Aim: To highlight the widespread metastatic potential of the cutaneous melanoma, as well as its tendency for unusual presentation of metastatic disease. Introduction: Melanoma is an aggressive, highly malignant disease that is derived from melanocytes. The incidence of melanoma is significantly increasing. Melanoma has a strong tendency for metastasis. After primary excision of tumour, about 30% of all patients shall develop distant metastasis within first 5 years after tumour diagnosis. Case report: A 48-year-old female patient had undergone a hysterectomy because of myomatous uterus. After pathohistological examination metastasis of melanoma was diagnosed in one of multiple leimyoma. Diagnosis was confirmed with positive immunohistochemical staining with MART1 and S100 protein. Insight into the medical records, revealed that patient was diagnosed with superficially spreading melanoma (Clark IV, Breslow III) on skin above her left breast, as well as 2 regional tumour-involved lymph nodes (pT3aN2bM0), 2 years prior to this hysterectomy. Uterine leiomyoma was the first diagnosed distant metastasis of cutaneous melanoma. Diagnosis of stadium IV melanoma was established. Conclusion: Melanoma is a particularly aggressive disease with unpredictable evolution, so the occurrence of metastases in unusual and unexpected localizations, as is the distant benign tumour in the presented case, shall probably happen more often in the future.

The Norvegian University of Science and Technology is the largest educational institution in Norway. It was founded in 1760 as the Trondheim Academy. The Faculty of Medicine and Health Sciences is part of the St Olav’s Hospital in Trondheim, and being there, as participant of the Annual Cytology Tutorial of the European Federation of Cytology Societies, was an outstanding experience. Colleagues from all over the world had the opportunity to meet and learn from experts in various fields of cytology. Particularly, differences between conventional and Thin Prep Pap smears, as well as immunocytochemistry of air-dried smears were thoroughly discussed.

The presentation will reflect on a one-month period of education that the author spent with the Cleveland Clinic soft tissue pathology team. Cleveland is a US city in the state of Ohio. One of its nicknames is
“The Rock and Roll Capital of the world”, due to the fact that the term R’n’R was coined in the 1950s by
a Cleveland-based disc jockey Alan Freed. The city hosts the Rock and Roll Hall of Fame, established in
1983. It is also home to the Cleveland Clinic, a multispecialty academic hospital currently ranked as the
#2 hospital by U.S. News & World Report1. In 2014, Cleveland Clinic had a total revenue of $11.63 billion, making it the #2 hospital in US on the Becker’s Hospital Review revenue list2. The author spent one
month on a UICC ICRETT fellowship in November 2016 with the Cleveland Clinic soft tissue pathology
team. The main strength of the soft tissue team is the presence of several internationally known experts
with diverse interests within the field of soft tissue and beyond, with team philosophy highlighting the
synergy of team work and individual reputation. Among various topics that were covered during the
one-month fellowship, certainly one of the most interesting was differentiation among different fibrohistiocytic neoplasms. Fibrohistiocytic tumors are among the most frequent soft tissue tumors and they
are most commonly encountered in the skin. “Fibrohistiocytic” is in fact a merely descriptive term for
cells that resemble both normal fibroblasts and histiocytes, and not a true line of differentiation3. Like
other soft tissue tumors, fibrohistiocytic neoplasms are divided into benign, intermediate and malignant
categories. In presentation, the author will reflect on the key points in the pathology diagnosis within this
category of tumors, and these are:
- being able to give a common denominator to numerous variants of benign fibrous histiocytoma
- awareness of the pitfalls in the diagnosis of dermatofibrosarcoma protuberans
- discrimination of malignant fibrohistiocytic skin-based tumors from other, more adverse cutaneous
malignancies.

Lung transplantation remains the definitive treatment for end-stage lung diseases and an option when
medical and surgical care has been exhausted. The first human single lung transplant was performed in
1963, and the patient, survived for 18 days. From 1963 to 1978, multiple attempts at lung transplantation
failed because of rejection and problems with anastomotic bronchial healing. It was only after the invention of the heart-lung machine, coupled with the development of immunosuppressive drugs, that organs
such as the lungs could be transplanted with a reasonable chance of patient recovery. The first clinically
successful long-term single lung transplant was performed in 1983, and since then over 25,000 lung transplants performed worldwide.

