The application of a multidisciplinary approach in the diagnosis of Castleman disease and Castleman-like lymphadenopathies: A 20-year retrospective analysis of clinical and pathological features.

BACKGROUND: Castleman disease (CD) comprises a group of rare and heterogeneous haematological disorders, including unicentric (UCD) and multicentric (MCD) forms, the latter further subdivided into HHV8-MCD, POEMS-MCD and idiopathic-MCD (iMCD). However, according to the Castleman Disease Collaborative Network guidelines, the diagnosis of CD can only be achieved through collaboration between clinicians and pathologists. METHODS: We applied these clinical and pathological criteria and implement with clonality testing to a retrospective cohort of 48 adult and paediatric Italian patients diagnosed with reactive lymphadenitis with CD-like histological features. RESULTS: We confirmed the diagnosis of CD in 60% (29/48) of the cases, including 12 (41%) UCD and 17 (59%; five HHV8-MCD, three POEMS-MCD and nine iMCD) MCD. Of the remaining 19 cases (40%) with multiple lymphadenopathy, 5 (26%) were classified as autoimmune diseases, 1 (5%) as autoimmune lymphoproliferative disorder, 1 (5%) as IgG4-related disease, 11 (83%) as reactive lymphadenitis and 1 (5%) as nodal marginal zone lymphoma. CONCLUSIONS: Our study emphasizes the importance of the multidisciplinary approach to reactive lymphadenitis with CD-like features in order to achieve a definitive diagnosis and choose the appropriate treatment.

Considerations on chemical composition of psammoma bodies: Automated detection strategy by infrared microspectroscopy in ovarian and thyroid cancer tissues.

Ectopic calcifications are observed in many soft tissues and are associated with several diseases, including cancer. The mechanism of their formation and the correlation with disease progression are often unclear. Detailed knowledge of the chemical composition of these inorganic formations can be very helpful in better understanding their relationship with unhealthy tissue. In addition, information on microcalcifications can be very useful for early diagnosis and provide insight into prognosis. In this work the chemical composition of psammoma bodies (PBs) found in tissues of human ovarian serous tumors was examined. The analysis using Micro Fourier Transform Infrared Spectroscopy (micro-FTIR) revealed that these microcalcifications contain amorphous calcium carbonate phosphate. Moreover, some PB grains showed the presence of phospholipids. This interesting result corroborates the proposed formation mechanism reported in many studies according to which ovarian cancer cells switch to a calcifying phenotype by inducing the deposition of calcifications. In addition, other techniques as X-ray Fluorescence Spectroscopy (XRF), Inductively Coupled Plasma Optical Emission Spectroscopy(ICP-OES) and Scanning electron microscopy (SEM) with Energy Dispersive X-ray Spectroscopy (EDX) were performed on the PBs from ovary tissues to determine the elements present. The PBs found in ovarian serous cancer showed a composition comparable to PBs isolated from papillary thyroid. Based on the chemical similarity of IR spectra, using micro-FTIR spectroscopy combined with multivariate analysis, an automatic recognition method was constructed. With this prediction model it was possible to identify PBs microcalcifications in tissues of both ovarian cancers, regardless of tumor grade, and thyroid cancer with high sensitivity. Such approach could become a valuable tool for routine macrocalcification detection because it eliminates sample staining, and the subjectivity of conventional histopathological analysis.

A novel scoring system for TIGIT expression in classic Hodgkin lymphoma.

