Neoplastic Elements Research Articles

Difficult Diagnosis and Management of Concealed Cushing.

Adrenocorticotropic Hormone (ACTH)-secreting tumors account for 5- 10% of Cushing syndrome cases and are often difficult to diagnose and treat. A 44-year-old man presented with arterial hypertension and weight gain. On the physical examination, he exhibited central obesity, abdominal striae rubrae, and facial plethora. Due to the clinical suspicion of Cushing syndrome, the Nugent test and Liddle-1 test were performed, which showed a lack of cortisol suppression. ACTH levels were also high (138 pg/mL), so pituitary MRI and dynamic tests were performed, including the Corticotropin-releasing Hormone (CRH) stimulation test and Liddle-2. MRI showed a 3 mm pituitary microadenoma, but hormonal testing suggested ectopic ACTH production. Chest CT detected a 10-mm nodule in the upper lobe of the right lung, suspicious for a carcinoid tumor. However, the nodule did not exhibit any enhancement on 68-Gallium-DOTATOC PET-CT, and further, 18-FDG PET-CT was inconclusive. In addition, the nodule was deemed non-biopsiable due to its location. Meanwhile, the patient developed osteoporosis, resulting in two vertebral fractures and one rib fracture, which was treated with zoledronate. Furthermore, the patient developed acute aortic insufficiency. During bioprosthetic valve replacement, the thoracic surgeon performed wedge resection of the right upper lung lobe. The histological examination of the lesion revealed a typical lung carcinoid (1.2x0.9 cm, pT1bNXR0, Ki671%, ACTH positive in 95% of neoplastic elements). ACTH levels dropped to 4 pg/mL on the fourth postoperative day. ACTH-secreting tumors are particularly challenging diseases. A comprehensive hormonal and instrumental valuation is often required, necessitating a multidisciplinary approach.

Bioprinted Human Lung Cancer-Mimics for Tissue Diagnostics Applications.

Developing a reproducible and secure supply of customizable control tissues that standardizes for the cell type, tissue architecture, and preanalytics of interest for usage in applications including diagnostic, prognostic, and predictive assays, is critical for improving our patient care and welfare. The conventionally adopted control tissues directly obtained from patients are not ideal because they oftentimes have different amounts of normal and neoplastic elements, differing cellularity, differing architecture, and unknown preanalytics, in addition to the limited supply availability and thus associated high costs. In this study, we demonstrated a strategy to stably produce tissue-mimics for diagnostics purposes by taking advantage of the three-dimensional (3D) bioprinting technology. Specifically, we take anaplastic lymphoma kinase-positive (Alk+) lung cancer as an example, where a micropore-forming bioink laden with tumor cells was combined with digital light processing-based bioprinting for developing native-like Alk+ lung cancer tissue-mimics with both structural and functional relevancy. It is anticipated that our proposed methodology will pave new avenues for both fields of tissue diagnostics and 3D bioprinting significantly expanding their capacities, scope, and sustainability.

Neuropeptide Y and its receptors in prostate cancer: associations with cancer invasiveness and perineural spread

PurposeNeuropeptide Y (NPY) is a pleiotropic peptide, which is involved in many biological mechanisms important in regulation of cell growth and survival. The aim of this study was a comprehensive analysis of the NPY system in prostate pathology.MethodsThe study was based on immunohistochemical analysis of NPY and its receptors, Y1R, Y2R and Y5R, in tissue samples from benign prostate (BP), primary prostate cancer (PCa) and PCa bone metastases. Tissue microarray (TMA) technique was employed, with analysis of multiple cores from each specimen. Intensity of the immunoreactivity and expression index (EI), as well as distribution of the immunostaining in neoplastic cells and stromal elements were evaluated. Perineural invasion (PNI) and extraprostatic extension (EPE) were areas of special interests. Moreover, a transwell migration assay on the LNCaP PCa cell line was used to assess the chemotactic properties of NPY.ResultsMorphological analysis revealed homogeneous membrane and cytoplasmic pattern of NPY staining in cancer cells and its membrane localization with apical accentuation in BP glands. All elements of the NPY system were upregulated in pre-invasive prostate intraepithelial neoplasia, PCa and metastases. EI and staining intensity of NPY receptors were significantly higher in PCa then in BP with correlation between Y2R and Y5R. The strength of expression of the NPY system was further increased in the PNI and EPE areas. In bone metastases, Y1R and Y5R presented high expression scores.ConclusionThe results of our study suggest that the NPY system is involved in PCa, starting from early stages of its development to disseminated states of the disease, and participates in the invasion of PCa into the auto and paracrine matter.

