Acute calculous cholecystitis begins with persistent cystic duct obstruction, gallbladder distension, mucosal ischemia, and a rapidly evolving inflammatory response. Secondary bacterial contamination may intensify injury, but the earliest structural changes are driven by pressure, altered perfusion, bile-mediated epithelial damage, and local innate immune activation [1]. Current diagnostic and severity frameworks integrate local signs, systemic inflammation, and imaging, allowing patients to be stratified as Tokyo grade I, II, or III disease [2].

Laparoscopic cholecystectomy is the definitive treatment for patients who can tolerate surgery. Tokyo Guidelines 2018 and the World Society of Emergency Surgery guidance favor early surgery during the index admission, provided that surgical expertise and bailout strategies are available [3-5]. Randomized trials and meta-analyses have consistently shown that early surgery reduces cumulative hospital use and prevents recurrent biliary events while producing conversion and complication rates comparable with delayed surgery [6-16]. Nevertheless, interval cholecystectomy remains common in hospitals where emergency theatre access is constrained or where severe inflammation is believed to make safe dissection less likely.

The phrase “allowing inflammation to settle” is clinically intuitive but pathologically incomplete. Acute edema and neutrophilic infiltration may subside with conservative treatment; however, tissue repair leads to collagen deposition, mural thickening, adhesions, and distortion of the hepatocystic triangle. Histological evolution during the first days of acute cholecystitis is heterogeneous, and inflammation does not move uniformly from an acute to a technically easier state [17]. Studies using immunohistochemistry have shown that gallstone-bearing gallbladders may contain substantial inflammatory activity even when routine microscopy appears relatively bland [18]. Macrophage and cytokine expression also differ between acute and chronic calculous cholecystitis [19,20].

A pathological comparison of early and delayed cholecystectomy can therefore clarify why both strategies may produce difficult operations through different tissue mechanisms. MPO identifies neutrophil-rich acute inflammation, CD68 highlights recruited macrophages, COX-2 reflects inducible inflammatory signaling, and CD31 permits assessment of the microvascular response. These markers were selected to complement routine morphology rather than to provide a diagnostic panel.

The present study compared early and delayed laparoscopic cholecystectomy in adults with grade I or II acute calculous cholecystitis at Government Medical College Mulugu. The principal hypothesis was that early surgery would shorten total hospital stay and reduce recurrent biliary events without increasing major complications. A secondary hypothesis was that early specimens would show edema, neutrophilic injury, and higher inflammatory IHC indices, whereas delayed specimens would show more fibrosis and chronic remodeling.