Clinical use of immune-checkpoints inhibitors (anti PD-1/PD-L1) resulted very effective for the treatment of relapsed/refractory classic Hodgkin Lymphoma (CHL). Recently, T cell Ig and ITIM domains (TIGIT) has been recognized as an immune checkpoint receptor able to negatively regulate T cell functions. Herein, we investigated the expression of TIGIT in CHL microenvironment in order to find a potential new target for inhibitor therapy. TIGIT, PD-1 and PD-L1 expression was evaluated in 34 consecutive patients with CHL. TIGIT expression in T lymphocytes surrounding Hodgkin Reed-Sternberg (HRS) cells was observed in 19/34 patients (56%), of which 11 (58%) had advanced stages. In 16/19 (84%) cases, TIGIT+ peritumoral T lymphocytes showed also PD-1 expression. All 15 TIGIT- patients had PD-L1 expression in HRS cells (100%) while among 19 TIGIT+ patients, 11 (58%) were PD-L1+ and 8 (42%) were PD-L1-. Using a new scoring system for TIGIT immunoreactivity, all TIGIT+ cases with higher score (4/19) were PD-L1-. Our results confirm co-expression of TIGIT and PD-1 in peritumoral T lymphocytes. Of relevance, we demonstrated a mutually exclusive expression of TIGIT and PD-L1 using new TIGIT scoring system able to identify this immunocheckpoints' modulation. These results pave the way to new therapeutic strategies for relapsed/refractory CHL.

Morphometric analysis of atypical glandular cells correctly classifies normal, reactive, and atypical cells in cervical smears.

The 2014 Bethesda System diagnostic criteria for atypical glandular cells (AGC) aid in the classification of atypical cells in cervical cytology. Anyway, AGC diagnosis remains challenging, due to low frequencies of this finding (approximately 0.5%-1% of Pap test results), abundance of AGC mimics, and significant interobserver variability. We developed an algorithm based on nuclear areas parameter that can help to differentiate AGC from Normal and Reactive glandular cells. Nuclear areas and perimeters were measured on 16 Pap smears with AGC and 18 with Reactive glandular cells of women aged between 30 and 77. Glandular cells from nonpathological Pap smears were used as controls. For each case, the means, medians, standard deviations, and the minimum and maximum values of both nuclear areas and perimeters of the cells of interest were calculated. The nuclear area analysis showed a 100% specificity in discriminating Normal from Altered cells (either Reactive or AGC), whereas the nuclear perimeter analysis showed a lower specificity (87.5%). Both nuclear area and perimeter variability analysis resulted in high specificity values in distinguishing Reactive cells from AGC. Therefore, a stepwise two-step algorithm using nuclear areas to discriminate Normal from Altered cells, and nuclear area variability to distinguish Reactive from AGC, allowed us to reliably classify the cells into these three categories. The morphometric analysis of nuclear area is a valuable and reliable aid in AGC diagnosis and standardization, easily integrable into common automatic algorithms.

Transcriptional analysis distinguishes breast implant-associated anaplastic large cell lymphoma from other peripheral T-cell lymphomas.

Breast implant-associated anaplastic large cell lymphoma is a new provisional entity in the revised World Health Organization classification of lymphoid malignancies, the pathogenesis and cell of origin of which are still unknown. We performed gene expression profiling of microdissected breast implant-associated anaplastic large cell lymphoma samples and compared their transcriptional profiles with those previously obtained from normal T-cells and other peripheral T-cell lymphomas and validated expression of selected markers by immunohistochemistry. Our results indicate that most breast implant-associated anaplastic large cell lymphomas exhibit an activated CD4+ memory T-cell phenotype, which is associated with CD25 and FoxP3 expression. Gene ontology analyses revealed upregulation of genes involved in cell motility programs (e.g., CCR6, MET, HGF, CXCL14) in breast implant-associated anaplastic large cell lymphomas compared to normal CD4+ T-cells and upregulation of genes involved in myeloid cell differentiation (e.g., PPARg, JAK2, SPI-1, GAB2) and viral gene transcription (e.g., RPS10, RPL17, RPS29, RPL18A) compared to other types of peripheral T-cell lymphomas. Gene set enrichment analyses also revealed shared features between the molecular profiles of breast implant-associated anaplastic large cell lymphomas and other types of anaplastic large cell lymphomas, including downregulation of T-cell receptor signaling and STAT3 activation. Our findings provide novel insights into the biology of this rare disease and further evidence that breast implant-associated anaplastic large cell lymphoma represents a distinct peripheral T-cell lymphoma entity.

Primary cardiac MYC/BCL6 double hit non-Hodgkin lymphoma.

