A 45-year-old previously healthy man presents with rapidly progressive paroxysmal nocturnal dyspnea, orthopnea, and lower extremity edema. Echocardiogram reveals left ventricular dilation and an ejection fraction of 30%. Endomyocardial biopsy is performed for diagnostic purposes. Histologic sections of the myocardium are shown below. Ziehl Neelsen, PAS, and GMS stains are performed and are negative for organisms.

Figure 1: H&E 100x original magnification
Figure 2: H&E 200x original magnification
Figure 3: H&E 400x original magnification

Based on the history and photomicrographs, which of the following is the correct diagnosis?

  • Cardiac sarcoidosis
  • Fungal infection/myocarditis
  • Giant cell myocarditis
  • Eosinophilic myocarditis

The correct answer is ...

Giant cell myocarditis.

Giant cell myocarditis (GCM) is a rapidly progressive idiopathic disease that most often affects healthy young to middle-aged adults. Patients with GCM typically present with acute-onset congestive heart failure. GCM is characterized by a poor prognosis, with a median time from symptom onset to death or cardiac transplant of three months (1). The pathogenesis of GCM is thought to be autoimmune in nature. Proposed mechanisms include degranulation of eosinophils resulting in cardiomyocyte damage, as well as T lymphocyte-mediated immune dysregulation (1). 

Histopathologically, GCM is characterized by an extensive mixed inflammatory infiltrate with widespread myocyte damage. This infiltrate predominantly consists of macrophages, eosinophils, and lymphocytes. In addition, GCM displays multinucleated giant cells scattered throughout the myocardium, but lacks well-formed granulomas. Early in the disease, there is prominent cardiomyocyte necrosis with surrounding inflammatory cells. In later stages of the disease, giant cells become more rare, and reparative fibrosis dominates the histologic picture (2).

The differential diagnosis for GCM includes other types of granulomatous myocarditis, such as mycobacterial myocarditis, fungal myocarditis, and Chagas disease. These infectious etiologies more often affect immunocompromised patients. Microscopically, fungal myocarditis displays prominent neutrophilic inflammatory infiltrates and granulomas, and would be positive for organisms on PAS or GMS histochemical stains. 

The differential also includes cardiac sarcoidosis, which more commonly presents clinically with heart block and arrhythmias, and histopathologically with well-formed, GMS-negative epithelioid granulomas (3). Compared to the eosinophil-rich inflammatory infiltrate of GCM, cardiac sarcoidosis contains fewer eosinophils. Moreover, while both GCM and eosinophilic myocarditis can have prominent eosinophilic inflammation, eosinophilic myocarditis generally lacks abundant giant cells within the inflammatory milieu. 


  1. Ghaly M, Schiliro D, Stepczynski J. Giant Cell Myocarditis: A Time Sensitive Distant Diagnosis. Cureus. 2020;12(1):e6712. Published 2020 Jan 20. doi:10.7759/cureus.6712
  2. Leone O, Pieroni M, Rapezzi C, Olivotto I. The spectrum of myocarditis: from pathology to the clinics. Virchows Arch. 2019 Sep;475(3):279-301. doi: 10.1007/s00428-019-02615-8. Epub 2019 Jul 11. PMID: 31297595.
  3. Okura Y, Dec G, Hare JM, et al. A clinical and histopathologic comparison of cardiac sarcoidosis and idiopathic giant cell myocarditis. Journal of the American College of Cardiology. 2003;41(2):322-329. doi:10.1016/s0735-1097(02)02715-8.

Allison Kerper, M.D.

Resident, Anatomic and 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

Bone marrow banded chromosome analysis was ordered for a 30-year-old man with a suspected diagnosis of acute myeloid leukemia. Banded analysis (Figure 1) has a result of:  

45,X,-Y,add(7)(p11.2),der(8)t(8;21)(q22;q22),der(21)t(7;21)(p15;q22)[20].FISH for t(8;21)(q22;q22) (RUNX1T1/RUNX1) (Figure 2) has a result of: nuc ish(RUNX1T1,RUNX1)x3(RUNX1T1 con RUNX1x1)[369/500]/(RUNX1T1,RUNX1)x3(RUNX1T1 con RUNX1x2)[23/500]

Figure 1: Banded analysis
Figure 2: FISH with RUNX1T1 (red) and RUNX1 (green) probes. One fusion (yellow) is present.

What is the correct interpretation for this case?  

  • The t(7;21) results in a RUNX1/UPS42 fusion and is consistent with AML.
  • The t(8;21) results in a RUNX1/TRPS1 fusion and is consistent with AML.
  • The t(8;21) results in a RUNX1T1/RUNX1 fusion and is consistent with de novo or therapy-related AML.
  • The t(7;21) disrupted the RUNX1T1/RUNX1 fusion from the t(8;21) and is not consistent with AML.