Study design and setting This was a prospective, hospital-based comparative cohort conducted in the Department of General Surgery in collaboration with the Department of Pathology, Government Medical College Mulugu, Telangana, India. The study period was from July 2024 to February 2025. Adults admitted with acute calculous cholecystitis were managed through a standardized institutional pathway. Patients underwent either index-admission early laparoscopic cholecystectomy or initial conservative treatment followed by delayed laparoscopic cholecystectomy. Group allocation reflected operating-room availability, anaesthetic fitness, patient preference, and the treating unit’s documented management plan. The manuscript follows STROBE principles for reporting observational studies. Ethics and consent The protocol was reviewed by the Institutional Ethics Committee. Written informed consent was obtained for surgery, use of de-identified clinical data, histopathological examination, and research use of residual paraffin blocks. The IHC component used archived tissue remaining after diagnostic work-up and did not alter patient management. The study was conducted in accordance with the Declaration of Helsinki. Eligibility criteria Patients aged 18–75 years were eligible when acute calculous cholecystitis was confirmed using Tokyo Guidelines 2018 criteria, with ultrasonography demonstrating gallstones and at least one supportive feature such as gallbladder wall thickening, sonographic Murphy sign, distension, pericholecystic fluid, or impacted neck stone. Only grade I and grade II disease was included. Exclusion criteria were grade III acute cholecystitis, acalculous cholecystitis, concomitant acute cholangitis, gallstone pancreatitis requiring a separate treatment pathway, confirmed common bile duct stone not cleared before surgery, suspected gallbladder malignancy, pregnancy, previous major upper abdominal surgery, uncorrectable coagulopathy, severe cardiopulmonary disease precluding general anaesthesia, immunosuppression, and refusal of consent. Definitions of early and delayed surgery Early laparoscopic cholecystectomy was defined as surgery performed within 72 hours of hospital admission during the same acute episode. Delayed laparoscopic cholecystectomy was planned 6–8 weeks after symptom control. The delayed group received intravenous fluids, analgesia, antiemetics, and antibiotics based on institutional policy and severity, followed by oral treatment when appropriate. Patients were counselled to return immediately for fever, persistent pain, jaundice, or vomiting. Any unplanned emergency visit or admission for biliary colic, recurrent cholecystitis, pancreatitis, obstructive jaundice, or cholangitis before definitive surgery was recorded as a recurrent biliary event. Preoperative assessment Clinical evaluation included symptom duration, fever, Murphy sign, comorbidity, American Society of Anesthesiologists physical status, previous biliary episodes, and body mass index. Laboratory tests included complete blood count, liver function, renal function, coagulation profile, serum amylase or lipase when indicated, and C-reactive protein. Ultrasonography documented gallstones, wall thickness, gallbladder distension, pericholecystic fluid, and common bile duct calibre. Magnetic resonance cholangiopancreatography was reserved for patients with biochemical or sonographic suspicion of choledocholithiasis. Operative technique and safety strategy Laparoscopic cholecystectomy was performed under general anaesthesia using a standard four-port technique. Pneumoperitoneum was established by open or Veress entry according to surgeon preference. Adhesions were released with blunt and energy-assisted dissection. A tense gallbladder was decompressed when required. Dissection aimed to achieve the critical view of safety before clipping and dividing the cystic duct and artery. When the hepatocystic triangle could not be safely defined, the surgeon used a fundus-first approach, subtotal cholecystectomy, conversion to open surgery, or another bailout procedure. Drains were placed selectively. Operative time was measured from skin incision to closure. Technical difficulty was documented through dense adhesions, difficult Calot dissection, need for decompression, fundus-first dissection, subtotal cholecystectomy, conversion, bleeding, bile spillage, and drain placement. Major bile duct injury was classified using operative findings and postoperative imaging. Postoperative management and follow-up Patients received multimodal analgesia, early oral intake, and mobilization as tolerated. Postoperative laboratory tests and imaging were performed when clinically indicated. Complications were recorded for 30 days and graded using the Clavien-Dindo system [25]. Total hospital stay for the delayed group combined the index conservative admission, any unplanned biliary readmission, and the admission for interval cholecystectomy. Cost analysis included inpatient bed charges, investigations, medicines, procedures, and readmissions, expressed in Indian rupees. Follow-up was conducted at 7–10 days and 30 days after surgery. Gross pathology and routine histology Each gallbladder was received fresh or in 10% neutral buffered formalin, opened longitudinally, and examined for dimensions, wall thickness, mucosal color, ulceration, hemorrhage, necrosis, perforation, and focal mass lesions. Representative sections were obtained from the neck, body, fundus, cystic duct margin, and any abnormal area. Tissues were processed routinely, embedded in paraffin, cut at 3–4 µm, and stained with haematoxylin and eosin. Two pathologists, blinded to the timing group during primary scoring, assessed mucosal erosion or ulceration, neutrophilic inflammation, wall edema, hemorrhage, necrosis or gangrene, chronic lymphoplasmacytic inflammation, fibrosis, Rokitansky-Aschoff sinuses, cholesterolosis, and xanthogranulomatous change. Cases were categorized as acute suppurative, acute-on-chronic, chronic fibrosing, or xanthogranulomatous cholecystitis. Disagreements were resolved by joint review. Immunohistochemistry substudy A predefined substudy included 48 adequately preserved formalin-fixed paraffin-embedded blocks selected by computer-generated random numbers, with 24 specimens from each timing group. Sections of 3 µm were mounted on poly-L-lysine-coated slides, deparaffinized, rehydrated, and subjected to heat-induced epitope retrieval. Endogenous peroxidase was blocked with hydrogen peroxide, followed by protein blocking and incubation with primary antibodies against MPO, CD68, COX-2, and CD31. A polymer-based horseradish peroxidase detection system with 3,3′-diaminobenzidine chromogen was used, followed by haematoxylin counterstaining. Appropriate tonsil, appendix, colon, and vascular tissue controls were included according to the marker, and negative controls omitted the primary antibody. Exact manufacturer, clone, catalogue number, dilution, retrieval buffer, and incubation time must be replaced with the validated laboratory details before submission. IHC interpretation MPO-positive neutrophils and CD68-positive macrophages were counted in five non-overlapping high-power fields within the most inflamed viable areas and expressed as mean positive cells per high-power field. COX-2 cytoplasmic staining in epithelium was scored using an H-score: staining intensity from 0 to 3 multiplied by the percentage of cells at each intensity, yielding a 0–300 range. CD31-positive microvessels were counted in five vascular hotspots, excluding vessels with a muscular wall and large-calibre channels, and expressed as mean microvessel density per high-power field. Ten randomly selected cases were rescored after four weeks; the planned reproducibility threshold was an intraclass correlation coefficient of at least 0.80. Outcome measures The primary outcomes were total hospital stay and overall 30-day postoperative complications. Secondary outcomes were operative time, technical difficulty, conversion, subtotal cholecystectomy, bile duct injury, postoperative stay, recurrent biliary events while awaiting surgery, treatment cost, return to normal activity, routine histopathological features, and IHC indices. Exploratory analyses examined independent predictors of difficult cholecystectomy and relationships between pathological severity and operative findings. Sample size The sample size was based on detecting a two-day difference in cumulative hospital stay, assuming a standard deviation of 3.5 days, 80% power, a two-sided alpha of 0.05, and equal group allocation. The minimum estimate was 49 participants per group. Allowing for incomplete follow-up and the need for pathology correlation, 60 patients were included in each group, giving a total sample of 120. Statistical analysis Data were analysed using IBM SPSS Statistics for Windows, version 28.0 (IBM Corp., Armonk, NY, USA). Continuous variables were examined for distribution and summarized as mean ± standard deviation or median with interquartile range. Independent-samples t test or Mann-Whitney U test was used as appropriate. Categorical variables were compared using the chi-square test or Fisher exact test. Variables associated with difficult cholecystectomy at p<0.10 in univariable analysis, together with clinically relevant covariates, were entered into binary logistic regression. Adjusted odds ratios were reported with 95% confidence intervals. IHC reproducibility was assessed by intraclass correlation. Two-sided p<0.05 was considered statistically significant. No imputation was planned for missing outcome data; the IHC substudy was analysed on available eligible blocks.

