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| Web: | mayocliniclabs.com |
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| Email: | mcl@mayo.edu |
| Telephone: | 800-533-1710 |
| International: | +1 855-379-3115 |
| Values are valid only on day of printing | |
A 30-year-old immunocompromised woman living in the northeastern United States was found unresponsive by her boyfriend. She had never traveled outside of the area and worked as a retail clerk Autopsy reveals the following microscopic findings (see figures).
The correct answer is ...
Toxoplasma gondii.
All four of the following organisms can involve myocardium but can be distinguished based on morphology.
Trichinella spiralis larvae are able to be distinguished on low-power microscopic examination, but distinction between Toxoplasma, Trypanosoma, and Sarcocystis requires high-power examination under oil.
Sarcocystis hominis have a more tubular appearance, and Trypanosoma cruzi amastigotes are remarkable for the presence of kinetoplasts, a rod-shaped structure situated close to the nucleus.
Toxoplasma gondii can be seen in the form of encysted bradyzoites as well as individual tachyzoites. This case is an example of a single cyst within myocardium, containing organisms morphologically consistent with Toxoplasma gondii.
Michael Kritselis, D.O.
Fellow, Cardiovascular 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 71-year-old man presented to the emergency department with two weeks of recurrent fevers and chills. He had recently returned from a trip to his cabin in northern Minnesota approximately two weeks earlier. He recalled many mosquito bites but no tick bites. Laboratory evaluation showed elevated liver transaminases, mild anemia, and leukopenia. A peripheral smear of his blood is pictured below.
The correct answer is ...
West Nile virus.
This patient is infected with Babesia microti, a protozoan (Apicomplexan) tick-transmitted blood-borne parasite.1 Clinical disease typically begins 1–4 weeks after transmission from an infected tick. Typical symptoms include fatigue, malaise, fever, and chills, and frequent laboratory abnormalities include thrombocytopenia, elevated liver transaminases, and hemolytic anemia. Up to half of patients require hospital admission, and illness is more severe among asplenic and immunocompromised patients.2,3
Diagnostic testing for babesiosis includes direct examination of blood films for parasites and nucleic acid amplification (NAAT) detection. Giemsa-stained thick and thin blood smears should be examined and may detect as little as 0.0002–0.001% parasitemia.4 Microscopic features include delicate, pleomorphic ring forms, multiply‐infected erythrocytes, and extracellular forms.
The classic “Maltese cross” tetrad formation is occasionally seen and is pathognomic (Figure 1). Hemozoin, schizonts, and gametocytes are not seen with Babesia, and the presence of these elements suggests Plasmodium infection. NAATs are considered to have excellent sensitivity and specificity.4 While no NAATs are currently FDA-approved for the clinical diagnosis of babesiosis, reference laboratories may offer laboratory-developed molecular assays. Several NAATs are FDA-approved for testing of donor blood and tissue. Serology may be used for supportive or confirmatory testin; however, it cannot distinguish between recent and prior infection.5
In North America, the primary mode of transmission of Babesia is Ixodes ticks (the blacklegged “deer” tick). These ticks are endemic to the Northeast, upper Midwest, and South United States (I. scapularis) and the west coast (I. pacificus).2,6 Most cases of babesiosis occur during the summer and early fall in endemic areas where ticks and vertebrate reservoirs overlap with human activity.5,7 While B. microti is responsible for most clinical infections in the Unites States, other clinically important species include B. duncani, B. divergens, and B. venatorum. There are several other significant pathogens that may be carried by Ixodes ticks, and co-infection presents a challenge for both diagnostics and clinical management. These pathogens include Borrelia burgdorferi (Lyme disease), B. miyamotoi (hard tick-borne relapsing fever), Anaplasma phagocytophilum (human granulocytic anaplasmosis, HGA), Ehrlichia muris-like agent, and tick-borne flaviviruses including Powassan virus and tick-borne encephalitis virus.6
Co-infection appears to be common in nature, with up to 28% of ticks in endemic areas co-infected with either B. burgdorferi, A. phagocytophilum, or Babesia spp.8 In humans, up to 40% of patients with Lyme disease are co-infected with Babesia spp.6 There is growing evidence that co-infection may have important clinical consequences. Studies indicate that in patients with Lyme disease, co-infection with babesiosis or HGA may exacerbate and prolong symptoms.9,10 Clinicians practicing in endemic areas should maintain a high index of suspicion for co-infections, especially in cases of atypical or severe manifestations, or poor response to therapy.
West Nile virus is a mosquito-transmitted flavivirus maintained in reservoir bird populations. While most human infections with WNV are asymptomatic, around 20% develop fever, and less than 1% develop neurologic disease.2 Neurologic manifestations are diverse and include encephalitis, meningitis, cranial neuropathies, and acute flaccid paralysis. Mortality ranges from 4%–14% among patients with neurologic disease, and long-term sequalae are common.11 The diagnosis is most commonly made by detection of WNV-specific antibodies in acute or convalescent serum or cerebrospinal fluid.12
James Vaillant, M.D., M.S.
