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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 70-year woman with a right breast lump underwent a lumpectomy for a 1.5 cm mass with lobulated margins. The neoplastic cells stain positive for GATA3, CK5, CK7, and GCDFP-15 and negative for TTF-1. ER and PR are focally positive, and p63 is negative within the lesion.
The correct answer is ...
Tall cell carcinoma with reverse polarity (TCCRP).
Tall cell carcinoma with reverse polarity (TCCRP) is a type of invasive breast cancer with papillary architecture. It is characterized by circumscribed nests of tall and columnar epithelial cells lining the fibrovascular cores. The neoplastic cells show bland ovoid nuclei and usually abundant eosinophilic cytoplasm. The nuclei are characteristically present at the luminal/apical surface, hence the name "reverse polarity." Nuclear grooves and intranuclear cytoplasmic inclusions may be seen and require exclusion of metastasis from the thyroid using additional thyroid markers like TTF-1, thyroglobulin, etc. The tumor stains positive for GATA3, other breast markers such as mammaglobin and GCDFP-15, and both high- and low-molecular-weight cytokeratins.
These tumors are often triple negative (ER, PR, and HER2), however, some degree of low hormone receptor positivity may be present, in contrast to solid papillary carcinoma (in situ and invasive) of the breast, which is strongly and diffusely positive for estrogen receptor. Myoepithelial markers such as p63, calponin, and smooth muscle myosin, etc., can be used to differentiate these tumors from intraductal papillomas, which will show intact myoepithelial cells in the periphery and within the fibrovascular cores of papilloma, whereas TCCRP is invasive cancer and has an absence of myoepithelial layer. TCCRP has been shown to harbor mutations in the IDH2 gene, which is present in approximately 80% of the cases and can be used as a diagnostic aid in challenging cases.
Ameya Patil, M.B.B.S.
Resident, Anatomic & Clinical Pathology
Mayo Clinic
Malvika Solanki, M.B.B.S., Ph.D.
Consultant, Anatomic Pathology
Mayo Clinic
Assistant Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science
The patient was a 73-year-old woman with a palpable lesion in the right breast. Mammography confirmed a 1.8 cm focal asymmetry at 3 o’clock, located 13-15 cm from the nipple in the posterior depth. The patient had a history of common variable immunodeficiency and chronic lymphocytic leukemia but no history of breast disease or radiation. Several immunohistochemical studies were performed and are provided below.
The correct answer is ...
Angiosarcoma.
The hematoxylin-eosin-stained slide sections from the right breast core biopsy confirm an architecturally complex vascular proliferation comprised of well-formed small- to medium-sized anastomosing vessels that surround adipocytes and islands of adipose tissue. The vascular channels have angulated luminal centers with varying degrees of endothelial lining atypia.
SMA IHC highlights smooth muscle in vascular wall spaces, and an HHV8 study is negative, helping to exclude Kaposi sarcoma (IHC not shown here).
The combined morphology and ancillary testing findings are those a primary angiosarcoma of the breast. The majority of the disease in this small biopsy appears well differentiated. Importantly, grade has not been shown to correlate directly with outcomes/prognosis in primary angiosarcomas of the breast, and better differentiated tumors may metastasize.
Angiosarcoma is a malignant tumor arising from the endothelial cells lining the blood vessels. It is characterized by the proliferation of haphazardly arranged vascular spaces lined by morphologically aberrant endothelial cells. The vessels within angiosarcomas often form complex anastomosing channels. Tumor borders are infiltrative, and involvement of lobules is common. The nuclei of the lesional endothelial cells often show enlargement, hyperchromasia, and pleomorphism. Tumor cells may proliferate to form papillary tufts within vessel lumina. Angiosarcoma can present as a mass in the breast or as diffuse involvement of the breast tissue. Immunohistochemical studies for endothelial markers such as CD31, CD34, and factor VIII can be used to confirm the diagnosis.
Atypical vascular lesion is a benign lesion that can mimic angiosarcoma on histology. It is characterized by the presence of dilated lymphovascular channels in the dermis of the skin. These lesions lack significant atypia/pleomorphism and do not invade surrounding tissue or metastasize.
Hemangioma is a benign tumor composed of blood vessels and can appear similar to angiosarcoma on histology, especially in small core biopsy samples. Hemangiomas are usually well-circumscribed and composed of thin-walled blood vessels lined by flattened endothelial cells without significant nuclear atypia.
Angiolipoma is a benign tumor composed of mature adipose tissue and small, round, capillary-sized blood vessels. Angiolipomas are most often identified in the subcutis and are less common in the substance of the breast proper. Histologically, angiolipoma is characterized by a mixture of mature adipose tissue and small, thin-walled blood vessels. Fibrin thrombi may be seen in the blood vessels. The endothelial cells in angiolipoma are not atypical and lack the proliferation and nuclear atypia seen in angiosarcoma. The distinction between angiosarcoma and other benign entities is important, as breast angiosarcomas can be aggressive malignancies with high potentials for recurrence and metastases. Treatment of angiosarcoma usually involves surgical resection of the tumor, often followed by radiation therapy and/or chemotherapy. The prognosis for breast angiosarcoma is generally poor. Relevant benign differential diagnoses, on the other hand, are conditions that may not require further treatment and may be cured by simple excision.
