High endothelial venules in the pleura: MECA-79 expression in mesothelioma, pleural metastasis and pleuritis.

INTRODUCTION: High endothelial venules (HEVs) are vessels specialized in the extravasation of lymphocytes from the blood to the tissue implicated in the immune microenvironment of several tumors. Their presence has been never studied in the pleural tissue. MATERIAL AND METHODS: We retrospectively studied 149 surgical pleural biopsies by immunohistochemistry for MECA-79 expression, a marker specifically recognizing HEVs. The tissues included 44 (44 %) inflammatory and 105 (56 %) neoplastic diseases. The latter corresponded to 34 (22.8 %) mesotheliomas and 71 (47.7 %) metastases from lung (n=50) or breast (n=21) primaries. RESULTS: HEVs were present in 102 (68 %) of all pleural specimens with a mean number of foci containing HEVs of 13.33 (±20.64). Neoplastic pleural pathologies harbored HEVs in 73.3 % of the cases compared to the non-neoplastic pathologies which harbored HEVs in 56.8 % of the cases (p=0.048). Their presence did not differ between pulmonary or mammary metastasis (p=0.7). CONCLUSION: We show for the first time that HEVs are present in the pleural cavity probably participating in the immune microenvironment of inflammatory and neoplastic pleural disease.

Artefacts in Hysterectomies with a Special Focus on Vascular Pseudoinvasion.

BACKGROUND: Since the advent of laparoscopic hysterectomy, several studies have described artefacts, such as vascular pseudoinvasion, constituting potential pitfalls in the histological evaluation of these specimens. The use of an intrauterine manipulator is often suggested as the factor creating these artefacts. OBJECTIVES: To describe possible artefacts, such as vascular pseudoinvasion, myometrial clefts, and tumor cells in the lumen of the cervix, on the serosa, and in the tubal lumen, and to correlate them with clinical and pathological characteristics. MATERIAL AND METHODS: This is a retrospective monocentric study of 60 patients having been treated for benign (n = 27, 45%) or malignant (n = 33, 55%) uterine pathologies. RESULTS: Vascular pseudoinvasion was found in 13 (22%) adenocarcinomas and in one (2%) benign uterine pathology. Clefts within the myometrium were observed in 16 (27%) uteri. Cells in the tubal lumen were observed in six (10%) hysterectomies. True vascular emboli were not correlated with the use of an intrauterine manipulator (p = 0.47) or the type of surgery (p = 0.21). Vascular pseudoinvasion was correlated with the presence of tumor cells in the lumen of the cervix (p = 0.013) and the presence of clefts in the myometrium (p < 0.001), but not with the other factors studied. CONCLUSIONS: Overall, in our series, we did not observe any statistical association between the use of an intrauterine manipulator and the presence of true emboli or vascular pseudoinvasion during hysterectomy in women with malignant or benign uterine pathologies. Vascular pseudoinvasion was also associated with the presence of other artefacts.

Immunohistochemical characteristics of uterine lipoleiomyomas.

Lipoleiomyomas are rare variants of uterine leiomyomas rarely studied in the literature. We retrospectively studied 20 cases of uterine lipoleiomyomas showing that these lesions represent 0.7 % of all uterine leiomyomas diagnosed histologically. The patients did not experience any recurrence, and the tumors showed no morphological criteria of malignancy. They did not show significant p16, p53 or MiB1 expression. They showed diffuse and strong expression or estrogen and progesterone receptors by the smooth muscle component but without accompanying expression by the adipocytic component in one third of the cases. Androgen receptors were rarely expressed. They expressed in their majority HMGA2 in both components, while RB1 was usually not found. Fumarate hydratase (FH) is expressed by lipoleiomyomas, while they are negative for HMB45. In conclusion, uterine lipoleiomyomas are rare, benign tumors, characterized by HMGA2 expression, while they show no elements suspicious of malignancy, PEComas or FH deficiency. The role of RB1 in these tumors should be further explored.

The immune microenvironment of cancer of the uterine cervix.

