Pathways Case Studies: March 2022

A 20-year-old woman presented with right breast palpable mass. No prior history of any malignancy, surgery, trauma, or radiation is noted. Ultrasound-guided right breast mass biopsy was performed, and the hematoxylin and eosin-stained slides were reviewed. Several immunohistochemical studies were also performed and the pictures are shown below.

Figure 1: H&E 20x
Figure 2: H&E 40x
Figure 3: H&E 60x
Figure 4: CD31-40X
Figure 5: ERG-40X
Figure 6: MYC-40X

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

  • Papillary endothelial hyperplasia
  • Atypical vascular lesion
  • Primary angiosarcoma of the breast
  • Pseudoangiomatous stromal hyperplasia

The correct answer is ...

Primary angiosarcoma of the breast.

The hematoxylin-eosin stained slide section shows the malignant vasoformative neoplasm. Small- to medium-sized anastomosing neoplastic vessels dissect through the background fibroadipose tissue. Sheet-like solid area with malignant spindled cells and a few admixed epithelioid cells are present. Geographic necrosis is present, and mitotic figures are identified.

The immunohistochemical (IHC) study slides show the neoplastic cells to be immunoreactive with ERG and CD31. In addition, MYC is overexpressed by IHC in the neoplastic cells. The combined histology and clinical data are most consistent with a high-grade primary (non-radiotherapy related) mammary angiosarcoma. MYC overexpression has been reported in a few primary angiosarcomas but is more commonly associated with post-radiation angiosarcomas in the breast. The prognostic significance of the MYC positivity is uncertain.

These tumors are typically located in deep breast parenchyma with infiltrative or poorly circumscribed border. The neoplastic vascular channels in angiosarcoma have dilated, compressed, or angulated lumina. The lining endothelial cells range from bland to variably atypical, usually spindled, hyperchromatic nuclei that may be plump or flattened. Poorly differentiated angiosarcomas have solid, cellular foci comprising of spindled to epithelioid cells intermingled with variably formed anastomosing vascular channels, associated with prominent blood-lakes, mitotic figures and areas of necrosis. 

Angiosarcomas express endothelial markers with strong, membranous CD31 staining and nuclear ERG immunoexpression noted. Variable CD34, FLI1, and D2-40 possibly can be seen. Most tumors lack MYC protein overexpression; however, some primary angiosarcoma can show MYC protein overexpression.


  1. Stephan A Vorburger et al: Angiosarcoma of the breast. Cancer 2005 Dec 15;104(12):2682-8. PMID: 16288486; DOI: 10.1002/cncr.21531.
  2. PP Rosen et al: Mammary angiosarcoma. The prognostic significance of tumor differentiation. Cancer. 1988 Nov 15;62(10):2145-51. doi: 10.1002/1097-0142(19881115)62:10< 2145:aid-cncr2820621014>;2-o.
  3. Ming Yin et al: Prognosis and treatment of non-metastatic primary and secondary breast angiosarcoma: a comparative study. 
    BMC Cancer. 2017 Apr 27;17(1):295. doi: 10.1186/s12885-017-3292-7.

Fnu Sakshi, M.B.B.S.

Fellow, Surgical Pathology
Mayo Clinic

Charles Sturgis, M.D.

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

During the autopsy of a 72-year-old woman, the lesion shown below was identified in the right atrium in the vicinity of the fossa ovalis. Grossly, the lesion was dark red, soft, and slightly raised from the endocardium.

Figure 1
Figure 2
Figure 3
Figure 4

Based on the histology below, what is your diagnosis?

  • Atrial thrombus
  • Cardiac hemangioma
  • Cardiac myxoma
  • Intracardiac varix

The correct answer is ...

Intracardiac varix.

