Pathology
Mayo Clinic
@LuisaRicaurteMD
Amy Swanson, M.D.
Senior Associate Consultant, Anatomic Pathology
Mayo Clinic
Assistant Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science
A 30-year-old man presents with unexplained fever, cervical lymphadenopathy, cutaneous rash on the anterior trunk, and erythematous palms of the hands. Laboratory findings include total bilirubin 6.9, AST 49, ALT 87, ALP 283, negative autoimmune serology, negative viral hepatitis serology, and a negative infectious disease workup. A liver biopsy was performed with the histologic features seen in the images. The iron stain was negative for hemosiderosis. The trichrome stain showed no significant fibrosis. The CMV and HSV immunostains were negative.
The correct answer is ...
Kawasaki disease.
Kawasaki disease (KD), previously known as mucocutaneous lymph node syndrome, is an acute, febrile, systemic vasculitis that usually effects infants and young children <5-years-old; however, some cases can occur in adults. The classic clinical presentation includes fever, mucocutaneous changes, and cervical lymphadenopathy. KD often involves the larger coronary arteries and is the most common cause of acquired heart disease in children. KD can also present with liver dysfunction and elevated transaminases, which is more common in adult-onset KD.
Histologically, the liver can show a vasculitis-induced chronic biliary tract disease pattern of injury. Medium-sized arteries and veins in the liver show injury secondary to inflammation. This can lead to ischemic-type injury to the biliary tree. Histologic findings include portal inflammation with increased neutrophils, acute cholangitis, bile ductular reaction, portal vein blood flow impairment, and Kupffer cell hyperplasia. Hepatic arterial flow insufficiency can also cause subtle hepatocellular change specifically manifested as concurrent increase in mitosis and apoptosis.
KD can commonly cause biliary tract injury with histologic findings that can appear similar to that of PSC, including portal inflammation, acute cholangitis, and bile ductular proliferation. However, classic PSC shows inflammation involving large ducts, causing chronic obstructive changes in the small portal tracts. Chronic cholestatic change and increased fibrosis, particularly peri-ductal concentric fibrosis, are characteristic findings. KD-induced bile duct injury is often acute linking to ischemia and infection. KD is the most correct answer.
The identification of portal granulomas brings sarcoidosis into the differential diagnosis. The clinical presentation and additional histologic findings makes sarcoidosis less likely. KD is the most correct answer.
KD can commonly cause biliary tract injury with histologic findings that can appear similar to that of PBC, including portal inflammation, granulomatous inflammation, and bile ductular proliferation. However, the characteristic histologic feature of PBC is florid ductal lesion with increased plasma-cell rich portal inflammation, with or without interface activity. To find features of chronic cholestatic change is also important for diagnosis of PBC. KD-induced bile duct injury is often acute linking to ischemia and infection. Given the negative autoimmune serology and clinical presentation of this patient, KD is the most correct answer.
Rachel Horton, D.O.
Fellow, Gastroenterology & Liver Pathology
Mayo Clinic
Eric Chen, M.D., Ph.D.
Consultant, Anatomic Pathology
Mayo Clinic
Associate Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science
This case is from a 37-year-old man with a remote history of a left temporal lobe low-grade glial tumor, status post-resection. The patient recently presented with a witnessed tonic-clonic seizure, and brain MRI demonstrated a large intra-axial lesion exhibiting moderate diffuse enhancement arising in the previous resection cavity of the left temporal lobe.
The correct answer is ...
Oligosarcoma, IDH-mutant and 1p19q co-deleted.
Histologically shown is brain parenchyma with a high-grade neoplasm composed of spindle cells arranged in intersecting fascicles. The pericellular reticulin deposition and loss of immunohistochemical glial markers (OLIG2 and GFAP) supports a sarcomatous component of the tumor (Fig. 4). Focally, regions of tumor showed a classic oligodendroglial morphology characterized by tumor cells with round nuclei and with perinuclear clearing (Fig. 3). This subset of tumor cells retained expression of OLIG2 and GFAP, and likely represents the precursor glial tumor to the sarcomatous component. The tumor was positive for mutant IDH1 and retained expression of ATRX. The tumor showed elevated mitotic activity, necrosis, and microvascular proliferation, which are features of a high-grade CNS neoplasm (Fig. 2). Further additional molecular studies were performed. Chromosomal microarray identified the co-deletion of the whole arms of 1p and 19q, and homozygous loss of CDKN2A and CDKN2B (Fig 6). Next-generation sequencing confirmed the presence of a IDH1 mutation, as well as a TERT promoter, NF1, and NF2 mutation. Whole genome methylation analysis performed at the Pathology Laboratory, National Cancer Institute, indicated a methylation profile of diffuse glioma, IDH-mutant and 1p19q codeleted/Oligosarcoma, IDH-mutant.
Oligosarcoma, IDH-mutant is rare CNS diffuse glioma that can be diagnostically challenging. Oligosarcomas are most associated with oligodendroglioma but can occur in patients without a known history. Oligosarcomas are histopathologically characterized by an infiltrating spindle cell neoplasm demonstrating large degrees of sarcomatous or leiomyosarcomatous differentiation and abundant pericellular reticulin deposition. Studies support that the sarcomatous components of oligosarcomas represent a differentiated population of tumor cells, which is highlighted by the immunohistochemical loss of glial markers. The transformation of these tumor cells is further supported by immunoreactivity for smooth muscle actin which has been documented in a large proportion of oligosarcomas. Oligosarcoma shares several molecular features with oligodendroglioma, including the diagnostic IDH1/2 mutation, and frequently the 1p19q co-deletion. However, oligosarcomas appear to more frequently harbor molecular changes associated with overall worse outcomes in CNS tumors, including CDKN2A/B homozygous deletion and TERT promoter mutations.
Lastly, a recent study examining the tumor methylation profile of a large cohort of oligosarcomas shows these tumors form a distinct DNA methylation group. To date, the precise delineation between oligosarcoma and oligodogliomas remains unclear. While the definitive grading of the oligosarcoma is not well established, oligosarcomas overall have a poor clinical outcome and demonstrate aggressive behavior.
Blake Ebner, M.D., Ph.D.
Fellow, Anatomic & Clinical Pathology
Mayo Clinic
Jorge Trejo-Lopez, M.D.
Senior Associate Consultant, Anatomic Pathology
Mayo Clinic
Assistant Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science
