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C3 Glomerulopathy: Overview on a New Disease Entity

C3 Glomerulopathy: Overview on a New Disease Entity

 

*Rahman DA,1 Banu SG2

 

  1. *Dr. DM Arifur Rahman, Assistant Professor, Pathology, TMSS Medical College, Bogura. arifurrahmandm@gmail.com
  2. Sultana Gulshana Banu, Associate Professor, Pathology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka.

 *For correspondence

 Abstract

The diagnosis of membranoproliferative glomerulonephritis (MPGN) has recently undergone change from an electron microscopy-based classification scheme to one based largely on immunofluorescence findings. Recent advances in our understanding of the disease pathology of membranoproliferative glomerulonephritis has resulted in its re-classification as complement C3 mediated glomerulopathy (C3G) and immune complex-mediated glomerulonephritis (IC-GN). The new concept is based on its underlying pathogenesis, with a key pathogenetic role for the complement alternative pathway (AP), rather than on histomorphological characteristics. This overview summarizes the current state of knowledge about the C3 glomerulopathy.

 [Journal of Histopathology and Cytopathology, 2020 Jan; 4 (1):48-54]

 Keywords: C3 glomerulopathy, Dense deposit disease, C3 glomerulonephritis, Membranoproliferative glomerulonephritis

 Introduction

C3 glomerulopathy (C3G) is an emerging kidney disease caused by dysregulation of the alternative complement pathway.1,2,3 The characteristic pathology of this disease is glomerular depositions of dominant C3 with absent or weak immunoglobulins. Therefore, C3G is basically diagnosed by immunofluorescence (IF) and it can reveal various patterns of glomerular injuries by light microscopy(LM).4,5 Following the recent trend of pathogenesis-based reclassification of glomerular diseases, glomerulonephritis associated with alternative complement dysregulation is collectively referred to as C3G.6 Because laboratory detection of alternative complement dysregulation is still uncommon in current practice, predominant C3 deposition by IF is an initial finding that suggests C3G. However, glomerular diseases caused by mechanisms other than alternative complement dysregulation may occasionally satisfy “C3-dominant deposition with scanty immunoglobulins” as stated in the current consensus report.4 Clearly, pathogenesis based classification in glomerular diseases is an important prospect for appropriate therapies, but the entity of C3G still presents dilemmas in diagnostic practice by lack of clear definition and pathogenic basis. We review the current status of C3 glomerulopathy, histological, immunofluorescence findings and treatment

MPGN and C3 Glomerulopathy

Understanding the limitations of current MPGN classification requires a brief review of complement activation pathways. There are two main pathways of complement activation: the classic pathway, which is activated when IgG or IgM antibodies bind to antigens; and the alternative pathway, which does not require the presence of antibodies and can be auto activated by spontaneous cleavage of C3 to C3b, leading to the formation of C3 convertase. The electron microscopy-based classification can result in overlap between types I and III. Both types have been considered to be immune complex-mediated glomerulonephritis but, observations suggest that some cases of MPGN type I or MPGN type III are mediated by complement, not immune complexes.7,8,9

So, the historical classification required modification. It is not based on pathogenesis and there is significant overlapping, which is described earlier. In recent years, there have been great advances in our understanding of the pathogenesis of MPGN, particularly in the area of complement-mediated C3 glomerulopathies, including DDD and C3 glomerulonephritis. 4,10

It is proposed that MPGN be classified into two major groups: immunoglobulin (Ig)-mediated and complement-mediated (C3G). If immunoglobulins are present on IF studies, the evaluation should include a work-up for infections, autoimmune diseases, and monoclonal gammopathies, including cryoglobulins. It should be kept in mind that Ig-mediated MPGN also is associated with extensive C3 (and C4) deposition along the capillary walls via activation of the classic pathway of complement. On the other hand, if the IF studies show predominantly C3 and are negative or show no significant staining for Igs, an in-depth study of the AP is warranted. Ig-mediated MPGN is more likely to be present in adults whereas complement-mediated MPGN is more likely to be present in children and young adults. It is likely that C3G noted in children and young adults is due to genetic mutations in complement-regulating proteins, whereas it is acquired in adults as a result of development of autoantibodies to complement-regulating proteins. Initial evaluation of AP should include serum MAC levels, an alternative pathway functional assay, and hemolytic complement assays. If the initial screening is positive, it should be followed by genetic analysis for mutations and enzyme-linked immunosorbent assays for the presence of autoantibodies to complement-regulating proteins.11-14

The current approach, therefore, distinguishes those forms of MPGN with isolated C3 deposits (including DDD and C3GN) as alternative complement pathway-mediated C3G from those cases of MPGN that are mediated by the classical complement pathway with deposits of Ig and complement.