The correct answer is ...

The t(8;21) results in a RUNX1T1/RUNX1 gene fusion and is consistent with de novo or therapy-related acute myeloid leukemia (AML).

The patient’s karyogram demonstrates the presence of both a derivative chromosome 8 from a 8;21 translocation and a derivative chromosome 21 from a 7;21 translocation, along with additional chromatin of undetermined origin attached to the short arm of chromosome 7 and a missing Y chromosome. The t(8;21)(q22;q22) that was the origin of the derivative chromosome 8 results in the fusion of RUNX1T1 and RUNX1, which is associated with AML. FISH subsequently confirmed the presence of the RUNX1T1/RUNX1 fusion gene.

The atypical component of this case was the t(7;21)(p15;q22). The breakpoints for both translocations are the same on chromosome 21. RUNX1 is located on chromosome 21 and RUNX1T1 is located on chromosome 8. The t(8;21) results in different gene fusions on der(8) and der(21). It is the RUNX1T1/RUNX1 fusion gene on der(8) that creates a new oncogenic transcription factor that promotes leukemic transformation. Therefore, even if the fusion product on der(21) is involved in a t(7;21), the fusion product on der(8) remains intact, which is important for this patient’s diagnosis and prognosis.

FISH shows that in the majority of cells, there is one fusion (likely the gene fusion on der(8)) which suggests that the RUNX1T1/RUNX1 fusion on der(21) may be disrupted by the t(7;21) translocation. Regardless of the t(7;21), the presence of the RUNX1T1/RUNX1 fusion is consistent with AML and has a favorable prognosis. 

Lauren Choate

Lauren Choate, Ph.D.

Resident, Laboratory Genetics and Genomics
Mayo Clinic

Jess F Peterson Square Profile pic

Jess Peterson, M.D.

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

The patient is a 34 year-old woman with a history of Diamond-Blackfan anemia. At age 25 she was diagnosed with myelodysplastic syndrome with 5q- syndrome. She began treatment with lenalidomide and continued for nine years with a complete response. Conventional chromosome analysis demonstrated a 5q deletion (Fig.1A). However, fluorescence in situ hybridization (FISH) was discordant and identified two intact copies of EGR1 (5q31) (Fig.1B). Chromosomal microarray was performed to further characterize the breakpoints of the 5q deletion (Fig.1C). 

Figure 1: A B and C

Why did the chromosome study not correlate with FISH?

  • The 5q interstitial deletion is telomeric to EGR1 (at 5q31).
  • The 5q interstitial deletion encompasses EGR1 and the FISH results do correlate.
  • It is best to investigate in the laboratory and inquire about a possible specimen mix-up.
  • Flow sorted cells for myeloid markers should have been used for FISH.

The correct answer is ...

The 5q interstitial deletion is telomeric to EGR1 (at 5q31).

Chromosomal microarray revealed that this bone marrow specimen contained two mosaic interstitial deletions on 5q involving loss of 5q22.1q22.2 and loss of 5q31.3q33.3 (including RPS14 and PDGFRB). Patients with atypical Diamond-Blackfan anemia can have somatically acquired 5q deletions involving RPS14 hapoloinsufficiency. Relying only on FISH using classic probes for the evaluation of MDS (including EGR1 at 5q31) will not represent the complete genomic profile of this malignancy. There is great value in the whole genome approach afforded by chromosome analysis in myeloid malignancies since they divide readily and not all 5q deletions are the same. 

Although it is never incorrect to investigate for a specimen mix-up, the integrated data do support that the FISH result is correct, because the array indicates the deletion is telomeric to EGR1

FISH testing is performed on direct specimen and therefore does not require sorted cells. 


  1. Arenillas L, Mallo M, Ramos F, Guinta K, Barragán E, Lumbreras E, Larráyoz MJ, De Paz R, Tormo M, Abáigar M, Pedro C, Cervera J, Such E, José Calasanz M, Díez-Campelo M, Sanz GF, Hernández JM, Luño E, Saumell S, Maciejewski J, Florensa L, Solé F. Single nucleotide polymorphism array karyotyping: a diagnostic and prognostic tool in myelodysplastic syndromes with unsuccessful conventional cytogenetic testing. Genes Chromosomes Cancer. 2013 Dec;52(12):1167-77. doi: 10.1002/gcc.22112. Epub 2013 Oct 7. PMID: 24123380.
  2. Shaffer LG, Ballif BC, Schultz RA. The use of cytogenetic microarrays in myelodysplastic syndrome characterization. Methods Mol Biol. 2013;973:69-85. doi: 10.1007/978-1-62703-281-0_5. PMID: 23412784.
  3. Vlachos A, Farrar JE, Atsidaftos E, Muir E, Narla A, Markello TC, Singh SA, Landowski M, Gazda HT, Blanc L, Liu JM, Ellis SR, Arceci RJ, Ebert BL, Bodine DM, Lipton JM. Diminutive somatic deletions in the 5q region lead to a phenotype atypical of classical 5q- syndrome. Blood. 2013 Oct 3;122(14):2487-90. doi: 10.1182/blood-2013-06-509935. Epub 2013 Aug 13. PMID: 23943650; PMCID: PMC3790513.

