Pathways Case Studies: December 2022


A 51-year-old woman presents to the ED with right upper quadrant abdominal pain. Contrast CT reveals four hypodense lesions in the right lobe of the liver. The largest lesion, measuring 1.7 cm in greatest dimension, is biopsied. 

Figure 1: H&E 20x
Figure 2: H&E 40x
Figure 3: (left to right) CD31, CAMTA1, ERG

What is your diagnosis?

  • Epithelioid angiosarcoma
  • Epithelioid hemangioendothelioma
  • Metastasis to the liver
  • Epithelioid hemangioma

The correct answer is ...

Epithelioid hemangioendothelioma.

Epithelioid hemangioendothelioma (EHE) is a malignant vascular neoplasm composed of epithelioid endothelial cells in a characteristic myxohyaline stroma. A vast majority of cases (>90%) are characterized by a t (1;3) (p36; q23-q25) resulting in a WWTR1-CAMTA1 fusion, which is demonstrated by CAMTA1 expression by immunohistochemistry. A small subset of EHE cases also undergo a separate translocation event, YAP1-TFE3, which shows a distinct morphology and expresses immunopositivity for TFE3 (which was negative in our case).

EHE most often arises in somatic soft tissue, but can occur in any visceral organ, often arising in liver and lungs. Clinically, it presents as a solitary, often painful mass. Tumors involving preexisting vessels can present with vascular occlusion-type symptoms such as edema and thrombophlebitis. It has a wide age distribution with a slight female predilection. It most commonly occurs in adults age 30-50 years, and rarely occurs in children. Interestingly, these tumors are often multifocal at presentation, which was the case here; our patient had four distinct tumors in the liver.

Morphologically, EHE shows an infiltrative growth pattern consisting of cords and nests of epithelioid cells in a variably myxoid and hyaline stroma. Angiocentric tumors grow outward from vessel walls and spread centrifugally into surrounding tissue. The tumor cells have moderate amounts of eosinophilic cytoplasm and round nuclei with inconspicuous nucleoli. Characteristic intracytoplasmic vacuoles (“blister cells”) representing primitive vascular lumina are often present and may contain erythrocytes.

EHE with YAP1-TFE3 fusion shows distinctive histology characterized by brightly eosinophilic cytoplasm with a solid growth pattern, and often form vascular channels. Notably, this latter feature is not seen in the classic form of EHE. Also, a small subset (<10%) of EHEs have atypical features such as nuclear pleomorphism, increased mitotic activity, solid sheet-like growth, and necrosis. This may resemble epithelioid angiosarcoma, and thus the diagnosis of EHE must be supported with ancillary studies.

The WWR1-CAMTA1 fusion can be demonstrated via immunohistochemistry with positive nuclear expression of CAMTA1, or via molecular testing. EHE also positively expresses endothelial markers CD31 and CD34, as well as ERG and FLI-1. Keratin markers are positive in up to 40% of cases, often with weak and/or focal expression. SMA, desmin, S100, and EMA are negative. As mentioned before, tumors harboring the YAP1-TFE3 fusion shows positive nuclear expression of TFE1.

Prognosis is largely dependent on anatomical location(s). EHE is indolent in most cases, but metastasis is observed in 20%-30% of patients. Tumors can also recur locally (10%-15%). Features that portend a more aggressive clinical course include tumor size >3 cm, elevated mitotic activity (>3 mitoses/50 HPF), severe cytologic atypia, spindled morphology, and the presence of necrosis. Treatment occurs by wide surgical excision with negative margins, and there is no proven role for adjuvant chemotherapy or radiation. 