Tao Zhang, M.D.
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 74-year-old woman from the upper Midwest presented to the ED with acute onset ataxia and altered mentation. She has regular outdoor exposure in wooded areas, with known mosquito and tick exposures (Figure 1), and frequently feeds wild deer. A CBC on CSF demonstrated 127 cells with lymphocytic predominance. Microbiological workup and imaging were consistent with aseptic meningitis/encephalitis. Given the exposures, testing for arboviruses was performed. A Powassan virus IgM and Powassan virus PCR on blood were both positive.
The correct answer is ...
Powassan IgM testing should be performed on patients with >7 days of symptoms.
Powassan virus (POWV) is a single-stranded, positive-sense RNA virus and member of the Flavivirus genus, which includes West Nile virus (WNV), Zika virus, yellow fever virus, and dengue viruses. POWV is an emerging arboviral pathogen, transmitted by Ixodes sp. ticks (primarily I. scapularis, I. marxi, and I. cookei). Following infection, the incubation period for POWV can range from 1-4 weeks, with ~60% of infected individuals remaining asymptomatic or developing only mild, self-limiting symptoms, including headache, fever, arthralgia, and myalgia. Severe manifestations can occur, including development of neuroinvasive disease in approximately 30% of symptomatic patients, with long-term sequelae remaining in half of those individuals and an associated mortality rate of 10%–15%. Between 2012–2021, the CDC reported 202 cases, with 189 of these being neuroinvasive. Zero deaths have been reported from non-neuroinvasive cases, and 13% of neuroinvasive cases were fatal.
Risk factors for POWV infection include living and travel to Ixodes-endemic areas during the late spring, summer, and fall. While not specific to POWV, the Infectious Disease Society of America (IDSA) recommends that evaluation of co-infections with other tick-borne pathogens be performed in patients with Lyme disease for whom symptoms may suggest a co-infection.
Diagnosis of POWV infection can be established via serologic and/or real-time PCR (PCR) testing; however, appropriate test selection can be challenging and should be guided by the symptom timeline. Patients presenting with <7 days of symptoms are likely to be negative by serologic testing but may be positive by PCR on blood, urine, and/or CSF. The utility of PCR testing is limited to this narrow window due to the rapid decrease in viremia within approximately one week of symptom onset (Figure 2). However, POWV RNA can be detected for longer in urine compared to other sources, as has been documented for WNV and other flaviviruses. Importantly, a negative molecular result for POWV does not exclude the possibility of POWV infection, and serologic testing should be performed if POWV is suspected.
For patients with ≥7 days of symptoms, it is recommended that anti-POWV serologic testing be ordered. Available POWV serologic testing methods include IgM/IgG ELISAs, IgM capture (MAC) ELISAs, immunofluorescence assays (IFA), and plaque-reduction neutralization test (PRNT), the latter of which remains the reference method for arboviral antibody detection. Thus, confirmatory PRNT for samples positive by ELISA or IFA may be considered. IgM antibody levels become detectable after 7 days and may remain detectable for weeks to months. IgG antibody levels will become detectable within months and may remain detectable for decades.
Although targeted antiviral therapy is not available for POWV, accurate diagnosis of infection is important for discontinuation of unnecessary antimicrobial therapy, for prognostic information and allows us to continue to monitor the epidemiology of this virus.
Josh Shirley, Ph.D.
Fellow, Clinical Microbiology
Mayo Clinic
Elitza Theel, Ph.D.
Consultant, Clinical Microbiology
Mayo Clinic
Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science
An 82-year-old man with a history of smoking and asbestos exposure presented with recurrent large pleural effusions that were historically negative by cytologic examination. PET-CT revealed a new large pleural effusion associated with moderately avid pleural thickening. Repeat thoracentesis was performed.
The correct answer is ...
Sarcomatoid.
Mesothelioma is a rare and aggressive malignancy of the pleura that is strongly associated with asbestos exposure. Currently, per the WHO 2021 classification, mesothelioma can be subtyped into epithelioid, biphasic, and sarcomatoid variants. The histological subtype of the tumor is the best pathological indicator of overall prognosis,1 and of these subtypes, the sarcomatoid variant is associated with the worst overall prognosis.2
The diagnosis of mesothelioma in pleural effusions has been augmented greatly with ancillary testing. Immunohistochemistry for BRCA1-associated protein 1 (BAP1) and methylthioadenosine phosphorylase (MTAP) are highly specific and reliably differentiate mesothelioma from reactive mesothelial cells. The expected staining pattern in malignancy (as illustrated in this case) is a loss of protein expression with retained expression in internal controls (Figure 1, panel C).3 p16 fluorescence in situ hybridization testing for deletions of CDKN2A can also be utilized to establish the diagnosis.4 Given their variable sensitivity, it is currently recommended to use multiple immunohistochemical markers to establish mesothelial lineage.