While several treatment choices exist for cervical cancer, such as surgical therapy, chemotherapy, and radiotherapy, some patients will still show poor prognosis. HPV infection is a principal factor for cervical cancer development, from early inflammation to proliferation, angiogenesis, and neoplastic growth. While HPV T-cell responses exist, the tumor seems to evade the immune system upon its tolerance. The latter suggests the existence of a confluent tumor microenvironment responsible for the evasion tactics employed by the neoplasm. Therefore, novel biomarkers governing prognosis and treatment planning must be developed, with several studies tackling the significance of the tumor microenvironment in the genesis, development, proliferation, and overall response of cervical cancer during neoplastic processes. This review aims to analyze and contemplate the characteristics of the tumor microenvironment and its role in prognosis, progression, evasion, and invasion, including therapeutic outcome and overall survival.

The detailed histopathological characteristics of ovarian fibroma compared with thecoma, granulosa cell tumor, and sclerosing stromal tumor.

BACKGROUND: Ovarian fibromas are benign tumors that can present peculiar morphological features not studied sufficiently. MATERIAL AND METHODS: In this retrospective study, 75 consecutive cases of ovarian fibroma were morphologically compared with 46 thecomas, 16 granulosa cell tumors, and 5 sclerosing stroma tumors for the following factors: the growth pattern as diffuse or nodular, the presence of hyaline plaques, necrosis, keloid-like sclerosis, calcifications, cystic degeneration, fibrous or edematous stroma, prominent vascularity, lutein cells, cellularity, scant or abundant cytoplasm, prominent cell membranes, nuclear grooves, atypia, and mitotic activity. RESULTS: The tumors differed significantly in terms of hyaline plaques presence, nuclear grooves, growth pattern, stroma type, tumor cellularity, cytoplasm, prominence of cell membranes, atypia, mitotic activity, and prominent vascularity. CONCLUSION: Ovarian fibromas can present some maybe unexpected features rather frequently, such as cystic degeneration, hyaline plaques, prominent vascularity, increased cellularity, and some mitotic activity, thus their presence should not always prompt to an alternative diagnosis.

Immunohistochemical and Molecular Characteristics of Anogenital Papillary Hidradenomas.

BACKGROUND: Papillary hidradenomas (PHs) of the anogenital region are uncommon tumors whose immunohistochemical and molecular profile have been infrequently studied. MATERIAL AND METHODS: We studied 15 PHs by next-generation sequencing and 10 immunohistochemical markers (PAX8, GATA3, HER2, MSH6, PMS2, estrogen, progesterone and androgen receptors, CK14, and NKX3.1). RESULTS: All cases expressed GATA3, whereas none expressed PAX8, and rare tumor cells were NKX3.1-positive. Almost all cases expressed estrogen receptors (ER), progesteron receptors (PR), and androgen receptors (AR). CK14 was expressed by myoepithelial cells, whereas only rarely by the epithelial tumor cells. HER2 showed no significant expression. Immunohistochemical expression for the mismatch repair proteins showed persistence in all cases. Molecular analysis often showed PIK3CA mutations, as well as KRAS , SMO , and MAP2K1 mutations. CONCLUSION: Anogenital PHs frequently harbor PIK3CA mutations and show a PAX8-, GATA3/ER/PR/AR + immunohistochemical profile.

Gastrointestinal Tactile Corpuscle-Like Bodies: Report of Two Cases and Review of the Literature.

Gastrointestinal tactile corpuscle-like bodies are a rare, incidental, entirely benign finding. It is mainly reported in the colorectum and esophagus/gastro-esophageal junction. Rare cases have been documented in the stomach. Here, we present two cases of gastric and colonic tactile corpuscle-like bodies of a 38-year-old female and a 55-year-old male, respectively. Endoscopically, the colonic lesion was resected as an adenomatous polyp, while the gastric biopsies were taken to rule out Helicobacter pylori (H. pylori) gastritis. Microscopically, both specimens revealed the same histopathologic aspects of eosinophilic fibrillary material with round to oval cells and peripherally placed nuclei. Immunohistochemically, these lesions were positive for anti-S100, confirming the diagnosis of tactile corpuscle-like bodies. A thorough literature review is provided.

Uterine inflammatory myofibroblastic tumor with THBS1-INSR fusion.

Uterine inflammatory myofibroblastic tumors (IMTs) are rare and, as in other localisations, they are associated with ALK rearrangements and ALK immunohistochemical expression. They are more frequently found during pregnancy, and in this context, they show different characteristics compared to other uterine IMTs. Here, we report the case of a uterine IMT discovered during delivery, and being associated with a previously unreported THBS1-INSR fusion.