Fellow, Clinical Microbiology
Mayo Clinic
Bobbi Pritt, M.D.
Consultant, Laboratory Medicine and Pathology
Consultant and Division Chair, Clinical Microbiology
Mayo Clinic
Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science
A 2-year-old boy was referred for evaluation of excessive bleeding and easy bruising since birth. As an infant, he was circumcised on day two of life and developed bleeding complications requiring stitches. He also had a history of epistaxis secondary to trauma that required nasal packing, antifibrinolytics, and fresh frozen plasma to control bleeding. His mother also bruises easily.
Activated partial thromboplastin time (APTT), PT, thrombin time, platelet count, fibrinogen levels, and alpha 2 antiplasmin levels done previously were normal.
The correct answer is ...
Factor XIII deficiency.
In Factor XIII deficient individuals, standard clotting test time, activated partial thromboplastin time, prothrombin time, and thrombin time are normal as the clotting endpoint is not affected, but the quality of clot is poor. Additional testing with factor XIII levels should be requested in suspicious cases with appropriate history.
Congenital Factor XIII deficiency (FXIIID) is a rare bleeding disorder. The worldwide incidence of FXIIID, inherited as an autosomal recessive disorder, is approximately one per 1 million–3 million people. Its prevalence is higher in areas where consanguineous marriage is common. Clinically, most patients present with lifelong bleeding and rebleeding, notably 80% bleed from the umbilical stump; 30% die of intracranial hemorrhage.
For our patient, two prior factor XIII screens came out normal, since the testing was conducted following the administration of fresh frozen plasma. Additional testing on this visit resulted an abnormal factor XIII screen. Subsequently, quantitative factor XIII assay revealed 10% activity, confirming congenital factor XIII deficiency.
Factor XIII, also known as the "fibrin stabilizing factor," circulates in plasma as a protransglutaminase of tetrameric structure (A2B2) that converts the loose fibrin polymer into a firm organized structure by forming peptide bonds between adjacent fibrin monomers. It also binds α2 antiplasmin to provide resistance to thrombolysis.
The action of thrombin converts fibrinogen to fibrin monomer.
Initial fibrin clot is crosslinked through the action of thrombin activated factor XIIIa, making the final fibrin clot insoluble.
Initial fibrin clot (soluble hydrogen bonds)
Factor XIIIa ⇩
(This function is not tested
by the PT, aPTT, or TT)
Crosslinked fibrin clot (insoluble covalent bonds)
In the absence of factor XIII, initial fibrin clot held together by hydrogen bonds can be dissolved by 5 M urea or weak acid solutions.
Factor XIII screen is the Clot solubility test (CST), a qualitative test for factor XIII activity.
The plasma sample (patient and control) is clotted by the addition of an excess of calcium and incubated at 37°C for 30 minutes. Subsequently, a solubilizing agent is added and observed over two hours for abnormal clot dissolution.
Although easy to perform, the test lacks sensitivity and standardization. In addition, the test is unable to detect mild or moderate deficiency, including heterozygous carriers, and leads to delayed or missed diagnosis.
The quantitative FXIII activity assay is based on the transglutaminase reaction in the cross-linking process and is the recommended first-line screening test for FXIIID whenever possible.
Incorrect answer explanation: Factor VIII and Factor V deficiency is unlikely with a normal APTT and PT, respectively. Dysfibrinogenemia is less likely due to a normal thrombin time.
Saadiya Nazli, M.D.
Resident, Anatomic and Clinical Pathology
Mayo Clinic
@docsaadiya
Meera Sridharan, M.D., Ph.D.
Consultant, Hematology
Mayo Clinic
Assistant Professor of Medicine
Assistant Professor of Oncology
Mayo Clinic College of Medicine and Science
A 57-year-old woman presented with a mass in her right colon. Biopsy and resected samples were sent to Mayo Clinic for consultation. Positive immunostains include NUT, CD99, and Vimentin. Negative immunostains include AE1/3, TdT, CD3, CD79, DOG1, CDX2, Synaptophysin, SMA, MOC31, SMARCB1, as well as clonal Kappa and Lambda light chains.
The correct answer is ...
NUTM1-rearranged colorectal sarcoma.
This is a case of NUTM1-rearranged colorectal sarcoma. The patient's tumor is primarily situated in the muscular wall of the right colon, infiltrating into the mucosa and submucosa. The tumor comprises sheets of uniform epithelioid/rhabdoid cells with eosinophilic cytoplasm and eccentrically placed nuclei. Immunohistochemistry reveals that the tumor cells are positive for NUT (diffuse pattern), CD99, and Vimentin, but negative for markers for common colorectal mesenchymal tumors, lymphoma, and primitive neuroectodermal tumor, and poorly/undifferentiated carcinoma. Further molecular testing has uncovered MXI1::NUTM1 fusion. The overall histological features and molecular analysis result support the diagnosis of NUTM1-rearranged colorectal sarcoma.