Alaa Koleilat, Ph.D.

Resident, Laboratory Genetics and Genomics
Mayo Clinic

Patricia Greipp, D.O.      

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

Skin biopsy from a non-healing crater-shaped ulcer on the forehead of a 30-year-old man from Minnesota, who recently returned from a wildlife adventure trip to Venezuela.

Figure 1
Figure 2

What is your diagnosis?

  • Histoplasma spp.
  • Trypanosoma cruzi
  • Leishmania spp.
  • Toxoplasma gondii

The correct answer is ...

Leishmania spp.

The biopsy shows dermal chronic inflammation, and intracellular organisms that are 2-5 µm in size, with identifiable nuclei and small, dash-shaped kinetoplasts. These intracellular organisms are consistent with amastigotes. In this case, the clinical history and the morphology are consistent with Leishmania spp. causing cutaneous leishmaniasis. Non-healing skin ulcers in a patient with recent travel to South America should prompt clinicians and diagnosticians to consider this entity. Definitive species identification is achieved by molecular methods in reference laboratories, and is important for treatment, prognosis, and for documenting epidemiological case exposures.

Although Trypanosoma cruzi amastigotes are morphologically indistinguishable from Leishmania, Chagas disease is not compatible with the described clinical presentation; it usually affects cardiac and smooth muscle of the heart and gastrointestinal tract. A chagoma, the skin manifestation of the bite of the triatomine bug, is described as a swelling that can be erythematous or indurated, different from the lesions in our case.

Toxoplasma gondii tachyzoites, the actively dividing form of the parasite, are 4-8 µm elongated structures; this parasite can also be seen as bradyzoites forming tissue cysts, characteristically in the brain.

Histoplasma spp. and other yeasts lack kinetoplasts, but can overlap in size and potentially cause skin lesions.


  1. Burza S, Croft, SL, Boelaert M. Leishmaniasis. The Lancet. 2018;392(10151), 951–970.

Santiago Delgado Fernandez, M.D.

Fellow, Clinical Microbiology
Mayo Clinic

Audrey Schuetz, M.D.

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

A 71-year-old woman with a history of autosomal dominant polycystic kidney disease (ADPKD) and polycystic liver disease, status post living donor transplant two years ago, was found to have a new lesion in the medial inferior left native kidney in a recent follow-up imaging. On CT scan, the lesion was described as an indeterminant heterogeneous and soft tissue attenuating/enhancing mass measuring approximately 6 cm. This mass was FDG-avid compared to the parenchyma and with cystic change on the comparison PET/CT (Figure 1). Given the strong consideration for a primary renal neoplasm, the patient underwent bilateral native kidney nephrectomy.  

Grossly, the cross section of the kidney showed a unifocal, well-circumscribed tumor with a yellow-tan, friable cut surface, in the background of polycystic parenchyma. Microscopic images and immunohistochemical staining are as shown (Figure 2,3). H&E-stained slides demonstrate tubules, microcysts, cords and papillary structures, lined by uniform cuboidal cells with conspicuous nucleoli (evident on medium-power magnification), embedded within a myxoid and focally hyalinized stroma. The tumor focally shows spindle cells morphology. The tumor cells are diffusively positive for CK7 and AMACR (p504s), but negative for c-Kit and CA-IX, with retained expression of fumarate hydratase (FH). Genetic studies revealed loss of chromosomes 1, 4, 6, 8, 9, 13, 14, 15, 22, and X, and gain of 5q31.1q35.3.

Figure 1: PET/CT imaging
Figure 2: Micrographs of different areas of the tumor (x100)
Figure 3: A. CK7, B. AMACR (p504s), C. Fumarate hydratase (FH)

What would be the most likely diagnosis?

  • Clear cell renal cell carcinoma
  • Papillary renal cell carcinoma
  • Mixed epithelial and stromal tumor
  • Clear cell papillary renal cell carcinoma
  • Renal cell carcinoma with sarcomatoid features
  • Mucinous tubular and spindle cell carcinoma
  • Tubulocystic renal cell carcinoma

The correct answer is ...

Mucinous tubular and spindle cell carcinoma.