The Premetastatic Lymph Node Niche in Gynecologic Cancer.

It has been suggested that a primary tumor can "prepare" the draining of lymph nodes to "better accommodate" future metastatic cells, thus implying the presence of a premetastatic lymph node niche. However, this phenomenon remains unclear in gynecological cancers. The aim of this study was to evaluate lymph-node draining in gynecological cancers for premetastatic niche factors, such as myeloid-derived suppressor cells (MDSCs), immunosuppressive macrophages, cytotoxic T cells, immuno-modulatory molecules, and factors of the extracellular matrix. This is a monocentric retrospective study of patients who underwent lymph-node excision during their gynecological-cancer treatment. In all, 63 non-metastatic pelvic or inguinal lymph nodes, 25 non-metastatic para-aortic lymph nodes, 13 metastatic lymph nodes, and 21 non-cancer-associated lymph nodes (normal controls) were compared for the immunohistochemical presence of CD8 cytotoxic T cells, CD163 M2 macrophages, S100A8/A9 MDSCs, PD-L1+ immune cells, and tenascin-C, which is a matrix remodeling factor. PD-L1-positive immune cells were significantly higher in the control group, in comparison to the regional and distant cancer-draining lymph nodes. Tenascin-C was higher in metastatic lymph nodes than in both non-metastatic nodes and control lymph nodes. Vulvar cancer-draining lymph nodes showed higher PD-L1 values than endometrial cancer and cervical cancer-draining lymph nodes. Endometrial cancer-draining nodes had higher CD163 values and lower CD8 values, compared to vulvar cancer-draining nodes. Regarding regional draining nodes in low- and high-grade endometrial tumors, the former showed lower S100A8/A9 and CD163 values. Gynecological cancer-draining lymph nodes are generally immunocompetent, but vulvar cancer draining nodes, as well as high-grade endometrial cancer draining nodes, are more susceptible to harboring premetastatic niche factors.

Crystal-Storing Histiocytosis: The Iceberg of More Serious Conditions.

Crystal-storing histiocytosis is a rare condition that is histologically characterized by intracellular cytoplasmic crystalline inclusions. It usually presents monoclonal immunoglobulins that deposit within histiocytes, which accumulate and affect different organs of the human body and are commonly associated with lymphoproliferative conditions, especially those with plasmacytic differentiation. The prognosis of this condition is variable and related to the underlying clinical disease. In this review article, we aim to describe and discuss the clinical and pathological characteristics of crystal-storing histiocytosis based on the available literature and to provide a thorough differential diagnosis.

Uterine inflammatory myofibroblastic tumor.

Inflammatory myofibroblastic tumor (IMT) is recognized as a true neoplasm of unknown etiology, but its pathogenesis is related to abnormalities in the ALK gene. This is an uncommon tumor with a wide anatomic distribution and often constitutes a challenging diagnosis owing to its histological similarities with other tumors. Uterine IMTs are rare and their detailed characteristics should be described based on case reports and small case series. Thus, we performed a comprehensive review of the literature showing that uterine IMTs show a wide range of age at diagnosis (median, 39 years), and a symptomatology similar to that of common leiomyomas, only rarely presenting with inflammatory manifestations. IMTs represent 0.1% of "leiomyomas," an estimate that increases to 10% for pregnant women and to 14% for the smooth muscle tumors of uncertain malignant potential (STUMP) category of tumors, implying that tumors excised during pregnancy, STUMPs, and leiomyosarcomas should be systematically screened with ALK immunohistochemistry, as this is a targetable abnormality. Most reported cases are ALK-positive; the fusion partners vary, but in pregnancy-associated tumors, TIMP3 prevails. Almost 25% of the patients will show an aggressive course, and this is associated with older age, non-pregnancy-associated tumors, larger tumors, infiltrative tumor border, absence of abundant inflammation, atypia, important mitotic activity, and necrosis.

Primary endometrial gastric (gastro-intestinal)-type carcinoma: A practical approach.