The majority of mesothelioma diagnosed via effusion cytology are epithelioid in histologic type.5 As such, pleural biopsy remains the primary diagnostic modality for the sarcomatoid variant.6
Aswath Padmanabhan Chandrasekar, M.B.B.S.
Resident, 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
@MelanieBoisMD
A 68-year-old man with a history of multiple non-melanoma skin cancers presented with a well-circumscribed, firm, pink-yellow lesion on the scalp. The lesion was biopsied and signed out as sebaceous carcinoma.
The correct answer is ...
It occurs most frequently in children and young adults.
Sebaceous carcinoma is a malignant neoplasm with sebaceous differentiation that typically presents as a tan-pink to yellow lesion around the eyelid. It usually arises in older adults; the median age at time of diagnosis is 73 years. While the periocular region is the most common site, sebaceous carcinoma can also occur at extra-ocular sites, as in this case.
Some sebaceous carcinomas are characterized by defective mismatch repair; most of these cases are somatic mutations, rather than germline. Patients with multiple sebaceous tumors, especially extraocular, should be assessed for Muir-Torre syndrome, which is characterized by germline mutations in mismatch repair genes MLH1, MSH2, MSH6, and PMS2. Muir-Torre syndrome is a variant of hereditary, non-polyposis colorectal cancer and confers an increased risk of colorectal carcinoma. Lastly, although not entirely specific, androgen receptor (AR) is often positively expressed in sebaceous tumors.
Amanda Nguyen, M.D.
Resident, Anatomic & Clinical Pathology
Mayo Clinic
@AmandaJNguyenMD
Ray Guo, M.D., Ph.D.
Consultant, Anatomic Pathology
Mayo Clinic
Associate Professor of Laboratory Medicine and Pathology; Associate Professor of Dermatology
Mayo Clinic College of Medicine and Science
A 3-year-old boy with no clinical information is referred for FMR1 testing. Results of the repeat primed PCR revealed two alleles, both with normal repeat size (as shown below). The test was repeated, and the results were the same.
The correct answer is ...
Cytogenetic studies.
FMR1 disorders include fragile X syndrome (FXS), fragile X-associated tremor/ataxia syndrome (FXTAS), and fragile X-associated primary ovarian insufficiency (FXPOI). FXS is nearly always characterized by developmental delay and intellectual disability along with a variety of behavioral issues. FXTAS is characterized by late-onset, progressive cerebellar ataxia and intention tremor followed by cognitive impairment. Age of onset is typically between 60 and 65 years. FXPOI is characterized by hypergonadotropic hypogonadism before 40 years of age.
FMR1 disorders are the result of CGG trinucleotide repeat expansion in the 5' UTR of FMR1 with abnormal gene methylation for most alleles with >200 repeats. FXS requires the presence of a full-mutation repeat size (>200 CGG repeats), while FXTAS or FXPOI is associated with a premutation-sized repeat (55-200 CGG repeats).
Polymerase chain reaction (PCR) is used to detect expanded CGG trinucleotide repeats of FMR1. Early PCR techniques failed to amplify full mutations. Currently, PCR techniques such as repeat primed PCR can be utilized to identify large FMR1 expansion mutations. Methylation status of a full mutation can be assessed by PCR-based methods independent of measuring the number of CGG repeats. Southern blot analysis detects all FMR1 alleles including normal, larger-sized premutations, and full mutations. In addition, it determines methylation status of the FMR1 promoter region.
In this case, repeat primed PCR has revealed this patient has two alleles with normal range repeats size. These results are not consistent with an expansion variant of the FMR1 gene. A diagnosis of FXS or other FMR1-related disorders is highly unlikely. No further testing is needed to interrogate the expansions in the FMR1 gene or methylation status. However, the results reveal two unique alleles of FMR1 (which is located on the X chromosome) in an individual reported to be male. As this may indicate a sex chromosome aneuploidy or duplication, cytogenetic studies are recommended.
Two possibilities to consider is that this individual is XX or XXY. In this case, microarray analysis at an outside institution confirmed that this individual is XXY. Klinefelter syndrome is the result of two or more X chromosomes in a phenotypic male. The clinical phenotype includes tall stature, small testes, gynecomastia, and azoospermia. Individuals may also have mild learning disability and psychosocial adjustment issues. Importantly, Klinefelter syndrome has an estimated prevalence of between 1:500 to 1:1000 males. Testing for FMR1 or other genes on the X chromosome may incidentally detect sex chromosome aneuploidy consistent with Klinefelter syndrome.
Further cytogenetic studies for this case were not received at our institution and this patient was lost to follow-up.
Sara Cook, M.D., Ph.D.
Fellow, Molecular Genetic Pathology
Mayo Clinic
Ande Rumilla, MD
Consultant, Laboratory Genetics and Genomics
Mayo Clinic
Assistant Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science