Clinical Presentation

Membranoproliferative glomerulonephritis or C3G are rare diseases with an estimated incidence of 1–2 per million per total population.15  Patients with C3G present with a variety of symptoms, ranging from a mild disease with asymptomatic microhaematuria and/or proteinuria to a severe disease with nephritic or nephrotic syndrome and renal impairment. Renal survival was worse if the GFR at diagnosis is <60 ml/min/1.73 m2.16

The kidney is the major target, possibly due to the morphological specificities of the glomerular capillaries, in particular the fenestrated endothelium, with exposure of the glomerular basement membrane to serum (complement). Although low levels of C3 are considered a hallmark feature of C3G, in one study low C3 levels were only detected in about 50 % of the patients. Therefore, a normal C3 level does not rule out C3G.17

Nasr et al., 2009 studied 32 paediatric and adult patient of dense deposit disease and Lu., et al 2012 studied 92 children and adult patient of dense deposit disease. Both of the studies reveal at presentation, almost all patients have proteinuria usually with haematuria. Nephrotic-range proteinuria is present in two thirds of the patients. Full nephrotic syndrome in 12% to 65% in different series conducted by Lu et al., 2006 and Servais et al., 2012. Persistently, low serum levels of C3 are found in most patients (approximately 80%). Servais et al have reported the clinical features in 56 patients with C3 glomerulopathy without dense deposits (C3GN) and compared them with 29 patients with DDD and 49 patients with immune complex MPGN type 1. The mean age at diagnosis for C3GN was 30, which was significantly higher than for DDD; 25% of patients were below16 years of age. Twenty-seven percent of patients with C3GN had nephrotic syndrome at presentation as compared with 38% of patients with DDD and 65% of patients with MPGN type I.18,19,20

 Light Microscopy

Light microscopic findings in C3 glomerulopathy can range from membranoproliferative lesions to mesangioproliferative or endocapillary proliferative lesions with or without presence of crescents. In rare instances, light microscopy might be normal. The electron dense osmophilic deposits as seen characteristically in DDD are found within the glomerular basement membrane, and as rounded deposits in the mesangium. In many cases, deposits are also seen in Bowman’s capsule and tubular basement membranes. C3 glomerulopathy, in which deposits do not completely fulfill criteria for dense deposits, are classified as C3GN. Electron microscopy in C3GN shows a complex pattern of mesangial increase and glomerular basement membrane thickening. Differing combinations of subendothelial, intramembranous, and subepithelial deposits are noted.21,22,23

DDD is defined by the presence of dense osmiophilic transformation of the GBM on EM, and on light microscopy, the morphology is variable. While it is clear that a membranoproliferative pattern of glomerular injury with increased lobulation, mesangial expansion, and capillary wall thickening with segmental double contours is common, a range of other patterns of glomerular involvement also occur. Walker et al., 2007 collected 69 cases of DDD from centers in North America, Europe, and Japan. They identified four distinct histologic patterns on light microscopy: membranoproliferative (25%), mesangial proliferative (45%), crescentic (18%), and acute proliferative and exudative (12%).21 In the Columbia series conducted by Nasr et al., 2009 which includes 32 cases of DDD, the frequencies were MPGN (44%), mesangial proliferative(28%), endocapillary proliferative (19%), and crescentic GN (9%). These reports emphasize that fewer than 50% of cases of DDD have MPGN morphology. Morphologically, most C3GN cases show either a mesangial proliferative or membranoproliferative pattern.18

The dense deposits are recognized on light microscopy by thickening of the GBMs by ribbon-like glassy intramembranous deposits. They stain strongly with eosin and appear somewhat refractile (hyaline). They are intensely periodic acid-Schiff (PAS) positive, and the trichrome stain shows them to be fuchsinophilic (red) although this reactivity varies among specimens.23

 Immunofluorescence findings

Immunofluorescence shows characteristic C3 fragment deposition in C3GN.16  But the deposition of C3 is not always isolated. According to the current consensus report, the term ‘‘isolated’’ was replaced by “dominant staining of C3 defined as at least two orders of C3 intensity greater than that of any other immune reactant.” 4

Nasr et al., 2009, Walker et al., 2007, West and McAdams, 1998 studied the immunofluorescence findings. The invariable finding in DDD and C3GN is the presence of C3 in the glomeruli. Intense staining for C3 is noted along the glomerular capillary walls and often in the glomerular mesangial regions. The C3 deposition is usually diffuse and global. The GBM staining may be continuous or discontinuous. The early components of complement, C1q and C4, are usually absent, although occasionally C1q is found.  Immunoglobulins are usually absent or show only focal and segmental staining. If they are present, they often stain much less intensely than C3 and they are usually of the IgM type with a segmental distribution; IgG and especially IgA are less common.18,21,24

Treatment and Prognosis

Modality of treatment of MPGN is difficult and its prognosis is also guarded. About 50% develop chronic renal failure within 10 years. There is a high incidence of recurrence in transplant recipients, particularly in dense-deposit disease. Treatments with steroids, immunosuppressive agents, and antiplatelet drugs have not been proved to be materially effective.25