Cardiac and pericardial involvement by malignant lymphoma is a rare condition. The present case report describes a case of primary cardiac MYC/BCL6 double hit non-Hodgkin lymphoma in the pericardium, and highlights the importance of a prompt diagnosis and aggressive pharmacologic treatment of this disease. In a symptomatic patient, a minimally invasive 3 cm sub-xiphoidal incision was performed under deep sedation with spontaneous ventilation to perform a pericardial biopsy. A 5 cm × 3 cm portion of pericardium was removed from above the right ventricle, thus ameliorating the extrinsic compression on the right chambers. The patient received 6 cycles of immuno-chemotherapy (rituximab plus cyclophosphamide, vincristine, and methylprednisolone), with no complications, achieving complete remission with no symptoms. Malignancies must be excluded in every case of acute pericardial disease with imaging techniques, and lymphomas should be always considered in the differential diagnosis of cardiac tumors. Complete surgical removal of the tumor is not necessary to achieve complete remission, and minimally invasive surgical approaches are an effective tool to confirm diagnosis and allow a precise histologic characterization. .

PD-1/PD-L1 expression in extra-medullary lesions of multiple myeloma.

Multiple myeloma patients may develop extraosseous involvement in the course of the disease making prognosis very poor and new drugs clearly needed. The PD-1/PD-L1 axis has emerged as a master immune checkpoint in antitumor responses and recent studies investigated the role of PD-L1 in multiple myeloma cells; no data however are still available about PD-L1 expression in extramedullary localizations. We demonstrate PD-L1 expression in 4/12 cases of extraosseous myeloma suggesting that these lesions represent a specialized microenvironment. We found presence of PD-1+ infiltrating lymphocytes in all observed cases supporting the relevance of PD-1/PD-L1 checkpoint in extramedullary myeloma. We also investigated the correlation in PD1/PD-L1 staining between marrow staining and EMP lesions.

Rituximab as Single Agent in Primary MALT Lymphoma of the Ocular Adnexa.

Ocular Adnexal Lymphomas are the first cause of primary ocular malignancies, and among them the most common are MALT Ocular Adnexal Lymphomas. Recently systemic immunotherapy with anti-CD20 monoclonal antibody has been investigated as first-line treatment; however, the optimal management for MALT Ocular Adnexal Lymphomas is still unknown. The present study evaluated retrospectively the outcome of seven consecutive patients with primary MALT Ocular Adnexal Lymphomas, of whom six were treated with single agent Rituximab. All patients received 6 cycles of Rituximab 375 mg/mq every 3 weeks intravenously. The overall response rate was 100%; four patients (67%) achieved a Complete Remission, and two (33%) achieved a partial response. In four patients an additional Rituximab maintenance every 2-3 months was given for two years. After a median follow-up of 29 months (range 8-34), no recurrences were observed, without of therapy- or disease-related severe adverse events. None of the patients needed additional radiotherapy or other treatments. Rituximab as a single agent is highly effective and tolerable in first-line treatment of primary MALT Ocular adnexal Lymphomas. Furthermore, durable responses are achievable with the same-agent maintenance. Rituximab can be considered the agent of choice in the management of an indolent disease in whom the "quality of life" matter is of primary importance.

Second surgery for recurrent endometriomas is more harmful to healthy ovarian tissue and ovarian reserve than first surgery.

OBJECTIVE: To evaluate the excised specimen with histologic analysis and to assess the antral follicle count (AFC) at follow-up. This is to determine whether excisional surgery for recurrent endometriomas is more harmful to ovarian tissue and to the ovarian reserve than first surgery. DESIGN: Prospective controlled study. SETTING: University hospital. PATIENT(S): Consecutive patients with pelvic pain and/or infertility undergoing laparoscopic excision of a monolateral ovarian endometrioma for the first time (17 patients) or for recurrence after previous surgery (11 patients). INTERVENTION(S): Laparoscopic excision of ovarian endometrioma and ultrasonographic evaluation 3 months after surgery. MAIN OUTCOME MEASURE(S): Cyst wall histologic evaluation (specimen thickness, presence and morphology of ovarian tissue) and evaluation of ovarian reserve with AFC and ovarian volumes of both the operated and contralateral, nonoperated ovary at follow-up. RESULT(S): The cyst wall specimen was significantly thicker in the recurrent endometrioma group than in the first surgery group (1.7 ± 0.3 mm vs. 1.1 ± 0.3 mm). Both main components of the cyst specimen (i.e., endometriosis tissue and ovarian tissue) were more represented in the recurrent endometrioma group than in the first surgery group. At sonographic follow-up, the operated ovary had a significantly lower AFC and volume than the contralateral nonoperated ovary in the recurrent endometrioma group, but not in the primary surgery group. CONCLUSION(S): Surgery for recurrent endometriomas is associated with evidence of a higher loss of ovarian tissue and is more harmful to the ovarian reserve evaluated by AFC and ovarian volume, if compared with endometriomas operated for the first time. Indications to surgery for recurrent endometriomas should be reconsidered with caution.

