Turkish Journal of Pathology - 2021; 37(2)

A Nobel-Winning Scientist: Aziz Sancar and the Impact of his Work on the Molecular Pathology of Neoplastic Diseases

2021-05-01

Aziz Sancar, Nobel Prize winning Turkish scientist, made several discoveries which had a major impact on molecular sciences, particularly disciplines that focus on carcinogenesis and cancer treatment, including molecular pathology. Cloning the photolyase gene, which was the initial step of his work on DNA repair mechanisms, discovery of the �Maxicell� method, explanation of the mechanism of nucleotide excision repair and transcription-coupled repair, discovery of �molecular matchmakers�, and mapping human excision repair genes at single nucleotide resolution constitute his major research topics. Moreover, Sancar discovered the cryptochromes, the clock genes in humans, in 1998, and this discovery led to substantial progress in the understanding of the circadian clock and the introduction of the concept of �chrono-chemoterapy� for more effective therapy in cancer patients. This review focuses on Aziz Sancar�s scientific studies and their reflections on molecular pathology of neoplastic diseases. While providing a new perspective for researchers working in the field of pathology and molecular pathology, this review is also an evidence of how basic sciences and clinical sciences complete each other.

Evaluation of the mir-126, mir-182, and mir-486-5p Expression Signature of Head and Neck Squamous Cell Carcinomas and Lung Squamous Cell Carcinomas

2021-05-01

Objective: Although squamous cell carcinomas (SCCs) originating from different anatomic localizations display a similar histological appearance under light microscopy, they may differ in terms of epigenetic and genetic features. The aim of this study was to analyze mir-126, mir-182, and mir-486-5p expression levels in head and neck SCCs and lung SCCs, and to identify localization-specific miRNA expression profiles. Material and Method: The expression levels of mir-126, mir-182, and mir-486-5p were analyzed in lung, oral cavity, laryngeal, and hypopharyngeal SCCs in 40 patients, using quantitative real-time polymerase chain reaction. Results: The findings showed that lung, oral cavity, laryngeal, and hypopharyngeal SCCs have distinct mir-126 and mir-486-5p expression profiles. It was also observed that mir-126 and mir-486-5p expression levels were highly specific to the tumor localization. Conclusion: These findings highlighted that SCCs originating from different anatomic localizations have different miRNA expression profiles. miRNA expression analysis can be used to predict the primary localizations of those SCCs.

Expression of Calretinin, Marker of Mesothelial Differentiation, in Pancreatic Ductal Adenocarcinoma: A Potential Diagnostic Pitfall

Gokce ASKAN, Olca BASTURK — 2021-05-01

Objective: Pancreatic ductal adenocarcinoma is one of the most common causes of �peritoneal carcinomatosis� and has an insidious growth pattern. Thus, it falls into the differential diagnosis of other peritoneal malignancies including malignant mesothelioma. Recently, we have encountered an undifferentiated pancreatic carcinoma presenting with peritoneal disease and exhibiting immunoreactivity to calretinin, mimicking mesothelioma. In this study, we explored the incidence of calretinin expression in pancreatic ductal adenocarcinoma. Materials and Methods: Calretinin immunohistochemical staining was performed on the tissue microarrays (TMAs), which were created using three 0.6 mm diameter punches per tumor (n=113). Distribution and intensity of expression were evaluated. Results: The TMAs contained 86 well/moderately differentiated and 27 poorly differentiated/undifferentiated carcinomas. Calretinin was positive in nine tumors (8%); six with diffuse and strong staining, three with focal and/or weak staining. The incidence of calretinin expression was 15% in poorly differentiated/undifferentiated carcinomas (vs. 6% in well/moderately differentiated carcinomas, p=0.03). Conclusions: Pancreatic ductal adenocarcinomas, especially when poorly differentiated/undifferentiated, may be diffusely and strongly positive for calretinin creating a potential diagnostic challenge with malignant mesothelioma. Therefore, caution should be exercised when using this marker to explore a diagnosis of malignant mesothelioma. Tumors expressing calretinin without other mesothelial markers should prompt a careful evaluation of the morphologic and immunohistochemical features to exclude other malignancies. If the diagnosis of pancreatic ductal adenocarcinoma is considered, ductal differentiation can be demonstrated by using additional immunohistochemical markers such as mucin-related glycoproteins (MUC1, MUC5AC) and/or oncoproteins (CEA, B72.3, CA125).

