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.

Expression Patterns of GATA3 in Classical Hodgkin Lymphoma: A Clinico-Pathological Study.

GATA3 is a transcription factor involved in T-cell maturation and has been previously shown to be aberrantly overexpressed in malignant Hodgkin and Reed-Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL). However, the immunophenotypes of the cell types expressing GATA3 have not been precisely characterized so far in cHL tissues. In this single-center retrospective cohort study we analyzed the expression patterns of GATA3 alone and in combination with B, T, NK or macrophage-associated markers in 73 cases with newly diagnosed cHL and investigated for a possible correlation with clinical and laboratory parameters. Immunohistochemistry (single and double) was performed using GATA3 alone and in combination with CD20, CD3, CD56, CD68, CD30 or CD15. Clinical and laboratory parameters were collected and correlated with the expression of GATA 3. GATA3 nuclear expression was found in HRS cells in 39/73 (54%) cases of cHL. The Nodular Sclerosis (NS) subtype showed the highest positivity rate (35/56, 63%), followed by mixed cellularity (MC; 4/14, 29%) and lymphocyte rich (LR; 0/3). Double immunostainings showed that GATA3 was expressed by CD30+ or CD15+ HRS cells and a few CD3+ T-cells, whereas GATA3 expression was not detected in CD20, CD56 or CD68+ cells. GATA3-negative cHL was significantly associated with unfavorable prognostic factors such as older age at diagnosis and increased levels of serum ß2-microglobulin. The heterogenous expression patterns of GATA3 in HRS cells that were observed in a substantial proportion of cHL, mainly in the NS subtype, further support the biological heterogeneity of cHL.

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.

Primary Bone Lymphoma: A Review of the Literature with Emphasis on Histopathology and Histogenesis.

Primary bone lymphoma (PBL) is a rare neoplasm of malignant lymphoid cells presenting with one or more bone lesions without nodal or other extranodal involvement. It accounts for approximately 1% of all lymphomas and 7% of malignant primary bone tumors. Diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS) represents the predominant histological type and constitutes over 80% of all cases. PBL may occur at all ages with a typical diagnosis age of 45-60 years and a slight male predominance. Local bone pain, soft tissue edema, palpable mass and pathological fracture are the most common clinical features. Diagnosis of the disease, which is frequently delayed due to its non-specific clinical presentation, is based on the combination of clinical examination and imaging studies and confirmed by combined histopathological and immunohistochemical examination. PBL can develop in any part of the skeleton, although it occurs most commonly in the femur, humerus, tibia, spine and pelvis. The imaging appearance of PBL is highly variable and unspecific. In terms of the cell-of-origin, most cases of primary bone DLBCL (PB-DLBCL), NOS belong to the germinal center B-cell-like subtype and specifically originate from germinal center centrocytes. PB-DLBCL, NOS has been considered a distinct clinical entity based on its particular prognosis, histogenesis, gene expression and mutational profile and miRNA signature. PBL carries a favorable prognosis, especially when treated with combined chemoradiotherapy.

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.

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.

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.

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.

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.

Performance of Indocyanine Green Compared to 99mTc-Nanocolloids for Sentinel Lymph Node Detection in Early Vulvar Cancer.

STUDY OBJECTIVE: The aim of this study was to evaluate the performance of indocyanine green (ICG) compared to that of the gold standard 99mtechnetium (99mTc-nanocolloids) in detecting sentinel lymph nodes (SLN) in early vulvar cancer. MATERIAL AND METHODS: A single-center retrospective cohort study comparing SLN detection by 99mTc-nanocolloids and ICG was performed in patients presenting early vulvar cancer (T1/2), with clinically negative nodes. All SLN showing a radioactive and/or fluorescent signal were resected. The primary endpoints were the sensitivity, positive predictive value (PPV) and false negative (FN) rate of ICG in detecting SLN compared to 99mTc-nanocolloids. RESULTS: Thirty patients were included and 99 SLN were identified in 43 groins. Compared to 99mTc-nanocolloids, ICG had a sensitivity of 80.8% (95% CI [72.6; 88.6%]), a PPV of 96.2% (95% CI [91.8; 100%]) and a FN rate of 19.1% in detecting SLN. Seventeen (17.1%) infiltrated (positive) SLN were identified out of the 99 SLN detected. Compared to 99mTc-nanocolloids, ICG showed a sensitivity of 82.3% (95% CI [73.1; 91.5%]), a PPV of 100% and a FN rate of 17.6% (3/17) in detecting infiltrated SLN. CONCLUSION: Despite its many advantages, ICG cannot be used as the sole tracer for the detection of SLN in early vulvar cancer and should be employed in conjunction with 99mTc-nanocolloids.