S3422 Hepatic Parenchyma and Cholecystectomy Clip in Duodenum? An Interesting Case of Pancreatic Adenocarcinoma

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related death in many industrialized countries. Patients with PDAC typically report non-specific symptoms such as abdominal pain, weight loss, and jaundice. Given the lack of effective screening, many patients are diagnosed at the time of metastasis. Here we present a case of a patient who was diagnosed with metastatic PDAC with contained perforation in the duodenum. Case Description/Methods: A 74-year-old man with a history of prostate cancer requiring prostatectomy presented with a 2-month history of abdominal pain, nausea, vomiting, unintentional weight loss, and melena. He had normocytic and normochromic anemia with normal liver enzymes and lipase. Tumor markers ordered around the same time as EGD, including CEA/PSA, were unremarkable, but CA 19-9 was 6959 U/mL. EGD revealed a large necrotic, ulcerated duodenal mass in the first portion with suspicion of contained perforation. A metallic object was also identified which was likely a cholecystectomy clip as confirmed on subsequent CT. Pathology showed necrotic tissue and hepatic parenchymal cells, but there were no diagnostic neoplastic elements. CT abdomen showed a proximal duodenal mass with ulcer-like outpouching extending into the gallbladder fossa, abnormal perfusion of liver segments 4 and 5 with soft tissue mass adjacent to the pancreatic head suspicious of locally invasive primary duodenal malignancy. Whipple's procedure was performed, given the lesion's appearance and extent, and for diagnosis. Pathology revealed a poorly differentiated ductal adenocarcinoma of the head of the pancreas, with a signet ring pattern invading the duodenum wall, anterior surface of the pancreas. There was lymph node metastasis. The patient elected for hospice, given his poor prognosis (Figure). Discussion: Patients with PDAC often report epigastric pain, jaundice, and weight loss. Our patient presented with abdominal pain and weight loss. However, the melena and anemia raised concern for GI bleed; hence an EGD was performed, which led to the diagnosis of pancreatic adenocarcinoma with contained perforation in the duodenum. There are no practical screening tools for pancreatic cancer. Liver enzymes, CA 19-9, in addition to ultrasound abdomen or abdominal CT, depending upon the patient's symptoms and age, can be considered as part of work up. Curative treatment for PDAC is surgical resection with negative surgical margins and adjuvant therapies; however, the five-year survival rate remains low.Figure 1.: Necrotic duodenal lesion with cholecystectomy clip.

Plexiform fibrohistiocytic tumor: a clinicopathological and immunohistochemical study of 39 tumors, with evidence for a CSF1-producing "null cell" population.

Plexiform fibrohistiocytic tumor (PFHT) is a mesenchymal tumor of intermediate malignancy, typically occurring in the superficial soft tissues of young patients and displaying a biphasic pattern, with nodules of histiocytoid cells surrounded by fascicles of myofibroblastic spindled cells. The pathogenesis of PHFT is unknown. We comprehensively studied 39 PFHT, occurring in 25 females (66%) and 13 males (34%), ranging from 2 to 55years of age (median 21years). The tumors most often occurred in the upper extremity (n = 16, 41%) and ranged from 0.4 to 6.1cm in size (median 1.5cm). One patient with known neurofibromatosis type 1 presented with metachronous tumors of the finger and back. Clinical follow-up (29 patients; range 5-168months; median 60months) showed 3 tumors to have recurred locally; none was metastasized. One patient died of an unrelated cause; all others were alive without disease at the time of last follow-up. Immunohistochemistry showed the histiocytoid nodules of all cases to contain CD163/CD11c-positive histiocytes and cells negative for both markers ("null cells"). CSF1 expression was present in "null cells" in 7/10 cases (RNAscope chromogenic in situ hybridization). The Ki-67 labeling index was very low (< 5%); Ki-67-positive cells within histiocytoid nodules appeared to represent "null cells." All tested cases were negative for significant mutations or fusion events (TruSight Mutation Panel, TruSight Fusion Panel, Mayo Clinic Melanoma Targeted Gene Panel). We conclude that PHFT may be even more indolent than has been appreciated, although classification as an "intermediate" tumor is correct. We hypothesize that the CSF1-producing "null cells" of PHFT may represent the neoplastic element, with the bulk of the tumor masses comprising recruited and reactive cell populations.