Mucinous tubular and spindle cell carcinoma (MTSCC) of the kidney is a rare, usually asymptomatic renal neoplasm that can mimic more common renal neoplasms due to its heterogenous morphological features. MTSCC can occur over a wide age range and is more common in women (3-4:1). The staging category is often low (pT1, pT2) at the time of diagnosis, and the tumor is curable by partial or complete nephrectomy. The usual location of MTSCCs is renal cortex. Grossly, they can present as a white or gray to yellow, tan, or even pink mass with a solid cut surface. Typically, MTSCC presents a tubular morphology lined by bland cuboidal cells with areas of spindle cell proliferation in a mucinous background. 

In some cases, MTSCC may present in a “mucin" poor form with elongated and spindled tubular structures as well as focal papillary growth pattern, resembling type 1 PRCC. Immunophenotypically, MTSCC is positive for AMACR, which is normally expressed in proximal collecting tubules of the kidney. However, AMACR is also expressed in other RCCs including PRCC, albeit less so in the sarcomatoid PRCC. Both MTSCC and PRCC also express CK7 and EMA. Additionally, RCC-Ma, high-molecular weight cytokeratin (HMWK), and c-kit are all negative in both MTSCC and papillary RCC. 

Despite the similar morphology and immunophenotypic profile, recent studies have shown that at the molecular level, MTSCC and PRCC are distinct. Multiple genetic abnormalities including losses in chromosomes 1, 4, 6, 8, 9, 13, 14, 15, and 22 are present in MTSCC. However, the characteristic PRCC genetic aberration including trisomy chromosome 7 and 17, and the loss of chromosome Y, have not been reported in MTSCC. Chromosomal microarray performed on our case showed multiple chromosomal losses, and in conjunction with the morphology, supported the diagnosis of MTSCC. 

Due to its spindled component, MTSCC may also be misdiagnosed as sarcomatoid RCC, especially in cases with spindle cell predominance. Considering the poor prognosis of sarcomatoid RCC compared to MTSCC, it is clinically important to distinguish between these morphologically similar entities. The absence of large hyperchromatic, pleomorphic nuclei or significant mitotic activity help distinguish MTSCC from more aggressive RCCs. 

On the other hand, the tubular morphology in MTSCC can be mistaken with other entities such as tubulocystic carcinoma. Microscopically, the latter features tightly packed tubules and cysts with cuboidal to columnar cell lining within a bland fibrous stroma. The cysts can measure up to a few millimeters in diameter, and along with the fibrotic stroma could help distinguish this carcinoma from MTSCC 

Less commonly, MTSCC may display a clear cell pattern within its tubular component, including cytoplasmic pallor, and vacuolisation, but not to the extent that resembles a typical clear cell RCC. Clear cell RCCs may also show variable morphologic patterns (including strong circumferential membranous pattern), but, in contrast to MTSCC, they uniformly express CA-IX and are usually negative or only focally positive for CK7.  

RCCs reported in the background of PCKD include CCRCC, tubulocystic RCC and PRCC. To our knowledge, this is the first report of MTSCC in this context.


  1. Ren Q et al: Mucinous tubular and spindle cell carcinoma (MTSCC): A genome-wide copy number analysis of MTSCC and Its histologic mimickers. Mod Pathol. 28: 2 (Suppl.):254A, 2015
  2. Peckova K et al: Mucinous spindle and tubular renal cell carcinoma: analysis of chromosomal aberration pattern of low-grade, high-grade, and overlapping morphologic variant with papillary renal cell carcinoma. Ann Diagn Pathol. 19(4):226-31, 2015
  3. Srigley JR et al: The International Society of Urological Pathology (ISUP) Vancouver Classification of Renal Neoplasia. Am J Surg Pathol. 37(10):1469-89, 2013
  4. Srigley JR, Delahunt B.Uncommon and recently described renal carcinomas., Mod Pathol. 2009 Jun;22 Suppl 2:S2-S23.
  5. Dhillon J et al: Mucinous tubular and spindle cell carcinoma of the kidney with sarcomatoid change. Am J Surg Pathol. 33(1):44-9, 2009
  6. Argani P et al: Papillary renal cell carcinoma with low-grade spindle cell foci: a mimic of mucinous tubular and spindle cell carcinoma. Am J Surg Pathol. 32(9):1353-9, 2008
  7. Kuroda N et al: Mucinous tubular and spindle cell carcinoma with Fuhrman nuclear grade 3: a histological, immunohistochemical, ultrastructural and FISH study. Histol Histopathol. 23(12):1517-23, 2008
  8. Cossu-Rocca P et al: Renal mucinous tubular and spindle carcinoma lacks the gains of chromosomes 7 and 17 and losses of chromosome Y that are prevalent in papillary renal cell carcinoma. Mod Pathol. 19(4):488-93, 2006

Amir Nazem, M.D., Ph.D.

Resident, Anatomic Pathology and Neuropathology
Mayo Clinic

Maryam Shahi, M.D.

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

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