Innovation in pathogenesis and management of aortic aneurysm

Aortic aneurysm(AA)refers to the persistent dilatation of the aorta,exceeding three centimeters.Investigating the pathophysiology of this condition is important for its prevention and management,given its responsibility for more than 25000 deaths in the United States.AAs are classified based on their location or morphology.various pathophysiologic pathways including inflammation,the immune system and atherosclerosis have been implicated in its development.Inflammatory markers such as transforming growth factorβ,interleukin-1β,tumor necrosis factor-α,matrix metalloproteinase-2 and many more may contribute to this phenomenon.Several genetic disorders such as Marfan syndrome,Ehler-Danlos syndrome and Loeys-Dietz syndrome have also been associated with this disease.Recent years has seen the investigation of novel management of AA,exploring the implication of different immune suppressors,the role of radiation in shrinkage and prevention,as well as minimally invasive and newly hypothesized surgical methods.In this narrative review,we aim to present the new contributing factors involved in pathophysiology of AA.We also highlighted the novel management methods that have demonstrated promising benefits in clinical outcomes of the AA.

Giant cavernous aneurysms occluded by aneurysmal thrombosis,calcification,parent artery occlusion:A case report and review of literature

BACKGROUND Patients with giant intracranial aneurysms(GIAs)are at a high risk of rupture,morbidity,and mortality even after surgical or endovascular treatment.We described a case of a spontaneously occluded GIA secondary to gradual growth of the GIA,continuously progressed aneurysmal thrombosis,complete aneurysmal calcification and complete occlusion of the parent artery-the right internal carotid artery(RICA).CASE SUMMARY A 72-year-old female patient complained of sudden pain in her right eye upon admission to our hospital.She had been diagnosed with a GIA[30 mm(axial)×38 mm(coronal)×28 mm(sagittal)]containing an aneurysmal thrombus located in the cavernous sinus segment of RICA diagnosed by magnetic resonance imaging(MRI),enhanced MRI,and magnetic resonance angiography more than 14 years ago.Later,with slow growth of the cavernous carotid GIA,aneurysmal thrombosis progressed continuously,spontaneous occlusion of the RICA,complete aneurysmal calcification,and occlusion of the GIA occurred gradually.She had no history of subarachnoid hemorrhage but missed the chance for endovascular therapy at an early stage.As a result,she was left with severe permanent sequelae from the injuries to the right cranial nerves Ⅱ,Ⅲ,Ⅳ,V1/V2,and Ⅴ.CONCLUSION The risk of rupture of the cavernous carotid GIAs was relatively low and possibly further be reduced by the stasis flow and spontaneous occlusion of the parent artery internal carotid artery(ICA)induced by the mass effect of the cavernous carotid GIAs and the extremely rare aneurysmal calcification.However,nowadays,it is advisable to recommend early endovascular treatment for the cavernous carotid GIAs to prevent injuries to the surrounding intracranial nerves and occlusion of the ICA,mainly caused by the mass effect of the cavernous carotid GIAs.

Thoracoscopic resection of giant left atrial appendage aneurysm: A case report

Left atrial appendage aneurysm(LAAA)was first reported in the 1960s.1 LAAA is a rare condition,with just over 100 congenital or acquired cases reported to date.2 LAAA is frequently diagnosed incidentally during echocardiography or computed tomography(CT)scans.Most patients with LAAA are asymptomatic,while a few exhibit nonspecific symptoms,such as dyspnea,palpitation,and chest tightness.Patients with LAAA frequently present with atrial arrhythmias and systemic thromboembolism,such as stroke or multiorgan infarctions,due to the formation of a left atrial appendage thrombus.3 The lesion may be cured using aneurysm resection.Considering it as the potential cause of atrial arrhythmias and thromboembolism,the lesion must be identified on time and cured using a suitable treatment approach.