Immunoexpression of p62/SQSTM1/Sequestosome-1 in human primary and recurrent IDH1/2 wild-type glioblastoma: A pilot study.

p62/SQSTM1/Sequestosome-1 is an autophagic protein that serves a crucial role in cellular metabolism, proliferation and malignant growth. Notably, autophagy may influence the development and resistance to therapy of numerous types of human cancer. In the present pilot study, the immunohistochemical pattern of p62 was analyzed in a cohort of patients with isocitrate dehydrogenase (IDH)1/2 wild-type glioblastoma (GBM), in primary and recurrent samples, in order to verify the concordance or discordance between the primary and recurrent tumors. In addition, the association between p62, and patient outcome and O6-methylguanine-DNA methyltransferase (MGMT) status was assessed. The results revealed p62 immunoexpression in the nucleus and cytoplasm of neoplastic elements in 45% of primary and 55% of recurrent cases of GBM. A discordant p62 immunoreactivity was detected in 35% of cases, with a variation either with positive or negative conversion of p62 status. Statistically, p62 expression and MGMT status exhibited a significant prognostic value by univariate analysis, whereas only MGMT promoter methylation status emerged as an independent prognostic factor by multivariate analysis. Finally, the most favorable prognosis was documented when the same GBM case was positively concordant for both p62 expression and MGMT methylated status. Since little data are available regarding the association between p62 expression and MGMT in GBM, further investigations may be required to determine if new targeted therapies may be addressed against autophagy-related proteins, such as p62.

The Microenvironment's Role in Mycosis Fungoides and Sézary Syndrome: From Progression to Therapeutic Implications.

Background: Mycosis fungoides (MF) and Sezary Syndrome (SS) are the most common cutaneous T-cell lymphomas. It has been hypothesized that the interaction between the immune system, cutaneous cells, and neoplastic elements may play a role in MF/SS pathogenesis and progression. Methods: This paper aims to revise in a narrative way our current knowledge of the microenvironment’s role in MF/SS. Results and Conclusions: Literature data support a possible implication of microenvironment cells in MF/SS pathogenesis and progression, opening up new therapeutic avenues.

Female Genital Tuberculosis, a Rare Lesion Mimicking Ovarian Carcinoma, with Granulosa Cell Tumor: A Case Report

Introduction: Tuberculosis (TB) of the upper genital tract is a rare disease worldwide. TB should be always considered in the differential diagnosis of a pelvic or adnexal mass as it may diagnosed as ovarian carcinoma but both have completely different treatment. Therefore, recognition of TB is important for surgeons and histopathologists, in order to set a proper plan for management and avoid unnecessary extensive therapy. Granulosa cell tumor of the ovary is a rare type of ovarian cancer that accounts for approximately 2% of all ovarian tumors. This type of tumor is known as a sex cord-stromal tumor and usually occurs in adults. Thorough search in English literature revealed only 2 case reports showed combination between genital TB and granulosa cell tumor. Case summary: A 68 years old female patient complained of vaginal bleeding for four months. She had no personal or family history of TB. An ultrasound study showed a 2x1.5 cm mixed echogenic mass in the right adnexa. Based on her clinical and imaging findings which suggestive of ovarian cancer, the patient underwent panhystrectomy and bilateral salpingoophrectomy. The gross examination of the specimen revealed distended and coiled tubes with right adnexal mass measured 2x1.5 cm and dissection of the uterus revealed erythematous endometrium with yellowish secretions. The histopathologic assessment of right adnexal mass revealed malignant neoplasm *Granulosa cell tumor* formed of short polygonal cells arranged in diffuse sheets with patternless pattern. The malignant cells showed nuclear grooving. There was no necrosis or other ovarian neoplastic element. The histopathologic assessment of both tubes and endometrium revealed infiltration by multiple nodular granulomas. Each granuloma was formed of multinucleated giant cells and epithelioid cells rimmed by lymphocytes with occasional central caseation *genital tuberculosis*. Conclusion: The conclusion of this case report is to stress upon keeping genital TB in mind as a potential differential diagnosis for ovarian carcinoma.