References

  1. Anderson T, Zhang L, Hameed M, Rusch V, Travis WD, Antonescu CR. Thoracic epithelioid malignant vascular tumors: a clinicopathologic study of 52 cases with emphasis on pathologic grading and molecular studies of WWTR1-CAMTA1 fusions. Am J Surg Pathol. 2015 Jan;39(1):132-9. doi:10.1097/PAS.0000000000000346. PMID: 25353289; PMCID: PMC4268225.
  2. Antonescu CR, Le Loarer F, Mosquera JM, Sboner A, Zhang L, Chen CL, Chen HW, Pathan N, Krausz T, Dickson BC, Weinreb I, Rubin MA, Hameed M, Fletcher CD. Novel YAP1-TFE3 fusion defines a distinct subset of epithelioid hemangioendothelioma. Genes Chromosomes Cancer. 2013 Aug;52(8):775-84. doi:10.1002/gcc.22073. Epub 2013 Jun 5. PMID: 23737213; PMCID: PMC4089994.
  3. Deyrup AT, Tighiouart M, Montag AG, Weiss SW. Epithelioid hemangioendothelioma of soft tissue: a proposal for risk stratification based on 49 cases. Am J Surg Pathol. 2008 Jun;32(6):924-7. doi:10.1097/pas.0b013e31815bf8e6. PMID: 18551749.
  4. Errani C, Zhang L, Sung YS, et al. A novel WWTR1-CAMTA1 gene fusion is a consistent abnormality in epithelioid hemangioendothelioma of different anatomic sites. Genes Chromosomes Cancer. 2011;50(8):644-653. doi:10.1002/gcc.20886
  5. Mentzel T, Beham A, Calonje E, Katenkamp D, Fletcher CD. Epithelioid hemangioendothelioma of skin and soft tissues: clinicopathologic and immunohistochemical study of 30 cases. Am J Surg Pathol. 1997 Apr;21(4):363-74. doi: 10.1097/00000478-199704000-00001. PMID: 9130982.
  6. Rosenbaum E, Jadeja B, Xu B, et al. Prognostic stratification of clinical and molecular epithelioid hemangioendothelioma subsets. Mod Pathol. 2020;33(4):591-602. doi:10.1038/s41379-019-0368-8
  7. Rubin BP, Doyle AL, Deyrup AT, et al. Soft tissue tumours / Vascular tumours / Epithelioid haemangioendothelioma. In: WHO Classification of Tumours Editorial Board. Soft tissue and bone tumours. Lyon (France): International Agency for Research on Cancer; 2020. (WHO classification of tumours series, 5th ed.; vol. 3). https://publications.iarc.fr/588.
  8. Tanas MR, Sboner A, Oliveira AM, et al. Identification of a disease-defining gene fusion in epithelioid hemangioendothelioma. Sci Transl Med. 2011;3(98):98ra82. doi:10.1126/scitranslmed.3002409

David Cook, M.D.

Resident, Anatomic Pathology/Neuropathology 
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 34-year-old man with a family history of premature cardiac disease and ankle xanthoma presented to his primary care provider’s office for annual exam. A glance at the patient’s chart in the electronic health record showed a Best Practice Advisory (BPA) alert. Patient’s LDL-C level was 195 mg/dL.

Figure 1

Which of the following is the best point to implement this BPA alarm?

  • When the patient leaves the office.
  • When the patient is being roomed.
  • When the patient checks in for their appointment.
  • When the provider is seeing the patient.

The correct answer is ...

When the provider is seeing the patient.

With a prevalence ranging from 0.25% (1:400) to 0.52% (1:192) depending on ethnicity. Many patients with familial hypercholesterolemia (FH) are unaware of their diagnosis and consequently miss proper medical treatment. A provider can establish the diagnosis based on history, physical examination, and simple laboratory tests. Applying Dutch criteria, this patient presented with a family history of premature CVD (1 point), tendon xanthoma (6 points), and elevated LDL-C in the range of 190-249 mg/dL (5 points), resulting in a “definite” diagnosis overall score (>8) for FH. Genetic testing is available for this condition but may not be needed unless there is a need to evaluate risk in other family members. Pharmacological therapy is indicated along with lifestyle modifications (diet, exercise, and smoking cessation). 

Physicians may rely on clinical decision support (CDS) tools embedded within the electronic medical record (EMR) to detect abnormal LDL-C results that are associated with FH. This Best Practice Advisory (BPA) is an example of one such CDS tool. This tool will take an input (e.g., lipid panel blood results), apply one or more rules to that input, and use the results of those rules to decide to execute (or not to execute) a specific action. In this example, the BPA triggers an alert offering the provider the option to prescribe high-intensity statin to this patient given the patient’s LDL-C was 190 mg/dL or greater.

The CDS Five Rights Model is one framework to use for the proper design, implementation, and sustainability of a CDS tool. The model consists of the right information, the right person, the right CDS intervention format, the right channel, and the right time in a workflow. Success of the CDS intervention is contingent on the success of each of these components individually. 

The right information is the data and evidence being used to generate a BPA. Adhering to data and interoperability standards assures the timeliness and the integrity of data. The right person is the user who needs to make an intervention based on the CDS; in this case it is the provider. CDS has various formats (reminders, alarms, and order sets). Reminders can be silent and may not interrupt workflows. Alarms may be needed for high-impact instances of care. Right channels can be EHR, paper flowsheets, or mobile device apps. In this case, EHR was better suited as a channel due to regulatory and business needs. 

