Revisiting the role of histopathology in acute intracerebral hemorrhage: Detecting missed secondary lesions beyond neuroimaging

Abstract

Background:

Intracerebral hemorrhage (ICH) is commonly due to hypertension, but secondary causes such as vascular malformations and tumors may be radiographically occult. While advanced imaging has improved preoperative detection, some lesions remain undetected. This study reassessed the diagnostic value of routine histopathological analysis of hematoma specimens in such cases.

Methods:

We retrospectively reviewed 93 surgically treated ICH cases (2015–2024) with no preoperative suspicion of secondary etiology. All specimens underwent histopathological evaluation, and diagnostic yield was assessed.

Results:

Histopathology revealed secondary causes in 27 cases (29%): cerebral amyloid angiopathy (n = 18), vascular malformations (n = 6), and metastatic tumors (n = 2). In several patients, pathology disclosed clinically significant diagnoses that were not evident on computed tomography, magnetic resonance imaging, or angiography, directly impacting management.

Conclusion:

Routine histopathological evaluation of hematoma specimens remains valuable in ICH surgery, even in the modern imaging era. This simple, low-burden practice identified otherwise occult etiologies in nearly one-third of cases and should be considered a standard adjunct to neuroimaging for accurate diagnosis and optimized care.

INTRODUCTION

Surgical evacuation of intracerebral hemorrhages is a common and well-established treatment modality in the field of neurosurgery, supported by extensive clinical evidence. While the majority of intracerebral hemorrhages (ICHs) are attributed to hypertensive etiologies, a subset of cases arises from secondary causes with identifiable bleeding sources, which can complicate acute-phase management. As early as the 1950s, Courville described the pathology and pathogenesis of intracerebral hemorrhages, particularly highlighting hypertensive arteriosclerotic rupture as the principal cause.[3] In the 1960s, William F. McCormick systematized the pathology and clinical features of spinal vascular malformations, which marked the seminal step toward a unified pathophysiological understanding of cerebrospinal vascular lesions.[9] Recent surgical series have shown that routine histopathological examination of evacuated hematomas provides actionable diagnostic information in 37.8–44.3% of cases where imaging was inconclusive.[7,8,12,13] When neuroimaging findings are atypical, further diagnostic evaluation – such as cerebral angiography – is warranted to rule out secondary causes. With advances in imaging techniques, the proportion of cases in which hematoma specimens provide the first definitive diagnosis has decreased. We hypothesized that certain underlying pathologies may remain undetectable despite comprehensive imaging. In such cases, we focused on a fundamental yet underutilized diagnostic approach: histopathological evaluation of hematoma specimens obtained during surgical evacuation. At our hospital, we routinely submit hematoma specimens for pathological analysis in ICH cases undergoing surgical treatment. We have successfully diagnosed several cases of secondary ICHs that were not suspected preoperatively. Herein, we present representative cases and discuss the significance of our approach.

CASE 1

An 85-year-old man presented with motor aphasia, right hemiparesis, and impaired consciousness. Glasgow coma scale (GCS) E3V3M4.

Noncontrast head computed tomography (CT) showed a left subcortical hemorrhage [Figures 1a and 1b]. Craniotomy for hematoma evacuation was performed; the hematoma specimen was submitted for histopathological analysis. Postoperative recovery was well. Neurological status improved after surgery. Postoperative imaging of contrast-enhanced magnetic resonance imaging (MRI) revealed a 5-mm enhancing mass in the contralateral posterior lateral ventricle [Figures 1c and 1d].

Figure 1:

(a and b) Preoperative CT shows a solitary subcortical hemorrhage (arrow) was identified in the left temporal to parietal region. (c and d) Postoperative contrast T1 enhanced MRI of the brain revealed marked edema surrounding the hemorrhagic tumor (arrow). In addition, a small lesion measuring approximately 5 mm was observed in the posterior horn of the right lateral ventricle (arrowhead).

Histopathological examination (HPE) is that the hematoma contains solid proliferation of small tumor cells with hyperchromatic nuclei and scant cytoplasm [Figures 2a-c]. Immunohistochemistry was positive for antigen etrieval 1 (AE1)/3, cytokeratin7 (CK7), thyroid transcription factor 1 (TTF-1) [Figure 2d], and synaptophysin, consistent with metastatic small cell lung carcinoma. Bronchoscopy confirmed primary small cell carcinoma. The patient was ineligible for chemotherapy due to advanced age and low activity of daily living (ADL) and was transferred to palliative care.

Figure 2:

Pathological findings. (a-c) Hematoxylin staining (×40, ×100, ×400) shows hematoma contains solid proliferation of small tumor cells with hyperchromatic nuclei and scant cytoplasm (black arrow). (d) TTF-1 stain was positive.

