Review of tissue diagnosis & its role in cancer care: One year experience from a regional cancer care Institute of Eastern India

Materials & Methods

An observational descriptive retrospective cross-sectional study was planned in the department of Laboratory Medicine, Chittaranjan National Cancer Institute, Kolkata, West Bengal, India, a regional cancer care institute of Eastern India (catering predominantly West Bengal with nearby States of Jharkhand, Bihar, Sikkim, North Eastern provinces) of three months (November 2024 to January 2025). The relevant details were collected from laboratory information system and the departmental archive, after obtaining ethical approval from Institutional Ethics Committee. The centre handles average 2000 large biopsies (20-25 blocks per case on an average), 1500 small biopsies, 2000 cytology (fluid cytology and fine needle aspiration cytology) and 400 bone marrow cases per year. All the cases undergoing review (both slides and tissue blocks) in the period between June 2023 to May 2024 were included in the study. At the end of the study, the data were tabulated and analysed.

The review process was performed by the pathologists under the department of laboratory medicine working during the period with experience ranging from two to 25 yr and cases with discrepancy were independently confirmed by two pathologists. Discrepancy in diagnostic entity (in type of cancer, benign diagnosed as malignant, malignant diagnosed as benign) was designated as category 1 and staging discrepancy as category 2. Category 3 discrepancy was used to denote the discrepancy in any other parameter that significantly changes the treatment protocol [margin status, lympho-vascular space invasion (LVSI), peri neural invasion (PNI), extensive in situ component etc]; and lastly, discrepancy in diagnosis between premalignant and frank invasive malignancy was denoted as category 4.

Results

Total number of submitted cases within the study duration was 2551. Twenty-four of them caused extreme diagnostic difficulty because of processing issues. In 14 cases, no reporting was possible; non-conclusive opinion was offered in six cases and one led to diagnostic discordance. The diagnosis in rest three, corroborated. Among the fourteen non-reportable cases were two resection cases, which could not be reported due to near complete autolysis- these cases posed significant obstacles on further patient management, as no residual mass was there, from where we could perform a re-biopsy. The entire process is summarised in figure.

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Figure.

Flow chart showing the essence of the entire process.

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Significant diagnostic discrepancy was noted in 171 (6.7%) cases. Frequencies of category-wise and system-wise diagnostic discrepancies are provided in table. Category 1 discrepancy having gross diagnostic mismatch was found in 104 cases (4.1%). Of them, cancer subtype was changed in 77 cases after review and in 27 cases lesions diagnosed as benign was found to be malignant and vice-versa. Thirteen cases (0.5%) revealed category 2 discrepancies, which drastically changed the tumour stage. Category 3 discrepancy was found in 5 cases (0.2%), which prove to be crucial for subsequent therapeutic interventions. The rest 49 cases (1.9%) were under category 4 discrepancy, where a premalignant diagnosis was offered in the place of frank malignancy, mostly in cases of squamous cell carcinoma (SCC) and adenocarcinoma, at least some of which may be attributed to inter-observer variation. The detailed list of category 1 discrepancies is presented in supplementary table.

It is in these cases mainly, where a repeat tissue sampling was advised to rule out/confirm invasive malignancy. Coupled with the cases associated with processing issues (20), the total number of cases were 69 (2.7%), where a re-biopsy was found to be essential (Figure). In total 54 cases (out of the 171 cases showing diagnostic discrepancy), immunohistochemistry was useful as a diagnostic adjunct.

Mostly category 2 discrepancy was found in cases of transurethral resection of bladder Tumour in relation to deep muscle involvement. Isolated metastatic tumour deposit (non-contiguous spread) detected in ipsilateral adrenal gland in a case of clear cell renal cell carcinoma involving lower pole of left kidney upstaged a case to M1 disease². Metastatic deposit was discovered in para-aortic node in a case of uterine leiomyosarcoma, which was previously missed. Staging of penile squamous cell carcinoma was changed as the normal anatomy and its histological reflection in sections are often confusing to many pathologists. Among the cases containing category 3 discrepancy, extensive in situ component was identified in two lumpectomy specimens, for which further modified radical mastectomy was planned. Extra nodal extension found in a case of oral squamous cell carcinoma led to change of adjuvant protocol. Demonstration of lymphovascular space invasion in an otherwise localized case led to regional lymph node exploration. In a case of papillary carcinoma of thyroid diagnosed in a young lady, classical caseating granulomas were found in the resected lymph nodes as an associated finding, which initiated workup for tuberculosis.

Discussion

Diagnostic pitfalls often arise on being non coherent to local anatomy and on confusion on diagnostic mimics. The normal structure of ampullary region, containing confluence of ducts and loose muscle bundles are notorious to be mistaken for adenocarcinoma in small biopsy, if not caution is taken³. We encountered a case where the seminal vesicle structures sampled in biopsy were reported as acinar adenocarcinoma of prostate. Pseudo-epitheliomatous hyperplasia in oral cavity specimens, or squamo-proliferative lesions with reactive-regenerative atypia-often with formation of florid keratin pearls are important diagnostic pitfalls in squamous cell carcinoma. Acanthomatous subtype of advanced ameloblastoma is likely to be misdiagnosed as squamous cell carcinoma in small biopsy, even in an expert’s hand⁴. Recent inclusion of entities like non-invasive follicular thyroid neoplasm with papillary like nuclear features (NIFTP) with obvious prognostic significance is behind some of the discrepancies encountered in thyroid pathology⁵. The bewildering morphological spectrum of pleomorphic salivary adenoma should be borne in mind before stamping a salivary gland neoplasm as malignant. Entities like low grade appendicular mucinous neoplasm are often under-recognised in practice. There is a drastic change in our understanding of neuro-endocrine neoplasms especially in the past few years. The cases we encountered, classified as neuro-endocrine carcinoma were proved to be neuro-endocrine tumour (NET). The staging of these two entities along with therapy are radically different⁶. Many of the peripheral laboratories do not have an infrastructure for immunohistochemistry. Lung and oesophagus are two sites where both squamous cell carcinoma and adenocarcinoma can occur, and the diagnosis is offered on small biopsy harvested by endoscopy or core needle biopsy. Poorly differentiated squamous cell carcinoma, in such cases, is often difficult to separate from poorly differentiated adenocarcinoma; although the distinction is crucial as the treatment options are radically different. Along with immunohistochemistry, choice of markers and their interpretation are important. We encountered a case in a young adult which was diagnosed outside after running exhaustive panel of markers as rhabdoid tumour, which finally was found to be anaplastic large cell lymphoma. The common lymphoma markers for screening are often negative in ALCL with expression of markers like EMA, which is an important diagnostic pitfall⁷. T cell lymphoma, a less cultivated domain for conventional histopathologists is itself a difficult area.