The last component is the right timing. The provider mostly needs to see this alarm when the patient is present at the point of care. Firing the alarm not at the point of care may disrupt other workflows and may not lead to effective intervention and redundancy. Silent reminders can be used outside the point of care, as they are less likely to interrupt the workflow. 

Firing the alarm when the patient checks in or out is inappropriate due to unsuitable timing (patient is in the waiting room) and inappropriate person (front desk staff). Similarly, interruption may occur to nursing staff if this alarm fires. The alarm is most productive when it fires when the provider is at the point of care and the patient is being roomed (right time and right person). Using an alarm BPA in an EHR environment based on quality data standards and evidence-based rules will complete the full house of the Five Rights in a CDS. 

References

  1. Toft-Nielsen F, Emanuelsson F, Benn M. Familial hypercholesterolemia prevalence among ethnicities-systematic seview and meta-analysis. Front Genet. 2022 Feb 3;13:840797. doi:10.3389/fgene.2022.840797. PMID: 35186049; PMCID: PMC8850281. 
  2. https://www.cdc.gov/genomics/disease/fh/medical_options.htm 
  3. McGowan MP, Hosseini Dehkordi SH, Moriarty PM, Duell PB. Diagnosis and treatment of heterozygous familial hypercholesterolemia. J Am Heart Assoc. 2019 Dec 17;8(24):e013225. doi:10.1161/JAHA.119.013225. Epub 2019 Dec 16. PMID: 31838973; PMCID: PMC6951065.
  4. https://www.mayoclinic.org/diseases-conditions/familial-hypercholesterolemia/diagnosis-treatment/drc-20353757 
  5. Stone NJ, Robinson JG, Lichtenstein AH, et al. American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014 Jul 1;63(25 Pt B):2889-934. doi:10.1016/j.jacc.2013.11.002. Epub 2013 Nov 12. Erratum in: J Am Coll Cardiol. 2014 Jul 1;63(25 Pt B):3024-3025. Erratum in: J Am Coll Cardiol. 2015 Dec 22;66(24):2812. PMID: 24239923.
  6. Safarova MS, Kullo IJ (2016, June 1). My approach to the patient with familial hypercholesterolemia. Mayo Clin. Proc. Retrieved Nov. 9, 2022; https://www.mayoclinicproceedings.org/article/S0025-6196(16)30121-5/fulltext 
  7. Fry C. Development and evaluation of best practice alerts: Methods to optimize care quality and clinician communication. AACN Adv Crit Care. 2021 Dec 15;32(4):468-472. doi:10.4037/aacnacc2021252. PMID: 34879138.
  8. Semler, SC. LOINC: Origin, development of and perspectives for medical research and biobanking – 20 years on the way to implementation in Germany. Journal of Laboratory Medicine, vol. 43, no. 6, 2019, pp. 359-382. https://doi.org/10.1515/labmed-2019-0193 
  9. Sirajuddin AM, Osheroff JA, Sittig DF, Chuo J, Velasco F, Collins DA. Implementation pearls from a new guidebook on improving medication use and outcomes with clinical decision support. Effective CDS is essential for addressing healthcare performance improvement imperatives. J Healthc Inf Manag. 2009 Fall;23(4):38-45. PMID: 19894486; PMCID: PMC3316472.
  10. Douthit BJ, Musser RC, Lytle KS, Richesson RL. A closer look at the "right" format for Clinical Decision Support: methods for evaluating a storyboard bestpractice advisory. J Pers Med. 2020 Sep 23;10(4):142. doi:10.3390/jpm10040142. PMID: 32977564; PMCID: PMC7712422.

    EzzAddin Al Wahsh, M.D., M.B.A.

    Fellow, Clinical Informatics
    Mayo Clinic

    Justin Juskewitch, M.D., Ph.D.

    Senior Associate Consultant, Transfusion Medicine
    Mayo Clinic
    Assistant Professor of Laboratory Medicine and Pathology
    Mayo Clinic College of Medicine and Science


    A 42-year-old man presented for management of scrotal abscess and was found to have a 3.6 cm endophytic renal mass in the mid-right kidney on imaging. Ultrasound-guided right kidney mass biopsy was performed, and the hematoxylin and eosin-stained slides were reviewed. Several immunohistochemical studies were also performed and the figures are shown below.