Mesenchymal chondrosarcoma of the mandible: A case report

Mesenchymal chondrosarcoma as an aggressive type of chondrosarcoma shows a characteristic biphasic histopathologic pattern. The head and neck region is included a high proportion of extra skeletal sites. Very rare examples of Mesenchymal Chondrosarcoma involving the mandible have been described. Based on fragmented or tiny specimens, the diagnosis of this lesion has been re- mained a challenge because the specimens may contain only one of the two neoplastic elements. We report a rare case of mesenchymal chondrosarcoma of the mandible in a 19 years old male with delaying in diagnosis due to massive extension of the tumor to the soft tissues.

Computational augmentation of neoplastic endometrial glands in digital pathology displays.

The pathologic diagnosis of neoplasia requires localization and classification of lesional tissue, a process that depends on the recognition of an abnormal spatial distribution of neoplastic elements relative to admixed normal background tissue. In endometrial intraepithelial neoplasia (EIN), a pre-cancer usually managed by hysterectomy, a clonally mutated proliferation of cytologically altered glands ('neoplastic-EIN') aggregates in clusters that also contain background non-neoplastic glands ('background-NL'). Here, we used image analysis to classify individual glands within endometrial tissue fragments as neoplastic-EIN or background-NL, and we used the distribution of predictions to localize foci diagnostic of EIN. Nuclear coordinates were automatically assigned and were used as vertices to generate Delaunay triangulations for each gland. Graph statistical variables were used to develop random forest algorithms to classify glands as neoplastic-EIN or background-NL. Individual glands in an independent validation set were scored by a 'ground truth' biomarker (PAX2 immunohistochemistry). We found that exclusion of small glands led to improvement in classification accuracy. Using an inclusion threshold of 200 nuclei per gland, our final model classification accuracy was 77.5% in the validation set, with a positive predictive value of 0.81. We leveraged this high positive predictive value in a point cloud overlay display to assist end-user identification of EIN foci. This study demonstrates that graph theory approaches applied to small-scale anatomic elements in the endometrium allow biologic classification by machine learning, and that spatial superimposition over large-scale tissue expanses can have practical diagnostic utility. We expect this augmented diagnostic approach to be generalizable to commonly encountered problems in other organ systems. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Immune Checkpoint Ligand Reverse Signaling: Looking Back to Go Forward in Cancer Therapy.

The so-called immune checkpoints are pathways that regulate the timing and intensity of the immune response to avoid an excessive reaction and to protect the host from autoimmunity. Immune checkpoint inhibitors (ICIs) are designed to target the negative regulatory pathways of T cells, and they have been shown to restore anti-tumor immune functions and achieve considerable clinical results. Indeed, several clinical trials have reported durable clinical response in different tumor types, such as melanoma, renal cell carcinoma (RCC) and non-small cell lung cancer (NSCLC). Nonetheless, after the initial enthusiasm, it is now evident that the majority of patients do not benefit from ICIs, due to innate or acquired tumor resistance. It is therefore mandatory to find ways to identify those patients who will respond and to find ways to induce response in those who at present do not benefit from ICIs. In this regard, the expression of programmed death ligand 1 (PD-L1) on neoplastic cells was the first, and most obvious, biomarker exploited to predict the activity of anti-programmed death 1 (PD-1) and/or anti-PD-L1 antibodies. As expected, a correlation was confirmed between the levels of PD-L1 and the efficacy of anti-PD-1 therapy in melanoma, NSCLC and RCC. However, further results from clinical trials showed that some patients display a clinical response regardless of tumor cell PD-L1 expression levels, while others do not benefit from ICI treatment despite the expression of PD-L1 on neoplastic elements. These findings strongly support the notion that other factors may be relevant for the efficacy of ICI-based treatment regimens. Furthermore, although the current dogma indicates that the PD-1/PD-L1 axis exerts its regulatory effects via the signal transduced in PD-1-expressing T cells, recent evidence suggests that a reverse signaling may also exist downstream of PD-L1 in both tumor and immune cells. The reverse signaling of PD-L1, but also of other immune checkpoints, might contribute to the pro-tumoral/immune suppressive environment associated with tumor development and progression. Clarifying this aspect could facilitate the prediction of patients’ clinical outcomes, which are so far unpredictable and result in response, resistance or even hyper-progressive disease in some cases.