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.

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.

Prognostic role of immune microenvironment in pleural metastases from breast and lung adenocarcinomas.

Background: Pleural metastatic disease is a common disease with dismal prognosis. The immune microenvironment of metastatic pleural tissue remains largely unknown. Thus, we aimed to investigate the presence of different immune cell populations, and to compare them with clinical characteristics. Methods: We included 70 patients with lung and breast adenocarcinoma (ADC) diagnosed with pleural metastasis during a 2-year period with the primary endpoint to investigate if the main immune cell populations are present in pleural metastases and if they have any prognostic role. Secondary endpoints were to detect any differences in their presence between lung and breast primaries and to search for any correlation with the macroscopic (thoracoscopic) findings. We used immunohistochemical techniques for the detection of CD4+, CD8+, CD20+, CD163+ and S100+ cells in whole tissue pleural biopsies of lung and breast metastases. Results: Primary endpoint: all these populations are present in the biopsies from lung and higher stromal and intratumoral CD4 counts, as well as higher stromal CD20 cells were positive prognostic factors for lung cancer metastases, while higher S100 intratumoral counts were positive prognostic factors in lung and marginally breast cancer metastases. Secondary endpoints: significant higher values for the stromal CD163 group (P=0.04) and for the intratumoral S100 group (P=0.006) were seen in lung compared to breast metastases. Interesting correlations were also noted between thoracoscopic findings (nodules, masses, pachypleuritis) and the different factors studied. Conclusions: Our data show that the immune microenvironment may be important in this advanced tumoral setting and that possible targets of the nowadays numerous treatment strategies implicating the immune system may merit further exploration in this poor prognosis disease.

Clinical correlation of lymphovascular invasion and Silva pattern of invasion in early-stage endocervical adenocarcinoma: proposed binary Silva classification system.

Silva invasion pattern can help predict lymph node metastasis risk in endocervical adenocarcinoma. We analysed Silva pattern of invasion and lymphovascular invasion to determine associations with clinical outcomes in stage IA and IB1 endocervical adenocarcinomas. International Federation of Gynecology and Obstetrics (FIGO; 2019 classification) stage IA-IB1 endocervical adenocarcinomas from 15 international institutions were examined for Silva pattern, presence of lymphovascular invasion, and other prognostic parameters. Lymph node metastasis status, local/distant recurrences, and survival data were compared using appropriate statistical tests. Of 399 tumours, 152 (38.1%) were stage IA [IA1, 77 (19.3%); IA2, 75 (18.8%)] and 247 (61.9%) were stage IB1. On multivariate analysis, lymphovascular invasion (p=0.008) and Silva pattern (p<0.001) were significant factors when comparing stage IA versus IB1 endocervical adenocarcinomas. Overall survival was significantly associated with lymph node metastasis (p=0.028); recurrence-free survival was significantly associated with lymphovascular invasion (p=0.002) and stage (1B1 versus 1A) (p=0.002). Five and 10 year overall survival and recurrence-free survival rates were similar among Silva pattern A cases and Silva pattern B cases without lymphovascular invasion (p=0.165 and p=0.171, respectively). Silva pattern and lymphovascular invasion are important prognostic factors in stage IA1-IB1 endocervical adenocarcinomas and can supplement 2019 International Federation of Gynecology and Obstetrics staging. Our binary Silva classification system groups patients into low risk (patterns A and B without lymphovascular invasion) and high risk (pattern B with lymphovascular invasion and pattern C) categories.