The latest WHO classification of the female genital tract tumors introduces a new type of carcinoma: the primary gastric-type (or gastro-intestinal type) carcinoma of the endometrium. This type of neoplasm tends to have a poor outcome, making its correct diagnostic important. As little is known about this entity and given its quite challenging diagnosis, we aim to review existing data about it and propose a practical diagnostic approach. There are currently 11 cases published in 8 articles fitting the precise definition of a primary gastric-type carcinoma of the endometrium. Three main differential diagnoses must be excluded before considering this tumor: endometrioid adenocarcinoma with mucinous (Müllerian-type) differentiation, endocervical primary, and gastro-intestinal primary. Morphological aspects of this tumor can be heterogeneous and confusing; in this context, immunochemistry can be helpful to highlight the gastric or intestinal differentiation, but also to eliminate a mucinous endometrioid adenocarcinoma of Müllerian-type, by the constant negativity of estrogen receptors. A metastasis of a primary gastro-intestinal tract carcinoma must also be excluded by clinical, endoscopic and imaging work-up. Finally, an endometrial extension of a primary endocervical gastric-type carcinoma should be ruled out by complete sampling of the cervix. Intestinal type endocervical adenocarcinoma is easier to eliminate since this is an HPV-associated neoplasm.

Death due to unsuspected acute myeloid leukaemia: an unusual forensic diagnosis.

Acute myeloid leukaemia (AML) is a rare haematologic cancer with a rapid increase in blast cells, which need to be rapidly diagnosed and treated. The aim of this report is to analyse the rare phenomenon of AML diagnosed at autopsy after sudden death. We report three cases of AML and perform a literature review using the mesh terms "sudden death" and "leukaemia". We report the cases of three young women diagnosed with AML only after autopsy. We found seven articles which reported sudden death due to AML diagnosed at autopsy. Diagnosis of AML during autopsy is rare but can raise forensic issues. A complete autopsy with pathology analysis is needed.

The Presence of the Autophagic Markers LC3B and Sequestosome 1/p62 in the Hydatidiform Mole.

Autophagy is implicated in normal pregnancy and various pathologic pregnancy conditions. Its presence in hydatidiform moles (HM) is unknown. We immunohistochemically studied 36 HM for LC3B and p62 to precisely determine their expression in the decidua, endometrium, and villi. Nineteen nonmolar pregnancies were also studied. LC3B was found in almost half of the villi and p62 was found in almost all villi. LC3B expression was significantly higher in complete HM than in partial HM. LC3B showed different expression patterns in trophoblast layers. LC3B and p62 expression was higher in molar than nonmolar pregnancies. Autophagic markers are present in HM and their expression differs between complete and partial moles.

EGFR-dependent aerotaxis is a common trait of breast tumour cells.

BACKGROUND: Aerotaxis, the chemotactism to oxygen, is well documented in prokaryotes. We previously reported for the first time that non-tumorigenic breast epithelial cells also display unequivocal directional migration towards oxygen. This process is independent of the hypoxia-inducible factor (HIF)/prolyl hydroxylase domain (PHD) pathway but controlled by the redox regulation of epidermal growth factor receptor (EGFR), with a reactive oxygen species (ROS) gradient overlapping the oxygen gradient at low oxygen concentration. Since hypoxia is an acknowledged hallmark of cancers, we addressed the putative contribution of aerotaxis to cancer metastasis by studying the directed migration of cancer cells from an hypoxic environment towards nearby oxygen sources, modelling the in vivo migration of cancer cells towards blood capillaries. METHODS: We subjected to the aerotactic test described in our previous papers cells isolated from fresh breast tumours analysed by the Pathology Department of the Saint-Etienne University Hospital (France) over a year. The main selection criterion, aside from patient consent, was the size of the tumour, which had to be large enough to perform the aerotactic tests without compromising routine diagnostic tests. Finally, we compared the aerotactic properties of these primary cells with those of commonly available breast cancer cell lines. RESULTS: We show that cells freshly isolated from sixteen human breast tumour biopsies, representative of various histological characteristics and grades, are endowed with strong aerotactic properties similar to normal mammary epithelial cell lines. Strikingly, aerotaxis of these primary cancerous cells is also strongly dependent on both EGFR activation and ROS. In addition, we demonstrate that aerotaxis can trigger directional invasion of tumour cells within the extracellular matrix contrary to normal mammary epithelial cells. This contrasts with results obtained with breast cancer cell lines, in which aerotactic properties were either retained or impaired, and in some cases, even lost during the establishment of these cell lines. CONCLUSIONS: Altogether, our results support that aerotaxis may play an important role in breast tumour metastasis. In view of these findings, we discuss the prospects for combating metastatic spread. TRIAL REGISTRATION: IRBN1462021/CHUSTE.

