A 64-year-old man presented with an ulcerated lesion on his fifth finger. Biopsy demonstrated epithelioid malignant appearing cells with nuclear expression of ERG, resulting in a diagnosis of “malignant mesenchymal neoplasm” favoring angiosarcoma. Tumor cells also expressed cytokeratin AE1/AE3. Subsequent amputation specimen (Figures 1 and 2) showed an infiltrative neoplasm composed of malignant epithelioid cells, focally forming pseudovascular spaces. Immunohistochemistry for INI-1 showed loss of nuclear expression. AE1/AE3 was positive and repeated IHC for ERG was negative.

Figure 1
Figure 2

Which of the following statements are true regarding epithelioid sarcoma? 

  • Epithelioid sarcoma shows a predilection for bone metastases.
  • Epithelioid sarcomas may mimic granulomatous inflammatory processes.
  • Most epithelioid sarcomas harbor deletions in the SMARCA4 gene.
  • Approximately 50% of epithelioid sarcomas express CD31.

The correct answer is ...

Epithelioid sarcomas may mimic granulomatous inflammatory processes.

Epithelioid sarcomas may mimic granulomatous inflammatory processes, in part due to an interstitial growth pattern of tumor cells that often show limited cytologic atypia, and thus may be prone to misinterpretation as histiocytes. Additionally, there may be necrosis similar to what may be seen in infectious processes. Epithelioid sarcomas show a predilection for lymph node metastases (not bone metastases). The majority (approximately 95%) of epithelioid sarcomas harbor genetic deletions of SMARCB1, and loss of INI1 expression in tumor cell nuclei is often used as a surrogate marker for this event. By contrast, SMARCA4 gene deletions are seen in fewer than 5% of epithelioid sarcomas, and loss of BRG1 nuclear expression can be used as a surrogate. Finally, CD34 expression occurs in approximately 50% of epithelioid sarcomas. ERG expression can also be seen in up to 40% of cases. Expression of these markers may lead to a misinterpretation as angiosarcoma, particularly when combined with a pseudovascular morphologic pattern. However, CD31 (a relatively specific vascular marker) is consistently negative in epithelioid sarcomas.


  1. Oda, Y., Nielsen, T.O., Dal Chin, P., et al. World Health Organization Classification of Tumours, Bone and Soft Tissue Tumours, 5th ed. 2020. International Agency for Research on Cancer. 33, 127.

Suzanna Logan, M.D., Ph.D.

Fellow, Bone and Soft Tissue Pathology
Mayo Clinic

Ray Guo, M.D., Ph.D.

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

A 32-year-old woman presented with a palpable retroareolar right breast mass. Ultrasound examination showed a well-circumscribed mass measuring 2 cm in the greatest dimension at the 5:00 position. She underwent a biopsy and a subsequent local excision.

Figure 1: H&E, 10x
Figure 1: H&E, 40x
Figure 1: p63, 40x
Figure 1: CD117, 40x

What is your diagnosis?

  • Collagenous spherulosis.
  • Adenomyoepithelioma.
  • Adenoid cystic carcinoma.
  • Ductal carcinoma in situ (DCIS), cribriform pattern.

The correct answer is ...

Adenoid cystic carcinoma.

Adenoid cystic carcinoma (AdCC) of the breast is a rare entity, and it usually presents in elderly women as a palpable mass, but it can affect younger women and men as well. The retroareolar region is the most frequently affected site but it can arise in any quadrant. Complete excision with negative margins is recommended. Lymph node metastasis and recurrence are rare. 

Histologically, AdCC is an invasive carcinoma composed of neoplastic epithelial and myoepithelial cells. It is arranged in tubular, cribriform and solid patterns and it is associated with basophilic matrix. Three subtypes have been defined: classic AdCC, solid-basaloid AdCC, and AdCC with high-grade transformation. Immunoperoxidase studies demonstrate two distinct cell populations. Myoepithelial cells, which are positive for p63, smooth muscle actin, calponin and cytokeratins 14 and 17. Not all tumors will be positive for all myoepithelial markers. Luminal cells are positive for low molecular weight keratins, epithelial membrane antigen, carcinoembryonic antigen, and CD117. AdCC is predominantly negative for ER, PR and Her2. The most common finding is a chromosomal translocation: t(6;9)(q22-23;p23-24) resulting in a MYB-NFIB gene fusion. 