Synovial sarcoma of the anterior tibialis tendon.

We report the clinical features, radiographic findings, management and results of a patient with a post-traumatic synovial sarcoma of the anterior tibialis tendon. Our patient was managed operatively and with radiotherapy with good clinical results. No evidence of recurrence or metastatic disease was seen at 3-year follow-up.

A singular observation of a giant benign Brenner tumor of the ovary.

INTRODUCTION: Brenner tumors are rare transitional cell tumors of the ovary. They are usually benign neoplasms, of solid or solid-cystic structure and small size. We describe the case of a benign, predominantly cystic Brenner tumor measuring 39 cm in diameter. CASE REPORT: A 62-year-old woman presented to the outpatient visit complaining about vague abdominal symptoms such as constipation and meteorism. Ultrasonography and CT scan showed the presence of a voluminous cystic mass, with fluid content, displacing other intra-abdominal organs. The patient underwent elective surgical excision, and there were no complications. Definitive pathological examination showed a metaplastic benign Brenner tumor. CONCLUSION: The largest benign Brenner tumors reported in literature have been up to 30 cm in size, and greater size has been thought to be a predictor of malignancy. We have seen, however, that it is possible for larger lesions of this type to have a completely benign behavior; consequently, a benign nature should not be excluded even in the event of a large ovarian lesion.

Histologic analysis of specimens from laparoscopic endometrioma excision performed by different surgeons: does the surgeon matter?

OBJECTIVE: To evaluate whether the amount of ovarian tissue inadvertently removed along with the endometrioma cyst wall at laparoscopy differs in relation to the operating surgeon's level of expertise. DESIGN: Multicenter, prospective trial. SETTING: Four tertiary care university hospitals. PATIENT(S): Fifty patients, aged 25 to 40 years, with monolateral ovarian endometriomas who underwent laparoscopic excision. INTERVENTION(S): Operation with the stripping technique by surgeons with specific expertise in endometriosis surgery in four centers (groups A, B, C, and D) and by residents with average training in laparoscopic surgery (group E). MAIN OUTCOME MEASURE(S): Histologic examination for the evaluation of the mean thickness of the cyst wall from each specimen, and the mean thickness and morphologic characteristics of any ovarian tissue removed. RESULT(S): No statistically significant differences were present in the rate of presence of ovarian tissue in the endometrioma wall specimens from the different groups (44%, 45%, 55%, 56%, and 60% in groups A, B, C, D, and E, respectively). For groups A+B+C+D versus group E, a statistically significant difference was found in the mean thickness of the tissue specimens (1.51 mm vs. 1.91 mm, respectively) and in the mean thickness of ovarian tissue inadvertently excised (0.49 mm vs. 0.97 mm, respectively). CONCLUSION(S): Level of expertise in endometriosis surgery is inversely correlated with inadvertent removal of healthy ovarian tissue along with the endometrioma capsule.

Percutaneous ultrasound-guided ablation of BW7756-hepatoma using ethanol or acetic acid in a rat model.