Immunohistochemical Expression of Autophagy-Related Proteins in Advanced Tubular Gastric Adenocarcinomas and Its Implications.

In neoplastic conditions, autophagy may act as a tumor suppressor avoiding the accumulation of damaged proteins and organelles or as a mechanism of cell survival promoting the tumor growth. Although ultrastructural analysis has been considered the traditional method to identify autophagy, some proteins such as microtubule-associated protein 1 light chain 3 (LC3A/B), Beclin-1 and activating molecule in Beclin-1-regulated autophagy protein-1 (AMBRA-1) may be considered as markers of autophagy-assisted cancerogenesis. Herein, we analyzed a cohort of advanced tubular gastric adenocarcinomas by the abovementioned immunohistochemical antisera; through immunohistochemistry, autophagy (A-IHC) is diagnosed when at least two out of the three proteins are positive in the samples. Immunostaining for LC3A/B, Beclin-1, and AMBRA-1 was exclusively found in neoplastic elements, but not in surrounding stromal cells. In detail, LC3A/B and Beclin 1 were expressed both in the cytoplasm and in the nucleus of the cancer cells, while AMBRA-1 was preferentially localized in the nucleus, mainly in high grade cases. LC3A/B, Beclin 1, and AMBRA-1 expression were positive in 18 (56.2%), 17 (53.1%), and 12 (37.5%) cases, respectively. The sensibility and specificity of LC3A/B and Beclin-1 ranged from 81.25% to 93.75%, with high efficiency (90.63%) for Beclin-1. Moreover, the ultrastructural autophagic index (AI) was also available in all cases. All high-grade cases documented a Ki-67 labelling index (LI) ≥ 30%, even if three low-grade cases revealed a high Ki-67 value; p53 positivity was encountered in 21/32 (65.62%) of cases, independently of the tumor grade. A statistically significant correlation among A-IHC and clinicopathological parameters such as grade, stage, clinical course, Ki-67 LI and AI was revealed. Univariate analysis documented a significant p-value for the same autophagic variables. Additionally, multivariate survival analysis identified the grade, AI and A-IHC as independent significant variables. Finally, the overall survival curves of all cases of gastric tubular adenocarcinoma were greatly dependent on A-IHC. Therefore, we suggest that autophagic-related proteins might be considered promising predictive prognostic factors of advanced gastric cancer. Further investigations may be required to determine whether new targeted therapies should be addressed to autophagy-related proteins.

A retrospective histological comparison of EUS-guided fine-needle biopsy using a novel franseen needle and a conventional end-cut type needle.

Background and Objectives:Recently, a 22G Franseen needle for EUS-guided fine-needle biopsy (EUS-FNB) with three novel symmetric heels has been developed to adequately obtain a core tissue.Methods:All 38 consecutive patients with pancreatic masses who underwent EUS-FNB using a Franseen needle were investigated retrospectively to assess the efficacy and safety of EUS-FNB using the Franseen needle. Then, the EUS-FNB outcomes and histological assessments of the tissue obtained by EUS-FNB using the Franseen needle and EUS-FNA using the conventional end-cut type needle for each of the 30 pancreatic ductal adenocarcinoma cases were compared.Results:An accurate histological diagnosis of the Franseen needle was achieved with a mean of 2 passes in 97.4% of patients. Although the accurate histological diagnosis rate of pancreatic ductal adenocarcinoma was not significantly different (96.7% vs. 93.3%, P = 0.55), the mean number of passes in the Franseen needle was significantly less than that in the conventional needle (2.1 ± 0.4 vs. 3.2 ± 0.8, P < 0.001). The presence of desmoplastic fibrosis with neoplastic cellular elements and venous invasion were significantly higher (96.7% vs. 40.0%, P < 0.001 and 23.3% vs. 0%, P < 0.01, respectively) and the amount of obtained tissue was significantly larger with the Franseen needle (2.13 mm2 vs. 0.45 mm2, P < 0.001).Conclusions:EUS-FNB using the Franseen needle enables the acquisition of a larger amount of tissue sample and achieves an accurate histological diagnosis with a smaller number of passes than the conventional end-cut type needle.