Differences and Correlations of Morphological and Hemodynamic Parameters between Anterior Circulation Bifurcation and Side-wall Aneurysms

Objective:The objective of this research was to explore the difference and correlation of the morphological and hemodynamic features between sidewall and bifurcation aneurysms in anterior circulation arteries,utilizing computational fluid dynamics as a tool for analysis.Methods:In line with the designated inclusion criteria,this study covered 160 aneurysms identified in 131 patients who received treatment at Union Hospital of Tongji Medical College,Huazhong University of Science and Technology,China,from January 2021 to September 2022.Utilizing follow-up digital subtraction angiography(DSA)data,these cases were classified into two distinct groups:the sidewall aneurysm group and the bifurcation aneurysm group.Morphological and hemodynamic parameters in the immediate preoperative period were meticulously calculated and examined in both groups using a three-dimensional DSA reconstruction model.Results:No significant differences were found in the morphological or hemodynamic parameters of bifurcation aneurysms at varied locations within the anterior circulation.However,pronounced differences were identified between sidewall and bifurcation aneurysms in terms of morphological parameters such as the diameter of the parent vessel(Dvessel),inflow angle(θF),and size ratio(SR),as well as the hemodynamic parameter of inflow concentration index(ICI)(P<0.001).Notably,only the SR exhibited a significant correlation with multiple hemodynamic parameters(P<0.001),while the ICI was closely related to several morphological parameters(R>0.5,P<0.001).Conclusions:The significant differences in certain morphological and hemodynamic parameters between sidewall and bifurcation aneurysms emphasize the importance to contemplate variances in threshold values for these parameters when evaluating the risk of rupture in anterior circulation aneurysms.Whether it is a bifurcation or sidewall aneurysm,these disparities should be considered.The morphological parameter SR has the potential to be a valuable clinical tool for promptly distinguishing the distinct rupture risks associated with sidewall and bifurcation aneurysms.

Unusual Presentation of Heart Failure Secondary to Ruptured Aneurysmal Sinus of Valsalva: A Case Report

Sinus of Valsalva Aneurysm (SOVA) arises from an abnormal dilation of the aortic root, leading to enlargement between the aortic annulus and the sinotubular junction. Although often presenting without symptoms, these aneurysms bear the potential for life-threatening complications, primarily from the looming risk of rupture. We present the case of a 42-year-old Malay gentleman with a history of bilateral pedal edema and dyspnea on exertion who was diagnosed with a ruptured sinus of Valsalva aneurysm. The patient underwent successful surgical repair of the aneurysm, leading to symptomatic improvement and favorable outcomes. This case highlights the importance of early diagnosis and prompt surgical intervention in managing this uncommon condition.

Hematochezia due to rectal invasion by an internal iliac artery aneurysm: A case report

BACKGROUND This case report presents the rare occurrence of hematochezia due to an internal iliac artery aneurysm leading to an arterioenteric fistula,expanding the differential diagnosis for gastrointestinal bleeding.It emphasizes the importance of considering vascular origins in cases of atypical hematochezia,particularly in the absence of common gastrointestinal causes,and highlights the role of imaging and multidisciplinary management in diagnosing and treating such unusual presentations.CASE SUMMARY A 75-year-old man with a history of hypertension presented with 12 d of hematochezia,experiencing bloody stools 7-8 times per day.Initial computed tomography(CT)scans revealed an aneurysmal rupture near the right internal iliac artery with suspected hematoma development.Hemoglobin levels progressively decreased to 7 g/dL.Emergency arterial angiography and iliac arterycovered stent placement were performed,followed by balloon angioplasty.Despite initial stabilization,minor rectal bleeding and abdominal pain persisted,leading to further diagnostic colonoscopy.This identified a neoplasm and potential perforation at the proximal rectum.An exploratory laparotomy confirmed the presence of a hematoma and an aneurysm invading the rectal wall,necessitating partial rectal resection,intestinal anastomosis,and ileostomy.Postoperative recovery was successful,with no further bleeding incidents and normal follow-up CT and colonoscopy results after six months.CONCLUSION In cases of unusual gastrointestinal bleeding,it is necessary to consider vascular causes for effective diagnosis and intervention.

Isolated Third Nerve Cranial Palsy: Complication of Brain Aneurysm

This case report highlights a critical and emergent condition, isolated third nerve cranial palsy due to a brain aneurysm. It emphasizes the importance of differential diagnosis and attentiveness to the physical exam in an emergency setting. The detailed progression from initial symptoms and misinterpretation to final diagnosis offers valuable insight into the dangers of overlooking critical diagnoses. A bilobed intracranial aneurysm arising from the internal carotid artery (ICA) caused symptoms in this patient that could have been attributed to a less malignant etiology, such as a complex migraine. Overlooking the urgency of the situation and missing the diagnosis could have had a grave and irreversible outcome.