This lesion is an example of an intracardiac varix. This is a rare, benign lesion which predominately affects the right atrium. Only few case reports of this entity in living individuals have been published and it can be challenging to diagnose by cardiac imaging. While still rare, intracardiac varices are more readily observed incidentally during autopsy cases such as this case. Intracardiac varix are hypothesized to arise from the dilated veins of the endocardium. Grossly they appear as endocardial-based red or venous blood-colored smooth masses. Histologically, they classically show a cystic structure with an endothelial lining. Diagnosis relies on the identification of a vessel wall associated with the cysts. An elastic marker, such as Verhoeff's stain, can be used to visual the vessel elastin. The cysts are frequently associated with a luminal thrombus and calcification. The majority of the reported intracardiac varix have been incidental findings; however, few reports of large varix have been hypothesized to be the source of cardiac emboli. 

Cardiac hemangioma are vascular neoplasms which can affect the pericardium or endocardium, also, predominately found in the right atrium. The most common subtype, cavernous, demonstrates numerous large, dilated vessels with a surrounding myxoid background. The vascular spaces typically show pools of blood within the vessels. Calcification can occur in hemangiomas but is not a hallmark feature as seen in an intracardiac varix.  

Differentiating an intracardiac varix from a thrombus can be challenging. Thrombi do not originate subendocardially, therefore histologically differentiating if the lesion is involving a vessel or a vessel lumen is key for the diagnosis. Cardiac myxomas are one of the most common cardiac neoplasms. Histologically they typically show elongated tumor cells with ovoid nuclei and amphophilic cytoplasm in a myxoid background. Although myxomas are most common in the left atrium, they also occur in the right atrium. Interestingly, bilateral myxomas have been reported in patients with Carney complex, a rare genetic neoplastic syndrome.  

Carney complex patients are at an increased risk of developing myxomas in addition to several other skin lesions and endocrine tumors. Myxomas typically are not associated with calcifications or cystic features. Myxomas predominately exhibit a benign behavior (with rare malignant variants), however they can be the source of systemic embolization.   


  1. Harrity, P.J., et al., Intracardiac varices of the right atrium: a case report and review of the literature. International Journal of Cardiology, 1995. 48(2): p. 177-181.
  2. Kato, K., et al., Intracardiac varix of the left atrium. Eur J Cardiothorac Surg, 2012. 41(4): p. 945-6.
  3. Okamoto, N., et al., Long-term follow-up of a rare calcified cardiac tumor: a case report. J Echocardiogr, 2012. 10(3): p. 95-7.
  4. Rajani, R., N. Sarangmath, and B. Mishra, Massive right atrial myxoma. Int J Cardiol, 2008. 128(1): p. 121-2.
  5. Thorsen, M.K., et al., Mobile intracardiac varix: a new echocardiographic entity. AJR Am J Roentgenol, 1982. 138(3): p. 574-6.
  6. WHO Classification of Tumours Editorial Board. Thoracic tumours. Lyon (France): International Agency for Research on Cancer; 2021. (WHO classification of tumours series, 5th ed.; vol. 5).

Blake Ebner, M.D., Ph.D.

Resident, Anatomic Pathology/ Neuropathology
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

A 40-year-old woman with a history of generalized anxiety disorder presents for evaluation of episodic, mild bruising on her extremities without any inciting trauma. The bruises are always preceded by a prodrome of intense itching and swelling, which resolves after a day, at which point a minor ecchymosis appears and persists for seven to 10 days. She states that she first noticed these symptoms arising after the birth of her first child, and particularly after stressful situations. She takes aspirin for occasional migraines. There is no family history of bleeding or thrombotic disorders. The patient denies gingival bleeding, excessive menstrual bleeding, or bleeding complications with previous surgeries. Laboratory evaluation is as follows.

Figure 1: Lab Values

What is the most likely explanation for the patient’s symptoms?

  • Medication effect
  • Gardner-Diamond syndrome
  • Von Willebrand disease
  • Acquired factor VIII inhibitor

The correct answer is ...

Gardner-Diamond syndrome.