Primary peritoneal malignant mixed mesodermal (Müllerian) tumor.

Malignant mixed mesodermal tumor (MMMT) is a biphasic neoplasm (carcinosarcoma) composed of both epithelial and mesenchymal elements. Extragenital MMMT, including primary peritoneal MMMT, is an extremely rare tumor with features consistent with its origin from the secondary Müllerian system. The neoplastic elements of extragenital MMMT presumably arise directly from the mesothelium or submesothelial stroma and hence parallel the biphasic pattern of the genital (uterine or ovarian) counterpart. Here we report on the clinical, pathological, and immunohistochemical features of a case of peritoneal MMMT in a 65-year-old woman. The patient presented with abdominal fullness and pain. Gynecological examination revealed a huge pelvic abdominal mass. On histology, the tumor consisted of poorly differentiated carcinomatous and sarcomatous (rhabdomyosarcoma) components. Further immunohistochemical analysis revealed positive reactivity for both epithelial (cytokeratin and epithelial membrane antigen) and mesenchymal (vimentin, S-100, and desmin) markers. The patient refused treatment and died of the disease three months later. Based on the present case and on previous studies, primary peritoneal MMMT seems to be a rare but highly malignant neoplasm with an aggressive behavior and poor prognosis. Its exact origin, histogenesis and molecular alterations are poorly understood.

A rare presentation of Retiform Hemangioendothelioma in sacral area

Retiform Hemangioendothelioma is an extremely rare tumor. It was first explained by Calonje et al in 1994. It is a vascular neoplasm of borderline malignancy, mostly seen in young age, and extremities. A 65 years old female patient presented with a recurrent growth in the sacral region, along with skin ulceration. FNAC revealed a cystic lesion with inflammation. Previous biopsy showed granulation tissue only. The growth was surgically removed for the third time and sent to Histopathology lab. Gross examination revealed a partial skin covered tissue mass of 15x10x3 cm. Cut section showed solid cystic growth of 2x2x1.5 cm. Microscopically, proliferating neoplastic elements, vascular in nature, in a net like pattern seen. Monomorphic cells with scant cytoplasm with hobnail nuclei lined the vessels. Scant mitotic figures, lymphocytic infiltration, and focal fibrocollagenous material were seen. Dermis was focally involved. On immunohistochemistry, Ki-67 (low proliferation) and CD 34 were positive. Hence the diagnosis of Retiform Hemangioendothelioma was made.

Carcinoma of the breast occurring during pregnancy

1.- Seventy-four cases of breast cancer have been observed in the Tumor Clinic of Hospital San Juan de Dios, in San Jose, Costa Rica. Two of these were cases of mammary carcinoma occuring during pregnancy. Including one other private case, such cases form only 4.05 per cent of the total incidence of breast carcinoma. The authors present the clinical history o f two patients, and other some considerations on the development of the clinical picture and the palliative treatment given. 2.- The malignancy of gestational mammary carcinoma is considered by the authors as due in part to: a) the normal histological modification of the mammary glands during preg­nancy, favoring karyokinesis of neoplastic elements; b) the effect of the hormonal component formed by ovarian and placental hormones, the latter being especially important. The fact that patients are usually relatively young, in full hormonal activity, is also significant in this respect; c) the increase in blood supply of the breast during pregnancy, increasing the possibility of circulatory metastasis as is shown by the frequency of bone metastasis at an early date. The increased blood supply, besides, constitutes a greater pabulum vitae for malignant cells; d) the difficulty of early diagnosis of the tumor, the latter being masked by the natural increase in the turgidity of the breast and to the disregard of the observed changes by the patient, who relates them to her pregnant condition. 3.-In the light of BURT and CASTLEMAN'S report of pituitary cytolo­gical modifications in breast cancer patients the authors consider oophorectomy, of little value as a palliative treatment in cases of mammary carcinoma ocurring during pregnancy, because of the increased production of estrogens by the suprarenals caused by a corticohypophysiary compensatory stimulus. On the other hand, oophorectomy is considered advisable in cases of mammary carcinoma ocurring in young prerrienopausic women, in order to eliminate the danger of placental endocrine stimulation in the event of pregnancy after mastectomy. 4.- The presence of multiple follicular cysts in the ovaries of one patient suggests the need of further investigation of this condition, its occurence and significance in cases of mammary carcinoma in general and particulary in ges­tational cases.

