A 75-year-old white man presents to the clinic with a rapidly enlarging mass around his left knee over the course of four months. He has no known injury to the area, but has experienced increasing pain and erythema. Aspiration yielded no fluid. Imaging revealed a solid mass involving the tendon measuring 5.3 cm in greatest dimension. History includes prostate cancer and squamous cell carcinoma of the face. Needle biopsies were taken from the mass and submitted for pathologic evaluation. 

Figure 1: HE
Figure 2: AE13
Figure 3: Synapto
Figure 4: CK20
Figure 5: MCPyV

What is the most likely diagnosis based on the presentation, histologic morphology, and immunohistochemical staining?

  • Basal cell carcinoma
  • Merkel cell carcinoma
  • Squamous cell carcinoma
  • Amelanotic melanoma

The correct answer is ...

The correct answer is: Merkel cell carcinoma.

This presentation with the associated IHC findings are most consistent with Merkel cell carcinoma (MCC). This neuroendocrine skin tumor is positive for synaptophysin and chromogranin. The characteristic salt and pepper chromatin is visible on the H&E stain, and one may be able to see nuclear molding and rosette-like structures. Mitoses are often abundant. MCCs typically express epithelial markers such as AE1/AE3 and CK20. CK7 may also be positive. CK20 typically shows a paranuclear “dot-like” staining pattern. MCPyV can be detected by immunohistochemistry in a subset of MCC cases. 

Development of MCC is associated with ultraviolet radiation and clonal integration of the MCPyV and is most commonly found on sun-exposed areas of skin. The tumor presents with a rapidly growing nodule, which can mimic basal cell carcinoma (BCC), squamous cell carcinoma (SCC), amelanotic melanoma, lymphoma, and others. Histologically, the differential diagnosis includes metastatic neuroendocrine tumor. While the etiology of MCC has been further elucidated, the cell of origin still remains somewhat of a mystery, despite being referred to as Merkel cell carcinoma. Because Merkel cells are terminally differentiated, it is thought that they may not be the true origin for the carcinoma. 

MCPyV is thought to be part of the commensal skin flora and commonly can be found in the general population. It is for this reason that incidence of MCC increases in immunocompromised populations and on areas of the skin where chronic sun exposure or damage is common. There may be a synergistic component to the UV damage and localized immunosuppression in combination with the presence of the MCPyV that allows for the development of MCC. 

The acronym AEIOU was developed to help aid in the recognition of the otherwise nonspecific features of MCC presentation: asymptomatic, expanding rapidly, immunosuppressed, older than age 50, and UV-exposed.


  1. Becker JC, Stang A, DeCaprio JA, Cerroni L, Lebbé C, Veness M, Nghiem P. Merkel cell carcinoma. Nat Rev Dis Primers. 2017 Oct 26;3:17077. doi: 10.1038/nrdp.2017.77. PMID: 29072302; PMCID: PMC6054450.
  2. Elder D, Massi D, Scolyer R, Willemze R et al. WHO Classification of Skin Tumours. Lyon: International Agency for Research on Cancer; 2018.
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Philip Hurst, M.D.

Resident, Anatomic and Clinical Pathology
Mayo Clinic


Daniel Rowan, M.D.

Associate Consultant – Clinical, Anatomic Pathology
Mayo Clinic

A 63-year-old man presents with abdominal pain and jaundice. His labs are significant for elevated AST, ALT, alkaline phosphatase, and CA 19-9. An MRCP shows marked dilatation of intrahepatic biliary ducts, and an MRI is suspicious for a biliary mass of the right hepatic lobe. He undergoes right hepatectomy; gross exam and microscopy reveal the lesion pictured below. It is situated within the bile ducts and there is focal invasion noted.

Figure 1: Gross1
Figure 2: Overall 2x
Figure 3: Intrabiliary
Figure 4: Papillary
Figure 5: Invasive 2 10x

If immunohistochemistry for antibodies against MUC1 and MUC2 was performed on this lesion, which of the following staining patterns would you expect?

  • MUC1 (-), MUC2 (-)
  • MUC1 (+), MUC2 (-)
  • MUC1 (-), MUC2 (+)
  • MUC1 (+), MUC2 (+)

The correct answer is ...

The diagnosis in this case is: MUC1 (+), MUC2 (-).

The gross photograph shows a well-circumscribed mass contained within a dilated bile duct. Microscopy shows papillary projections of biliary epithelium seated within a bile duct with focal invasion. This leads to a diagnosis of invasive carcinoma arising within an intraductal papillary neoplasm of the bile duct (IPNB). 