Clinicopathological Features and Treatment Challenges in Triple Negative Breast Cancer Patients: A Retrospective Cohort Study

2021-05-01

Objective: As the genetic and molecular profiles of triple negative breast carcinoma (TNBC) are elucidated, multiple therapeutic targets have been produced. TNBC with less than 1% androgen receptor (AR) expression may respond to enzalutamide with greater response association in higher levels. A metronomic dose of capecitabine and docetaxel are effective developed drugs for angiogenic process inhibition. We aimed to demonstrate the treatment outcome of triple-negative breast cancer patients in correlation to their clinicopathological features. Materials and Methods: A retrospective cohort study of 80 TNBC patients was conducted. The patients underwent proper observation with the reporting of their treatment and follow-up data. Patients with a metastatic disease, neoadjuvant chemotherapy, follow-up drop or data shortage were excluded from the survival analysis. Results: The study results revealed a significant association between negative androgen expression and younger age ≤35 years, premenopausal status, higher grade, extracapsular extension, lymphovascular invasion, Ki 67, and CA15-3 (p=0.003, 0.02, <0.001, 0.001, 0.027, 0.005, 0.009 respectively). The three-year overall survival (OS) in patients who received bicalutamide was better than those patients who received capecitabine or docetaxel but of no significance (p=0.46). The three-year disease free survival (DFS) was significantly better in the bicalutamide arm versus the other two groups (p=0.012). Conclusions: We concluded that extended adjuvant antiandrogen such as bicalutamide and metronomic capecitabine are well tolerated with accepted compliance and affordability compared to docetaxel and are warranted for problem-solving and better DFS and OS in some TNBC patients.

Relationship of Tumor-Associated Macrophage Population Detected by CD68 PG-M1, CD68 KP1, and CD163 with Latent EBV Infection and Prognosis in Classical Hodgkin Lymphoma

2021-05-01

Objective: To evaluate the quantity of tumor-associated macrophages (TAMs) in cases of Hodgkin Lymphoma of classical type (cHL), and to reveal possible associations between TAM intensity and latent Epstein-Barr virus (EBV) infection, overall survival, progression-free survival, prognostic indices, and clinicopathological parameters. Materials and Methods: A total 46 cases of cHL with complete clinical records were selected and re-evaluated histopathologically. Staining for CD68 (PG-M1; KP1 clones) and CD163 was evaluated and the cut-off values were defined. Also, all cases were evaluated using the chromogen in situ hybridization (CISH) method with EBER (Epstein-Barr virus-encoded RNA) probes for the presence of possible EBV infection. Results: It was found that high expression levels of PG-M1 and high International Prognostic Scores (IPS) were associated with shortened overall survival (p=0.047, p=0.013). Cases with 2 or less areas of nodal region involvement were observed to have longer progression-free survival period (p=0.043). Higher expression levels of CD68 PG-M1, CD68 KP1, and CD163 were found to show significant associations with the presence of some clinical parameters such as the presence of B symptoms, spleen involvement, and the presence of EBV infection. Conclusions: Our findings suggest that increase of PG-M1+ TAM is associated with shortened overall survival, while higher expressions of all immunohistochemical markers are statistically significantly associated with the presence of EBV infection and clinical parameters mentioned above. These findings indicate that highlighting the TAM rate via macrophage markers in cases of cHL could be helpful in determining the prognostic risk groups and the relevant results should be mentioned in pathology reports.

Distribution and Expression of Programmed Death Ligand -1 (PD-L1) in Non-Small Cell Carcinomas of the Lung in a Tertiary Care Centre in South India

Sheba S K JACOB — 2021-05-01

Objective: Non-small cell lung carcinomas often present at an advanced stage with a grim prognosis. Immune checkpoint (ICP) inhibitors have drastically changed the scenario, and the response to ICP inhibitors is determined by analyzing the expression of PD-L1 by immunohistochemistry. PD-L1 immunohistochemistry helps in optimizing the treatment, and avoiding unnecessary exposure of patients to the toxic effects of the drugs that are ineffective and expensive in non-expressing tumors. This study was conducted to assess the prevalence of the expression of PD-L1 in non-small cell carcinomas of the lung diagnosed at our institution, which is a tertiary care center in South India. Material and Method: The PD-L1 immunohistochemistry of 77 cases of non-small cell carcinomas of the lung diagnosed over a period of two years were reviewed and analyzed (2018-2020). All tissues were fixed in 10% neutral buffered formalin and processed by standard methods, and the Ventana SP263 clone was used. Results: Seventy-seven cases of non-small cell lung carcinomas were reviewed and studied for (PD-L1) expression. 35/77 (45%) of the cases had PD-L1 expression (≥ 1%) and 14 (18 %) had high (PD-L1) expression. Also there was a male preponderance of 2.3:1. High PD-L1 expression was seen mostly in patients above 60 years of age and was usually associated with high tumor grade. Conclusion: It is important to assess PD-L1 expression in non-small cell carcinomas of patients especially with higher tumor grade and older age groups that they may benefit from immune checkpoint inhibitor therapy.