 Eculizumab, the first available anticomplement therapy, blocks at the level of C5 and has revolutionized the treatment of complement-mediated diseases as well as C3 glomerulopathy.13 This agent is a humanized monoclonal antibody that binds with great affinity to C5 proteins, inhibiting cleaving into C5a and C5b and blocking production of the C5b-9 membrane attack complex. Reports of individual cases showed improvement after treatment, with reduced serum creatinine and proteinuria. Bomback et al 2012, reported that, after 1 year of therapy with eculizumab, there was reduction in active glomerular proliferation and neutrophil infiltration three of five patients, consistent with effective C5 blockade.26

References

  1. Fakhouri F, Frémeaux-Bacchi V, Noël LH, Cook HT, Pickering MC. C3 glomerulopathy: a new classification. Nature Reviews Nephrology. 2010; 6(8):494.
  2. Barbour TD, Ruseva MM, Pickering MC. Update on C3 glomerulopathy. Nephrology Dialysis Transplantation. 2016;31(5):717-25.
  3. Barbour TD, Pickering MC, Cook Dense deposit disease and C3 glomerulopathy. InSeminars in nephrology 2013 Nov 1 (Vol. 33, No. 6, pp. 493-507). WB Saunders.
  4. Pickering MC, D’agati VD, Nester CM, Smith RJ, Haas M, Appel GB, Alpers CE, Bajema IM, Bedrosian C, Braun M, Doyle M. C3 glomerulopathy: consensus report. Kidney international. 2013; 84(6):1079-89.
  5. Cook HT, Pickering MC. Histopathology of MPGN and C3 glomerulopathies. Nature Reviews Nephrology. 2015; 11(1):14.
  6. Sethi S. Etiology-based diagnostic approach to proliferative glomerulonephritis. American journal of kidney diseases. 2014; 63(4):561-6.
  7. Levy M, Gubler MC, Sich M, Beziau A, Habib R. Immunopathology of membranoproliferative glomerulonephritis with subendothelial deposits (Type I MPGN). Clinical immunology and immunopathology. 1978; 10(4):477-92.
  8. Clardy CW, Judith F, Strife CF, West CD. A properdin dependent nephritic factor slowly activating C3, C5, and C9 in membranoproliferative glomerulonephritis, types I and III. Clinical immunology and immunopathology. 1989; 50(3):333-47.
  9. Neary JJ, Conlon PJ, Croke D, Dorman A, Keogan M, Zhang FY, Vance JM, Pericak-Vance MA, Scott WK, Winn MP. Linkage of a gene causing familial membranoproliferative glomerulonephritis type III to chromosome 1. Journal of the American Society of Nephrology. 2002; 13(8):2052-7.
  10. Sethi S, Nester CM, Smith RJ. Membranoproliferative glomerulonephritis and C3 glomerulopathy: resolving the confusion. Kidney international. 2012; 81(5):434-41.
  11. Sethi S, Fervenza FC. Membranoproliferative glomerulonephritis: pathogenetic heterogeneity and proposal for a new classification. In Seminars in nephrology 2011 Jul 1 (Vol. 31, No. 4, pp. 341-348). WB Saunders.
  12. Sethi S, Fervenza FC. Membranoproliferative glomerulonephritis – a new look at an old entity. New England Journal of Medicine. 2012; 366(12):1119-31.
  13. Bomback AS, Appel GB. Pathogenesis of the C3 glomerulopathies and reclassification of MPGN. Nature Reviews Nephrology. 2012; 8(11):634.
  14. Rabasco Ruiz C, Rabasco-Ruiz C, Huerta Arroyo A, Huerta-Arroyo A, Caro Espada J, Caro-Espada J, Gutiérrez Martínez E, Gutiérrez-Martínez E, Praga Terente M, Praga-Terente M. C3 glomerulopathies. A new perspective on glomerular diseases. Nefrología (English Edition). 2013 Mar 1;33(2):164-70.
  15. Medjeral-Thomas NR, O’Shaughnessy MM, O’Regan JA, Traynor C, Flanagan M, Wong L, Teoh CW, Awan A, Waldron M, Cairns T, O’Kelly P. C3 glomerulopathy: clinicopathologic features and predictors of outcome. Clinical Journal of the American Society of Nephrology. 2014; 9(1):46-53.
  16. Master Sankar Raj V, Gordillo R, Chand DH. Overview of C3 glomerulopathy. Frontiers in pediatrics. 2016; 4:45.
  17. Servais A, Noël LH, Roumenina LT, Le Quintrec M, Ngo S, Dragon-Durey MA, Macher MA, Zuber J, Karras A, Provot F, Moulin B. Grü nfeld JP, Niaudet P, Lesavre P, Frémeaux-Bacchi V: Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies. Kidney Int. 2012; 82:454-64.
  18. Nasr SH, Valeri AM, Appel GB, Sherwinter J, Stokes MB, Said SM, Markowitz GS, D’Agati VD. Dense deposit disease: clinicopathologic study of 32 pediatric and adult patients. Clinical Journal of the American Society of Nephrology. 2009; 4(1):22-32.
  19. Lu Y, Shen P, Li X, Xu Y, Pan X, Wang W, Chen X, Zhang W, Ren H, Chen N. Re-evaluation of the classification system for membranoproliferative glomerulonephritis. In New Insights into Glomerulonephritis 2013 (Vol. 181, pp. 175-184). Karger Publishers.
  20. Servais A, Frémeaux-Bacchi V, Lequintrec M, Salomon R, Blouin J, Knebelmann B, Grünfeld JP, Lesavre P, Noël LH, Fakhouri F. Primary glomerulonephritis with isolated C3 deposits: a new entity which shares common genetic risk factors with haemolytic uraemic syndrome. Journal of medical genetics. 2007; 44(3):193-9.
  21. Walker PD, Ferrario F, Joh K, Bonsib SM. Dense deposit disease is not a membranoproliferative glomerulonephritis. Modern pathology. 2007; 20(6):605-16.
  22. Joh K, Aizawa S, Matsuyama N, Yamaguchi Y, Kitajima T, Sakai O, Mochizuki H, Usui N, Hamaguchi KI, Mitarai T. Morphologic variations of dense deposit disease: Light and electron microscopic, immunohistochemical and clinical findings in 10 patients. Pathology International. 1993; 43(10):552-65.
  23. Habib R, Gubler MC, Loirat C, Maiz HB, Levy M. Dense deposit disease: a variant of membranoproliferative glomerulonephritis. Kidney international. 1975; 7(4):204-15.
  24. West CD, McAdams AJ. Glomerular paramesangial deposits: association with hypocomplementemia in membranoproliferative glomerulonephritis types I and III. American journal of kidney diseases. 1998; 31(3):427-34.
  25. Kumar V, Abbas AK, Fausto N, Aster JC. Robbins and Cotran pathologic basis of disease, professional edition e-book. elsevier health sciences; 2014 Aug 27.
  26. Bomback AS, Smith RJ, Barile GR, Zhang Y, Heher EC, Herlitz L, Stokes MB, Markowitz GS, D’Agati VD, Canetta PA, Radhakrishnan J. Eculizumab for dense deposit disease and C3 glomerulonephritis. Clinical Journal of the American Society of Nephrology. 2012; 7(5):748-56.
  27. Röth A, Dührsen U. Treatment of paroxysmal nocturnal hemoglobinuria in the era of eculizumab. European journal of haematology. 2011; 87(6):473-9.
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Comparison between Bethesda System and Conventional System for Standardization of Reporting Thyroid Cytopathology