PD-L1 expression in head and neck cancer tissue specimens decreases with time.

BACKGROUND: PD-L1 immunohistochemical expression is used as an important theranostic marker in various malignancies, including head and neck squamous cell carcinoma (HNSCC) where the combined positive score (CPS) guides treatment decisions. Despite indirect evidence that there is loss of antigenicity for archived tissues, there is no direct comparison between PD-L1 expression of the same tissue upon arrival and after its storage. MATERIAL AND METHODS: We compared the immunohistochemical expression of PD-L1 (22C3) in 106 HNSCC upon their arrival and after their storage (interval ranging from 20 to 48 months, mean 30.8 months). The evaluation was performed by two different pathologists' groups. RESULTS: We found a statistically significant decrease in the PD-L1 tumor proportional score (TPS), immune cells expression (IC) and CPS between the initial and the newly stained slides. CONCLUSION: This is the first study comparing PD-L1 expression between a tissue and "himself" later in time, highlighting an important decrease in expression by tumor and immune cells, and suggesting that an immediate rather than a retrospective assay of PD-L1 expression should be preferable in the routine practice. DATA AVAILABILITY: Data are available upon reasonable request.

Pathological Analysis and Clinical Evolution After Radiological Removal of Retrievable Vena Cava Filters.

OBJECTIVE: Retrievable inferior vena cava filters (IVCF) have been developed because permanent filters have been associated with an increased risk of recurrent deep venous thrombosis. There is no data on the interactions of IVCF with the inferior vena cava (intrafilter thrombi, insertion through the venous wall) even though this may alter the course after retrieval of the IVCF. METHODS: A review of 85 consecutive patients undergoing retrieval of IVCF placed at a single center was performed from January 1, 2010 and December 31, 2014. Inferior vena cava filter were examined for presence of intrafilter thrombus at time of retrieval. Filter position and presence of intraluminal thrombus were examined. Patient outcomes, including recurrence of deep vein thrombosis (DVT) and death, were captured at 3 month followup. RESULTS: Eighty five patients were identified, with intrafilter thrombi found in 69 (81%) patients and venous wall fragments found in 75 (88%) patients. However, their presence was not associated with an increased risk of recurrent venous thromboembolism (VTE) or death during follow up. CONCLUSIONS: Intrafilter thrombi and venous wall fragments are frequently found in removed IVCF but are not associated with a worse prognosis. They may not modify the therapeutic management of patients.

Autophagic factors in Paget disease.

BACKGROUND: Despite autophagy being a principal mechanism of tumor progression, its role has been never studied in Paget disease, a difficult to treat intraepithelial neoplasia affecting mainly the breast and the vulvar regions. MATERIAL AND METHODS: Twenty seven cases (17 extramammary and 10 mammary) of Paget disease were immunohistochemically studied for the expression of the two principal autophagic factors, LC3B and p62. RESULTS: The majority of Paget diseases showed strong cytoplasmic expression of p62 in contrast to nearby keratinocytes which presented nuclear-only p62 staining. LC3B was negative or only mildly positive in neoplastic cells. No difference was seen between mammary and extramammary cases. CONCLUSION: The immunohistochemical autophagic profile of Paget disease suggests a down-regulated autophagic process which, thus, may be implicated in the invasive potential of these cells.

Autophagy and cellular senescence in classical Hodgkin lymphoma.

Autophagy and cellular senescence are interrelated cellular stress responses important for cellular homeostasis and they have been implicated in the pathogenesis of classical Hodgkin lymphoma (cHL). However, the presence of autophagy and cellular senescence and their relation with clinical and laboratory parameters needs further elucidation. Thus, autophagy (LC3B and p62 immunohistochemical expression) and cellular senescence (p16 immunohistochemical expression and SenTraGor™ staining) were studied in tissue sections from 59 patients with cHL. Autophagy and cellular senescence-associated markers were detected in variable proportions of Hodgkin and Reed-Sternberg (HRS) cells in cHL cases. High nuclear p62 immunohistochemical expression in HRS cells showed significant positive correlation with relapse of the disease (p = 0.037). Heterogeneous autophagy and cellular senescence patterns were revealed in HRS cells suggesting biological heterogeneity of cHL. The detection of high nuclear p62 expression in HRS cells may identify a subset of cHL with more aggressive clinical behavior.