IPNB is essentially the biliary counterpart to intraductal papillary mucinous neoplasm (IPMN) of the pancreas. Similar to IPMN, IPNB has four morphologic subtypes. The distinction of these subtypes can be aided by their staining patterns for antibodies against two mucin core (MUC) proteins, MUC1 and MUC2.

The pancreaticobiliary subtype displays tall, columnar cells that approximate normal biliary epithelial cells. This is the most common subtype of IPNB, as well as the one most associated with invasive components, and is also the one seen in this case. It is typically positive for MUC1 and negative for MUC2.

The intestinal subtype consists of villous architecture with columnar epithelial cells resembling small intestine tissue. It is generally MUC1 negative and MUC2 positive.

The gastric subtype approximates the foveolar epithelium of the stomach and grows in a tubular pattern. It is typically negative for both MUC1 and MUC2.

The oncocytic subtype shows plump cells with eccentrically-placed nuclei and prominently pink cytoplasm. It can show focal positivity for both MUC1 and MUC2.


  1. Odze and Goldblum, Surgical Pathology of the GI Tract, Liver, Biliary Tract, and Pancreas, Third Ed., 2015.
  2. Wan et al. Gallbladder papillary neoplasms share pathological features with intraductal papillary neoplasm of the bile duct. Oncotarget, 2017.
  3. Wan et al., Intraductal papillary neoplasm of the bile duct. World J Gastroenterol, 2013.
  4. WHO Classification of Tumours Editorial Board, Digestive System Tumours, 5th edition, 2019.
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Ryan Kendziora, M.D.

Resident, Anatomic and Clinical Pathology
Mayo Clinic


Lizhi Zhang, M.D.

Consultant, Anatomic Pathology
Mayo Clinic

Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science

A 35-year-old woman presented with gastric bleeding and was found to have a 3.4 cm mass involving the stomach and a 1.8 cm paracaval nodule. Previously, the patient had a paraganglioma removed from the abdomen.

Figure 1: Gastric mass, 400x magnification
Figure 2: Gastric mass, CD34, 200X magnification
Figure 3: Gastric mass, CD117, 200x magnification
Figure 4: Paracaval nodule, 400x magnification
Figure 5: Gastric mass, SDHB, 200x magnification
Figure 6: Paracaval nodule, SDHB, 200x magnification

For which predisposition syndrome would testing be most important for prognosis?

  • PTEN
  • CDH1
  • MMR (MLH1, PMS2, MSH2, MSH6)
  • SDHB

The correct answer is ...

The correct answer is: SDHB.

  • The gastric tumor is a gastrointestinal stromal tumor (positive for CD34 and CD117) and the abdominal tumor is a paraganglioma. These tumors can occur in a patient with succinate dehydrogenase (SDH) deficiency. In a younger person with synchronous or meta-synchronous GIST and paraganglioma, this suggests the possibility of a predisposition syndrome and can be further studied with SDHB immunohistochemistry. In this case, SDHB IHC was negative in the gastric GIST as well as the paracaval paraganglioma, indicating a possible correlation with SDHB deficiency syndrome (see figures 5 and 6).
  • PTEN is associated with Cowden syndrome, which predisposes to hamartomas in the esophagus and stomach and increased incidence of colorectal adenocarcinoma.
  • MMR (MSH2, MSH6, MLH1, PMS2) Mismatch repair protein deficiency is associated with Lynch syndrome and predisposition to colorectal adenocarcinoma.
  • CDH1 mutations predispose to gastric signet ring cell carcinoma. (Figures 5 and 6)


  1. WHO Classification of Tumours Editorial Board. Digestive system tumours [Internet]. Lyon (France): International Agency for Research on Cancer; 2019 [cited 2021 Mar 4]. (WHO classification of tumours series, 5th ed.; vol. 1). Available from: https://tumourclassification.iarc.who.int/.
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David Nolte, 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

Associate Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science


A 79-year-old man with a left testicular mass underwent left radical orchiectomy. On cut section, there is a 4.5 cm indurated, yellow-white solid mass at testicular hilum extending to epididymis and tunica vaginalis. Histological sections show an invasive, biphasic, malignant neoplasm with round to spindle cells with moderate pleomorphism and focal tubular formation. The tumor cells have vesicular nuclei and prominent nucleoli. There is variable mitotic activity and increased apoptosis. 

Pathways 2021 April Gilani Low Power Image
Figure 1: MM low-power image
Pathways 2021 April Gilani High Power Image
Figure 2: MM high-power image

Which of the following staining patterns is seen with BAP1 immunohistochemical stain in this entity?

  • Membraonus staining
  • Nuclear staining
  • Loss of nuclear staining
  • Nuclear and cytoplasmic staining

The correct answer is ...

The correct answer is: loss of nuclear staining.