    Figure 1. 42M NR-22-10655 20X
    Figure 2. 42M NR-22-10655 40X
    Figure 3. 42M NR-22-10655 60X CA-IX cup shaped
    Figure 4. 42M NR-22-10655 60X CK AE1-AE3
    Figure 5. 42M NR-22-10655 60X CK7
    Figure 6. 42M NR-22-10655 60X GATA3
    Figure 7. 42M NR-22-10655 60X PAX8

    Based on the histomorphology and immunohistochemical studies, what is the correct diagnosis?

    • Clear cell renal cell carcinoma.
    • Clear cell papillary renal cell tumor.
    • TFE3-rearranged renal cell carcinoma.
    • Papillary renal cell carcinoma.

    The correct answer is ...

    Clear cell papillary renal cell tumor.

    The hematoxylin-eosin stained slide sections show a mixture of tubular/acinar and papillary patterns in the background of hyalinized stroma. The tumor cells are cuboidal to low columnar cell with clear cytoplasm, and low-grade nuclei are horizontally arranged away from the basement membrane. Hemosiderin deposition, necrosis, foamy macrophages and psammoma bodies are absent.

    The immunohistochemical (IHC) study slides show the neoplastic cells are diffusely positive for CK AE1/AE3, CK7, PAX8, CA-IX, and GATA3. CA-IX staining is of characteristic “cup”-like pattern with apical surface of the tumor cells devoid of staining. The combined histology along with immunohistochemistry is most consistent with clear cell papillary renal cell tumor. 

    Clear cell papillary renal cell tumour (CCPRCT) is a recently described entity, recognized by the World Health Organization in 2016 that shares microscopic features with both clear cell renal cell carcinoma (CCRCC) and papillary renal cell carcinoma. CCPRCT is a low-grade and indolent tumor regarding its biological behavior. A substantial majority of cases demonstrate low pathologic staging at the time of presentation or initial diagnosis, with >90% of patients having primary tumor stage I. This tumor was originally described in the setting of end-stage kidney disease; since then, multiple studies have demonstrated that CCPRCT occurs sporadically and is the fourth most common RCC subtype. Partial nephrectomy or total nephrectomy is generally the treatment provided for a solitary tumor when surgical resection is feasible. As this tumor is generally indolent, active surveillance with strict follow-up may be possible for selective cases and if the diagnosis can be reliably established preoperatively such as by a core biopsy.

    Clear cell renal cell carcinoma has predominantly clear cells with sharp cell borders with fine arborizing vascularity that surround essentially every nest of tumor cells. High nuclear grade, the immunohistochemical positivity for CD10, CA-IX (box-like) and negativity of cytokeratin 7 and AMACR, and loss of chromosome 3p or VHL gene alterations can achieve the final diagnosis of clear cell RCC.

    Papillary renal cell carcinoma has papillary and tubular architecture with cuboidal to columnar cells (often basophilic) with foamy macrophages and psammoma bodies. Positivity for cytokeratin 7 and AMACR and polysomy of chromosomes 7 and 17 and loss of chromosome Y can lead to the diagnosis of papillary RCC. Clear cell change in papillary RCC is usually in combination with hemosiderin deposition and/or necrosis, and this cytoplasmic clearing may reflect phagocytic activity of carcinoma cells 

    In TFE3-rearranged renal cell carcinoma, papillary architecture, voluminous tumor cells, psammoma bodies or hyaline nodules may be observed. Nuclear TFE3 and negativity for epithelial markers may be helpful in the distinction between CCPRCT and TFE3-rearranged RCC.

    References

    1. Griffin BB, Lin X. Cytomorphologic analysis of clear cell papillary renal cell carcinoma: Distinguishing diagnostic features. Cancer Cytopathol. 2021 Mar;129(3):192-203. doi:10.1002/cncy.22355. Epub 2020 Oct 9. PMID: 33036062.
    2. Jianping Zhao, Eduardo Eyzaguirre; Clear Cell Papillary Renal Cell Carcinoma. Arch Pathol Lab Med 1 September 2019; 143 (9): 1154–1158. doi:https://doi.org/10.5858/arpa.2018-0121-RS
    3. Sayeed S, Lindsey KG, Baras AS, Jackson C, Powers CN, Uram-Tuculescu C, Smith SC. Cytopathologic features of clear cell papillary renal cell carcinoma: A recently described variant to be considered in the differential diagnosis of clear cell renal epithelial neoplasms. Cancer Cytopathol. 2016 Aug;124(8):565-72. doi:10.1002/cncy.21721. Epub 2016 Apr 7. PMID: 27062008. https://pubmed.ncbi.nlm.nih.gov/27062008/
    4. Kuroda N, Ohe C, Kawakami F, Mikami S, Furuya M, Matsuura K, Moriyama M, Nagashima Y, Zhou M, Petersson F, López JI, Hes O, Michal M, Amin MB. Clear cell papillary renal cell carcinoma: a review. Int J Clin Exp Pathol. 2014 Oct 15;7(11):7312-8. PMID: 25550767; PMCID: PMC4270541.

