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.

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.

Villoglandular Pattern in HPV-associated Endocervical Adenocarcinoma is Associated With Excellent Prognosis: A Reappraisal of 31 Cases Using IECC and Silva Pattern Classification.

Villoglandular adenocarcinoma of the cervix is a rare histologic entity that typically develops in young women, characterized by an association with oral contraceptives and excellent prognosis, though this point is controversial. These tumors have not been studied in the context of the International Endocervical Adenocarcinoma Criteria and Classification (IECC) or Silva Pattern Classification. We analyzed 31 cases that met strict diagnostic criteria, including being completely excised with negative margins. These were categorized according to IECC and Silva Pattern Classification and the association with various pathologic parameters analyzed. Most patients were young with a mean age of 41.1 (range 25-79). There were 14 (45.2%) pattern A, 11 (35.5%) pattern B, and 6 (19.3%) pattern C cases. Only 1 of 22 patients (4.5%) presented with lymph node metastasis at the time of diagnosis (pattern C, stage IB1) and 3 (9.7%) had lymphovascular invasion (2 pattern C, 1 pattern B). Overall survival was 100%, while recurrence-free survival was 96.2% for the entire cohort with only 1 case (3.2%) recurring 25 mo after surgery (IB2, pattern B). Kaplan Meier analysis (log rank test) revealed no significant correlation for recurrence-free survival at 5 and 10 yr associated with depth of invasion, tumor size, Silva pattern, FIGO stage, lymphovascular invasion, or lymph node metastasis. Cox univariate analysis demonstrated no independent prognostic factors predicting recurrence-free survival. These results indicate that completely excised villoglandular adenocarcinoma generally has an excellent prognosis and when Silva Pattern Classification is applied, those tumors that potentially have a higher chance for adverse outcomes can be identified.

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.

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.

Florid Lymphoid Hyperplasia or Lymphoma-like Lesion of the Lower Genital Tract: A 35-Year Literature Review in View of the New WHO Classification.

Florid lymphoid hyperplasias of the lower female genital tract, also known as pseudolymphoma or lymphoma-like lesions, are benign lesions displaying histologic features which mimic aggressive B-cell lymphomas. Initially described by Young and colleagues in 1985, fewer than 100 cases have been published, making this lesion rather uncommon and subject to misdiagnoses. However, given that this entity has now been included in the World Health Organization's most recent classification, greater clarity would be beneficial for pathologists and physicians. Thus, our report aims to review these entities and provide all available data. We reviewed the available literature according to PRISMA guidelines. We found that lymphoma-like lesions, regardless of their localization, display numerous superficial lymphoid B cells admixed with a polymorphic small lymphocytic and plasmocytic background and, sometimes, superficial ulceration. Large lymphoid cells show prominent nucleoli and mitotic figures. Immunohistochemistry can usually exclude large cell lymphomas, such as high-grade follicular lymphoma and Burkitt lymphoma, when a starry sky pattern is found, as well as Hodgkin Lymphoma; however, the exclusion of diffuse large B-cell lymphoma or marginal zone lymphoma is more difficult. Explorations seeking infectious agents may show Epstein-Barr virus or, rarely, Borrelia burgdorferi involvement. Molecular study occasionally finds a monoclonal B-cell population, but without the subsequent follow-up which would otherwise be worrisome. Despite its somewhat aggressive histologic features, the benignity of this entity must be highlighted to avoid misdiagnosis and complications due to overtreating.

Two years progression-free survival under vinorelbine metronomic therapy of a patient with metastatic epithelioid hemangioendothelioma.

Epithelioid hemangioendothelioma (EHE) is a very rare vascular tumor, originating from endothelial cells. The etiology of EHE is unknown, yet at the molecular level, different angiogenic stimulators may act as promoters of endothelial cell proliferation. The tumor affects more commonly the lung, the liver and the bones but it can affect any other organ. Due to its heterogeneous presentation and its rarity it is often misdiagnosed. No treatment is proved to be efficient in metastatic EHE and the median survival of patients with metastatic pleural disease is generally poor, less than one year. we report a case of a 57-year-old female with multiple metastatic EHE including pleural, diagnosed by medical thoracoscopy, with a progression-free survival of 24 months with oral vinorelbine as maintenance therapy after combination of cisplatin-vinorelbine. We believe that this therapy might be of value to test in this patient population as it has never been tested before.