Comparison between Bethesda System and Conventional System for Standardization of Reporting Thyroid Cytopathology

 *Saleheen S,1 Rahman DA,2 Chowdury MA,3 Haque MM,4 Habib S,5 Khan KH6

 

  1. * Saied Saleheen, Assistant Professor, Department of Pathology, Sheikh Hasina Medical College, Tangail. saleheen44@gmail.com
  2. DM. Arifur Rahman, Assistant Professor, Department of Pathology, TMSS Medical College, Gokul, Bogura,
  3. Mehdi Ashik Chowdury, Assistant Professor, Department of Pathology, Jahurul Islam Medical College, Bajitpur, Kishoreganj.
  4. Mohammad Mahbubul Hoque, Lecturer, Department of Pathology, Sheikh Sayera Khatun Medical College, Gopalganj.
  5. Saequa Habib, Associate Professor, Department of Pathology, Bangabandhu Sheikh Mujib Medical University, Dhaka.
  6. Kamrul Hasan Khan, Professor, Department of Pathology, Bangabandhu Sheikh Mujib Medical University, Dhaka.

 *For correspondence

Abstract

Background: Fine-needle aspiration cytology (FNAC) is considered as an effective test to screen and diagnose patients with thyroid swelling for surgical management. But FNAC still suffers because of its inherent limitations as well as variability in its diagnostic terminology.The Bethesda System of Reporting Thyroid Cytopathology (TBSRTC) may improve the state. This study was to report the experience in using this reporting system to redistribute the cytological diagnoses made by conventional system and also to evaluate the specificity, sensitivity, accuracy and predictive values as a tool to compare both the methods based on the correlation between cytopathology and histopathology.

Methods: A total of 73 patients presenting with thyroid swelling were subjected to FNAC and reporting was done according to the conventional system and TBSRTC. The cytological diagnosis was correlated with the histopathological diagnosis. The sensitivity, specificity, predictive values were calculated considering cytology as screening test.