CASE 2

A 58-year-old woman presented with headache and right upper limb weakness. She had a history of right nephrectomy for renal cell carcinoma (RCC) 3 years earlier with complete remission. GCS E4V4M5. CT and MRI revealed cerebellar hemorrhage, intraventricular hemorrhage, and subarachnoid hemorrhage in the cerebellopontine cistern and cisterna magna [Figures 3a and b]. Preoperative angiography showed no vascular malformations [Figures 3c and d]. Craniotomy for hematoma evacuation with ventricular drainage was performed; the hematoma specimen was submitted for histopathological analysis. However, the patient experienced repeated rebleeding and developed acute hydrocephalus. Postoperative imaging of contrast-enhanced MRI showed no additional lesions; the hemorrhagic lesion was considered a solitary metastatic focus. HPE showed the hematoma contains a few large atypical cells positive for AE1/AE3, consistent with metastatic carcinoma [Figures 4a-d]. Limited cell numbers precluded further immunohistochemical characterization. The patient died on postoperative day 40 due to aspiration pneumonia.

Figure 3:

(a) Preoperative imaging revealed an intracerebral hemorrhage extending from the right subcortical area to the thalamus accompanied by intraventricular extension (blue arrow) and resulting in acute hydrocephalus. (b) Due to the nonspecific findings, a head CT angiography (CTA) was performed; however, no apparent vascular malformation was identified. (c) Preoperative MRI also shows no sign of secondary intracerebral hemorrhage (blue arrow) in FLAIR enhanced. (d) Postoperative contrast-enhanced MRI demonstrated a single hemorrhagic mass lesion corresponding to the site of the initial hemorrhage (blue arrow).

Figure 4:

Pathological findings. (a and b) Immunohistochemistry was positive for AE (antigen retrieval) 1/3. (c and d) Hematoxylin staining (×40, ×100) showed the hematoma contains a few large atypical cells (black arrow).

CASE 3

A 52-year-old woman presented with headache. Glasgow coma scale (GCS) E3V2M2. On arrival, she had bilaterally dilated pupils. CT and MRI revealed a cerebellar hemorrhage adjacent to the fourth ventricle with intraventricular and subarachnoid hemorrhage [Figures 5a and 5b]. Given her relatively young age and atypical radiographic findings, a vascular malformation was suspected. Cerebral subtraction angiography, however failed to identify any definitive vascular abnormalities [Figures 5c and 5d]. Craniotomy for hematoma evacuation and ventricular drainage was performed. Intraoperatively, a vascular nidus was identified near the left posterior inferior cerebellar artery (PICA) and excised for pathological analysis. On postoperative day 1, the patient developed extensive posterior circulation infarction and hypotension. HPE revealed irregular, tortuous arterial and venous structures without intervening capillary beds or normal parenchyma [Figures 6a and b], and the elastic Van Gieson stain was positive [Figures 6c and d], consistent with a ruptured AVM. The patient died on postoperative day 4 due to extensive infarction and hemodynamic compromise.

Figure 5:

(a and b) Preoperative head CT and MRI FLAIR images revealed cerebellar hemorrhage, intraventricular hemorrhage extending from the fourth to the third ventricle (arrow), and subarachnoid hemorrhage in the cerebellopontine cistern and cisterna magna (Blue marked zone). (c and d) Preoperative cerebral digital subtraction angiography was performed, but no findings suggestive of vascular malformations were identified.

Figure 6:

Pathological findings. [a and b] Hematoxylin staining (×40, ×100) shows irregular, tortuous arterial and venous structures without intervening capillary beds or normal parenchyma (black arrow). [c and d] Elastic Van Gieson stain was positive.

MATERIALS AND METHODS

In our hosipital, most hematoma specimens from craniotomy or endoscopic evacuation are routinely submitted for pathological examination. We reviewed 286 surgically treated ICH cases from 2015 to August 2024 and included 93 cases where the hemorrhage source was not predicted preoperatively. In addition, our protocol consists of routine preoperative MRI, selective cerebral digital subtraction angiography to rule out suspected secondary hemorrhage, and exclusion of cases with known preoperative diagnoses.

RESULTS

In our institutional series of 93 surgically treated, radiographically cryptogenic ICHs, histopathological evaluation identified secondary causes in 27 cases (29%), including amyloid angiopathy (18), AVM (4), cavernous malformation (1), dAVF (1), and metastatic tumors (2). [Table 1] The procedures were performed either by board-certified neurosurgeons or by clinical fellows under their supervision, rather than by a single operating surgeon.

Table 1.

: Detection of secondary intracerebral hemorrhages from hematoma specimens despite negative imaging.