    Anu Abraham, M.B.B.S.

    Fellow, Surgical Pathology
    Mayo Clinic
    @Dr_AnuAbrahamMD

    Charles Sturgis, M.D.

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


    A 65-year-old woman presents with a history of bronchiectasis, asthma, previous fungal and non-tuberculous mycobacteria infection, and psoriatic arthritis status post methotrexate and other immunosuppressive treatment. A recent CT showed soft tissue masses concerning for malignancy in the left upper and lower lobes, but no associated activity on PET/CT is seen. Bronchoscopy showed white friable endobronchial masses corresponding to the CT masses, sampled by endobronchial biopsy.

    Figure 1: Intraluminal material (20x, H&E)
    Figure 2: Intraluminal material (40x, H&E)
    Figure 3: Intraluminal material (40x, H&E)
    Figure 4: Airway wall (20x, H&E)

    Based on the H&E morphology, what is the most common causative agent for this condition?

    • Fusarium vasinfectum
    • Mycobacteria abscessus
    • Aspergillus fumigatus
    • Histoplasma capsulatum
    • Candida albicans

    The correct answer is ...

    Aspergillus fumigatus.

    Biopsies of the mass demonstrate large amounts of mucin and proteinaceous exudates containing Charcot-Leyden crystals and numerous (often necrotic) eosinophils, arranged in a lamellar configuration, consistent with allergic mucin. 

    There are also fragments of benign airway mucosa with increased submucosal eosinophils, focal mucus cell hyperplasia, basement membrane thickening, and Charcot-Leyden crystals. No granuloma or malignancy are identified. The airway changes are compatible with asthma.

    Grocott Methenamine Silver and Ziehl-Neelsen stains were negative for fungal and mycobacterial organisms, respectively. 

    The presence of allergic mucin with background asthma-like airway changes, and a clinical history of asthma, is highly suggestive of allergic bronchopulmonary aspergillosis (ABPA). A positive GMS stain, typically showing scattered fragmented fungal hyphae, would have been diagnostic of ABPA.1 However, as in this case, fungi are not always identified on GMS in cases of ABPA. Thus additional clinical work-up will be necessary to confirm the diagnosis. In this patient, the masses seen on imaging likely  correspond to impacted mucus. 

    ABPA is caused by hypersensitivity to fungi, usually to Aspergillus species, particularly A. fumigatus, but may be caused by other fungi as well (e.g., Candida albicans, Fusarium vasinfectum, Curvularia lunata, Helminthosporium, etc.). Hence it is also known as allergic bronchopulmonary fungal disease.1

    Clinically, ABPA is seen mostly in patients with asthma, and occasionally those with cystic fibrosis.2 However, rare cases of ABPA without asthma or cystic fibrosis have been reported.As such, ABPA often presents as poorly controlled asthma and/or acute pneumonia secondary to bronchial obstruction. Expectoration of brownish mucus plugs is a characteristic symptom, but is seen only in a third of the patients. Some patients are asymptomatic.1,2

    On CT imaging, mucus impaction and upper-lobe bronchiectasis are typical findings. Although impacted mucus is commonly hypodense, the presence of high-attenuation mucus (denser than paraspinal skeletal muscle) indicates severe disease, and is considered pathognomonic for ABPA.The impacted mucus may also present radiographically as V- or Y-shaped densities or a “cluster of grapes” in the proximal bronchi, with associated distal collapse or consolidation. Rounded densities are a rare imaging finding in ABPA, and may cause confusion with neoplasms.1

    Pathologically, ABPA manifests most often as mucoid impaction of bronchi (MIB), frequently accompanied by eosinophilic pneumonia and/or bronchocentric granulomatosis. The histologic hallmark of MIB is the presence of allergic mucin, which is inspissated mucin with a characteristic lamellar appearance caused by alternating layers of degenerating cells (mostly eosinophils) and blue-gray to eosinophilic mucin, as seen in this case. Charcot-Leyden crystals — considered to be eosinophil breakdown products — are always present in allergic mucin. These crystals are greatly variable in size, and appear bipyramidal in longitudinal section, but hexagonal in cross section. Neutrophils are never numerous. GMS stains may highlight scattered, fragmented fungal hyphae in the mucin. Given the importance of allergic mucin for the diagnosis, intraluminal mucinous material in bronchiectasis should be sampled, and not washed out and discarded.1,2