Brain Metastases from Gynecologic Malignancies.

Background and Objectives: To present a series of brain metastases from gynecologic primaries and provide a summary of the relevant literature. Materials and Methods: We retrospectively review 18 patients with histologically confirmed brain metastases from gynecologic primaries and summarize the largest series of relative reports. Results: Six brain metastases were of endometrial primary and 12 of ovarian primary. In 3 cases (16.7%), diagnosis of brain metastases was made at presentation of the gynecologic primary; in the others, median time to development of brain metastasis was 34 (range, 6-115) months. Median survival after brain metastasis diagnosis was 5 (range, 1-89) months. Favorable prognostic factors were better performance status (p = 0.04) and, marginally, smaller metastasis size (p = 0.06). No differences in brain metastases between endometrial and ovarian primaries were found, except for the time interval from primary to brain metastases diagnosis, which was shorter for endometrial tumors (p = 0.05). A comprehensive summary of previous studies is provided. Conclusions: Performance status and smaller brain metastases size are good prognostic factors. Endometrial cancer brain metastases develop earlier than ovarian cancer brain metastases.

Autophagy and immune microenvironment in craniopharyngioma and ameloblastoma.

BACKGROUND: Craniopharyngiomas and ameloblastomas show remarkable histologic and molecular similarities. The immune microenvironment of craniopharyngiomas has been recently studied showing interesting findings, while its composition in ameloblastomas is unknown. Similarly, some evidence of autophagic activity, a process of cellular constituents' degradation has been found in ameloblastomas, but no studies exist in craniopharyngiomas. Thus, the aim of the study is to compare factors of the immune microenvironment and the autophagic apparatus between these two tumor types. METHODS: 26 craniopharyngiomas and 14 ameloblastomas were immunohistochemically studied for PD-L1, CD8, CD20, S100, CD163, MECA-79, LC3B and p62. RESULTS: Craniopharyngiomas showed higher LC3B tumor cell expression, higher CD8+ T cells and higher CD163+ macrophages in comparison to ameloblastomas. LC3B tumor cell expression was associated with overall survival in craniopharyngioma patients and p62 nuclear expression was associated with overall survival in ameloblastoma patients. CONCLUSION: This is the first study showing the presence of autophagic markers in craniopharyngiomas and describing the immune microenvironment of ameloblastomas.

Vascular Pseudoinvasion After Endometrial Ablation.

Vascular pseudoinvasion or displacement of tumor or normal endometrial tissue is a potential pitfall in uterine pathology. The proposed mechanisms of this phenomenon are mostly associated with the uterine manipulator used during minimally invasive hysterectomies. The aim of this report is to describe vascular pseudoinvasion in a still unreported setting, that of a postendometrial ablation hysterectomy, and to provide a summary of studies dealing with artifactual or nonmalignant myometrial vessel involvement by normal or neoplastic endometrial tissue.

FOXA1 Expression by Immunohistochemistry in Carcinosarcomas of the Endometrium and Ovary/Fallopian Tube.

FOXA1, a transcription factor essential for the binding of other transcription factors on chromatin, is associated with hormone receptor-associated cancers, such as breast and endometrial cancer. It is also considered an antagonist of epithelial-to-mesenchymal transition (EMT). In endometrial cancer, FOXA1 is considered a tumor suppressor; in carcinosarcoma, one of the most aggressive and rare subtypes of endometrial cancer, thought to be derived through an EMT mechanism, FOXA1 has not been studied. Thus, the aim of this study was to investigate the possible expression of FOXA1 in carcinosarcomas, and its correlation with clinicopathologic factors. This was a retrospective study of 31 patients diagnosed with carcinosarcomas of the uterus or the adnexa. Histologic and clinical factors were correlated with the immunohistochemical expression of FOXA1. FOXA1 was expressed by 38.7% of the carcinomatous components and 16.1% of the sarcomatous components. FOXA1-positive sarcomatous components were seen only with positive carcinomatous components (P=0.004). FOXA1 expression was not associated with age, primary tumor site, stage, metastases, overall survival, or tumor relapse. FOXA1 expression in the carcinomatous component was associated with an absence of lymphovascular invasion or the presence of heterologous components. FOXA1 expression in the sarcomatous component was associated with rhabdomyosarcoma, rather than the chondrosarcoma heterologous component. Carcinosarcomas harbor FOXA1 expression, although it is in their carcinomatous rather than sarcomatous components, suggesting a possible role of FOXA1 in the EMT of carcinosarcomas. FOXA1 shows no prognostic significance in this tumor group.