DISCUSSION

Intracerebral hemorrhages (ICHs) are broadly categorized as primary, most often hypertensive in origin, and secondary, arising from vascular malformations or neoplasms. Reported hemorrhage risks vary by lesion type: 0.25–4.5% in cavernous malformations, 2–4% in arteriovenous malformations (AVMs), 1.5–7.5% in dural arteriovenous fistulas (dAVFs), and 20–50% in metastatic brain tumors.[5,7,14]

Our series illustrates the diagnostic value of histopathological evaluation. In Case 1, a cortical hemorrhage in an elderly man without known malignancy was ultimately diagnosed as metastatic small cell lung carcinoma, undetectable by imaging or tumor markers. Especially, lung cancer metastasizes to the brain early in its course; approximately half of lung cancer patients exhibit brain metastases with no other systemic spread.[2] In Case 2, a patient with prior renal cell carcinoma developed a thalamic hemorrhage; pathological analysis of the hematoma revealed metastatic cells despite inconclusive radiological findings. Several studies have noted that AVMs may remain occult on initial MRI and cerebral angiography, with the diagnosis established only on subsequent follow-up imaging.[10,15]

Histopathological assessment, when incorporated, may further substantiate and secure the diagnosis. Case 3 demonstrated a cerebellar hemorrhage with angiographically occult AVM, where histology provided decisive diagnostic confirmation. These cases emphasize that imaging alone, even with CT, MRI, and angiography, may fail to identify underlying lesions, whereas hematoma pathology can reveal otherwise occult etiologies.

While the current international guidelines primarily emphasize comprehensive preoperative neuroimaging – including CT angiography (CTA), contrast-enhanced MRI, magnetic resonance angiography, and catheter angiography – for the evaluation of secondary causes of ICH, the role of routine HPE of evacuated hematoma specimens is less clearly defined.[6,11] However, pathological assessment is still performed when the etiology remains uncertain, given the possibility that small vascular malformations or occult neoplasms may escape detection on imaging. Such practice reflects local institutional protocols and accumulated clinical experience rather than formal guideline recommendations.

Detection rates in prior studies have been higher. For example, Wakai et al. reported vascular or neoplastic lesions in 20 of 29 angiographically occult ICH cases, and Elhammady et al. identified secondary causes in 7 of 9 cases.[4,14] More recent series likewise reported higher yields of secondary etiologies(37.8~44.3%), particularly vascular malformations.[7,12] There have also been reports of etiological assessment based on hematoma specimens under similar conditions, in which the potential utility of Congo red staining for the diagnosis of cerebral amyloid angiopathy was highlighted.[1] By contrast, the lower yield in our cohort likely reflects the improved sensitivity of modern preoperative MRI, CTA, and angiography, as well as our exclusion of patients with known lesions. Nonetheless, nearly one-third of cases still harbored an occult pathology identifiable only through histopathology. As noted above, follow-up imaging may eventually reveal the source of hemorrhage, a phenomenon frequently observed in clinical practice; however, no clear consensus exists in the literature regarding the optimal timing for repeat imaging.[9] In this context, histopathological findings can be highly valuable in guiding both the choice and timing of additional diagnostic studies.

Routine submission of hematoma specimens is technically straightforward, imposes minimal burden on pathology services, and remains cost-effective, at around 10 US dollars, even in emergent settings. From both clinical and economic perspectives, this practice serves as an essential adjunct to imaging, ensuring diagnostic accuracy and enabling appropriate management in patients with secondary ICH. In this context, the likelihood of establishing a definitive diagnosis from hematoma specimens is highly dependent on the accuracy of preoperative imaging. As imaging technologies continue to advance, we believe that it is of considerable importance to present updated data at regular intervals and to repeatedly reassess the validity of this approach.

CONCLUSION

This study demonstrated that histopathological evaluation of hematoma specimens obtained during craniotomy for ICH can facilitate the diagnosis of unexpected secondary causes in cases where preoperative imaging failed to identify a source of bleeding. Among 93 cases, secondary etiologies were identified in 27 patients (29%), including metastatic brain tumors and arteriovenous malformations – conditions with significant implications for treatment planning. Although advancements in neuroimaging have improved preoperative diagnostic accuracy, a subset of hemorrhagic lesions remains occult. Histological evaluation of hematoma specimens is both cost-effective and technically simple, even in emergency surgical settings. Routine submission of hematoma specimens should therefore be strongly considered as it provides critical diagnostic information. Continued pathological investigation may further enhance diagnostic precision and contribute to improved clinical outcomes in patients with ICH. The authors certify that there are no affiliations with or involvement in any organization or entity with financial or nonfinancial interests that could inappropriately influence the conduct or reporting of the present study.

Ethical approval:

Institutional review board at Eimeikai IRB approved the study . Approval number is 202507. Date is April, 13, 2025.

Declaration of patient consent:

The authors certify that they have obtained all appropriate patient consent.

Financial support and sponsorship:

Nil.

Conflicts of interest:

There are no conflicts of interest.

Use of artificial intelligence (AI)-assisted technology for manuscript preparation:

The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.

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