Results: In this study, TBSRTC was found superior because of higher sensitivity (91.66%) and specificity (97.77%) as compared to conventional system (80.76% and 87.23% respectively). Positive predictive value, negative predictive value and diagnostic accuracy of Bethesda system were 95.65%, 95.65% and 90.41% respectively which were also significantly higher as compared to those of conventional system (77.78%, 89.13% and 84.93% respectively).

Conclusions: TBSRTC may improve the efficacy of thyroid FNAC as a screening test.

 [Journal of Histopathology and Cytopathology, 2020 Jan; 4 (1):38-47]

 Keywords: Comparison, Thyroid FNAC, Bethesda system (TBSRTC), Conventional system, Histopathology, Standardization

Introduction

Fine Needle Aspiration Cytology (FNAC) is a quick, cost-effective and minimally invasive outpatient procedure used worldwide in the initial diagnosis of thyroid swellings. As it can distinguish between benign and malignant lesions quite effectively, it is the preoperative screening method of choice worldwide.1 Before the routine use of thyroid Fine Needle Aspiration (FNA), the percentage of surgically resected thyroid nodules that were malignant was 14%.2 With current thyroid FNA practice, the percentage of resected nodules that are malignant surpasses 50%.3

However, due to the lack of a standardized system of reporting, pathologists have been using different terminologies and diagnostic criteria, leading to confusion amongst clinicians in the interpretation of the cytopathology report and ultimately hindering a definitive clinical management.4 It has also hindered the sharing of clinically meaningful data among multiple institutions.5 To mitigate this confusion all the pathologists need to use the same diagnostic criteria and terminology.6

Various reporting formats of thyroid FNAs have been suggested in the literature since the 1970s when thyroid FNAs began to be the subject of publications, and new formats continued to emerge.7 Several classification schemes have been suggested by various authors based on personal/institutional experiences but there is general support for the utilization of a tiered classification system.5 With this background, the National Cancer Institute (NCI), Bethesda, Maryland, United States, published an atlas and guidelines using standardized nomenclature for the interpretation of thyroid FNAC known as The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC).4 It categorized the thyroid FNAC diagnoses into six groups with well-defined cancer risk and clear indications for further clinical management.8 It has also increased the interobserver reproducibility of cytopathological diagnoses of thyroid lesions.9-12

TBSRTC has been well received by both pathologists and clinicians and has been widely implemented by pathology laboratories in USA and in several European countries.13 Following publication of TBSRTC, the reporting system used in the United Kingdom since 2002, was updated by a working group of The Royal College of Pathologists and is now quite similar to TBSRTC.14 But TBSRTC still has to go a long way in getting acceptability in many countries of Asia and Africa.10

A good number of studies have been carried on in several countries in Asia (India, Pakistan, Iran, Korea and KSA) regarding usefulness of TBSRTC and it has been proved useful for management of patients with thyroid swelling in these countries.9,11,15-20 But this relatively recent six category scheme still needs to be validated by more prospective studies with histopathological correlation.16

In Bangladesh, there is no known reporting scheme using tiered classification system. The utility of thyroid cytopathology reporting according to TBSRTC in context of Bangladesh is also unexplored. Standardization of the reporting system by TBSRTC may result in improvement of the quality, homogenization and also reduce interobserver variability of thyroid cytopathology reports. In this context, this study was performed to assess the predictive values, sensitivity and specificity and accuracy of the TBSRTC in comparison with that of the conventional system used in the BSMMU, Dhaka, Bangladesh with histopathological correlation. The view was to observe the usefulness of Bethesda system for standardization of thyroid cytopathology reporting in the context of this country (Bangladesh).

 Methods

This is a cross sectional study carried out at the Department of Pathology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka during the period from March 2015 to February 2017. A total of 73 patients presenting with thyroid swelling were included in this study, who has undergone FNA followed by the biopsy of the thyroid lesions. Patients presenting with thyroid swelling in any lobe of thyroid detected by clinical palpation (multinodular, solitary nodule, diffuse goiter etc) were included except those unwilling to be involved into the study.

All clinical information were recorded in a pre-designed proforma including demographic features, address and telephone contacts (for histological follow up). Results of all the routine investigations with special attention to ultrasonography of neck, serum T3, T4, and TSH levels and thyroid scintigraphy were noted where available.     

FNA of all patients was performed at the Department of Pathology, BSMMU.  Smears were stained with Papaniculaou (PAP) and Hematoxylin and Eosin (H&E) stains. Cytological findings were recorded and diagnoses were made according to both conventional and TBSRTC for each cases. For the TBSRTC reporting the Atlas10was used as manual (Table I). Reports were issued according to conventional method.