This is a biphasic type malignant mesothelioma (MM) with epithelioid and sarcomatoid components. The epithelioid component is characterized by tubule formation and sarcomatoid component by spindle cell differentiation. 

BRCA-1 related protein-1 (BAP1) is a deubiquitinase enzyme that functions as a tumor suppressor gene. BAP1 deletion or loss of function mutation prevents damaged cells from undergoing apoptosis resulting in proliferation of cells harboring deleterious mutations. In MM, BAP1 somatic mutations or deletions are found in 60% of cases and germline mutations in <1% of cases.  

By immunohistochemistry BAP1 protein has a nuclear expression in normal cells. In MM, there is either a loss of nuclear expression with cytoplasmic accumulation or a complete loss of BAP1 protein expression. Cytoplasmic accumulation is seen as a result of loss of nuclear localization sequence. Membranous expression is not seen with BAP1 protein expression.

Most studies have described 100% loss of nuclear staining in BAP1 mutated MM. Partial loss of BAP1 nuclear staining is uncommon in MM; extensive loss with a small fraction of cells with retained BAP1 nuclear expression is considered as loss of BAP1 staining.


  1. Churg A, Naso JR. The Separation of Benign and Malignant Mesothelial Proliferations: New Markers and How to Use Them. Am J Surg Pathol. 2020 Nov;44(11):e100-e112. 
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Sarwat Gilani, M.B.B.S.

Fellow, Surgical Pathology
Mayo Clinic

Pingchuan Zhang, M.D., Ph.D.

Senior Associate Consultant, Anatomic Pathology
Mayo Clinic

Assistant Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science

A 38-year-old man presented with chronic cough associated with leukocytosis. Cough persisted for two months with chest CT findings compatible with right upper lobe lung (RUL) abscess. IR guided aspiration of the purulent material was negative for bacterial, mycobacterial and fungal cultures. Cytology performed was negative for malignancy. As the patient remained unresponsive to antibiotics, the RUL was surgically resected and the H/E stained and IHC slides showed the following:

Figure 1: CD15
Figure 2: CD20
Figure 3: CD30 20x
Figure 4

What is the most likely diagnosis?

  • Necrotizing sarcoidosis
  • Hodgkin's lymphoma
  • Fungal infection
  • Lymphomatoid granulomatosis

The correct answer is ...

The correct answer is: Hodgkins lymphoma.

Please note:

Hodgkin's lymphoma: Classic Reed-Sternberg (RS) cells are typically present within mixed inflammatory background, including small T- and B-cells, eosinophils, neutrophils, histiocytes, and plasma cells. RS cells are usually CD30 and CD15 positive, and CD20 negative (2/3) or CD20 weak-positive (1/3). 

Lymphomatoid granulomatosis: Atypical lymphoid cells may resemble Hodgkin's-Reed Sternberg cells. Angiocentric distribution of these cells is a key feature of this condition. Atypical lymphoid cells are usually CD20 strongly positive. 

Fungal infection: Fungal microorganisms may be visible on H&E or special fungal stains like Grocott’s methenamine silver (GMS) stain. 

Necrotizing sarcoidosis: Typically has necrotizing granulomas that involve pulmonary vessels.


  1. Connors JM, Cozen W, Steidl C, Carbone A, Hoppe RT, Flechtner HH, Bartlett NL. Hodgkin lymphoma. Nat Rev Dis Primers. 2020 Jul 23;6(1):61. doi: 10.1038/s41572-020-0189-6. PMID: 32703953.
  2. Guermazi A, Brice P, de Kerviler E E, Fermé C, Hennequin C, Meignin V, Frija J. Extranodal Hodgkin disease: spectrum of disease. Radiographics. 2001 Jan-Feb;21(1):161-79. doi: 10.1148/radiographics.21.1.g01ja02161. PMID: 11158651.
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Ameya Patil, M.B.B.S.

Resident, Anatomic and Clinical Pathology
Mayo Clinic

April Chiu, M.D.

Consultant, Hematopathology
Mayo Clinic

Associate Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science

A middle-aged woman with a history of an autoimmune disorder and endocarditis presents to the ED with severe abdominal pain and neurologic defects. Imaging reveals multiple infarcts involving the abdominal viscera. An echocardiogram is negative. Lab values: creatinine 2.11mg/dL, Hgb 9.0 g/dL, PLT 64,000, PT 61.3, aPTT 32, dsDNA Ab 182 (H), beta-2 glycoprotein 1 IgG 69.9 (H), phospholipid Ab IgG 56.0 (H), DRVVT confirm >1.2, and ADAMTS13 activity >90%. Renal biopsy is pending. There is no history of recent hospitalization or medications. 