An important differential diagnosis is collagenous spherulosis (CS). Both AdCC and CS are composed of myoepithelial and luminal cells. Myoepithelial cells in CS are often positive for multiple immunohistochemical markers. Luminal cells are less likely to be positive for CD117 and are more frequently positive for ER and PR in CS. Other differential diagnoses include cylindroma, adenomyoepithelioma, ductal carcinoma in situ with a cribriform pattern, invasive cribriform carcinoma, and basal-like breast carcinoma.


  1. Allison, KH, Brogi, E, et al. WHO Classification of Tumors of Breast. Lyon, France: IARC; 2019. 
  2. Mastropasqua MG, Maiorano E, et al. Immunoreactivity for c-kit and p63 as an adjunct in the diagnosis of adenoid cystic carcinoma of the breast. Mod Pathol. 2005;18(10):1277-82.
  3. Azoulay S, Laé M, Fréneaux P, et al. KIT is highly expressed in adenoid cystic carcinoma of the breast, a basal-like carcinoma associated with a favorable outcome. Mod Pathol. 2005;18(12):1623-31.

Patricija Zot, M.D.

Fellow, Surgical Pathology
Mayo Clinic

Charles Sturgis, M.D.

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

A 35-year-old Caucasian woman presents with symptomatic aortic and mitral valve stenosis. She has no history of congenital heart disease,  is noted to have short stature, and has a history of vision problems. She undergoes aortic and mitral valve replacement. Hematoxylin and eosin-stained sections of her mitral valve is shown in Figure 1. 

Figure 1

Given the history and histologic findings, what pathologic diagnosis can be rendered?

  • Mitral annular calcification.
  • Myxomatous degeneration.
  • Chronic rheumatic mitral valve disease.
  • Valve disease associated with mucopolysaccharidosis.

The correct answer is ...

Valve disease associated with mucopolysaccharidosis.

Mucopolysaccharidosis is a lysosomal storage disease,wherein glycosaminoglycans are not properly degraded, and thus deposit and accumulate within bodily tissues including those of the heart valves. Valve disease associated with mucopolysaccharidosis is just one of several systemic manifestations. There are several subtypes of mucopolysaccharidosis depending on the enzyme affected and the particular glycosaminoglycan involved, and the disease spectrum can range from severe to attenuated. In this patient, a mutation in the alpha-L-iduronidase gene, IDUA, caused low enzyme levels associated with elevated urine and blood spot dermatan and heparan sulfate. These findings were consistent with mucopolysaccharidosis type I, Sheie type. As seen in Figure 1, sections of mitral valve show collections of vacuolated histiocytes present both within the fibrous and spongy layers of the mitral valve. Electron microscopy was performed and showed the histiocytes to contain floculent material, in keeping with a lysosomal storage disease. This case highlights the crucial role pathologists play in rendering unsuspected tissue diagnoses that directly impact a patient’s further clinical management. There are several known effective enzyme replacement therapies for mucopolysaccharidosis that may improve patient outcomes and slow disease progression.

Myxomatous degeneration is histologically characterized by expansion of the spongiosa layer of the valve; a consequence of constitutively activated valvular interstitial cells. Discrete vacuolated cells are not a feature. These histologic and gross features are commonly seen in association with valve prolapse.

Chronic rheumatic mitral valve disease falls within the category of post-inflammatory valve disease, and is caused by valvular scarring occurring secondary to an autoimmune reaction following group A streptococci infection, which usually presents as valvular stenosis many years after initial infection. The latent period between infection and symptomology is usually 20 to 40 years. Grossly, the valve tissue is diffusely white, thickened and scarred, with commisural and cordal fusion frequently encountered. Again, vacuolated cells are not a feature. Histologically, fibrosis, neovascularization, and mild chronic inflammation is seen. Calcification may also be appreciated.

Mitral annular calcification is a type of degenerative valve disease, which is most commonly seen in patients over 65 years of age. Gross findings, usually best appreciated at autopsy, demonstrate a calcified annulus with variable valvular leaflet thickening. Histology would show annular calcification, with some degree of leaflet thickening. Scattered vacuolated cells would also not be seen in this instance.


  1. Braunlin EA, Harmatz PR, Scarpa M, et al. Cardiac disease in patients with mucopolysaccharidosis: presentation, diagnosis and management. J Inherit Metab Dis. 2011;34(6):1183-1197. doi:10.1007/s10545-011-9359-8.
  2. Burke  AP, Aubry MC, Maleszewski JJ, Alexiev BA, & Tavora FR. 2017. Practical Thoracic Pathology: Diseases of the lung, heart and thymus. Wolters Kluwer.