The discovery of NUTM1 (NUT midline carcinoma family member 1) gene rearrangements began with aggressive thymic carcinoma.1 Subsequently, it has become evident that NUTM1 gene rearrangements are not only unique to NUT carcinoma but also observed in poroma/porocarcinoma, B-lymphoblastic leukemia/lymphoma, central nervous system embryonal tumors, myeloid neoplasms, and various undifferentiated sarcomas.1 NUTM1-rearragnged colorectal sarcoma is a recently recognized entity.1
The NUTM1 rearranged tumors can exhibit distinct morphological patterns, including a fibrosarcomatous pattern (characterized by intersecting fascicles of relatively uniform spindled cells), an epithelioid/rhabdoid pattern (marked by the sheet-like proliferation of primitive epithelioid to rhabdoid cells), and a hyalinized/nested pattern (with nests and cords of tumor cells within abundant hyalinized collagen).1,2
Immunohistochemical analysis reveals characteristic NUT positivity. Other possible positive markers include CD34, SMA, Synaptophysin, ERG, and CD99, though these may only be observed in fewer than 25% of cells.1 Molecular studies have unveiled multiple NUTM1 fusion partners, with BRD4 or BRD3 being the most common. The fusion of NUTM1 with any of these partners results in the overexpression of the NUTM1 protein, which can be detected through immunohistochemistry.1,2
While the overexpression of the NUT gene is recognized as an important mechanism in tumorigenesis, there is still a lack of targeted therapy.3,4 Traditional cancer treatments, such as surgery, radiotherapy, and chemotherapy, can improve survival but often fail to provide long-term control, except in isolated cases. The prognosis remains grim, highlighting the need for further research to enhance future outcomes.3,4
In summary, NUTM1-rearranged colorectal sarcoma is a rare entity with poor prognosis. Lymphovascular involvement is frequent. Morphologically, it should be differentiated from sarcomatoid undifferentiated carcinoma and primitive sarcomas. Positive NUT immunostain is characteristic for the tumor and the diagnosis should be confirmed by molecular studies to demonstrate the NUTM1 gene rearrangement.
Tommy Zhao, M.B., Ph.D.
Resident, Anatomic and Clinical 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
A 27-year-old woman was found to have a mass attached to the uterine wall and an additional cystic omental nodule. The tumor cells were immunohistochemically positive for CD10, WT-1, CK7 (partially), and inhibin; while negative for D2-40, calretinin, claudin, CDX2, GATA3, TRPS-1, DESMIN, SF-1, Melan-A, and HMB45. Representative photomicrographs of the lesion (images 1–3) are shown.
The correct answer is ...
Malignant epithelioid neoplasm with EWSR1:CREB1 fusion.
This is an example of the recently described entity “malignant epithelioid neoplasm with EWSR1/FUS-CREB fusion” that tends to arise in mesothelial-lined cavities, specifically peritoneal cavity, of young patients with a mean age of 36 years.1 Morphologic clues to this tumor include a fairly well-circumscribed tumor surrounded by a fibrous capsule, with prominent pericapsular lymphoid aggregates. The tumor is comprised predominantly of epithelioid cells. In some instances, the tumor may have mixed epithelioid and spindle morphology. Occasionally, cysts or microcysts can be identified within the tumor. Immunohistochemically, the tumor cells show evidence of epithelial differentiation, with positivity for cytokeratins and/or EMA. A subset of cases shows expression of WT1; however, other mesothelial markers (calretinin) were negative. From a molecular standpoint, this tumor harbors CREM-related (EWSR1-CREM and FUS-CREM) and EWSR1-ATF1 fusions.1 Little is known about the clinical behavior of this tumor; however, the available information demonstrates its malignant potential and propensity for both lymph node and distant spread.
The differential diagnosis for this tumor includes angiomatoid fibrous histiocytoma (AFH), epithelioid mesothelioma (EM), and intrahepatic cholangiocarcinoma, solid-tubulocystic variant.
AFH usually shows a combination of cystic changes, associated with hemorrhage and hemosiderin deposition, and brisk lymphocytic cuffing. However, the tumor cells are predominantly spindle. AFH usually harbors EWSR1-CREB1 fusions and follows an indolent clinical course with local recurrences if incompletely excised.2
EM demonstrates overlapping features with the aforementioned entity due to its predilection for peritoneal or pleural surfaces and immunoreactivity for cytokeratin, with coexpression of WT1 in a subset of cases. However, EM usually shows focal papillary architecture, lacks lymphoid cuffing, demonstrates expression of more mesothelial markers (calretinin), and shows loss of expression of BAP1 [1].