Given the above information, what is the most likely diagnosis? 

  • Cardioembolic event secondary to endocarditis
  • Antiphospholipid syndrome (APS)
  • Thrombotic thrombocytopenic purpura (TTP)
  • Catastrophic antiphospholipid syndrome (CAPS)

The correct answer is ...

The correct answer is: catastrophic antiphospholipid syndrome (CAPS).

Catastrophic antiphospholipid syndrome (CAPS) is an autoimmune process characterized by diffuse vascular occlusion secondary to anti-phospholipid antibodies. According to Asheron et al., the diagnostic criteria for CAPS includes:

  1. Evidence of involvement in >/= 3 organs
  2. Development of symptoms simultaneously or in <1 week
  3. Laboratory evidence of persistent antiphospholipid antibodies (lupus anticoagulant and/or anticardiolipin antibodies), at least 6 weeks apart
  4. Histopathologic confirmation of small vessel occlusion in at least one organ, with or without associated vasculitis 

Clinical manifestations of CAPS are the result of multi-organ ischemia/infarction. Patients may present with respiratory failure (acute respiratory distress syndrome or diffuse alveolar hemorrhage), stroke, acute renal failure, adrenal insufficiency, and cutaneous infarction. Based on the CAPS Registry, most patients with CAPS are women in their late thirties with manifestations usually triggered by a precipitating event (infection, surgery, drugs, etc.). The patient in the question stem is of the usual age/gender and demonstrated clinical evidence of involvement in >/= 3 organs (multi-organ infarction) within 24 hours. In conjunction with elevated antiphospholipid antibodies and the pending renal biopsy, a diagnosis of CAPS is most likely.

A triple-therapy strategy has reduced CAPS-associated mortality from 50% to 30%. This strategy includes heparin, high-dose glucocorticoids, and either IVIG or therapeutic plasma exchange (TPE). TPE is performed daily for a minimum of 3-5 days with plasma as replacement fluid. Plasma is thought to be beneficial as it provides natural anticoagulants including protein C, protein S, and antithrombin, the latter required for heparin-mediated anticoagulation. 

The Sydney Investigational Criteria lists diagnostic criteria for antiphospholipid syndrome (APS). These criteria include both clinical and laboratory findings. Clinical findings include otherwise unexplained obstetrical complications (recurrent miscarriage, stillbirth, preeclampsia, intrauterine growth restriction, etc.) and definitive evidence of vascular thrombosis (either by imaging or histopathology). Laboratory findings include medium/high titer anti-cardiolipin or anti-beta-glycoprotein IgG/IgM and demonstration of persistent lupus anticoagulant. Subtle but important differences in the diagnosis of APS (as compared to CAPS) include demonstrating persistent lupus anticoagulant over at least a 12-week period and the absence of vasculitis on microscopy. APS is generally treated with long-term anticoagulation, including warfarin, heparin (during gestation), and direct-acting oral anticoagulants (for venous thrombosis only). 

Given the negative transesophageal echocardiogram, a cardioembolic event is less likely. ADAMTS13 activity is within normal limits, thereby excluding a diagnosis of thrombotic thrombocytopenic purpura. A diagnosis of heparin-induced thrombocytopenia (HIT) may be considered. However, as the patient was not previously hospitalized and was not taking any medications, a diagnosis of HIT is unlikely.  


  1. Asherson RA, Cervera R, de Groot PG, Erkan D, Boffa MC, Piette JC, Khamashta MA, Shoenfeld Y; Catastrophic Antiphospholipid Syndrome Registry Project Group. Catastrophic antiphospholipid syndrome: international consensus statement on classification criteria and treatment guidelines. Lupus, 2003;12(7):530-4. doi: 10.1191/0961203303lu394oa. PMID: 12892393.
  2. “Clinical Manifestations of Antiphospholipid Syndrome.” UpToDate, http://www.uptodate.com/contents/clinical-manifestaions-of-antiphospholipid syndrome?source=history_widget
  3. Padmanabhan, Anand, et al. “Guideline on the Use of Therapeutic Apheresis in Clinical Practice – Evidence – Based Approach from the Writing Committee of the American Society for Apheresis: The Eighth Special Issue.” Journal of Clinical Apheresis, vol. 34, no. 3, 2019, pp. 171-354., doi: 10.1002/jca.21705 
  4. Shaz, Bet, et al. Transfusion Medicine and Hematostasis: Clinical and Laboratory Aspects. Elsevier Science, 2019.
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Michael McCarthy, M.D.

Resident, Anatomic and Clinical Pathology
Mayo Clinic

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Margaret DiGuardo, M.D.

Senior Associate Consultant, Transfusion Medicine
Mayo Clinic

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