Prenatal Diagnosis of an Apically Located Congenital Left Ventricular Aneurysm: A Rare Case

Congenital ventricular aneurysm is a very rare cardiac anomaly.A diagnosis can be made during the prenatal period using fetal echocardiography.This study presents a very rare apically located left ventricular aneurysm case,and the relevant literature was reviewed and discussed.In this case,a 35-year-old,gravida 2,parity 1 preg-nant woman at 24 weeks of gestation,displayed a wide aneurysmal image in the left ventricular apical wall on fetal echocardiography.There was a 1.79 mm muscular ventricular septal defect at the apical region of the interven-tricular septum.In the course of the color Doppler ultrasonography examination,an aberrantfibrous band within the left ventricle and consequent turbulentflow during systole were observed.The baby,born via cesarean section at 37 weeks of gestation,is now in its postnatal seventh month.However,during echocardiographic follow-ups,changes have been observed,including mild to moderate mitral insufficiency and a decrease in systolic function.Despite thesefindings,the clinical condition remains asymptomatic.It is of great importance to use a multidis-ciplinary approach in managing these rare cases that could lead to potential adverse outcomes during the antena-tal or postnatal periods.

Endovascular treatment of ruptured lobulated anterior communicating artery aneurysms:A retrospective study of 24 patients

BACKGROUND Lobulated intracranial aneurysm is a special type of aneurysm with at least one additional cyst in the neck or body of the aneurysm.Lobulated intracranial aneurysm is a complex aneurysm with complex morphology and structure and weak tumor wall,which is an independent risk factor for rupture and hemorrhage.Lobular aneurysms located in the anterior communicating artery complex account for 36.9%of all intracranial lobular aneurysms.Due to its special anatomical structure,both craniotomy and endovascular treatment are more difficult.Compared with single-capsule aneurysms,craniotomy for lobular intracranial aneurysms has a higher risk and complication rate.AIM To investigate the efficacy and safety of endovascular treatment for ruptured lobulated anterior communicating artery aneurysm(ACoAA).METHODS Patients with ruptured lobulated ACoAA received endovascular treatment in Sanming First Hospital Affiliated to Fujian Medical University from June 2020 to June 2022 were retrospectively included.Their demographic,clinical and imaging characteristics,endovascular treatment methods and follow-up results were collected.RESULTS A total of 24 patients with ruptured lobulated ACoAA were included,including 9 males(37.5%)and 15 females(62.5%).Their age was 56.2±8.9 years old(range 39-74).The time from rupture to endovascular treatment was 10.9±12.5 h.The maximum diameter of the aneurysms was 5.1±1.0 mm and neck width were 3.0±0.7 mm.Nineteen patients(79.2%)were double-lobed and 5(20.8%)were multilobed.Fisher's grade:Grade 2 in 16 cases(66.7%),grade 3 in 6 cases(25%),and grade 4 in 2 cases(8.3%).Hunt-Hess grade:Grade 0-2 in 5 cases(20.8%),grade 3-5 in 19 cases(79.2%).Glasgow Coma Scale score:9-12 in 14 cases(58.3%),13-15 in 10 cases(41.7%).Immediately postprocedural Raymond-Roy grade:grade 1 in 23 cases(95.8%),grade 2 in 1 case(4.2%).Raymond-Roy grade in imaging follow-up for 2 wk to 3 months:grade 1 in 23 cases(95.8%),grade 2 in 1 case(4.2%).Followup for 2 to 12 months showed that 21 patients(87.5%)had good functional outcomes(modified Rankin Scale score≤2),and there were no deaths.CONCLUSION Endovascular treatment is a safe and effective treatment for ruptured lobulated AcoAA.