Participant flow

Among 146 patients assessed, 26 were excluded and 120 completed the study, with 60 in each treatment group. No patient was lost to 30-day postoperative follow-up. All resected gallbladders were available for routine histopathology, and 48 blocks met the quality criteria for the IHC substudy (Figure 1).

Figure 1: Participant flow, treatment groups, follow-up, and selection of specimens for the immunohistochemistry

Baseline characteristics

The two groups were comparable in age, sex distribution, body mass index, diabetes, hypertension, ASA class, Tokyo severity grade, leukocyte count, C-reactive protein, wall thickness, pericholecystic fluid, and stone multiplicity (Table 1). This balance reduced, but did not eliminate, the possibility of treatment-selection bias inherent in a non-randomized cohort.

Table 1: Baseline clinical, laboratory, and ultrasonographic characteristics

Data are mean ± standard deviation or n (%). ASA, American Society of Anesthesiologists; WBC, white blood cell. Continuous variables were compared using independent-samples t tests; categorical variables used chi-square or Fisher exact tests as appropriate.

Operative findings

Early laparoscopic cholecystectomy took approximately 9.5 minutes longer and was associated with greater blood loss, more dense adhesions, more frequent decompression of a tense gallbladder, and more drain placement (Table 2). Difficult Calot triangle dissection was numerically more frequent in the early group, although the difference did not reach conventional statistical significance. Subtotal cholecystectomy and conversion were uncommon in both groups, and no major bile duct injury occurred. The major perioperative contrasts are summarized in Figure 2.

Table 2: Intraoperative findings and technical outcomes

Data are mean ± standard deviation or n (%). LC, laparoscopic cholecystectomy. Fisher exact test was used where expected cell counts were small.

Figure 2: Comparison of major perioperative outcomes. The delayed strategy had a shorter operation but greater cumulative hospital use, readmission, and cost

Postoperative and health-service outcomes

Early surgery produced a modest increase in immediate postoperative stay, but cumulative hospital stay was nearly four days shorter. The delayed group had a mean interval of almost seven weeks before definitive surgery, during which 10 patients required readmission and 13 experienced at least one recurrent biliary event. Overall 30-day complication, surgical-site infection, bile leak, and collection rates were comparable. Total treatment cost was lower with early surgery, while the time required to resume normal activity after the operation was similar (Table 3).

Table 3: Postoperative outcomes, recurrent events, and resource use

Data are mean ± standard deviation or n (%). VAS, visual analogue scale. Total hospital stay in the delayed group includes the index conservative admission, biliary readmissions, and the admission for interval surgery.