Adnexal tumors of the skin comprise heterogenous group with over 40 defined entities, classified by predominant differentiation into lesions with apocrine and eccrine, follicular, sebaceous, or multilineage differentiation. Some, but not all these entities are represented by benign and malignant counterparts. Their occurrence may be sporadic or as a part of inherited syndromes (e.g. Muir-Torre syndrome, Brooke-Spiegler Syndrome, or Cowden’s syndrome). Adnexal tumors may arise de novo or within hamartomatous lesions such as nevus sebaceous of Jadassohn. Adnexal carcinomas are very rare tumors (the incidence is less than 0.001%), with variable local recurrence, metastatic potential, and survival. Porocarcinoma, hidradenocarcinoma and sebaceous carcinoma (especially ocular type) are considered to have a poor prognosis, with the highest risk of local recurrence and distant metastases. Mortality of the patients with porocarcinoma is very high (65-80%) if regional or distant metastases are present. The treatment of malignant adnexal tumors is usually surgical or less frequently with radiation therapy. Patients with metastases are usually treated with chemotherapy, mostly with cytotoxic reagents, and rarely with estrogen receptor antagonists. The detailed knowledge of genetic features of adnexal tumors is still lacking. Most of the studies examined only few of the genes using low throughput techniques. Development of new generations of genome sequencing methods led to better understanding of tumors with apocrine and eccrine differentiation. For many of their subtypes, it is still unknown whether there are specific genetic changes, that could even be of diagnostic significance. Hotspot mutations in HRAS (p.G13X and p.Q61X) were found in a subset of eccrine poromas and porocarcinomas. These mutations were found in tumors with other lines of differentiation and suggesting overlapping genetical characteristics among adnexal tumors. Due to their similar histological features, cylindroma and spiradenoma are usually considered as phenotypic variations of the same entity. Their histological features can be mixed, in which case a diagnosis of spiradenocylindroma is made. In cylindroma, MYB is upregulated either by mutations in CYLD gene (syndromic cases) or due to a rearrangement of MYB gene (sporadic cases). Genetic characteristics of spiradenomas, including the status of CYLD and MYB genes, are largely unknown. It is still unclear if these two are both histological and genetical “relatives” and what is the level of heterogeneity among tumors arising sporadically or within syndromes. The presence of chromosomal rearrangements in adnexal tumors is also unexplored. TORC1-MAML2 and EWSR1-POU5F1 fusions were found in significant number of hidradenomas. Initially it was thought these fusions could be characteristic for clear cell variant of hidradenomas, but no true correlation with histology was found. Molecular alterations that differ between benign and malignant counterparts and could enable targeted therapy of adnexal carcinomas are unknown. Mutations in TP53, often UV-associated, are frequent in malignant tumors with eccrine and apocrine differentiation and can drive malignant transformation in such tumors. Porocarcinomas and ABSTRACTS 96 MATERIA MEDICA • Vol. 34 • Issue 1, suplement 1 • april 2018. hidradenocarcinomas harbor various molecular alterations affecting PI3K-AKT or MAPK pathways that could enable targeted therapy in the future. Actionable mutations in EGFR were not found in carcinomas with eccrine and apocrine differentiation thus far. Her2 amplifications are rarely found, mostly in hidradenocarcinomas, but its therapeutic potential has only been utilized only once.16,25 Mutations of PTCH1 and TCF7L1 in hidradenocarcinomas could also enable the treatment with the inhibitors of Hedgehog and WNT/Hippo signaling pathways. It seems that current knowledge gained from genomic studies of adnexal tumors is only a scratch on the surface. In addition, there is no data on epigenetic characteristics or transcriptome of adnexal skin tumors. Taken altogether, further and detailed investigation of genome, epigenome and transcriptome of adnexal tumors is necessary. Such integrated knowledge could explain mechanisms of their development, malignant alteration and progression, so the treatment of patients with metastatic adnexal carcinomas could be changed toward targeted therapy.