Endovascular treatment of direct carotid cavernous fistula resulting from rupture of intracavernous carotid aneurysm: A case report

BACKGROUND Direct carotid cavernous fistulas(CCFs)are typically the result of a severe traumatic brain injury.High-flow arteriovenous shunts secondary to rupture of an intracavernous aneurysm,resulting in direct CCFs,are rare.The use of a pipeline embolization device in conjunction with coils and Onyx glue for treatment of direct high-flow CCF resulting from ruptured cavernous carotid artery aneurysm in a clinical setting is not well documented.CASE SUMMARY A 58-year-old woman presented to our department with symptoms of blepharoptosis and intracranial bruits for 1 wk.During physical examination,there was right eye exophthalmos and ocular motor palsy.The rest of the neurological examination was clear.Notably,the patient had no history of head injury.The patient was treated with a pipeline embolization device in the ipsilateral internal carotid artery across the fistula.Coils and Onyx were placed through the femoral venous route,followed by placement of the pipeline embolization device with assistance from a balloon-coiling technique.No intraoperative or perioperative complications occurred.Preoperative symptoms of bulbar hyperemia and bruits subsided immediately after the operation.CONCLUSION Pipeline embolization device in conjunction with coiling and Onyx may be a safe and effective approach for direct CCFs.

Successful Surgical Treatment of a Giant Mediastinal False Aneurysm 30 Years after Bentall Operation

False aneurysm occurring after replacement of ascending aorta by a vascular prosthesis is a rare, but life-threatening complication. In spite of advances in endovascular techniques, surgery remains the treatment of choice in the majority of cases. We report the case of a huge pseudoaneurysm caused by late dehiscence of the right coronary ostium-aortic tubular graft anastomosis, occurred 30 years after replacement of aortic valve and ascending aorta by classical Bentall operation. A fistula originating from the aneurysmal sac extended across the sternum into the thoracic subcutaneous soft tissues and gave rise to a pulsatile mass well appreciable on the anterior chest wall. The surgical treatment, consisting of partial resection of the aortic tubular graft and sternal reconstruction was effective and uneventful.

Massive Epistaxis Revealing a Post-Traumatic Aneurysm of the Internal Carotid Artery: A Clinical Case and Review of the Literature

Internal carotid artery (ICA) aneurysms are an unusual but serious cause of epistaxis. This epistaxis is massive and sometimes uncontrollable threatening the vital prognosis of patients. We report the case of a 16-year-old adolescent received in emergency with severe bilateral epistaxis, asthenia and grade-3 left exophthalmos. In his history, the subject had been the victim of an assault six months before consultation. He had received blows on the cephalic extremity with light but repeated epistaxis. The treatment consisted to blood products transfusion and local compression by sterile gazes. An ICA aneurysm in sphenoid sinus has been confirmed in a craniofacial CT scan coupled to vascular opacification. Although the ICA has a variable course in contact with the sphenoid sinus, massive epistaxis would be the consequence of a pronounced dehiscence of the ICA in the sphenoid sinus, particularly in a traumatic context. In front of this type of epistaxis in our context, general practitioners must be able to suspect a ruptured ICA aneurysm in the presence of exophthalmos and a notion of old or recent cranio-encephalic injury. Additionally, due to the high morbidity and mortality of this condition, a monitoring algorithm is necessary for patients with head trauma to facilitate early detection.

Research Progress on Individualized Treatment of Splenic Aneurysm

Splenic artery aneurysm has a hidden onset and atypical symptoms.There are various diagnostic methods for splenic aneurysms,among which ultrasound is the first choice for aneurysm screening.The diagnostic rate of CTA and DSA reaches 100%.In clinical practice,it is necessary to integrate medical history,symptoms and signs,and multiple imaging results to improve the diagnostic rate.In terms of treatment plans,both intervention and surgical procedures have their strengths,and the application of intervention will be more extensive.We need to adhere to the principle of individualization and choose a reasonable treatment plan for patients.At present,there are many reports on pregnant women with large splenic aneurysms both domestically and internationally.Some scholars believe that large splenic aneurysms may be related to hormonal imbalances during pregnancy,and the specific pathogenic mechanism will become a hot topic in future research.

Safety and Efficacy of Endovascular Aortic Repair for Abdominal Aortic Aneurysms with a Hostile Neck Anatomy