Given the clinical presentation and the normal laboratory values, the most likely diagnosis is Gardner Diamond syndrome (GDS), also known as psychogenic purpura or autoerythrocyte sensitization syndrome. Gardner Diamond syndrome is a rare condition characterized by recurrent, superficial ecchymoses, which are often preceded by a short prodrome of warmth, pain, swelling, or itchiness in patients without a documented history of a bleeding disorder, often as a reaction to some inciting physical or emotional stressor. While the exact pathophysiology of GDS is still unknown, many patients with GDS also have concomitant psychiatric diagnoses such as depression or personality disorders. Laboratory evaluation in patients with Gardner Diamond syndrome is normal. GDS is a diagnosis of exclusion and requires a thorough hematologic and coagulation workup to rule out other bleeding disorders. Given that GDS is a dermal cutaneous disorder, there is no risk for systemic bleeding and prognosis is excellent.

Aspirin covalently attaches an acetyl group to a serine residue in the active site of the enzyme cyclooxygenase (COX), leading to irreversible COX-1 inhibition, and thereby inhibition of thromboxane A2 synthesis in platelets. This mechanism produces an inhibitory effect on platelet aggregation during the lifetime of the affected platelet (8-9 days). Laboratory values such as the PT and APTT are not affected. Aspirin-induced platelet inhibition can be reflected by a prolonged closure time on the collagen/epinephrine PFA-100 assay, as well as decreased aggregation with arachidonic acid on light transmission platelet aggregometry. Due to the patient having recently taken aspirin for her migraines, PFA-100 and platelet aggregometry testing were not initially performed, but should symptoms continue, they could be pursued at a later date when she has been off aspirin for several days. 

Von Willebrand factor (VWF) is a protein that binds to platelets via the GpIb receptor to facilitate platelet adhesion; VWF also protects factor VIII from degradation by proteins C and S in the circulation. Von Willebrand disease (VWD) arises from a deficiency or dysfunction of VWF. It is the most common bleeding disorder in humans. VWD is usually inherited in an autosomal dominant fashion, except in types 2N and 3 VWD, which are autosomal recessive. VWD type 1 is the most common subtype of this disorder and it often presents with mild bleeding symptoms such as easy bruising, epistaxis, gingival bleeding, and heavy menstrual bleeding. Some patients may experience excessive bleeding following hemostatic challenges such as surgery and childbirth. Laboratory evaluation for VWD type 1 often shows a proportional decrease in VWF activity and antigen levels, normal or mildly decreased factor VIII activity, and normal molecular weight multimers with decreased staining intensity. 

Acquired inhibitors against factor VIII are uncommon. They can occur postpartum or in association with lymphoproliferative diseases or autoimmune disorders. They may also occur without any associated condition. Acquired hemophilia classically presents with massive soft tissue bleeding and is associated with an increased morbidity and mortality. The most common screening laboratory abnormality seen is an isolated, prolonged APTT that does not correct on mixing study. PT, thrombin time, and platelet count will be normal. A normal factor VIII level and normal PTT rules out factor VIII inhibitor.


  1. Franchini, M., Lippi, G.; Acquired factor VIII inhibitors. Blood 2008; 112 (2): 250–255. doi:
  2. James, Paula D., et al. “Ash ISTH NHF WFH 2021 Guidelines on the Diagnosis of Von Willebrand Disease.” Blood Advances, vol. 5, no. 1, 2021, pp. 280–300., 
  3. Scharf RE. Drugs that affect platelet function. Semin Thromb Hemost. 2012 Nov;38(8):865-83. doi: 10.1055/s-0032-1328881. Epub 2012 Oct 30. PMID: 23111864.
  4. Sridharan, M., Ali, U., Hook, C., Nichols, W., & Pruthi, R. (2019). The Mayo Clinic Experience With Psychogenic Purpura (Gardner-Diamond Syndrome).

Kenneth Wee, D.O.

Resident, Anatomic and Clinical Pathology
Mayo Clinic

William Nichols, M.D.

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

A 74-year-old woman presented with hematuria and was found to have a complex cystic mass in left kidney on imaging. She had a remote history of hysterectomy for ovarian cysts elsewhere. The patient underwent left nephrectomy and grossly a 639.6 g, 16.1 x 12.1 x 5.6 cm kidney with a cystic tan multilobulated papillary mass was present in upper pole, measuring 5.3 x 4.7 x 3.8 cm. Microscopic images (figures 1 and 2) and immunohistochemical staining are as shown (figures 3, 4, 5 and 6). Microscopic sections showed a tumor with tubulo-papillary architecture lined by clear cells, focally exhibiting a linear arrangement of nuclei away from the basement membrane. This tumor was positive for cytokeratin 7, PAX8, carbonic anhydrase IX (CA-IX) (basolateral/”cup like” membranous localization pattern), GATA3, 34BE12, and negative for AMACR, cytokeratin 20, p63, and TTF-1.