Aim and introduction: Pediatric nodal marginal zone lymphoma (NMZL) is a rare, but distinct subtype of NMZL with characteristic clinical presentation, pathohistological and molecular features, therapy and prognosis. Results: We report the case of a 15-year-old boy with no remarkable past history, presented with painless enlargement of left submandibular lymph node (LN) for three months. He was admitted to the University Children’s Hospital in Belgrade in May 2016. The cervical ultrasound demonstrated moderate left submandibular lymphadenopathy, but also mild enlargement of two right submandibular LNs (17x7mm, 14x7mm). Physical examination, chest radiography and abdominal ultrasound revealed no hepatosplenomegaly and lymphadenopathy elsewhere. The result of blood count test was normal. Biochemistry showed elevated uric acid 499 umol/l, AST 45U/l, ALT 98U/l, and sedimentation rate (65mm/h). Urea, creatinine, alkaline phosphatase, LDH and CRP were normal. The patient underwent left submandibular LN excisional biopsy. The size of the LN was 47x37x20mm. The histopathological examination revealed partial architectural effacement: follicular hyperplasia and nodular B-cell infiltration with features of progressive transformation of germinal centers (PTGC) in the form of fragmentation of follicles. A CD20 immunostain shows an abnormal expansion of the marginal zone with infiltration of interfollicular space. These B-cells were negative for CD3, CD5, CD23, EBV-LMP1, bcl-6, CD10, EMA, CD30, CD15, MUM-1, and positive for bcl-2 and IgD. A CD21/ CD23/ fascin immunostain showed an expanded and disrupted follicular dendritic cell meshwork. Ki-67 highlighted residual follicular polarisation and a low proliferation rate in the interfollicular areas. Based on these pathohistological findings it was concluded that LN likely represent reactive follicular hyperplasia with atypical marginal zone hyperplasia or possible PNMZL, with APSTRAKTI 95 MATERIA MEDICA • Vol. 34 • Issue 1, suplement 1 • april 2018. recommendation of polymerase chain reaction (PCR) analysis of clonality. Additional IGH PCR analysis demonstrated biclonal heavy chain gene rearrangement. These findings were consistent with PNMZL. After consultation with members of International BFM study group for non-Hodgkin lymphomas, followup was recommended without any treatment. The patient has remained disease free for 22 months since diagnosis. Conclusion: We presented a rare case of PNMZL with morphological features of PTGC, but immunohistochemistry and additional PCR clonality analysis were crucial for final diagnosis. This case represents a diagnostic and therapeutic challenge because of their rarity in the pediatric population.

In preparation for the 8th edition of the TNM classification for lung cancer the International Association for the Study of Lung Cancer (IASLC) collected data on 94,708 cases of lung cancer diagnosed between 1999 and 2010, donated by 35 institutions in 16 countries. After exclusions, 77,156 remained for analysis: 70, 967 cases of non-small cell lung cancer (NSCLC) and 6,189 cases of small-cell lung cancer (SCLC). Analysis of the cases of NSCLC has allowed proposals for revisions to the T, N and M descriptors and TNM Stage groupings. Size remained an important determinant and a descriptor for all of the T categories. A new cut points at 1 and 4 cm have been proposed and as a result new T categories have been created: T1a ≤1 cm, T1b > 1 to 2 cm, T1c > 2 to 3 cm, T2a > 3 to 4 cm, T2b > 4 to 5 cm, T3 > 5 to 7 cm and T4 > 7 cm. However, measuring precise tumor size can be challenging since it is known that tumor gross size depends on whether the size measurement is performed on fresh or formalin-fixed specimen. In about 10% of cases, formalin fixation can cause down-staging of pathologic T category as a result of tumor shrinking. Tumors invading the diaphragm have been reclassified as T4, and tumors extending within 2cms of the carina without its invasion, or tumors associated with collapse or consolidation of the whole lung have been down-staged to T2. Tis and T1mi were introduced for adenocarcinoma in situ, squamous cell carcinoma in situ and minimally invasive adenocarcinoma, respectively. Visceral pleural invasion, defined as the involvement of its elastic layer, remains unchanged as T2 category, but specific analysis of visceral pleural invasion, showed that there is two types of invasion: PL1 where tumor invades beyond the elastic layer and PL2 where tumor invades pleural surface and that these two had different prognosis, PL2 being associated with the worst outcome. Elastic stains are recommended to clarify the status of visceral pleural invasion for cases in which initial hematoxylin-and-eosin-stained slides failed to show presence of invasion. Mediastinal pleura invasion disappears as a T descriptor. N categories remained the same as in 7th edition. 8th did not bring guidelines about the minimum number of lymph nodes that should be assessed for pathohistological analysis. In M descriptor category M1a retained, while M1b has been reassigned to describe a form of limited disease with a single metastatic deposit in one distant organ. A new category of M1c has been proposed and it is reserved for situations in which there are multiple metastases in one or more distant sites. Assessment of multifocal lung tumors and the distinction of synchronous primary tumors from intrapulmonary metastases represent an important problem as this decision significantly influences tumor staging, as well as treatment approach. Four different clinical presentation of lung cancer with multifocal lung involvement are described: second primary cancer, intrapulmonary metastasis, multifocal lung adenocarcinoma with ground glass/lepidic features, and pneumonic-type lung adenocarcinoma. The tumors are considered second primary tumor if it have clearly a different histology or have a different radiographic appearance, metabolic uptake growth pattern or different biomarkers. Each tumor is staged separately based on current TNM staging system. The nodules are considered to be intrapulmonary metastasis if exact matching breakpoints are identified by genetic hybridization or have similar clinical features such as radiographic appearance, growth pattern or significant nodal and systemic SPECIAL SESSION: DEPARTMENT OF PATHOLOGY, MEDICAL FACULTY, UNIVERSITY NOVI SAD, SERBIA 32 MATERIA MEDICA • Vol. 34 • Issue 1, suplement 1 • april 2018. metastasis. TNM staging depends on location of the nodule relative to the primary tumor site. If it is in the same lobe, the tumor is designated as T3, if it is in the same lung, but in different lobe as T4, and it it is in the contralateral lung as M1a. Tumors are considered multifocal lung adenocarcinoma if there are multiple subsolid nodules with at least one suspected or proven to be a cancer. Ground glass nodule <5 mm or lesion suspected to be AAH is excluded. T stage is based on highest T lesion with indicating the multiplicity. Tumor is categorized as a pneumonic-type adenocarcinoma if there is a diffuse pneumonic infiltrate or consolidation with regional distribution. Stage IA is divided into IA1, IA2 and IA3 to accommodate T1a, T1b and T1cN0M0 tumors. All N1 disease is staged IIB except for T3-T4N1M0 tumors which are stage IIIA. A new stage IIIC is created for T3-T4N3M0 tumors and stage IV is divided into IVA (M1a and M1b) and IVB (M1c). In conclusion, multi-disciplinary approach and the close cooperation among medical and radiation oncologists, pulmonologists, surgeons, radiologists and pathologists is important in properly staging of lung cancer as well as, in treatment plans.