Clinicopathological Evaluation of Acute Leukemias in a Tertiary Care Hospital: A Cross-Sectional Study

Gayatri N. PATEL, Rashmi GUDUR, Anand GUDUR , R. M. OSWAL, Sujatha KANETHKAR — 2021-05-01

Objective: Acute Myeloid Leukemia (AML) and Acute Lymphoblastic Leukemia (ALL) are clinically and biologically diverse phenotypic diseases amongst hematological malignancies. The current study objectives were to diagnose and classify cases of AL as per revised 4th edition of WHO 2016 classification of AL�s and study their clinicopathological profiles. Material and Method: This cross-sectional, observational study included 68 patients, diagnosed with AL were recruited. Diagnosis was based on peripheral blood smear examination, bone marrow aspiration, flowcytometry, and cytogenetic and molecular studies. Results: Sixty-eight cases of AL were diagnosed in a period of 2 years, where 25 cases were of ALL and 43 cases were of AML. In the subclassification of AML as per WHO 2016, 20 cases were of AML, RGA, 21 cases were of AML, NOS, and 2 cases were of AML, MRC. In AML, RGA, APL with PML-RARA positive cases were 10 out of 20 cases, AML with (8;21) RUNX1-RUNX1T1 were 7/20 cases; there were two cases of AML with mutated NPM1 gene and one case of AML with biallelic mutation of CEBPA. In AML, NOS subcategory AML with maturation was more common with 9/21cases. In subcategory of ALL, B-ALL was more common than T-ALL. B-ALL, NOS was more common than B-ALL, RGA and we had 1 case of NK cell Leukemia. Conclusion: The application of revised 4th edition WHO 2016 classification confers uniformity in reporting acute leukemia cases that aids in the treatment by using targeted therapies and helps in the prediction of prognosis. The WHO classification for acute leukemias is very objective, therapy oriented and the need of the hour.

Evaluation of Pulmonary Hypoplasia in Various Congenital Anomalies with a Comparison of Two Conventional Methods of Assessment: Radial Alveolar Count (RAC) and Lung Weight: Body Weight Ratio (LBW)

2021-05-01

Objective: Pulmonary hypoplasia is common in the perinatal period and causes death in newborn infants. It is commonly associated with a number of malformation syndromes. Various parameters are used to estimate pulmonary hypoplasia at fetal autopsy including Lung Weight Body Weight ratio (LW:BW), Radial Alveolar Count (RAC) and DNA estimation. Material and Method: This study was carried out as a retrospective analysis of 108 lung specimens of fetuses with congenital anomalies for a period of five years. All terminated fetuses with anomalies were received with 10% formalin. An inverted Y-shaped incision was made on the fetus to remove the lungs. Lung weight and body weight were measured and the ratio was calculated. Morphometric estimation of RAC was done microscopically by counting the number of alveoli using the Q capture software. RAC was calculated based on gestational age. Results: Among the restrictive lung diseases, pulmonary hypoplasia by the LW:BW ratio was prevalent in 43% while the same by RAC was 19%. Similarly, pulmonary hypoplasia by the LW:BW ratio was prevalent in 35% while the same by RAC was 26% among cases with non restrictive lung diseases. Oligohydramnios showed the highest prevalence of pulmonary hypoplasia (23.7%), followed by renal anomalies (16.9%) and CNS anomalies (15.2%). Conclusion: Pulmonary hypoplasia is a common occurrence in many congenital anomalies, premature rupture of membranes, and hydrops fetalis. Identifying the anomaly during the intrauterine period will help to anticipate and accordingly manage the baby in the postpartum period. Early diagnosis of correctable condition like oligohydramnios will also help in the early intervention and prevention of pulmonary hypoplasia.

Villous Adenoma Arising in the Urethra of a Female with Bladder Augmentation History: A Case Report and Review of the Literature

Hale DEMIR , Sel�uk CIN, Sinharib CITGEZ, Nesrin UYGUN — 2021-05-01

Villous adenomas (VAs) in the female urethra are rare with only seven cases in the English literature to our knowledge. In patients with bladder augmentation cystoplasty, the neoplasia development risk increases and most of these develop in the neobladder or anastomosis line. Only two cases of VA developing from the native bladder mucosa have been reported. Physical examination of a 76-year-old female who had a history of augmentation cystoplasty revealed a caruncula-like structure protruding from the urethral meatus. The urinary USG showed that the lesion had no relation with the bladder. The lesion was excised. Microscopically, it consisted of villous structures covered with pseudostratified intestinal type epithelium. Low-grade dysplasia was present in the epithelium but high-grade dysplasia or in-situ/invasive carcinoma was not observed. Immunohistochemical study showed positivity for CK7, CK20, EMA, CEA and CDX2. The case was reported as VA of the urethra. We presented the first VA case arising in the urethra of a female patient with intestinal bladder augmentation. Excision is curative for pure VAs. Transformation to carcinoma or recurrence has not been reported. However, in one third of the cases, a malignant tumor may accompany the lesion. Therefore, all excision material should be examined carefully. Routine endoscopic follow-up should be performed in cases with bladder augmentation.