Figure 1: H&E low power
Figure 2: H&E high power
Figure 3: Cytokeratin 7
Figure 4: CA-IX
Figure 5: GATA3
Figure 6: Cytokeratin 34be12

What would be the most likely diagnosis?

  • Clear cell renal cell carcinoma
  • MiT family translocation renal cell carcinoma
  • Papillary renal cell carcinoma
  • Clear cell papillary renal cell carcinoma

The correct answer is ...

Clear cell papillary renal cell carcinoma.

Clear cell papillary renal cell carcinoma (CCPRCC) is a subtype of renal cell carcinoma (RCC) included in 2016 WHO classification. The tumor was first described in kidneys with end-stage renal disease, however, the majority of cases reported subsequently have been sporadic. It is important to recognize this subtype as it follows an indolent course. 

Clear cell papillary renal cell carcinoma accounts for 1%–4% of all resected renal tumors. The mean age at presentation is 60 years (range: 18 to 88 years) and there is no sex predilection. They are usually diagnosed as low-stage tumors. They present as well-circumscribed nodules with a mean size <3.0 cm and are usually low grade (WHO/ISUP grade 1 or 2). Tumor necrosis, perineural invasion, and lymphovascular invasion have not been observed. A single metastatic case has been reported.1,2 These tumors have much better prognosis than (conventional) papillary and clear cell renal cell carcinomas (RCCs). 

Tumors show a variable mixture of tubular (commonly predominant), papillary, acinar, cystic, cords, and solid growth patterns. Cuboidal or columnar cells with clear cytoplasm and nuclei uniformly arranged away from the basement membrane are the typical cytological features of these tumors. They may have overlapping features with conventional clear cell renal cell carcinoma, and immunohistochemical stains can help in this differential diagnosis.3

Clear cell papillary RCC are diffusely and strongly positive for cytokeratin 7 and show membranous CA-IX staining with absence of luminal staining (basolateral/ “cup-like” membranous localization). The hypothesized cell of origin is the distal nephron, as these tumors are frequently positive for GATA3 and high molecular weight cytokeratin. Specifically, GATA3 is considered a sensitive (76%) and specific (100%) marker for CCPRCC and can be used for accurate distinction from histologic mimics. The positive and negative predictive values are 100% and 74%, respectively. Coexpression of GATA3 and high molecular weight cytokeratin in most CCPRCC supports their origin from distal nephron.4 They are negative for AMACR, CD10, and RCC.5

Primary renal cell carcinomas with both papillary architecture and cells with clear cytoplasm can be diagnostically challenging, and the differential diagnosis includes clear cell RCC, papillary RCC, clear cell papillary RCC, and MiT family translocation RCC. Accurate diagnosis has prognostic implications and immunohistochemical stains can help establish the diagnosis.5

These tumors are mutationally silent and genomically stable. No specific molecular alterations have been identified other than accumulation of sugar alcohol sorbitol on metabolomic profiling, and this contrasts with clear cell renal cell carcinoma that have loss of function VHL alterations (mutation/deletions/epigenetic silencing).6

These are indolent tumors with a benign course and favorable prognosis. They usually present as low stage and low-grade tumors. In a follow-up study of 362 cases, no tumor recurrence, metastasis, or disease-related deaths were reported. Only a single case of metastatic behavior has been reported in the current English language literature.1,2