CD56 is Expressed in Uterine Smooth Muscle Tumors.

CD56 is used in gynecologic pathology, typically in the context of a neuroendocrine, sex cord or sex cord-like tumor. It has never been studied in uterine smooth muscle tumors, which can potentially enter their differential diagnosis, and thus CD56 positivity could potentially be a pitfall. Thus, the aim of this study was to explore its expression in this category of tumors. Seventy-eight uterine smooth muscle tumors, including 14 leiomyosarcomas, 46 leiomyomas and their variants, 14 smooth muscle tumors of uncertain malignant potential, and 4 intravenous leiomyomatoses were studied in regard to CD56 expression. Fifty-eight nearby myometria were also analyzed. Sixty-five (83.4%) tumors showed CD56 expression. Nearby myometrium showed CD56 expression in 15 cases (25.9%). Staining ranged from 10% to 100% of tumor or myometrial cells (median 80% and 50%, respectively). Among the tumor types, leiomyoma with bizarre nuclei, had the lowest extensive expression (P=0.01). Most uterine smooth muscle neoplasms express CD56; thus, it is not useful in attempting to discriminate from endometrial stromal or sex cord-like neoplasms.

Vascular Involvement: An Uncommon Histologic Finding of Rectal Endometriosis.

Deep infiltrating endometriosis frequently affects the rectosigmoid region. It clinically presents as a chronic painful condition affecting women in their reproductive time. Here, we present a case of a 28-yr-old female patient who had a history of dysmenorrhea, dyspareunia, chronic abdominal and pelvic pain, and constipation secondary to rectal wall endometriosis. Microscopic examination of the resected rectal segment showed endometriosis with vascular and lymph node involvement. Vascular involvement is an uncommon histologic finding that may raise concern for potential malignancy. The aim of this report is to alert pathologists and physicians about this infrequent pitfall that can be mistaken for a neoplastic process and to discuss the underlying pathophysiology of vascular involvement by endometrial tissue in otherwise benign conditions.

Patterns of brachyury expression in chordomas.

INTRODUCTION: Chordomas are rare malignant midline tumors, presumed to arise from notochordal remnants. This was further suggested by the discovery of the brachyury in chordomas pathogenesis. Its immunohistochemical expression has become the principal adjunct in the diagnosis of chordomas. However, studies about brachyury expression in chordomas are not fully comparable, mainly because they use different primary antibodies. Thus, the aim of this study is to investigate the expression of brachyury expression in a series of chordomas in conjunction to clinicopathological characteristics and to review the relevant literature providing all the details needed in the immunohistochemical study of brachyury. MATERIALS AND METHODS: This is a retrospective study of 62 chordomas, diagnosed over a 22-year period. No dedifferentiated or poorly differentiated cases were included. A monoclonal primary antibody (clone A-4) was used and brachyury expression was evaluated by the H-score. Clinicopathological parameters studied were age, sex, tumor localization, decalcification status and tissue age. Fetal notochords were used for comparison. RESULTS: Mean H-score of nuclear brachyury expression was 129.8. The tissue age significantly influenced brachyury expression, the older samples expressing less brachyury. Decalcification demonstrated a trend to weaken brachyury expression. Clinical characteristics were not correlated with the patterns of brachyury expression. Notochords were negative. Literature review reveals several polyclonal antibodies used and a positivity of 75%-100% in chordomas with even more variable results in notochords. CONCLUSION: In chordomas, as in other tumor types, an uniformization of studies about brachyury expression is needed, by considering the clone used, and the decalcification and the age of the sample, given the growing importance of brachyury in diagnosis and therapeutic steps.