Villitis of Unknown Etiology in the Placenta of a Pregnancy Complicated by COVID-19

2021-05-01

Villitis of unknown etiology (VUE) is noninfectious chronic villitis thought to be associated with fetal growth restriction and stillbirth. COVID-19 and the pandemic SARS-CoV-2 infection can cause an increased risk in pregnant women for potential maternal and fetal complications from an immunological mechanism. We report a 39-week-gestational-age infant delivered to a 37-year-old mother diagnosed with SARS-CoV-2 infection at 37 weeks gestation. The placental examination showed the morphological features of VUE. We showed immunohistochemically that macrophages and CD4-positive T cells predominated in the villous tissue, although elevated numbers of CD8-positive cells were also present. We hypothesize that VUE may represent a maternal anti-viral immune response, in this case to SARS-CoV-2.

ALK-Positive Histiocytosis: A Case Report and Literature Review

Omar Issa JABER, Doa� AL JARRAH, Mohammad HIASAT, Maysa AL HUSSAINI — 2021-05-01

ALK positive histiocytosis is a relatively new histiocytic proliferation disease with a characteristic gene translocation involving fusion of the ALK gene with different partners, mostly KIF5B. We report a case of ALK-positive histiocytosis with literature review. A 27-year-old male patient presented mainly with progressive lower limb weakness. Imaging studies showed an intradural extramedullary enhancing lesion at the L3 level. A 1.5 cm mass was excised from the sensory nerve root in the filum terminale at the level of L3. Histologic examination showed infiltration of the nerve by numerous histiocytes with moderate to abundant eosinophilic to clear-foamy and variably-vacuolated cytoplasm with irregular-to-smooth contoured nuclei. The histiocytes were positive for CD68 and ALK1 and negative for S100 and CD1a. KIF5B-ALK fusion was detected by real time-polymerase chain reaction. The patient is asymptomatic nine months after surgical excision. This is the first reported localized case occurring in the nerve root of an adult patient, thus expanding the clinical manifestations of this disease. An integrated histological, immunohistochemical and molecular approach is recommended for diagnosis. We recommend performing ALK1 immunohistochemical stain on all histiocytosis cases to increase awareness and detection of this newly described entity.

Laryngeal Chondrosarcoma of the Thyroid Cartilage

Selma ERDO�AN D�ZC�, Zeliha CO�GUN, Hesna M�zeyyen ASTARCI — 2021-05-01

Laryngeal chondrosarcoma is rare and accounts for 0.2% of all larynx malignancies. Although chondrosarcoma is the most common sarcoma seen in the larynx, laryngeal involvement by cartilage tumors is rare. In this article, we aimed to present the differential diagnosis of chondrosarcoma located in the thyroid cartilage, which is a rare site, in a 75-year-old male patient. The patient underwent total laryngectomy by the otolaryngology department. The macroscopy of the laryngectomy material sent to the pathology laboratory revealed a 3x2 cm tumor with a polypoid extension to the lumen from the bottom of the right vocal cord. Although clinical and radiological findings are important in the diagnosis, the definite diagnosis is based on the pathological examination. It is especially important to differentiate the lesion from chondromas.

Tall Cell Carcinoma with Reverse Polarity of Breast: Report of a Case with Unique Morphologic and Molecular Features

Mohamed JASSIM, Chennagiri S PREMALATA, Geeta V Patil OKALY, Chunduri SRINIVAS — 2021-05-01

Breast carcinomas are a heterogeneous group of malignancy, having variable clinical outcomes depending on their cellular and molecular properties. Tall cell carcinoma with reverse polarity (TCCRP) is a recently described rare entity, which shares morphological features with tall cell variant of papillary thyroid carcinoma but has a distinct morphological, immunohistochemical, and molecular profile. We describe a case of a 40-year-old female patient, who presented with lump in the breast. The patient underwent lumpectomy and was diagnosed as tall cell carcinoma with reverse polarity. Immunohistochemistry and bi-directional Sanger sequencing for IDH2 mutation were used for diagnosis. Tall cell carcinoma with reverse polarity is a rare and newly described entity with characteristic morphological and molecular findings, which carries an excellent prognosis.

About the Degeneration of a Mediastinal Bronchogenic Cyst

Mona MLIKA, Rahma AYADI, Faouzi MEZNI — 2021-05-01