Comprehensive studies on this angle from Indian perspective are rare, though a few are available from the western world. The comparison between them is difficult as defining the term ‘discrepancy’ or ‘discordance’ or its subheadings like ‘major’ and ‘minor’ is often problematic and varies with criteria set for individual study design. As per criteria, we have taken only those discordances which actually changed the management drastically (including rebiopsy), which can be equated with the ‘major’ discordances. The overall discrepancy rate of our centre is little bit higher as compared to the data of comprehensive cancer care centres from western world, as discussed by Strossberg et al⁸(2.2%), Farooq et al⁹ (4.7%) and Manion et al¹⁰ (2.3%), if the major discordances are taken into account. The discrepancy rates detected in individual systems show wide variation among studies from different comprehensive centres, which is inevitable again due to relative proportion of case load from each system based on the hospital’s clinical set up and expertise of different departments. Thus, it is difficult to extrapolate any particular pattern from it. Unusually high discrepancy rate is found in skin tumours from our centre, however, which has perhaps little significance as total number of encountered skin specimens was only 11. Farooq et al⁹ have found a high discordance rate in reporting thyroid FNAC and endocrine system, which matches with our findings. Middleton et al¹¹ found 6.2 per cent major discrepancy which changed the therapeutic protocol altogether, which is concordant with our findings. According to their perspective, a second opinion pathologic review is a patient safety mechanism that is often life-saving.

The study of Dey et al¹ from a tertiary oncology hospital in eastern India has found diagnostic concordance in 64 per cent of the 700 analysed cases and a major discordant diagnosis in 17 per cent. However, from our centre’s experience the discrepancy rate is much lower (6.7%), which partly may be due to larger sample size of 2551. The large corporate laboratory chains have now extended into remote places and the histopathology reports are usually signed by more than one learned pathologist now-a-days. It is true that advanced facilities like Immunohistochemistry may not be available in every centre, but it is instrumental in clinching diagnosis only in a few cases. Especially, the category ‘refinement of diagnosis’ (in Dey’s study)¹ was not taken into account in ours. The broad morphological diagnosis like ‘non Hodgkin lymphoma’ or ‘spindle cell sarcoma’ was taken as concordance, if our initial impression was also the same (none the less, that was later confirmed and further subcategorized by IHC). Still there may be enormous variation from centre to centre based on variables like catchment area, laboratory facilities, relative proportion of case load from each system based on the hospital’s clinical set up. As background Indian data is limited, it will be premature to assess the general trend and project it on the national landscape, particularly the overall good concordance rate, which has emerged as the finding of this study from our centre.

Few problematic areas need to be highlighted, which enormously influence the process of review. The pre-analytical factors like poor processing of tissue (especially the most notable part of fixation) often jeopardise the morphology severely to hinder adequate evaluation, as stated earlier; particularly, it becomes difficult to appropriately interpret immunohistochemistry (IHC) results¹² based on such tissues and offer a conclusive opinion. Adequate and appropriate sections are often missing in large biopsy cases limiting optimal evaluation of the type of tumour and its proper staging. As an associated finding from our centre, lack of standardised practice in documentation of patient particulars and slide/block ID was found to be problematic. The name and age documented in report are often not exactly the same to the patient’s actual name and age documented in the Institute as per national biometric database. A complete label containing laboratory identifications are often not found over slide or block; the ID written on the report only matches partially to that written over the material submitted for review. These things create immense dilemma for a pathologist, where there is certain obvious medico-legal aspects especially rendering a crucial diagnosis like cancer, and parallelly, lies the ethical issue and the risk of delay in management in critically ill patients, who often belong to a marginalized society and are barely literate to make out these complexities. As the pre-analytical factors (apart from poor tissue processing) were not under the purview of present study, actual extent of the issues like lack of standardisation in documenting patient particulars or specification of slide/block ID has not been quantified. Also, the discordance rate with respect to the proportion of small and large biopsy cases was not analysed in this study. Neurosurgery facility is not developed in our centre till now, thus CNS cases are very low in our study-only those coming for chemo-radiation are managed.

Finally, it should be emphasised that review is nothing else but a second opinion; - no reviewer has claimed ever to provide an absolute ‘the’ diagnosis. There are cases which have been proved to be misdiagnosed by the reporting pathologist as well as the reviewer. Although many a times the cost of review is expensive, a second opinion or pathologic review is a patient safety mechanism that is often lifesaving. Also, addressing at least a bare minimum universal standard of the pre-analytical issues like accurate specification of patient details, slide/block ID and tissue processing quality will be instrumental for smooth and efficient running of the hub-and-spoke model of cancer care, in a country like India.