  1. Gupta S, Inwards CY, Van Dyke DL, Jimenez RE, Cheville JC. Defining clear cell papillary renal cell carcinoma in routine clinical practice. Histopathology. 2020;76(7):1093-1095. doi:10.1111/his.14071
  2. Gupta S, Pitel BA, Knight SM, Halling KC, Jimenez RE, Cheville JC. Re: Stanley Weng, Renzo G. DiNatale, Andrew Silagy, et al. The Clinicopathologic and Molecular Landscape of Clear Cell Papillary Renal Cell Carcinoma: Implications in Diagnosis and Management. Eur Urol 2021;79:468–77. Eur Urol. 2021;80(2):e62-e63. doi:10.1016/j.eururo.2021.05.011
  3. Weng S, DiNatale RG, Silagy A, et al. The Clinicopathologic and Molecular Landscape of Clear Cell Papillary Renal Cell Carcinoma: Implications in Diagnosis and Management. Eur Urol. 2021;79(4):468-477. doi:10.1016/j.eururo.2020.09.027
  4. Mantilla JG, Antic T, Tretiakova M. GATA3 as a valuable marker to distinguish clear cell papillary renal cell carcinomas from morphologic mimics. Hum Pathol. 2017;66:152-158. doi:10.1016/j.humpath.2017.06.016
  5. Williamson SR. Clear cell papillary renal cell carcinoma: an update after 15 years. Pathology (Phila). 2021;53(1):109-119. doi:10.1016/j.pathol.2020.10.002

Ayesha Farooq, M.B.B.S.

Fellow, Surgical Pathology
Mayo Clinic

Sounak Gupta, M.B.B.S., Ph.D.

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

A 3-year-old boy was seen by their pediatrician for a “right eye deformity” which had been present since he was 1 year old. On clinical exam there is obvious leukocoria. He was born at 40 weeks gestation and has been healthy otherwise. No significant family history or other medical conditions. He has two healthy brothers. MRI of the orbits demonstrated a heterogeneous enhancing and calcified right intraocular mass. Enucleation specimen demonstrated an expansile whitish mass with calcifications growing into the vitreous space. The histologic specimen is illustrated in figures 1-7 (figure 7 is the optic nerve margin). 

Figure 1: H&E
Figure 2: H&E
Figure 3: H&E
Figure 4: H&E
Figure 5: H&E
Figure 6: H&E
Figure 7: H&E Optic nerve margin

What is a poor prognostic factor in this case and this type of tumor in general? 

  1. Tumor grading has no bearing on prognosis.
  2. Earlier age at diagnosis.
  3. Optic nerve involvement. 
  4. Absence of pineal gland involvement.

The correct answer is ...

Optic nerve involvement.

This is a case of retinoblastoma. It is the most common intraocular malignant tumor. These tumors arise from the neurosensory retina. There are a number of poor prognostic factors, but the most important is presence or absence of optic nerve involvement. The optic nerve should be inked by the surgeon and tumor at this margin is associated with categorization as a pT4, and these tumors have a very poor prognosis. Tumor at the retrolaminar aspect of the optic nerve margin leads to CNS involvement in approximately 90% of cases (Pathol Lab Med (2009) 133 (8): 1199–1202). The lamina cribrosa is the structure that helps to classify the tumor as prelaminar, laminar, or retrolaminar. The lamina cribrosa is a mesh-like collagenous structure in which unmyelinated retinal ganglion cells go from the retina and enter into the optic nerve. This patient had retrolaminar involvement and presented with CNS involvement around one year after initial diagnosis.

Earlier age at diagnosis is incorrect. Interestingly, grade increases with age at enucleation with retinoblastoma. So in summary, older children tend to have more poorly differentiated tumor. This is likely related to an accumulation of genetic mutations due to biallelic loss of retinoblastoma (J Pediatr Ophthalmol Strabismus. Jan-Feb 2008;45(1):22-5. doi: 10.3928/01913913-20080101-16).

Tumor grading has no bearing on prognosis is incorrect. Increasing degrees of anaplasia are associated with decreased overall survival and increased risk of mets (Am J Ophthalmol. 2015 Apr;159(4):764-76). Severe anaplasia/poor differentiation is characterized by very large hyperchromatic nuclei, extreme pleomorphism (angular, rhomboid, or fusiform), cell wrapping, numerous mitotic figures, and lack of resemblance to normal photoreceptors.