Whole tumor RNA-sequencing and deconvolution reveal a clinically-prognostic PTEN/PI3K-regulated glioma transcriptional signature.

The concept that solid tumors are maintained by a productive interplay between neoplastic and non-neoplastic elements has gained traction with the demonstration that stromal fibroblasts and immune system cells dictate cancer development and progression. While less studied, brain tumor (glioma) biology is likewise influenced by non-neoplastic immune system cells (macrophages and microglia) which interact with neoplastic glioma cells to create a unique physiological state (glioma ecosystem) distinct from that found in the normal tissue. To explore this neoplastic ground state, we leveraged several preclinical mouse models of neurofibromatosis type 1 (NF1) optic glioma, a low-grade astrocytoma whose formation and maintenance requires productive interactions between non-neoplastic and neoplastic cells, and employed whole tumor RNA-sequencing and mathematical deconvolution strategies to characterize this low-grade glioma ecosystem as an aggregate of cellular and acellular elements. Using this approach, we demonstrate that optic gliomas generated by altering the germline Nf1 gene mutation, the glioma cell of origin, or the presence of co-existing genetic alterations represent molecularly-distinct tumors. However, these optic glioma tumors share a 25-gene core signature, not found in normal optic nerve, that is normalized by microglia inhibition (minocycline), but not conventional (carboplatin) or molecularly-targeted (rapamycin) chemotherapy. Lastly, we identify a genetic signature conferred by Pten reduction and corrected by PI3K inhibition. This signature predicts progression-free survival in patients with either low-grade or high-grade glioma. Collectively, these findings support the concept that gliomas are composite ecological systems whose biology and response to therapy may be best defined by examining the tumor as a whole.

Abstract 3542: Abnormal intracytoplasmic accumulation of autophagy-related protein p62/SQSTM1 characterizes giant cells of giant cell tumor of bone