    Further to MIB, lung parenchyma adjacent to ABPA often shows eosinophilic pneumonia, featuring alveolar filling by eosinophils and macrophages. In airways distal to MIB, bronchocentric granulomatosis is often also present, showing airway-centric necrotizing granulomas that may destroy bronchioles. However, as bronchocentric granulomas may also appear in the settings of other infections, rheumatoid arthritis, and granulomatosis with polyangiitis, careful histologic assessment and clinical correlation is necessary, especially in patients without a known asthmatic history.1,2,4

    ABPA is typically diagnosed clinically, by combining clinical, immunologic/microbiological, and imaging findings. Diagnostic criteria generally include a history of asthma or cystic fibrosis, peripheral blood eosinophilia, elevated serum IgE (total and aspergillus-specific), bronchiectasis on CT, and immediate cutaneous reactivity to aspergillus antigens. However, a widely accepted diagnostic criteria has yet to be established.1,2,5

    Treatment for ABPA involves corticosteroids and sometimes antifungal agents. Anti-IgE agents such as omalizumab are sometimes used as second-line treatment. Early diagnosis and treatment of ABPA is important, especially in cases without clinical suspicion, as recurrences are common in untreated cases and may lead to irreversible fibrosis.1,2

    References

    1. Katzenstein, AL., Diagnostic Atlas of Non-Neoplastic Lung Disease : A Practical Guide for Surgical Pathologists. 2016: Demos Medical.
    2. Agarwal R, Muthu V, Sehgal IS, Dhooria S, Prasad KT, Aggarwal AN. Allergic bronchopulmonary aspergillosis. Clin Chest Med. 2022 Mar;43(1):99-125. doi:10.1016/j.ccm.2021.12.002. PMID: 35236565.
    3. Kaur P, Kumar P, Randev S, Guglani V. Allergic bronchopulmonary aspergillosis without asthma or cystic fibrosis. Paediatr Int Child Health. 2020 Aug;40(3):199-201. doi:10.1080/20469047.2020.1744872. Epub 2020 Apr 2. PMID: 32238049.
    4. Rosen Y. Pathology of Granulomatous Pulmonary Diseases. Arch Pathol Lab Med. 2022 Jan 2;146(2):233-251. doi:10.5858/arpa.2020-0543-RA. PMID: 33905479.
    5. Saxena P, Choudhary H, Muthu V, et al. Which are the optimal criteria for the diagnosis of allergic bronchopulmonary aspergillosis? A latent class analysis. J Allergy Clin Immunol Pract. 2021 Jan;9(1):328-335.e1. doi:10.1016/j.jaip.2020.08.043. 

    Cheuk Ki (Jackie) Chan, M.D.

    Fellow, Pulmonary Pathology
    Mayo Clinic

    Marie-Christine Aubry, M.D.

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


    The patient is a 33-year-old woman who is two months post-partum. She has a past medical history of mild pregnancy-associated hypertension during her first pregnancy six years ago. During her most recent pregnancy, she was hospitalized for possible preeclampsia, and she received treatment with magnesium sulfate. Serum creatinine was noted to be elevated at 2.19 mg/dL on admission and was 2.13 mg/dL at discharge. She was non-hypertensive at discharge. On follow-up, her serum creatinine was 1.98 mg/dL, and her serum albumin was normal at 4.3 g/dL. She did not have significant proteinuria and has no family history of renal disease. 

    Figure 1: Low-power view of kidney core biopsy, demonstrating a focus of fibrosis with associated moderate mononuclear inflammation. Even from low-power magnification, tubular nucleomegaly is striking (H&E, 4x). 
    Figure 2: Many proximal tubular nuclei show pleomorphic and enlarged nuclei. Some nuclei have bizarre shapes (H&E 10x). 
     
    Figure 3: Electron micrograph of the tubules shows enlarged nuclei with irregular nuclear contours. Some nuclei have prominent nucleoli (EM, 1.5kx)

    What is the most probable cause of the nuclear findings in the tubules? 

    • Genetic mutation
    • Radiation therapy
    • Magnesium sulfate effect
    • Viral infection

    The correct answer is ...

    Genetic mutation.

    This is a case of karyomegalic interstitial nephritis (KIN), also known as karyomegalic nephropathy or systemic karyomegaly, which is a rare chronic tubulointerstitial nephritis most frequently caused by a genetic mutation in the FAN1 gene. In this case, whole exome sequencing later revealed a pathogenic homozygous frameshift mutation in FAN1 resulting in premature FAN1 protein truncation. Along with the morphologic and clinical findings, this further supports a diagnosis of autosomal recessive KIN.