Absence of pineal gland involvement is incorrect. Children with pineal gland involvement points to a phenomenon called “trilateral retinoblastoma,” which can be seen in about 5% of patients with a germline mutation in the Rb gene. This means that a morphologically similar tumor as retinoblastoma develops within the brain, most commonly in the pineal gland, and is often diagnosed at the same time as retinoblastoma. This is because the pineal gland has embryologic/genetic overlap with cells of the retina and thus there is a predisposition of tumors in the pineal gland in those with a germline Rb mutation (Lancet Oncol. 2014 Sep;15(10):1157-67).


  1. Pathol Lab Med (2009) 133 (8): 1199–1202.
  2. J Pediatr Ophthalmol Strabismus. Jan-Feb 2008;45(1):22-5. doi: 10.3928/01913913-20080101-16.
  3. Am J Ophthalmol. 2015 Apr;159(4):764-76.
  4. Lancet Oncol. 2014 Sep;15(10):1157-67.
Photo of Caseu Gleue

Casey Gleue, M.D.

Resident, Anatomic and Clinical Pathology
Mayo Clinic

Jorge Trejo-Lopez, M.D.

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

A 24-year-old man presents with an anterior mediastinal mass that was incidentally found when he was treated for COVID-19. Intra-operatively, a giant fatty tumor measuring  35 x 22 x 10.5 cm was identified in the prevascular mediastinum extending toward the right chest causing compression atelectasis of the right lower lobe of the lung.

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

What is your diagnosis?

  • Thymoma
  • True thymic hyperplasia
  • Thymolipoma
  • Lipofibroadenoma

The correct answer is ...


Thymolipoma is an uncommon benign, slow-growing thymic tumor. They have been shown to be associated with autoimmune diseases such as myasthenia gravis, aplastic anemia, hypogammaglobulinemia, lichen planus, and Graves’ disease. [3] There have been several theories to explain the pathogenesis of these lesions, but the evidence so far points to it being a neoplasm of adipose tissue within the involuting thymus. Cytogenetic studies in one case report have demonstrated a t[12;14](q15q32) translocation involving the HMGA2 gene, which is also seen in about two-thirds of lipomas.[1]. These lesions could also arise due to fatty replacement in a background of true thymic hyperplasia in the same manner as in a normal thymus.

Grossly thymolipomas are well-circumscribed, encapsulated, and the cut surface is lobulated and homogenous. Histologically, it is characterized by mature adipose tissue interspersed with cords of thymic tissue with cortex and medulla and Hassall corpuscles, although the thymic tissue is usually attenuated and seen in form of strands. In contrast to thymolipomas, thymomas are comprised of cellular lobules intersected by fibrous bands. The lobules are comprised of various ratios of neoplastic epithelial cells and reactive thymocytes. Lipofibroadenomas show similar features as thymolipomas and in addition harbor areas with fibrosis that appear similar to fibroadenomas of the breast. 


  1. Hudacko R, Aviv H, Langenfeld J, Fyfe B. Thymolipoma: clues to pathogenesis revealed by cytogenetics. Ann Diagn Pathol. 2009 Jun;13(3):185-8. doi: 10.1016/j.anndiagpath.2008.02.006. Epub 2008 Jun 12. PMID: 19433298.
  2. Toyama T, Mizuno T, Masaoka A, Shibata K, Yamakawa Y, Niwa H, Torii K. Pathogenesis of thymolipoma: report of three cases. Surg Today. 1995;25(1):86-8. doi: 10.1007/BF00309395. PMID: 7749298.
  3. Rieker RJ, Schirmacher P, Schnabel PA, Moser K, Hoffmann H, Dienemann H, Pfannschmidt J. Thymolipoma. A report of nine cases, with emphasis on its association with myasthenia gravis. Surg Today. 2010;40(2):132-6. doi: 10.1007/s00595-009-4042-5. Epub 2010 Jan 28. PMID: 20107952.

Arpan Samaddar, M.B.B.S.

Resident, Anatomic and Clinical Pathology
Mayo Clinic

Anja Roden Profile

Anja Roden, M.D.

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

MCL Education

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