Sarah Thomas, M.D., M.S.

Fellow, Cardiovascular Pathology
Mayo Clinic

Joseph Maleszewski, M.D.

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

A 78-year-old woman is referred to a rheumatologist because she has been experiencing weakness and arthralgia. She complains of a skin rash; examination shows small, red, nonblanching nodules over her legs. She has a complex medical history, including systemic lupus erythematous (SLE) and rheumatoid arthritis (RA). Initial laboratory studies are remarkable for serum polyclonal hypergammaglobulinemia and hypocomplementemia (Figure 1). A cryoprecipitate was found and immunofixation electrophoresis was conducted on the pellet to look for a cryoglobulin (Figure 2).

Figure 1
Figure 2

Based on the gel in Figure 2, what type of cryoglobulinemia does she have?

  • Negative, no monoclonal protein.
  • Type I (monoclonal IgM kappa).
  • Type II (mixed monoclonal IgM kappa and polyclonal IgG).
  • Type III (polyclonal immunoglobulins).

The correct answer is ...

Type II (mixed monoclonal IgM kappa and polyclonal IgG).

Cryoprecipitation is a technique used to determine if a patient’s serum contains immunoglobulins (Igs) that precipitate out of solution at temperatures lower than body temperature (37 degrees Celsius). Cryoglobulins are associated with symptoms such as skin lesions, Raynaud phenomenon, arthralgias, peripheral neuropathy, and glomerulonephritis. Symptomology largely depends on the type of cryoglobulinemia, as the origin of the immunoglobulins is an important consideration for etiology. Treatment of any cryoglobulinemia will focus on treating the underlying disease process. If this test is positive, a small pellet will form, like shown in Figure 2 (left panel).

That pellet is then subjected to immunofixation electrophoresis (IFE) to determine the specific Igs contained within the pellet to help with diagnosis. Distinct, discrete bands in any lane correlates to a monoclonal population of immunoglobulins of the type indicated at the bottom of the lane (G, A, M, K, or L). A smear (lacking a distinct, defined band), or homogenous staining in a given lane indicates a polyclonal population of immunoglobulins.

Type II (mixed monoclonal IgM kappa and polyclonal IgG) – This patient has a cryoglobulinemia, likely associated with her autoimmune diseases. She has a history of systemic lupus erythematous (SLE) and rheumatoid arthritis (RA), both of which can be associated with cryoglobulinemia. This patient also has an overt hypocomplementemia. Hypocomplementemia is common in SLE, due to the excess immune complexes in circulation, which will activate the classical pathway of the complement system. Hypocomplementemia (low C3 and C4) is often employed as a marker of disease activity and is included in the 2019 ACR/EULAR SLE diagnostic criteria. Low levels of C3 and C4 may also be observed in recurrent infections, where consumption of the complement components takes place, but is unlikely to be the reason in this patient’s presentation. Complement components may get trapped in the cryoprecipitate and it is not uncommon to see hypocomplementemia in types II and III cryoglobulinemia — a true chicken-and-egg scenario in this patient’s case.

On the gel in Figure 2 (middle pane), a more distinct band is observed in the M and K lanes, which represents the monoclonal IgM kappa portion of the type II cryoprecipitate. The smear in the G lane represents the polyclonal IgG population of immunoglobulins. This cryoprecipitate, therefore, is of the type II (mixed) variety.

Type I (monoclonal) – A monoclonal cryoglobulin develops in the setting of a disease process that produces a monoclonal population of immunoglobulins, such as a B-cell lineage malignancy or monoclonal gammopathy of undetermined significance (MGUS). Since this patient does not have such a disease process, and her cryoglobulin isotyping IFE gel shows a mix of monoclonal IgM kappa plus polyclonal IgG, a type I cryoglobulinemia (which is the finding of a monoclonal population of immunoglobulins without polyclonal background) can be excluded.

Type III (polyclonal) – Cryoglobulins in this type of cryoprecipitate are composed of populations of polyclonal IgG and polyclonal IgM. Patients who are most susceptible to a type III cryoprecipitate are those with autoimmune disorders. No monoclonal immunoglobulins are seen in a type III cryoprecipitate.

Negative – A negative IFE gel would show no smears or distinct bands in any of the five lanes of the gels (the right panel on Figure 2, negative control). This would suggest the pellet is formed of something other than an immunoglobulin.