    The kidney biopsy contains tubules with pleomorphic, bizarre, and enlarged nuclei. Multinucleation and irregular nuclear membrane contours are frequently seen. Though rare macronucleoli are seen, nucleoli are generally inconspicuous to small. The tubular nuclei are approximately 2-5x larger than usual. Viral cytopathic effect is not appreciated. Overall, there is moderate tubular atrophy and interstitial fibrosis with associated mononuclear inflammation. Immunofluorescent microscopy studies are essentially negative. Electron microscopy reiterates the nuclear irregularities and enlargement in the tubules and the absence of viral cytopathic effect. These findings are most consistent with karyomegalic interstitial nephritis (KIN).

    Karyomegalic interstitial nephritis (KIN) is rare, with approximately 50 cases reported in the literature. The known cases have generally presented in young adults (median: 33 years) and mostly in individuals of European and Maori descent. Presentation is variable: early-onset end-stage kidney disease is often seen, and cases may also exhibit elevated serum markers of hepatocyte damage, mild anemia, and recurrent upper respiratory infections. Most cases have been linked to autosomal recessive mutations in FAN1, which encodes Fanconi anemia-associated nuclease-1, a protein that repairs DNA interstrand crosslink damage and controls DNA ploidy in renal tubular cells. This protein is most highly expressed in kidney, liver, and neuronal tissue. Nuclear changes can be seen in these other tissues, but the kidney is most likely to be affected pathologically by fibrosis and inflammation. Often, along with the characteristic karyomegaly, kidney biopsies will show chronic inflammatory changes — interstitial fibrosis, tubular atrophy, and mononuclear inflammation, as in this case. Ki67 expression is typically reduced, and mitotic figures are usually absent. Of note, karyomegalic cells can shed in urine and can mimic viral cytopathic effect or even carcinoma in urine cytology specimens.

    Patients often slowly but inevitably progress to renal failure, likely due to inadequate DNA repair after injury. Though kidney malignancies with FAN1 mutations have not been reported, FAN1 mutations have been implicated as risk factors in colorectal and pancreatic cancers. There is no effective treatment available for KIN. At least one reported case has shown recurrence of KIN in an allograft kidney transplant, though the donor kidney was the patient’s sibling, raising the possibility of quiescent KIN present in the donor. 

    Though KIN is sometimes associated with chemotherapeutic agents (particularly ifosfamide) and mycotoxins (particularly ochratoxin), there is no known association with magnesium sulfate use. This patient has no history of radiation therapy; further, radiation therapy effect tends to be more restricted in distribution. Viral cytopathic effect from adenovirus, polyomaviruses, and CMV can be somewhat similar in appearance, but electron microscopy and immunohistochemistry can help with the diagnosis in difficult cases. Viral infections also tend to have more tubulitis and can have plasma cells if longstanding. There is no known association between autoimmune disease and KIN. 

    References

    1. Zhou W, Otto EA, Cluckey A, Airik R, Hurd TW, Chaki M, Diaz K, Lach FP, Bennett GR, Gee HY, Ghosh AK, Natarajan S, Thongthip S, Veturi U, Allen SJ, Janssen S, Ramaswami G, Dixon J, Burkhalter F, Spoendlin M, Moch H, Mihatsch MJ, Verine J, Reade R, Soliman H, Godin M, Kiss D, Monga G, Mazzucco G, Amann K, Artunc F, Newland RC, Wiech T, Zschiedrich S, Huber TB, Friedl A, Slaats GG, Joles JA, Goldschmeding R, Washburn J, Giles RH, Levy S, Smogorzewska A, Hildebrandt F. FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair. Nat Genet. 2012 Jul 8;44(8):910-5.
    2. Thongthip S, Bellani M, Gregg SQ, Sridhar S, Conti BA, Chen Y, Seidman MM, Smogorzewska A. Fan1 deficiency results in DNA interstrand cross-link repair defects, enhanced tissue karyomegaly, and organ dysfunction. Genes Dev. 2016 Mar 15;30(6):645-59.
    3. Isnard P, Rabant M, Labaye J, Antignac C, Knebelmann B, Zaidan M. Karyomegalic interstitial nephritis: a case report and review of the literature. Medicine (Baltimore). 2016 May;95(20):e3349.
    4. Palmer D, Lallu S, Matheson P, Bethwaite P, Tompson K. Karyomegalic interstitial nephritis: a pitfall in urine cytology. Diagn Cytopathol. 2007 Mar;35(3):179-82.
    5. Monga G, Banfi G, Salvadore M, Amatruda O, Bozzola C, Mazzucco G. Karyomegalic interstitial nephritis: report of 3 new cases and review of the literature. Clin Nephrol. 2006 May;65(5):349-55. 
    6. McCulloch T, Prayle A, Lunn A, Watson AR. Karyomegalic-like nephropathy, Ewing's sarcoma and ifosfamide therapy. Pediatr Nephrol. 2011 Jul;26(7):1163-6. 
    7. Ravindran A, Cortese C, Larsen CP, Wadei HM, Gandhi MJ, Cosio FG, Sethi S. Karyomegalic interstitial nephritis in a renal allograft. Am J Transplant. 2019 Jan;19(1):285-290.
    8. Colvin RB, Chang, AC. Systemic Karyomegaly. In "Diagnostic Pathology: Kidney Diseases" (2019) (3rd ed., pp. 744–747). Elsevier.