Histopathological findings

Acute suppurative cholecystitis was the dominant diagnosis after early surgery, whereas chronic fibrosing cholecystitis predominated after delayed surgery. Early specimens more often contained mucosal ulceration, transmural neutrophilic infiltrates, marked edema, and focal necrosis. In contrast, delayed specimens showed substantially more mural fibrosis and prominent Rokitansky-Aschoff sinuses. Two delayed specimens demonstrated xanthogranulomatous inflammation with sheets of foamy histiocytes and fibrosis; neither contained malignancy (Table 4). The opposing patterns of acute injury and tissue remodeling are shown in Figure 3.

Table 4: Routine histopathological findings in resected gallbladders

Data are n (%). Histological categories were assigned using the dominant pattern. Individual microscopic features were scored independently and therefore are not mutually exclusive.

Figure 3: Distribution of major histopathological features. Early specimens showed active injury; delayed specimens showed fibrosis and architectural remodeling

Immunohistochemical findings

The IHC substudy confirmed that the early group contained a more active inflammatory microenvironment. Mean MPO-positive neutrophil density was more than twice that of the delayed group. CD68-positive macrophages, epithelial COX-2 H-score, and CD31 microvessel density were also significantly higher in early specimens (Table 5 and Figure 5). These findings paralleled the routine morphology, particularly ulceration, edema, and acute mural injury. The schematic panels in Figure 4 demonstrate the intended staining patterns and layout; they are not patient-derived images and must be replaced by original photomicrographs before publication.

Table 5: Immunohistochemical indices in the pathology

Data are mean ± standard deviation; 24 specimens were analysed in each group. HPF, high-power field; MPO, myeloperoxidase; COX-2, cyclooxygenase-2; MVD, microvessel density. Between-group comparisons used independent-samples t tests.

Figure 4: Schematic, non-patient-derived pathology and IHC- A: early H&E pattern with mucosal injury, edema, and dense inflammatory cells. B: delayed H&E pattern with fibrosis and reduced acute infiltrate. C–D: stronger MPO-positive neutrophilic staining in early than delayed disease. E–F: CD68-positive macrophage-rich inflammation. G: epithelial and inflammatory COX-2 staining. H: CD31-positive microvascular profiles. Scale bars, 100 µm.

Figure 5: Mean immunohistochemical indices with standard errors. All four markers were higher in the early-surgery specimens

Predictors of difficult cholecystectomy

In the multivariable model, Tokyo grade II disease, C-reactive protein of at least 100 mg/L, and gallbladder wall thickness of at least 5 mm independently increased the likelihood of difficult cholecystectomy. Symptom duration beyond 72 hours and the early-treatment strategy itself were not independent predictors after adjustment. In the IHC subset, above-median MPO density was associated with difficult dissection in exploratory analysis, but this postoperative tissue variable was not included in the preoperative prediction model.

Table 6: Multivariable logistic regression for difficult cholecystectomy

OR, odds ratio; CI, confidence interval; CRP, C-reactive protein. The model is illustrative and must be recalculated using actual patient-level data.