  1. https://www.uptodate.com/contents/overview-of-cryoglobulins-and-cryoglobulinemia
  2. Arranger et al. Arthritis Rheumatol. 2019 Sep;71(9):1400-1412. 
  3. Garcia-Carrasco, M., et al. (2001). "Cryoglobulinemia in systemic lupus erythematosus: prevalence and clinical characteristics in a series of 122 patients." Semin Arthritis Rheum 30(5): 366-373.
  4. Gorevic, P. D. (2012). "Rheumatoid factor, complement, and mixed cryoglobulinemia." Clin Dev Immunol 2012: 439018.
  5. Karimifar, M., et al. (2013). "Serum cryoglobulins and disease activity in systematic lupus erythematosus." J Res Med Sci 18(3): 234-238.
  6. McDuffie, F. C., et al. (1973). "Hypocomplementemia with Cutaneous Vasculitis and Arthritis: Possible Immune Complex Syndrome." Mayo Clin Proc 48: 340-348.

    I would like to thank Drs. Anne Tebo, Melissa Snyder, and David Murray for their expertise on this case submission.

Ria Fyffe-Freil, Ph.D.

Fellow, Clinical Chemistry
Mayo Clinic

Maria Alice Willrich, Ph.D.

Maria Alice Willrich, Ph.D.

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

A 60-year-old woman with history of intrahepatic cholangiocarcinoma presented with severe thoracic pain secondary to a large left-sided thoracic mass with extension to the thoracic spine and the pleural cavity. The patient underwent a resection of the tumor.

Figure 1: Histopathology of the thoracic mass shows a neoplastic glandular proliferation, with focal follicular-like growth and luminal secretions.
Figure 2: Microphotograph show neoplastic cells arranged in nests, back-to-back glands, and focal trabecular and follicular-like growth.
Figure 3: The neoplastic cells show ample eosinophilic cytoplasm and large, round, pleomorphic nuclei with prominent nucleoli.
Immunohistochemistry: The neoplastic cells are positive for AE1/AE3, MOC31, Albumin ISH (subset), focally positive for CK7 and negative for synaptophysin, CD56, chromogranin, GATA3, Pax 8, SOX10, TTF1, CDX2, Hep-Par1, Arginase, Glypican 3, beta catenin, mucin, SF-1, and trypsin. The Ki-67 proliferative moderately elevated at around 20%. 

What is your diagnosis?

  • Metastatic breast carcinoma with neuroendocrine differentiation.
  • Metastatic intrahepatic cholangiocarcinoma, cholangioblastic variant.
  • Well-differentiated neuroendocrine neoplasm.
  • Metastatic acinar cell carcinoma of the pancreas.
  • Metastatic intrahepatic cholangiocarcinoma, large duct type.

The correct answer is ...

Metastatic intrahepatic cholangiocarcinoma, cholangioblastic variant.

Cholangiocarcinomas (CCA) are classified into intrahepatic, perihilar, and extrahepatic CCA. Intrahepatic cholangiocarcinomas are now generally subdivided into two broad categories: the large duct and small duct types. The large duct subset is usually perihilar and characterized by infiltrative glands in a desmoplastic stroma; these subtype of CCA frequently harbor mutations in KRAS and TP53. The small duct subset is typically peripherally located within the liver parenchyma characterized by glands lined by cuboidal cells embedded in an hypocellular sclerotic stroma. This subtype is frequently associated with mutations in IDH1 or IDH2, or with gene fusions involving the FGRF2.

A new NIPBL-NACC1 gene fusion has been identified in a subset of intrahepatic cholangiocarcinomas. This histologic entity has been called cholangioblastic variant of intrahepatic cholangiocarcinoma. (CbvICCA).

Histologically, these tumors present a variety of architectural patterns, including nested/organoid and trabecular architecture. Of note, neoplastic cells may be arranged in acinar structures with pink luminal secretions resembling thyroid gland follicles, so called ‘follicular-like’ type architecture. This architectural pattern is considered distinctive and should raise this diagnostic possibility in the right clinical context. Cytologically, neoplastic cells are usually large, characterized by abundant eosinophilic cytoplasm and large nuclei with vesicular chromatin, and occasional prominent nucleoli.

CbvICCA are characterized by a diffuse strong immunoreactivity for inhibin A and show patchy expression of neuroendocrine markers, such as synaptophysin and chromogranin, but no labeling for INSM1.