    Salvatore Mignano, D.O.

    Fellow, Renal Pathology 
    Mayo Clinic

    Mary Fidler, M.D.

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


    A 53-year-old man diagnosed with Babesia microti two weeks ago status-post atovaquone and azithromycin for one week and clindamycin and primaquine for five days presents with worsening jaundice and anemia. Labs showed: hemoglobin 6.0g/dL (13.3g/dL two weeks ago), total bilirubin 2.6mg/dL, LDH 1855U/L, and reticulocytes 18%. Normal platelets and creatinine. Parasitemia <0.1% by peripheral smear. Direct antiglobulin test 2+ for IgG and 2+ for C3. No recent transfusions. History of pancreatic adenocarcinoma status-post Whipple procedure and splenectomy.

    What is the most probable cause of this patient’s worsening anemia?

    • Severe Babesiosis
    • Transfusion reaction
    • Autoimmune hemolytic anemia
    • Drug-induced oxidative hemolysis

    The correct answer is ...

    Autoimmune hemolytic anemia.

    Autoimmune hemolytic anemia is a rare complication of Babesiosis. The onset is two to three weeks after the initial diagnosis. Risk factors include asplenia and immunocompromise. Laboratory findings include decreased hemoglobin, elevated hemolysis labs (i.e., bilirubin, LDH, reticulocytes), and a direct antiglobulin test positive for IgG with or without C3. Cases have been successfully treated with steroids and rituximab. 

    Although severe Babesiosis can cause significant hemolytic anemia due to merozoite egress, this patient has been on two weeks of appropriate antimicrobials and has a peripheral smear showing <0.1% parasitemia. In cases of severe Babesiosis, red blood cell exchanges every day until parasite burden is <5% is an ASFA Category II indication.

    Drug-induced oxidative hemolysis can occur with primaquine in the setting of G6PD deficiency. In this case, the G6PD status of the patient was not known. However, drug-induced hemolysis has an onset within 24 hours. This patient has been on primaquine for five days, making this diagnosis less likely. 

    A delayed hemolytic transfusion reaction can present with elevated hemolysis labs as well as a positive direct antiglobulin test. However, in this case the patient’s history was negative for any recent transfusions. 

    References

    1. Harewood J, Ramsey A, Master SR. Hemolytic Transfusion Reaction. [Updated 2022 Jul 18]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK448158/
    2. Rajapakse P, Bakirhan K. Autoimmune Hemolytic Anemia Associated With Human Babesiosis. J Hematol. 2021 Apr;10(2):41-45. doi: 10.14740/jh820. Epub 2021 Apr 27. PMID: 34007364; PMCID: PMC8110228.
    3. Woolley AE, Montgomery MW, Savage WJ, et al. Post-Babesiosis warm autoimmune hemolytic anemia. N Engl J Med. 2017;376:939-46.
    4. Narurkar R, Mamorska-Dyga A, Nelson JC, Liu D. Autoimmune hemolytic anemia associated with babesiosis. Biomark Res. 2017;5:14.
    5. Barcellini W, Fattizzo B. How I treat warm autoimmune hemolytic anemia. Blood. 2021 Mar 11;137(10):1283-1294. doi:10.1182/blood.2019003808. PMID: 33512406.

    Edwin Lin, M.D., Ph.D.

    Resident, Anatomic/Clinical Pathology 
    Mayo Clinic

    Anand Padmanabhan, M.B.B.S., Ph.D.

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


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