Objective This study aimed to investigate the safety and efficacy of endovascular aortic repair(EVAR)for the treatment of an abdominal aortic aneurysm(AAA)with a hostile neck anatomy(HNA).Methods From January 1,2015 to December 31,2019,a total of 259 patients diagnosed with an AAA who underwent EVAR were recruited into this study.Based on the morphological characteristics of the proximal neck anatomy,the patients were divided into the HNA group and the friendly neck anatomy(FNA)group.The patients were followed up for up to 4 years.Results The average follow-up time was 1056.1±535.5 days.Type I endoleak occurred in 4 patients in the HNA group,and 2 patients in the FNA group.Neither death nor intraoperative switch to open repair occurred in either group.The time of the operation was significantly longer in the HNA group(FNA vs.HNA,99.2±51.1 min vs.117.5±63.8 min,P=0.011).There were no significant differences in short-term clinical success rate(P=0.228)or midterm clinical success rate(P=0.889)between the two groups.The overall mortality rate was 10.4%,and Kaplan-Meier survival analysis indicated that the two groups had similar cumulative survival rates at the end of the follow-up period(P=0.889).Conclusion EVAR was feasible and safe in patients with an AAA with a proximal HNA.The early and midterm results were promising;however,further studies are needed to verify the long-term effectiveness of EVAR.

Portal vein aneurysm-etiology,multimodal imaging and current management

Portal vein aneurysm(PVA)is a rare vascular abnormality,representing 3%of all venous aneurysms in the human body,and is not well understood.It can be congenital or acquired,located mainly at the level of confluence,main trunk,branches and bifurcation.A PVA as an abnormality of the portal venous system was first reported in 1956 by Barzilai and Kleckner.A review from 2015 entitled“Portal vein aneurysm:What to know”considered fewer than 200 cases.In the last seven years,there has been an increase in the number of PVAs diagnosed thanks to routine abdominal imaging.The aim of this review is to provide a comprehensive update of PVA,including aetiology,epidemiology,and clinical assessment,along with an evaluation of advanced multimodal imaging features of aneurysm and management approaches.

Open surgical approach for two coincidental splenic artery aneurysms:a case report

Several factors can contribute to the formation of aneurysms,including hemodynamic changes,polyarteritis nodosa,bacterial endocarditis,vasculitis,fibromuscular dysplasia,vascular malformation,and cystic medial necrosis.^([1,2]) Surgery is recommended for splenic artery aneurysms (SAAs) greater than 25 mm in diameter,and several surgical approaches are used,including open surgery,laparoscopic surgery,and percutaneous embolization.Laparoscopic surgery might be associated with an increased risk of pancreatic leakage compared to the open surgery approach.

Trehalose attenuates abdominal aortic aneurysm formation by inducing autophagy in smooth muscle cells

BACKGROUND Trehalose is a naturally occurring disaccharide,which has been identified as an autophagy inducer and ex-hibits protective effect in cardiovascular diseases such as myocardial infraction and atherosclerosis.However,the functional role of trehalose in abdominal aortic aneurysm(AAA)remains undefined.METHODS To study the effect of trehalose in AAA,trehalose(1 g/kg per day)were given for 14 continuous days in a mouse model of elastase-induced abdominal aortic aneurysm.On day 14,ultrasound was performed to measure aortic diameter before the abdominal aortas were harvested and processed for further analysis.Verhoeff-Van Gieson staining and TUNEL staining were performed on paraffin sections to evaluate vascular histology and apoptosis,immunofluorescence staining and Western-blot were performed to evaluate expression of autophagy markers.RESULTS Echocardiography and in situ pictures demonstrated that trehalose attenuated infrarenal aorta dilation.Verhoeff-Van Gieson staining showed elastin degradation was improved in trehalose-treated group.Compared with vehicle-treated mice,trehalose treatment restored smooth muscle cell contractile phenotype with increasedα-SMA,Calponin and Myh11 expression.Furthermore,trehalose also attenuated cell apoptosis and leukocytes infiltration.Importantly,trehalose induced autophagy with decrease SQSTM1/p62 accumulation,increased lamp2 expression and LC3B conversion.CONCLUSION Trehalose attenuated AAA progression with decreased inflammation and restored SMC contractile phenotype by inducing autophagy.These results demonstrated the therapeutic potential of trehalose in AAA.