BACKGROUND: To compare tumor necrosis in hepatoma induced in rats by a single percutaneous injection of ethanol (PEI) or acetic acid (PAI). METHODS: BW7756 hepatomas of 1 mm3 were implanted in the liver of 40 male healthy rats. After 14 days, the 36 surviving rats were treated, in a single session, by ultrasound-guided injection of 300 microl of 95% ethanol (n = 17) or 100 microl of 50% acetic acid (n = 19). They were sacrificed 14 days after treatment and explanted tumoral livers were examined. The same PAI procedure was repeated on 13 additional rats to exclude a suspected occurrence of technical failures during the experiment, due to a surprisingly high rate of deaths within 30 minutes after PAI. RESULTS: Four rats died within four days after tumor implantation; after PEI, 1/17 (6%) died, whereas after PAI 9/19 (47%) died. The remaining 26 rats, after 14 days post-percutaneous ablation, were sacrificed. Gross and microscopic examinations showed that the hepatoma's nodules treated with PEI had 45.3 +/- 19.4% tumor necrosis compared to 49 +/- 23.3% (P = NS) for those treated with PAI. Complete tumor necrosis was not found in any animal. Peritoneal invasion was present in 4/16 (25%) and 2/10 (20%) rats treated with PEI or PAI, respectively (P = NS). Autopsy was performed in the 5 additional rats that died within 30 minutes after PAI. CONCLUSION: Our results show that there is no significant difference in the percentage of tumor necrosis between two local ablation methods in spite of the different dosages used. However, mortality in the PAI-treated group was greater than in PEI-treated group, presumably due to greater acetic acid systemic diffusion and its metabolic side effects. In human subjects, HCC occurs in the setting of cirrhosis, where the non-tumoral tissue is firmer than the tumor structure, with consequent reduction of drug diffusion. This could be the reason why some human studies have concluded similar or even better safety and efficacy with PAI compared to PEI.

Histologic analysis of endometriomas: what the surgeon needs to know.

OBJECTIVE: To evaluate by thorough pathologic analysis the histologic features of the endometrioma wall excised at laparoscopy. DESIGN: Prospective series of consecutive patients. SETTING: Tertiary care, university hospital. PATIENT(S): Fifty-nine patients with ovarian endometriomas. A total of 70 cysts were examined. INTERVENTION(S): Patients underwent operative laparoscopy with the stripping technique for excision of the ovarian endometrioma. MAIN OUTCOME MEASURE(S): A thorough histologic examination was performed on the entire cyst wall specimen. RESULT(S): Histologic examination confirmed the endometriotic nature of the cyst in 100% of the cases. The inner wall of the endometrioma was covered by endometriotic tissue on 60% of the surface. The mean cyst wall thickness was 1.4 mm. The mean value of maximal depth of endometriosis penetration in the endometrioma wall was 0.6 mm. In 99% of the cases the maximal penetration of the endometriotic tissue was <1.5 mm. CONCLUSION(S): In the present study, we demonstrate that the endometrioma wall contains endometriotic tissue in 100% of the cases. However, the endometriotic tissue may cover the inner cyst wall for a surface that varies between 10% and 98% of the entire wall (median value 60%). This tissue may reach a depth of 2 mm, but for most of the surface it does not penetrate >1.5 mm. These histologic data may help the gynecologic laparoscopist select the surgical approach that maximally preserves healthy ovarian tissue.

An increase of CA 19.9 as the first clinical sign of ileocecal valve metastasis from breast cancer.

CASE REPORT: The case of a breast cancer patient with a progressive increase of CA 19.9 that indicated gastrointestinal metastasis is reported. After the observation of an increased CA 19.9 serum value (104.00; n.v. 0.0-37.00) a colonoscopy was performed. This examination showed the presence of an erythematous and granular zone near the ileocecal valve. Histological examination of biopsies taken during the colonoscopy revealed atypical monomorphic cells between the organoid pattern of the colon-type ducts. Immunohistochemical staining was positive for cytokeratin 7 and for estrogen receptors, consistent with metastatic epithelial malignancy. After eleven months, the patient presented with signs of intestinal obstruction, requiring an ileocolic bypass. At definitive histological examination, the tumor exhibited features of mammary metastases. CONCLUSION: This is the first report in the literature of an ileocecal valve metastasis from breast cancer diagnosed by an increase of CA 19.9, which is a marker of primary colorectal carcinoma.