The new discovered fusion gene associated with this entity, NIPBL-NACC1, connects exon 8 of NIBPL to exon 2 of NACC1. NIPBL-NACC1 gene fusion may result in dysregulated expression of a substantially intact NACC1 protein, neoplastic development, as observed in other malignancies. Small series studies suggest that these tumors tend to occur more frequently in young patients and is associated with a more aggressive behavior. Additional studies are needed to further understand this fusion, its biology, and association with prognosis.

The differential diagnosis of this entity is broad, and immunohistochemical techniques significantly assist in narrowing the differential diagnosis, mostly in ruling out other sites of origin.

The main clinicopathologic differential diagnosis for these neoplasms is that of well-differentiated neuroendocrine neoplasms metastatic to the liver. Of note, before the gene fusion NIPBL-NACC1 was described, many of these tumors were previously classified as well-differentiated neuroendocrine neoplasms given the morphology and immunohistochemical profile. Although cholangiocarcinoma can be patchy positive for synaptophysin and chromogranin, the characteristic morphology along with INSM1 negativity should raise this diagnostic possibility.

Typically, a well-differentiated neuroendocrine neoplasm with abundant eosinophilic cytoplasm would demonstrate diffuse labeling for neuroendocrine markers including synaptophysin and INSM1.

On the other hand, other primaries that also have patchy neuroendocrine marker expression, such as metastatic breast carcinoma with neuroendocrine differentiation and metastatic acinar cell carcinoma of the pancreas, should also be considered.


  1. Argani P, Palsgrove DN, Anders RA, Smith SC, Saoud C, Kwon R, Voltaggio L, Assarzadegan N, Oshima K, Rooper L, Matoso A, Zhang L, Cantarel BL, Gagan J, Antonescu CR. A Novel NIPBL-NACC1 Gene Fusion Is Characteristic of the Cholangioblastic Variant of Intrahepatic Cholangiocarcinoma. Am J Surg Pathol. 2021 Nov 1;45(11):1550-1560. doi: 10.1097/PAS.0000000000001729. PMID: 33999553; PMCID: PMC8516671.
  2. Liau JY, Tsai JH, Yuan RH, Chang CN, Lee HJ, Jeng YM. Morphological subclassification of intrahepatic cholangiocarcinoma: etiological, clinicopathological, and molecular features. Mod Pathol. 2014 Aug;27(8):1163-73. doi: 10.1038/modpathol.2013.241. Epub 2014 Jan 10. PMID: 24406866.
  3. Braxton DR, Saxe D, Damjanov N, Stashek K, Shroff S, Morrissette JD, Tondon R, Furth EE. Molecular and cytogenomic profiling of hepatic adenocarcinoma expressing inhibinA, a mimicker of neuroendocrine tumors: proposal to reclassify as "cholangioblastic variant of intrahepatic cholangiocarcinoma". Hum Pathol. 2017 Apr;62:232-241. doi: 10.1016/j.humpath.2017.02.001. Epub 2017 Feb 21. PMID: 28232156.

Maria Olave Martinez, M.D.

Fellow, Surgical Pathology
Mayo Clinic

Rondell P. Graham, M.B.B.S.

Rondell Graham, M.B.B.S.

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

A 56-year-old man with a past medical history of acute myeloid leukemia with chemotherapy-induced pancytopenia presents to Station 94 at Mayo Clinic to receive one unit of RBCs due to anemia (pre-transfusion Hb is 6.0). 320/330 mL of the transfusion was in when the patient developed itching hives on the chest, abdomen, and right arm. He also endorsed mild facial edema and hoarseness. The transfusion was subsequently stopped, the patient given IV Benadryl with symptom resolution, and the blood bank was notified and performed their transfusion reaction investigation, which showed satisfactory clerical check, no pre- or post-specimen hemolysis, and a negative DAT. 

What is the most likely diagnosis of this transfusion reaction?

  • Mildly severe allergic reaction.
  • Transfusion-associated dyspnea.
  • Moderately severe allergic reaction.
  • Transfusion-associated circulatory overload.

The correct answer is ...

Moderately severe allergic reaction.


  1. Harmening, Denise M. (2019). Modern Blood Banking and Transfusion Practices
  2. Gil, Morayma Reyes, et al. Transfusion Medicine and Hemostasis: Clinical and Laboratory Aspects. Elsevier Science, 2019.
  3. “National Healthcare Safety Network Biovigilance Component Hemovigilance Module Surveillance Protocol” by Division of Healthcare Quality Promotion, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA

Phuong-Lan Nguyen, M.D.

Fellow, Hematopathology
Mayo Clinic

Photo of Dr. Justin Kreuter

Justin Kreuter, M.D.

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

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