Koss’ Diagnostic Cytology and its histopathologic bases21 was followed conventionally as reference book in this department. The diagnoses made by conventional system are mostly based on its reference. The diagnoses were: Non-neoplastic lesions: Nodular goiters (NG) including cystic degeneration (CD), Lymphocytic thyroiditis (LT), Hashimoto thyroiditis (HT), Nodular goiter with co-existent thyroiditis, Multinodular goiter (MNG).

 Cellular follicular lesion (CFL): Cellular smears on cytology that included goiters with adenomatous changes, follicular adenomas and carcinomas, as well as the follicular variant of papillary carcinomas. In BSMMU suspicious cytology, atypia of undetermined significance and other gray zone cytology are also included within this diagnosis.

 Neoplastic lesions: Papillary thyroid carcinoma (PTC), suggestive of papillary carcinoma, medullary thyroid carcinoma (MTC) etc.

Biopsy specimens or histopathological reports of the patients undergoing surgery following the FNA interpretation under this study were collected. The histopathological findings were correlated with cytopathological findings and were recorded accordingly.

Descriptive analytical statistics was calculated. Thyroid FNA was considered as a ‘screening test’ and histopathology as gold standard. FNA benign was considered to be negative and the remaining categories were considered to be positive because they indicated significant risk of malignancy and led to a recommendation of surgery.8 Sensitivity, specificity, accuracy, the positive predictive value (PPV) and negative predictive value (NPV) were calculated from the available data by statistical formulae. In this study, Thyroid FNA has been considered as a screening method as TBSRTC is formed by NCI as a screening method to triage the patients effectively into groups that need surgery and the other that do not.5

For calculating statistical parameters nondiagnostic (ND) and AUS/FLUS cases were excluded as non-definitive diagnoses and categories, SFM and malignant were put together in most of the studies.15,16,22-24 In this study, the inadequate/ND cases were reaspirated and have been included rationally in other categories. Those which were still inadequate, had been excluded from statistical analysis.

 Results                                                                                                                          

Out of the 73 cases 62(84.9%) were female and 11(15%) were male. The age of the patients ranged from 16 to 70 years with average age around 40 years.

According to the conventional system forty five (61.64%) cases were diagnosed nodular goiter. Five (11.11%) of these lesions were found to be neoplastic (one benign and 4 malignant) on histopathology. Although all PTC and suggestive of PTC categories were found neoplastic and also malignant, 60% of the cellular follicular lesions (9 out of 15) were neoplastic (one benign and 8 malignant) and the rest were benign on final histological diagnosis.

The lesions when redistributed according to the Bethesda system: 46 (63%), 04 (5.4%), 03 (4.1%), 08 (10.95%), 12(16.4%) of the lesions were diagnosed as Cat-II, Cat-III, Cat-IV, Cat-V and Cat-VI respectively. The redistribution of the lesions after application of Bethesda system is shown in Table-II.

Out of 73 cases, 64 (22 neoplastic and 42 non-neoplastic) cytological diagnoses were concordant on both the conventional and Bethesda systems. One lesion was non-neoplastic on conventional but diagnosed neoplastic on Bethesda system while 04 neoplastic lesions by conventional system were categorized as non-neoplastic by Bethesda system. Three non-neoplastic and one neoplastic case according to conventional system were categorized as Cat- III (AUS) by Bethesda system. The CFL on conventional system were distributed by the Bethesda system into various categories that matched well (Table-III) with final histological diagnoses.

All the neoplastic lesions irrespective of benign and malignant neoplasm were considered positive for both the histological and cytological diagnoses, as they recommend for surgical excision. The concordances of the cytological diagnoses made by two methods with the final histological diagnoses are shown in Table IV.

Granulomatous thyroiditis: GT, Follicular adenoma: FA, Follicular carcinoma: FC, FVPTC: Follicular Variant of PTC, WDTUMP: Well differentiated tumor of uncertain malignant potential.

Diagnoses made according to TBSRTC shows increased overall concordance with hisotoathological diagnosis than that of the conventional system.

FNA interpretation by conventional method yielded significant false positive (6) and false negative (5) diagnoses. While analyzing the smears by the Bethesda system had decreased both the false positive (1) and false negative (2) interpretations. The sensitivity, specificity, accuracy and predictive values calculated for both the methods by using the statistical formulas are compared to each other in the Table V.

Sensitivity and positive predictive value (PPV) of the Bethesda system were found better (91.66% and 95.65% respectively) when compared to that the conventional system (80.76% and 77.78% respectively). The specificity and negative predictive values (NPV) were also found higher for Bethesda system (97.77% and 95.65%) in comparison to that of the conventional system (87.23% and 89.13% respectively). Diagnoses according to the Bethesda categories were 90.41% accurate where accuracy for the conventional system was 84.93%.

 Discussion

Reporting according to the conventional system included 41 (about 56.16%) patients into benign category, while category-II (Benign) in the Bethesda system included 44 (60.27%) patients. All (12) the suspicious for malignancy and malignant diagnoses on conventional system corresponded to category V and VI of Bethesda system. It reflects that there was actually no significant change in diagnosis of unequivocally benign and malignant cases according to the two systems of reporting.