Aim: The aim of this study was to investigate the association of local tumor survivin expression and serum concentration with clinical and histopathological parameters in melanoma patients. Introduction: Survivin is a multifunctional protein abundantly expressed in tumors of various types, including melanoma. There are still sparse data regarding relationship of melanoma cell survivin expression with accepted histopathological characteristics as well as serum concentration. Material and Methods: The level of survivin expression was determined immunohistochemically in tumor tissue and with ELISA test in the serum of 84 melanoma patients with melanoma. Results: Survivin expression was significantly higher in the patients whose tumor had ulceration, higher mitotic index, higher Clark and Breslow stage, that made vascular invasion or spread through lymphatic vessels in primary tumor, and in the patients with metastatic disease. The patients with high survivin expression score had almost double shorter disease free interval DFI comparing to those with weak local survivin expression and a small number of survivin cells (9 - 7 vs 19 - 13 months, respectively). The degree of tumor infiltrating lymphocytes presence in tumor tissue was significantly inversely associated with serum survivin concentration. Conclusion: Conclusion Survivin expression in tumor tissue and its serum concetration significantly correlate with clinical and histopathological parameters. Serum levels could be important in initial follow-up as indicators of those patients that would have aggressive local tumor growth and spreading.

Lung carcinoma is the leading cause of increases in the morbidity and mortality rates of malignant diseases worldwide. Adenocarcinoma has been the most common histological type in the last decades due to: changes in the tobacco industry, smoking habits and the use of immunohistochemistry. Among more than half of patients, lung adenocarcinoma is diagnosed in an advanced stage of the disease. The discovery of mutations in epidermal growth factor receptor (EGFR) in lung adenocarcinoma is a major advancement in molecular pathology and a new approach to the treatment of these patients. Patients with EGFR mutated lung adenocarcinoma receive a targeted therapy (Tyrosine Kinase Inhibitors-TKI) which leads to improvements in disease prognosis and quality of life. Real-time polymerase chain reaction (PCR) is the most widely used and most reliable method since it requires a minimum amount of starting material and allows the amplification of the desired DNA segment up to a billion times. In this way, deletions in exon 19 are detected in approximately 90% of cases, more often in women, non-smokers and in the territory of Asia. The following may be used for EGFR testing: fresh tissue, fast-frozen tissue, tissue molded into paraffin blocks after fixation in formalin and cytological material obtained by scraping from glass tiles. Tissue processed by decalcination, acid treated or heavy metal treated tissue should be avoided. Although surgical samples represent the golden standard in determining EGFR mutations, the results obtained are compatible with the results obtained by bronchoscopic biopsy and thus eliminate the need for invasive diagnostic procedures. Bronchoscopy is an invasive diagnostic method, whose objectives are to diagnose lung tumors, determine the endoscopic spread of the disease and assess tumor operability. The presence of a tumor may be indicated by a different bronchoscopic aspect of the endobronial mucosa. The sensitivity and specificity of this method depends on: bronchologist’s skills, endoscopic findings, the number of biopsy samples, the professional competence of pathologist-cytologist and the obtained tumor amount. The tumor amount is generally small and depends on the histological type, endoscopic findings, sampling technique and the presence of other cells. It is recommended to take three to five biopsy samples, used for diagnosing but also for molecular testing. Targeted therapy is applied based on the obtained results. Given that biopsy samples molded in paraffin are cut into multiple histological sections, and that the tumor amount decreases, it is necessary to minimize the “consumption”. The concentration of isolated DNA does not differ among patients with wt EGFR and mutated EGFR adenocarcinoma. To date, there has been no consensus regarding the number of tumor cells necessary to determine EGFR mutations, and it is recommended to take samples with a minimum of 200 to 400 tumor cells. Invalid results obtained by using the PCR method are most commonly the result of a small number of preserved tumor cells in a biopsy sample. Blood and necrosis may be limiting factors for molecular testing, but not exclusion factors for the same. Bronchoscopic biopsy sample is adequate for the determination of EGFR mutations because the majority of biopsy samples have more than 100 tumor cells, the difference between the concentration of isolated DNA in EGFR mutated and wt EGFR adenocarcinomas is not statistically significant, EGFR mutations are also detected in samples with a small number of tumor cells when using highly sensitive tests.