Intrahepatic cholangiocarcinoma, solid-tubulocystic variant is a recently described entity that tends to affect young females. Morphologically the tumor is comprised of sheets and large nests of tumor cells alternating with tubular and cystic areas recapitulating sex cord-like morphology. Immunohistochemically, the tumor cells are positive for cytokeratin, CK7, and inhibin. From a molecular standpoint, these tumors show focal and large-scale copy number changes, and no recurrent pathogenic mutations.3
Audai Alrwashdeh, M.B.B.S.
Fellow, Surgical Pathology
Mayo Clinic
@Audai92
Maryam Shahi, M.D.
Consultant, Anatomic Pathology
Mayo Clinic
Assistant Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science
@Marykingir
A 59-year-old man is admitted to the hospital after experiencing several weeks of dyspnea, fatigue, weight loss, and progressive neurologic decline. He has a past medical history of autologous hematopoietic stem cell transplant and living donor allograft kidney transplant in the setting of multiple myeloma and associated immunoglobulin light chain (AL) amyloidosis. Diagnostic work-up revealed bacteremia and multifocal lesions in the lungs and brain. Magnetic resonance imaging of one of the lesions and a histologic section from this area are shown below.
The correct answer is ...
Nocardia spp.
The patient, given his medical history that includes both hematopoietic stem cell transplant and solid organ transplant, had been treated with chronic immunosuppressive therapy over the course of multiple years. He was found to have disseminated infection with blood cultures returning positive for Nocardia farcinica and Nocardia kroppenstedtii. His neurologic function continued to decline as he progressed to septic shock. Despite aggressive treatment, the patient died in the hospital three weeks after admission. At autopsy, gross examination revealed numerous similarly appearing abscesses in multiple organs (lungs, brain, liver, thyroid, kidney, and heart). The example shown in the question stem was a 1.4 cm cerebral abscess involving the right hippocampus at the level of the lateral geniculate nucleus. Given the patient's clinical history, blood culture results, and autopsy findings, disseminated nocardiosis due to sequelae of multiple myeloma was determined to be the cause of death.
Nocardia spp. are Gram-positive, branching filamentous, obligate aerobic, weakly acid-fast bacilli that are ubiquitous in soil and can cause localized or disseminated infection in immunocompromised hosts. Inhalation leading to pulmonary disease is the most common route of primary infection. Hematogenous dissemination can involve any organ system, and frequently involves the central nervous system (CNS).
Within the CNS, Nocardia spp. exhibit tropism for the brain, where they can cross the blood-brain barrier and preferentially infect and replicate within astrocytes and microglia. In the brain, surface receptors on Nocardia bind to host capillary endothelial cells and glia. Virulence factors such as catalase and superoxide dismutase also facilitate CNS infection by inhibiting neutrophil killing. Impaired cell-mediated immunity is a major risk factor for CNS nocardiosis.
Nocardia spp. is one of the most common abscess-causing pathogens in the CNS. Among the common species, N. farcinica is known to be highly neurotropic and more often leads to CNS disease than N. asteroides. The microscopic appearance of Nocardia spp. can be very similar to that of Actinomyces spp., which are also Gram-positive, branching filamentous bacilli. Thus, microbiology studies are important for definitive diagnosis. In contrast to Nocardia, Actinomyces spp. are obligate anaerobes and are not acid-fast. Actinomyces infections most often occur in cervicofacial tissue or the lungs and can spread to adjacent organs, including to the CNS. However, Actinomyces spp. lack the aforementioned neurotropic virulence factors possessed by Nocardia and are thus far less likely to cause CNS infection.
On microscopy, the general evolution of a cerebral abscess is thought to occur in four stages:
Collagen deposition continues to occur; the capsule gradually thickens, and the abscess enlarges by expanding into the white matter over subsequent weeks-months. Capsular thickening occurs to a greater extent in subcortical brain tissue than in the deep white matter, where it tends to remain relatively thin. Hematogenously spreading CNS infections tend to be less encapsulated than those caused by direct local spread. Clinical presentation of cerebral abscess is variable and may include headache, fever, epilepsy, nausea, vomiting, altered sensorium, nuchal rigidity, or focal neurologic signs depending on location. The early changes of focal cerebritis may be seen on magnetic resonance imaging before any abnormality is apparent on computerized tomography. The overall mortality of cerebral abscess is approximately 20%. Of the patients who survive, approximately 50% will have persistent epilepsy, cognitive impairment, and/or focal neurologic signs as long-term complications.
David Cook, M.D.
Resident, Anatomic & Neuropathology
Mayo Clinic
Ross Zumwalt, M.D.
Senior Associate Consultant, Anatomic Pathology
Mayo Clinic