15 (20.54%) CFL diagnosed by conventional system was the major field where the Bethesda system varied markedly. So, CFL was a “gray zone” diagnosis that included some benign (26.67%) and malignant (53.33%) cases.25 These cases when reclassified by the Bethesda system yielded more specific results with good histological correlation (Table IV). This difference can be explained by- i) Subjective underscoring of some neoplastic cytologies which are of SFM category in more objective Bethesda system and  ii) Assigning the follicular lesion diagnosis for some hyper cellular smears of goiter arranged in folded sheet appearance.

The 06 false-positive FNA diagnoses in conventional system included cellular smears of histologically nodular goiters that were interpreted as CFLs. Four of these cases were interpreted benign (category-II) by Bethesda system and 01 case was designated category-IV (suspicious for Hurthle cell neoplasm) because of relative abundance of Hurthle cells showing pleomorphism. Five cases were false negative for conventional method, 04 of which were due to compromised cytology samples. The rest one case diagnosed conventionally as nodular goiter that was histologically follicular adenoma and Category-IV (SFM) in Bethesda system.

When compared with other studies using TBSRTC with histological follow up, sensitivity and NPV of the present study were consistent with most of the studies (Table VI). The specificity and PPV were higher than most of the other studies, which may be due to small sample size in this present study.

Conclusion

By dint of its higher sensitivity, specificity, predictive values and accuracy TBSRTC has been proved to be better than  conventional system for reporting thyroid cytopathology. So, it should be useful for standardization of thyroid cytopathology reporting. However, studies needed to explore its effect in reducing inter-observer variation of reporting thyroid cytopathology as well as its usefulness to the clinicians in decision making.

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Histopathological Spectrum of Prostatic Lesions Evaluated in a Tertiary Hospital

Histopathological Spectrum of Prostatic Lesions Evaluated in a Tertiary Hospital

 *Sultana SS,1 Hossain S,2 Rahman A3

 

  1. *Dr. Sk Salowa Sultana, Assistant Professor, Department of Pathology, Ad-Din Women’s Medical College. salowasultana257@gmail.com
  2. Shahadat Hossain, Associate Professor, Department of Pathology, Ad-Din Women’s Medical College.
  3. Afiqur Rahman, Professor of Urology, Department of Urology, Ad-Din Women’s Medical College.

*For correspondence

 Abstract

Objective: To determine the age distribution of various prostatic lesions, to evaluate histopathological  pattern  of prostatic lesions  and  to analyze adenocarcinoma  of prostate according to Gleason  system.

Methods: This was a retrospective study comprising of 178 cases, carried out at the department of Pathology, Ad-din Women´s  Medical College Hospital during the  period of January 2017 to December 2019.

Results: Out of 178 cases, 159(89.32%) were diagnosed as benign lesion, nodular hyperplasia being the commonest one. Prostatic adenocarcinoma was found in 16(9%) cases, majority of which belonged to Gleasons score 7.

Conclusion: Histopathological examination of prostatic biopsy specimen is essential for diagnosis of benign and malignant lesions, to rule out the incidental carcinoma and HGPIN.

 [Journal of Histopathology and Cytopathology, 2020 Jan; 4 (1):33-37]

 Keywords: Nodular hyperplasia of prostate, prostatic carcinoma, HGPIN

Introduction

The  prostate that weights up to 20 gm in normal adult depends for its subsequent growth and differentiation on androgenic hormones.1,2  Lesions of prostate are extremely common over the age of 50 years and important cause of morbidity and mortality in male in advance age. Pathological processes affecting this organ include inflammation, benign nodular enlargement and tumor.1 The clinical incidence of the diseases is only 8% during the 4th decade  but it reaches 50% in the 5th decade and 75% in the 8th decade.2 Benign prostatic  hyperplasia(BPH) and carcinoma are increasingly frequent with advancing age.3  BPH results from hyperplasia of both stromal and epithelial cells, gradually being enlarged, compress and narrow the urethral canal and often leads to urinary obstruction. Inflammation of prostate is known as prostatitis and divided into acute, chronic and granulomatous prostatitis. Prostatic carcinoma is one of the most common malignancies affecting men, also it is the sixth leading cause of cancer death in male.4 Among the prostatic malignancies 95% is adenocarcinoma. premalignant lesion of prostatic adenocarcinoma  is known as high grade intraepithelial neoplasia (HGPIN). The objective of this study was to determine the age distribution of various prostatic lesions, to evaluate histopathological  pattern  of prostatic lesions  and  to analyze adenocarcinoma  of prostate according to Gleason  system.