Principal findings This comparative study supports early laparoscopic cholecystectomy as the more efficient definitive strategy for grade I and II acute calculous cholecystitis. Early surgery required a somewhat longer and more demanding operation, but it did not increase conversion, major bile duct injury, or overall postoperative complications. Its principal advantages were shorter cumulative hospital stay, avoidance of recurrent biliary events while waiting, and lower total treatment cost. The pathology results explain why the technical character of surgery differed between groups. Early operations encountered a swollen, friable, hypervascular gallbladder with mucosal damage and neutrophil-rich inflammation. Delayed operations encountered less active neutrophilic injury but more fibrosis, Rokitansky-Aschoff sinus formation, and chronic remodeling. Thus, delayed surgery did not restore normal anatomy; it replaced edema-dominant difficulty with scar-dominant difficulty. Comparison with surgical evidence The present clinical pattern is consistent with randomized trials by Lai et al., Lo et al., and Kolla et al., which found that early laparoscopic cholecystectomy was feasible and reduced total hospitalization [6-8]. The ACDC multicentre trial further demonstrated that surgery within 24 hours of admission reduced morbidity and cost compared with conservative treatment followed by delayed surgery [9]. Trials including patients with more than 72 hours of symptoms also challenged the historical belief that a strict 72-hour cutoff should determine operability [10]. Meta-analyses have generally shown similar bile duct injury, conversion, and morbidity between early and delayed strategies, with a consistent advantage for early surgery in cumulative hospital stay [11-16]. Differences among studies often reflect how “early” is defined, whether the delayed group includes failed conservative treatment, and whether all index and readmission days are counted. In the present analysis, cumulative resource use was deliberately measured because it reflects the patient’s full treatment burden rather than only the postoperative admission. The longer operation and more frequent decompression in the early group are clinically credible. An acutely distended gallbladder is difficult to grasp, and inflamed tissue may bleed with traction. These problems can be addressed through decompression, deliberate exposure, critical-view-of-safety technique, and timely bailout. The absence of a major bile duct injury in either group should not be interpreted as evidence of zero risk; the sample is too small for a rare outcome. Safe steps and bailout strategies remain essential [3]. Pathological interpretation Gallbladder inflammation evolves through overlapping phases rather than a simple linear progression. Recent sequential histology has shown that necrosis, neutrophilic inflammation, fibroblastic activity, and repair may coexist during the first ten days [17]. Our early specimens reflected this overlap: acute suppuration was common, yet a substantial proportion already had acute-on-chronic disease. The high rates of ulceration and transmural neutrophils indicate that active injury often extends beyond the mucosal surface. The delayed group showed greater fibrosis and Rokitansky-Aschoff sinus formation, features of long-standing mechanical and inflammatory stress. These changes may tether the gallbladder to adjacent structures and obscure tissue planes even when systemic inflammatory markers have normalized. The two xanthogranulomatous cases illustrate an extreme macrophage-rich fibrosing response that can imitate malignancy clinically and radiologically [24]. Routine histopathological examination remains important because unexpected dysplasia, carcinoma, granulomatous disease, and other lesions cannot be reliably excluded by gross inspection alone. The IHC findings offer a mechanistic bridge between morphology and operative behavior. MPO is a robust marker of neutrophil accumulation and was highest in the early group, matching acute suppuration. CD68-positive macrophages were also increased early, consistent with phagocytic clearance and cytokine amplification. Prior gallbladder studies have shown differential macrophage and inflammatory cytokine expression in acute and chronic cholecystitis [19,20]. COX-2 elevation is biologically plausible in injured epithelium and activated inflammatory cells, while increased CD31 microvessel density may reflect vascular dilation, endothelial activation, and repair. The IHC results should be viewed as exploratory tissue biology rather than as markers that select surgical timing. Clinical implications For a fit patient with grade I or II disease, the findings favor definitive surgery during the index admission when an experienced laparoscopic team and appropriate theatre support are available. The decision should not be delayed solely because the gallbladder is inflamed. Clinical severity, organ dysfunction, anaesthetic risk, imaging, surgeon expertise, and access to bailout techniques are more relevant than an arbitrary expectation that delayed tissue will be easier. Where delayed surgery is unavoidable, a confirmed interval date, explicit return precautions, and rapid access for recurrent symptoms are necessary. The 21.7% recurrent-event rate in this illustrative cohort is within the range reported in studies of patients discharged without definitive treatment. Readmissions add cost, expose patients to repeated antibiotics and imaging, and may lead to urgent surgery under less controlled circumstances. Pathology departments can improve the value of cholecystectomy reporting by documenting acute inflammation, necrosis, fibrosis, xanthogranulomatous change, and unexpected neoplasia. IHC is not required routinely for uncomplicated cholecystitis, but targeted markers may be useful in research or diagnostically difficult cases. CD68 can support xanthogranulomatous inflammation, while broad epithelial and mesenchymal panels may be required when malignancy is suspected. Strengths and limitations The study integrates clinical outcomes with systematic gross pathology, routine microscopy, and a prespecified IHC substudy. Cumulative hospital use and biliary events were measured, avoiding the misleading impression that interval surgery is a single short admission. Blinded pathological scoring and quantitative marker assessment strengthen the tissue comparison. The principal limitations are the single-centre design, non-randomized allocation, modest sample size, limited power for rare bile duct injuries, and potential influence of surgeon experience. Histology was available only after surgery and cannot serve as a preoperative decision tool. IHC sampling was restricted to selected blocks and may not capture whole-organ heterogeneity. Cost estimates are institution-specific. Most importantly, the numerical results and images in this draft are illustrative; a valid submission requires analysis of the original dataset, verified ethics information, reagent details, and authentic photomicrographs.

Early laparoscopic cholecystectomy for grade I and II acute calculous cholecystitis reduced cumulative hospital stay, recurrent biliary events, and total treatment cost without increasing conversion or postoperative morbidity. Early operations encountered active edema, neutrophil-rich inflammation, epithelial injury, and stronger MPO, CD68, COX-2, and CD31 expression. Delayed operations showed less acute injury but substantially greater fibrosis and structural remodeling. These findings support index-admission surgery in appropriately selected patients and show that waiting changes the nature of operative difficulty rather than reliably eliminating it.

Funding: None

Competing interests: None

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