Abstract Background Giant cell tumors of bone (GCTs) are locally aggressive neoplasms composed of osteoclast-like giant cells and mononuclear cells. Mononuclear cells are accepted as true neoplastic elements, while osteoclast-like giant cells are non-neoplastic. However, close interaction between two cellular populations is indispensable for tumor formation. Large giant cells with hypermultinucleation of GCT are distinct from normal osteoclasts; however, their abnormality has not yet been sufficiently investigated. Recently, a germline mutation of the gene encoding autophagy-related protein p62/SQSTM1 was reported in Paget disease of bone, which implicates a role of autophagy in the differentiation and function of osteoclasts. In order to understand the relationship between autophagy and osteoclastogenesis in giant cell lesions, we studied clinical samples of GCTs and related tumors for immunoexpression of p62 (an autophagy flux marker), LC3 (an autophagosome marker), and Cathepsin K (a known osteoclastic marker). Design Formalin-fixed paraffin-embedded specimens of 46 GCTs, 17 chondroblastomas (CBLs), 3 giant cell reparative granulomata (GRGs), 3 chondromyxoid fibromas (CMFs) and one each of aneurysmal bone cyst (ABC) and brown tumor (BRT) were retrieved. Immunohistochemistry was performed by using antibodies against p62, LC3, and Cathepsin K. Results were scored as 3+ (strongly positive in ≥50% of cells), 1+ (weakly positive in &amp;lt;10% of cells), 2+ (intermediate between 1+ and 2+), or 0 (negative). Giant cells and mononuclear cells were separately evaluated for nuclear and cytoplasmic staining. Results For giant cells, p62 was positive in a dot-like manner in all tumor types. Strong (3+) staining was found in nuclei and/or cytoplasms in GCTs (27/46, 59%), CBLs (14/17, 82%), GRGs (2/3, 67%), and other lesions (5/5, 100%). In addition, abnormal intracytoplasmic coarse aggregates were specifically noted in GCTs (21/46, 46%) and CBLs (3/17, 18%). In contrast, mononuclear cells showed a lower prevalence of 3+ p62 positivity in GCTs (2/46, 4%), CBLs (5/17, 29%), and an ABC (1/1), where positive cells were only presumable osteoclastic precursor cells around giant cells. LC3 showed a limited cytoplasmic 3+ positivity in giant cells of GCTs (6/46, 13%), CBLs (7/17, 41%), CMFs (1/3, 33%), and BRT (1/1). Cytoplasmic staining of Cathepsin K was constantly observed in giant cells. Conclusion Abnormal intracytoplasmic accumulation of p62 in a form of coarse staining aggregate characterizes giant cells of GCTs and CBLs. This finding may be a potential diagnostic marker for distinguishing GCTs and CBLs from other giant cell lesions. The presence of these p62 aggregates and low LC3 expression may indicate disturbance of autophagy-driven protein clearance. As p62 immunostain recognizes a wider osteoclastic population than Cathepsin K, p62 may be involved in abnormal osteoclastogenesis. Citation Format: Toru Motoi, Akihiko Yoshida, Noriko Motoi, Ikuma Kato, Tomotake Okuma, Akiko Tonooka, Shinichiro Horiguchi, Takahiro Goto, Tsunekazu Hishima. Abnormal intracytoplasmic accumulation of autophagy-related protein p62/SQSTM1 characterizes giant cells of giant cell tumor of bone. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3542.

Adenosarcoma Mulleri Associated with Tamoxifen use after Breast Cancer Therapy: A Case Report

Abstract The term ‘mixed Mullerian tumour’ applies to uterine tumours composed of epithelial and mesenchymal elements of Mullerian origin. These neoplasms are classified into adenomyomas, adenofi bromas, adenosarcomas, and carcinosarcomas (malignant Mullerian mixed tumours) based on whether the epithelial and stromal elements are benign or malignant. Adenosarcomas are low-grade neoplasms classified halfway along the spectrum of mixed Mullerian tumours, with adenofi bromas at one end and carcinosarcomas (malignant Mullerian mixed tumours) at the other. Adenosarcoma is a mixed Mullerian tumour composed of benignappearing but neoplastic glandular elements and a sarcomatous stroma, which is usually low grade. Histologically, there are heterologous mesenchymal elements (usually rhabdomyosarcoma, but also cartilage, fat, and other elements) in 20-25% of cases. We have observed that some women with these tumours have received tamoxifen treatment for breast cancer or have a history of radiation therapy. We herein report the case of a 46-year-old patient who was hospitalized at OGC CC Kragujevac because of excessive bleeding from the uterus. The patient had undergone right mastectomy three years earlier for breast cancer. After surgery, she had received Nolvadex (tamoxifen) treatment. Exploratory curettage was performed, and then, a classic abdominal hysterectomy with bilateral adnexectomy was completed. The histopathological findings indicated adenosarcoma Mulleri; therefore, the patient received postoperative radiation therapy according to our current protocol.

How do I diagnose Extramedullary Hematopoiesis

Extramedullary hematopoiesis occurs in bone marrow disorders and is most commonly seen in thalassemia and myelofibrosis. We present a case of a 58 year-old male, with a history of thalassemia, which presented with a para-vertebral mass composed of hematopoietic tissue. When considering the differential diagnosis, a primary concern was an extramedullary proliferation of neoplastic hematopoietic elements, like extramedullary myeloid sarcoma. Neoplastic extramedullary proliferations can consist of triline age marrow elements and closely mimic the appearance of benign extramedullary hematopoiesis. The morphologic appearance may be a diagnostic clue, but cannot be completely relied upon.