Methods

The study was conducted in the Department  of Pathology, Ad-din Women´s Medical College Hospital – a  tertiary level hospital of Dhaka, Bangladesh. The study period was from January 2017 to December 2019. The data were collected retrospectively from histopathology register. A  total of 178 TURP (Transurethral resection of prostate) were evaluated. The received specimen were fixed in 10% formalin and routine paraffin processing followed by hematoxylin and eosin staining was done and the slides were examined under light microscope. The specimens were ananlyzed as type of specimen, age of the patient, histopathological  pattern and final diagnosis. The tumour were classified according to 2016 WHO classification and histological grading was done using modified Gleason´s system. Data  were analyzed using tables, figures and percentage.

 Results

A total of 178 cases were included in our study, all of which (100%) were TURP specimen.  In the present study, most of the prostatic lesions were benign(89.32%) followed by malignant (9.6%) and HPIN (1.12%) and ratio of benign and malignant lesions is 1:9, approximately.

In the present study, benign lesions were mostly found (45%) in the age group of 61-70 years  and 34% in the age group of 51-60 years,  whereas malignant lesions were common  41% in the age group of 71-80 years and 29% in the age group of 61-70 years of age. In our study, benign lesions(159) were nodular hyperplasia of prostate 130(73.03%) and nodular hyperplasia of prostate with co-existing prostatitis 29(16.3%). Out of 29 cases of prostatitis, 24 cases were chronic non specific prostatitis, 2 cases were granulomatous prostatitis and 3 cases were acute prostatitis.  In our study, 2(1.12%) cases were diagnosed as HGPIN and 17(9.6%) cases were diagnosed as malignant. Most of the malignant cases 16(9%)  were prostatic adenocarcinoma and 1(0.56%) was metastatic adenocarcinoma. In this study, 41% cases of malignant belong to 71-80 years age group and 29% cases belong to 61-70 years age group. According to Gleason score, most commonly (81.25%) found grade was grade 7, in this study.

Discussion

We enrolled a total of 178 cases in our study, all of which (100%) were TURP specimen. Bhatta S et al5 have found 88.54% specimen of TURP in their study. Screening procedure like trans-rectal ultrasound, prostate specific antigen (PSA) are still used, but biopsy remains the gold standard for final diagnosis.6 In the present study, most of the prostatic lesions were benign (89.32%) followed by malignant (9.6%) and HPIN (1.12%). These findings are similar to the studies done by Bhatta S et al,5 Bal et al,7 Jehoram  et al,8 and Bhat S et al.9 They found (89.58%), (87%), (93%) and (92.4%) cases of BPH in their study, respectively. In our study, ratio of benign and malignant lesions is 1:9, approximately.

In the present study, benign lesions were mostly found 45% in the age group of 61-70  years  and 34% in the age group of 51-60 years,  whereas malignant lesions were common  41% in the age group of 71-80 years and 29% in the age group of 61-70 years of age. These findings are in concordance with other studies.10,11,12

In our study, benign lesions(159) were nodular hyperplasia of prostate 130(73.03%) and nodular hyperplasia of prostate with co-existing prostatitis 29(16.3%). Out of 29 cases of prostatitis, 24 cases were chronic non specific prostatitis, 2 cases were granulomatous prostatitis and 3 cases were acute prostatitis.  Bhatta S et al found 24(25%) cases of prostatitis associated with nodular hyperplasia of prostate, out of which 22 cases were chronic non specific prostatis and two cases were acuteprostatis.5 Prostatic carcinoma is one of the most common malignancies affecting men. In our study, 2(1.12%) cases were diagnosed as HGPIN and 17(9.6%) cases were diagnosed as malignant. Most of the malignant cases 16(9%)  were prostatic adenocarcinoma and 1(0.56%) was metastatic adenocarcinoma. Bhatta S et. al5found 2.08% of HGPIN and 8.34% of prostatic carcinoma. Also Deshmukh BD et. al11 and Bhat S et. al9 found similar observation. In this study, 41% cases of malignant  belong to 71-80 years age group and 29% cases belong to 61-70 years age group. Bhat S et. al12  found 75% cases of malignancy diagnosed after 60 years. All the cases of prostatic adenocarcinoma were graded according to Gleason score which determine the tumour aggressiveness.1  In this study, most commonly 13(81.25%) found grade was grade 7. Albasri et al.13 found Gleasons score 5-7 as the commonest among 71 cases of prostatic adenocarcinoma. Bhat S et. al9 found 56.16% of adenocarcinoma with Gleason score 8-9.

 Conclusion

Histopathological  examination of prostatic lesions is essential for diagnosis and management. Prostatic lesions are common in the age group of 60-70 years. All the specimen received were TURP. Benign prostatic hyperplasia (BPH) was predominant type among all the lesions. Majority of the malignant lesions were incidental diagnosis and most of the malignant lesions were prostatic adenocarcinoma. Emphasis should be  given to identify premalignant lesions.

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