A prospective cohort study on serum A20 as a prognostic biomarker of aneurysmal subarachnoid hemorrhage

BACKGROUND:A20 may be a neuroprotective factor.Herein,we aimed to investigate whether serum A20 levels were associated with disease severity,delayed cerebral ischemia(DCI),and outcome after aneurysmal subarachnoid hemorrhage(aSAH).METHODS:In this prospective cohort study containing 112 aSAH patients and 112 controls,serum A20 levels were quantified.At 90 d poststroke,Modified Rankin Scale(MRS) scores≥3 were defined as a poor outcome.All correlations and associations were assessed using multivariate analysis.RESULTS:Compared with controls,there was a significant elevation of serum A20 levels in patients(median 123.7 pg/mL vs.25.8 pg/mL;P<0.001).Serum A20 levels were independently correlated with Hunt-Hess scores(β 9.854;95% confidence interval [95% CI] 2.481-17.227,P=0.009) and modified Fisher scores(β 10.349,95% CI 1.273-19.424,P=0.026).Independent associations were found between serum A20 levels and poor outcome(odds ratio [OR] 1.015,95%CI 1.000-1.031,P=0.047) and DCI(OR 1.018,95% CI 1.001-1.035,P=0.042).Areas under the curve for predicting poor outcome and DCI were 0.771(95% CI 0.682-0.845) and 0.777(95% CI 0.688-0.850),respectively.Serum A20 levels ≥128.15 pg/mL predicted poor outcome,with a sensitivity of 73.9% and specificity of 74.2%,and A20 levels ≥160.55 pg/mL distinguished the risk of DCI with65.5% sensitivity and 89.2% specificity.Its ability to predict poor outcome and DCI was similar to those of Hunt-Hess scores and modified Fisher scores(both P>0.05).CONCLUSION:Enhanced serum A20 levels are significantly associated with stroke severity and poor clinical outcome after aSAH,implying that serum A20 may be a potential prognostic biomarker for aSAH.

Large Basilar Trunk Aneurysm Discovered Incidentally in a Patient with Ischaemic Stroke: Case Report

Summary: Many anomalies can be observed in the basilar trunk, such as aneurysms. Basilar trunk aneurysms are rare with a low reported prevalence. In this study, we describe a case of ischaemic stroke revealed by a basilar trunk aneurysm associated with venous thromboembolic disease. The patient was 60 years old and had no specific pathological history. She was seen for a sudden onset of right hemiplegia associated with dysarthria that had been present for 12 hours. The physical examination revealed a pyramidal syndrome and an altered general condition. An emergency cerebral computed tomography (CT) scan showed evidence of a cerebrovascular accident associated with a saccular aneurysm. We adopted the diagnosis of a deep left sylvian stroke associated with a superficial right sylvian stroke in the setting of an incidentally discovered basilar trunk aneurysm. On the 9ème day of hospitalisation, the patient experienced sudden onset of respiratory distress in conjunction with a warm, painful swelling of the right leg. TTE revealed signs of pulmonary embolism, with thrombi in the inferior vena cava and right atrium. Pulmonary embolism was highly probable, with a modified Geneva score of 15. We adopted the diagnosis of DVA complicated by pulmonary embolism in the setting of a basilar trunk aneurysm. The patient was transferred to the cardiology department, where she received oxygen therapy and thrombolysis with streptokinase. The immediate outcome 6 hours later was the sudden death of the patient due to the onset of cardiogenic shock.

Giant Aneurysmal Bone Cyst of the Right Femur about a Case

Aneurysmal bone cyst (ABC) is a rare bone tumor accounting for 1% - 4% of benign bone tumors. Its etiopathogenesis remains unknown. The main site is the metaphysis of the long bones. ABC occurs almost exclusively in young people, with a slight female predominance. We report an exceptional case of ABC of the femur with involvement of the right hip in a 16-year-old girl in the Medical Imaging Department of Pr Bocar Sidy Sall Hospital of Kati (Mali). We will discuss the clinical and radiological aspects of this pathology. Observation: Mrs N C., aged 16, was referred to the orthopaedic-traumatology department for an X-ray of the right thigh, indicated as having a large, disabling thigh. Clinical examination revealed a large thigh measuring 890 mm in circumference, compared with 300 mm on the contralateral side. Radiographically, the femur showed a blown appearance, with the cortex thinned and broken in places. Exceptionally, the lesion affected the entire femur. On CT scan, we found a voluminous fluid collection occupying the entire right femur, including the right femoral head and homolateral ischium. The cortex was interrupted in places, and the adjacent soft tissues were thinned or laminated, but not infiltrated. Histology revealed haemorrhagic and inflammatory elements compatible with the diagnosis of ABC. Conclusion: ABC is a tumor entity that is often difficult to diagnose. Medical imaging, topographical distribution and histology form an indissociable whole to establish a diagnosis of certainty.