Adenomatoid Tumor: A Review of Pathology With Focus on Unusual Presentations and Sites, Histogenesis, Differential Diagnosis, and Molecular and Clinical Aspects With a Historic Overview of Its Description.

Adenomatoid tumors have been described almost a century ago, and their nature has been the subject of debate for decades. They are tumors of mesothelial origin usually involving the uterus, the Fallopian tubes, and the paratesticular region. Adenomatoid tumors of the adrenal gland, the liver, the extragenital peritoneum, the pleura, and the mediastinum have been rarely reported. They are usually small incidental findings, but large, multicystic and papillary tumors, as well as multiple tumors have been described. Their pathogenesis is related to immunosuppression and to TRAF7 mutations. Despite being benign tumors, there are several macroscopic or clinical aspects that could raise diagnostic difficulties. The aim of this review was to describe the microscopic and macroscopic aspects of adenomatoid tumor with a special focus on its differential diagnosis and pathogenesis and the possible link of adenomatoid tumor with other mesothelial lesions, such as the well-differentiated papillary mesothelioma and the benign multicystic mesothelioma, also known as multilocular peritoneal cysts.

Pathology of the Fallopian Tube: Tubal Involvement by Ovarian Tumors and Incidental Findings in the Nontumoral Setting.

The fallopian tube is thought to be the site of origin of most high-grade serous carcinomas (HGSCs). However, how often the tube is abnormal in the setting of other ovarian tumors is unknown. The aim of this study is to define the frequency of tubal abnormalities in the tumoral (n = 245) and nontumoral (n = 184) setting. We found that in ovarian tumors, 52.2% of the tubes were normal, while 39.2% were affected by the tumor. Abnormal tubes were found in 80% of HGSCs, in 21% of mucinous carcinomas, in 83.3% of seromucinous carcinomas, in 33.3% of endometrioid carcinomas, in 20% of clear-cell carcinomas, and in 10.5% of borderline tumors. Among normal tubes, almost 70% were histologically normal; transitional metaplasia was present in 17.4%, endometriosis in 8.1%, and adenofibroma in 2.2%, and 1.1% had an incidental serous intraepithelial tubal carcinoma. To conclude, the fallopian tube is abnormal in most serous carcinomas, and in a smaller number of endometrioid, clear-cell and mucinous carcinomas as well as borderline tumors. It is often abnormal in seromucinous tumors, but larger series are needed to study this rare subtype.

Local Anesthesia Thoracoscopy with versus without Midazolam: A Randomized Controlled Trial.

BACKGROUND: Medical thoracoscopy is the gold standard for the diagnosis of pleural diseases. To date, no consensus exists regarding the choice of sedative and analgesic agents in patients undergoing local anesthetic thoracoscopy (LAT), and questions are raised as to whether sedatives may add to respiratory side effects. OBJECTIVE: The aim of the study was to test the hypothesis that administration of midazolam associated with lidocaine versus lidocaine alone in patients with LAT adds to respiratory side effects. METHODS: We randomly assigned 80 patients to a 1:1 study to 2 groups: local anesthesia by lidocaine (n = 40) versus lidocaine and midazolam (n = 40), with the primary end point being the mean lowest oxygen saturation. The secondary end points were cardiovascular parameters, complications, days of drainage, hospital stay, and patients' quality of life (QoL) as assessed by a visual analog scale (VAS). RESULTS: The mean age of all patients was 66.6 ± 13.1 years. The study comprised 50 males (62.5%). No difference was observed in the demographics between the 2 groups. No significant difference was observed between the 2 groups in oxygen saturation (primary end point). A significant difference was observed in favor of the midazolam group regarding the QoL assessed by VAS. CONCLUSION: Midazolam does not add to respiratory side effects when it is used with lidocaine for LAT, while patients' QoL is actually improved in this group. Therefore, in our department, we changed our startegy in favor of the association of lidocaine and midazolam.

Laryngeal Tumor Microenvironment.