Lung cancers are the most common cause of morbidity and mortality from malignant tumors in the World. The neodjuvant therapy in patients with locally advanced (IIIA-IIIB) lung cancer and affected N2 lymph nodes is one of the modes of multimodal treatment of patients with non-small cell lung cancer (NSCLC) in order to improve the outcome of their treatment. This involves converting patients from a higher to a lower stage of the disease - “downstaging”. There has been no significant connection between some forms of tumor response and types of therapy. Given the importance of complete pathological responses and tumor regression in the prediction of treatment outcomes, finding this relationship is of importance for the design of future neoadjuvant trails. In determining the histological tumor regression is very important measurement of area of residual tumor (ART). As the size of the tumor is one of the prognostic factors in patients with NSCLC who did not receive neoadjuvant therapy so the measurement of ART, as opposed to the macroscopic size of the tumor, one of the prognostic factors in patients with NSCLC, who had received neoadjuvant therapy. The ultimate goal of neoadjuvant therapy should be resectability and “downstaging” that could provide overall oncology benefit in specific clinical situations. The main objectives of this research were: to objectively estimate the size of ART in tumor tissue of lung and lymph nodes; to estimate the relation between the surface of ART with the size of the tumor on postoperative surgical material after neoadjuvant therapy; to analyze and estimate the relation between histomorphological parameters in tumor regression induced by neoadjuvant therapy and spontaneous tumor regression in tumors of the lung and lymph nodes in the postoperative surgical material and depending on the histological type of cancer; to estimate the relation between clinical response to neoadjuvant therapy according to criteria of the World Health Organization and histological parameters in lung tumors and lymph nodes in the postoperative surgical material after neoadjuvant therapy; to estimate the correlation of the pathological ypTN with clinical ycTN stage of the disease and the degree of tumor regression induced by neoadjuvant therapy and pathological ypTN and estimation of the relation between clinical and pathological involvement of N2 lymph nodes after neoadjuvant therapy. Measurement of the total size of the preserved ART is the most important objective parameter in the assessment of the grade of tumor regression. Size of residual tumor did not correlate with the size of the tumor after neoadjuvant therapy. There was a significant difference in the histological picture of tumor regression induced by neoadjuvant therapy and spontaneous tumor regression. There was no significant difference between the histologic type of tumor and histological tumor regression. There is no significant correlation between clinical response and the grade of tumor regression after neoadjuvant therapy. There is no correlation between clinical and pathological staging of the diseaSPECIAL SESSION: DEPARTMENT OF PATHOLOGY, MEDICAL FACULTY, UNIVERSITY NOVI SAD, SERBIA 34 MATERIA MEDICA • Vol. 34 • Issue 1, suplement 1 • april 2018. se after neoadjuvant therapy. There is no correlation between the grade of tumor regression induced by neoadjuvant therapy and ypTN stage of the disease. There is no correlation between the clinical and the pathological involvement of the N2 lymph nodes to neoadjuvant therapy. The grade of tumor regression and measurement ART after neoadjuvant therapy determined by histopathological analysis of the resected tumor is the most objective criterion for evaluation of chemotherapeutic response and prediction of treatment outcome in patients.