Tumor microenvironment has been extensively studied in various forms of cancer, like head and neck squamous cell carcinoma. Progress in the field revealed the prognostic significance of the various components of the tumor's ecosystem and led to changes in treatment strategies, like including immunotherapy as an important tool. In this chapter, the microenvironment of tumors with a special interest in laryngeal cancer will be described. The issues assessed include innate immune response factors, like neutrophils, neutrophil extracellular traps (NET), platelets, macrophages M1 or M2, dendritic cells, natural killer cells, as well as adaptive immunity aspects, like cytotoxic, exhausted and regulatory T cells, and immune checkpoints (PD-1/PD-L1, CTLA4). Also, stroma-associated factors, like fibroblasts, fibrosis, extracellular matrix, vessels and perineural invasion, hypoxia and cancer metabolism aspects, as well as the pre-metastatic niche, exosomes and cGAS-STING, are reviewed.

Secondary Tumors of the Gynecologic Tract: A Clinicopathologic Analysis.

Although the spread of extragenital tumors to individual female genital tract organs, particularly the ovary, has been much studied, histologic data with regard to secondary tumors involving the whole gynecologic tract are largely lacking. Thus, the aim of the study was to investigate the pathologic and clinical features of these tumors in order to better understand their features. This is a retrospective study of 196 secondary lesions involving the gynecologic tract. The parameters studied were the primary site, its histologic type and grade, the presence of mucous production, the type of secondary involvement, defined as distant metastasis, direct extension or locoregional recurrence, and the time to metastasis. Organs involved were the ovary (50%), the vagina (22%), the myometrium (10.7%), the cervix (10.2%), the endometrium (3.6%), the vulva (2%), and the Fallopian tube (1.5%). Most often, primary tumors were colorectal (39.8%), endometrial (15.3%), breast (12.7%), ovarian (10.7%), and gastric (5.6%). Secondary tumors were metachronous in 43.9% of the cases with a mean time to recurrence of 55.5 mo. Distant metastases were the most common type of secondary involvement (64.8%), followed by direct extension (19.9%) and local recurrence (15.3%). Gastrointestinal tumors involved mostly the ovaries, endometrial tumors the vagina, ovarian tumors the myometrium, and urothelial tumors the cervix/vagina (P<0.0001). Vaginal lesions endometrial origin presented with only superficial invasion (P=0.0002). The primary tumor's features dictate a different pattern of secondary involvement of the gynecologic tract. Endometrial tumors produce mostly superficial vaginal recurrences, mucus-producing gastrointestinal tumors present with ovarian metastases, whereas breast tumors affect the entire gynecologic tract and present the tumors with the most late recurrences.

Expression of CD3, PD-L1 and CTLA-4 in mammary and extra-mammary Paget disease.

BACKGROUND: Mammary and extra-mammary Paget disease is a rare form of intra-epithelial glandular neoplasm which is characteristically recurrent and necessitates multiple excisions that have an important impact on morbidity. Local immuno-modulating treatments have been applied with promising results, but the local immune markers of Paget disease have not been studied. AIM OF THE STUDY: To investigate the local immune micro-environment of Paget disease. MATERIALS AND METHODS: Sixty-four specimens from 41 patients, including cases with multiple recurrences and underlying primary neoplasm, have been studied for their expression of CD3, PD-L1 and CTLA-4. RESULTS: Nineteen cases were mammary; 22 were extra-mammary and involved the vulva, the anus, the inguinal region and the lower extremity. PD-L1 was not expressed by any neoplastic lesion or the associated lymphocytes. CTLA-4 expression was found in nine cases. Higher stromal CD3 expression and moderate levels of intra-epithelial CD3 expression were present in most cases. Biopsies, subsequent excision specimens and recurrences showed the same immunohistochemical profile of CD3 and PD-L1, although there were different levels of CTLA-4 in a few cases. The underlying lesions in mammary Paget disease showed the same immunohistochemical profile as the intra-epithelial neoplastic cells. The expression of the markers did not correlate with age, sex, localization or recurrence. CONCLUSION: Paget disease is characterized by an intense lymphocytic response, devoid of the immune-suppressive impact of the PD-L1 pathway, but with occasional CTLA-4 expression.