Dimitra Grapsa

Value of Endoscopic Retrograde Cholangiopancreatography-Guided Brushings in Preoperative Assessment of Pancreaticobiliary Strictures : What's New?

Brush cytology plays a prominent role in confirming the presence of extrahepatic biliary tract malignancy. However, its value is limited by its relatively low and widely variable sensitivity values. Various factors seem to influence the accuracy of cytologic diagnosis and are attributed to sampling, technical and interpretation errors. Ancillary methods, such as immunocytochemistry, flow cytometry, image analysis, fluorescence in situ hybridization (FISH) and the newly discovered method of global analysis of gene expression are helpful in resolving cases with inconclusive cytology and are vigorously investigated for their value in assessing the expression of novel tumor markers for the diagnosis and prognosis of pancreatic and bile duct carcinomas. However, their routine use in clinical practice remains in doubt. To increase the sensitivity of brush cytology and strengthen its role in the preoperative assessment of patients with pancreaticobiliary malignancies, the following are of the utmost importance: improvement of current sampling and cytopreparation techniques, introduction of a uniform system for reporting epithelial abnormalities based on strict and clearly distinct morphologic criteria for each pathologic entity and incorporation of experience and knowledge derived from standard cytologic methods and novel diagnostic technologies in clinical practice without compromising the high specificity associated with brush cytology.

Standardized categorical reporting of cytopathology results: the strengths and weaknesses of a constantly evolving and expanding system.

Since the success of the Bethesda nomenclature system in standardizing Pap smear results, there has been growing interest in adopting Bethesda‐like standardized categorical formats in areas of nongynecologic cytopathology. Standardized categorical reporting may have several advantages over descriptive reporting, in enhancing cytopathologist‐clinician communication and inter‐institutional exchange of information, providing better guidance for treatment planning, and facilitating statistical analysis for research purposes or quality control studies. On the other hand, descriptive reporting may be more effective as a tool of communication between cytopathologists, may better express the uncertainty of the observer in diagnostically difficult and equivocal cases and may better serve the purposes of training and continuing education of cytopathologists. Future studies on the pros and cons of the different reporting systems used in cytopathology may provide further insight on these issues. The most problematic areas need to be identified and optimal solutions decided. Despite the ongoing debate on the optimal reporting format in cytopathology, there is general agreement on the need for high quality cytology reports (whether descriptive or standardized) in terms of their diagnostic accuracy, clarity and clinical value. Diagn. Cytopathol. 2013;41:917–921.

Strongyloides stercoralis in a bronchial washing specimen processed as conventional and Thin-Prep smears: report of a case and a review of the literature.

Strongyloidiasis is an opportunistic infection which may result in a fatal hyperinfection syndrome in immunocompromised patients. We report the case of a pulmonary infection with Strongyloides stercoralis in a 61‐year‐old male with a history of a long‐term administration of corticosteroids. Cytologic examination of a bronchial washing specimen, processed both as conventional and as Thin‐Prep smears, revealed an abundance of the typical larvae of Strongyloides stercoralis, amidst a cellular population comprising several acute inflammatory cells as well as bronchial epithelial cells with features of basal cell hyperplasia or regenerative atypia. To the best of our knowledge there is only one previous report describing Strongyloides stercoralis in thin‐layer smears, and there are no previous studies comparing its morphology in conventional and thin‐layer preparations. Diagn. Cytopathol. 2009.

Nivolumab-Induced Recurrence of Rheumatoid Arthritis in a Patient With Advanced Non–Small Cell Lung Cancer: A Case Report

Background: Nivolumab (Opdivo, Bristol-Myers Squibb) is a human IgG4 monoclonal antibody with high affinity for the programmed death-1 receptor and is the first programmed death-1 immune checkpoint inhibitor approved by the U.S. Food and Drug Administration for second-line treatment of patients with advanced squamous and nonsquamous nonsmall cell lung cancer (1). Because of its unbalancing effect on the immune system, nivolumab may trigger immune-related adverse events (IRAEs), especially among patients with an autoimmune predisposition (2). Objective: To present a case of nivolumab-induced recurrence of rheumatoid arthritis successfully treated with concurrent administration of prednisolone in a patient with advanced nonsmall cell lung cancer. Case Report: A 76-year-old man with previously untreated stage IV lung adenocarcinoma and a history of rheumatoid arthritis that had been in clinical and laboratory remission for 25 years was referred to the oncology clinic of Sotiria Athens General Hospital for oncologic evaluation and treatment. The patient was treated with first-line carboplatinpemetrexed plus bevacizumab, maintenance pemetrexed plus bevacizumab, second-line carboplatinpaclitaxel, and third-line gemcitabinebevacizumab. Following disease progression after third-line therapy was begun, intravenous nivolumab treatment at 3 mg/kg of body weight every 2 weeks was initiated. Fifteen days after the first nivolumab infusion, a rheumatoid arthritis crisis occurred, with symmetrical polyarthritis of the upper extremities (particularly in the interphalangeal and metacarpophalangeal joints) and lower-extremity weakness accompanied by marked elevation of rheumatoid factor levels (251 IU/mL [reference range,<30 IU/mL]) and citrullinated peptide antibodies (104.3 U/mL [reference range,<5.0 U/mL]). Oral prednisolone therapy was begun at 20 mg/d and gradually tapered over 10 weeks; symptoms remitted within 5 days after treatment. Nivolumab therapy was continued during prednisolone treatment and after its completion without any modification of the initial protocol. Follow-up chest computed tomography 3 months after initiation of nivolumab therapy showed a partial response. Discussion: Patients with a history of autoimmunity are at increased theoretical risk for IRAEs (2, 3). In support of this hypothesis, serologic aggravation of autoimmune thyroiditis and induction of autoimmune hemolytic anemia in patients receiving nivolumab have been reported (4, 5). However, adequate clinical evidence to substantiate this concern is lacking, mainly because clinical trials of immune checkpoint inhibitors typically exclude patients with autoimmune disorders (2, 3). Therapeutic management of immune checkpoint blockadeinduced IRAEs generally includes interruption of the offending agent and suppression of lymphocyte activation with moderate to high doses of corticosteroids or other immunomodulatory drugs, such as azathioprine or tumor necrosis factor- antagonists, in the presence of steroid-refractory symptoms (2). Cautious use of immunosuppressive agents has nevertheless been advised in this setting because of concerns over a potential compromise of antitumor immunity (2). To our knowledge, this is the first reported case of a patient with cancer who had a nivolumab-induced clinical recurrence of a previously diagnosed autoimmune disorder that was successfully treated with corticosteroids without discontinuation of the culprit drug. It provides much-needed, real-world clinical evidence that nivolumab may induce clinical exacerbation of an underlying autoimmune condition even decades after its last manifestation. Furthermore, prednisolone successfully controlled the arthritis recurrence without the need to discontinue nivolumab therapy and, most important, without affecting antitumor response. Further studies are warranted to provide additional data on the efficacy and toxicity of nivolumab in patients with a history of autoimmune conditions, as well as to confirm the feasibility of its concurrent administration with corticosteroids in the presence of nivolumab-induced IRAEs.

“Immunocytochemical expression of P53, PTEN, FAS (CD95), P16INK4A and HPV L1 major capsid proteins in ThinPrep cervical samples with squamous intraepithelial lesions”

The aim of this study was to further investigate the immunocytochemical expression of p53, PTEN, Fas, p16, and HPV L1 capsid proteins in cervical smears with low and high grade squamous intraepithelial lesions (LSIL and HSIL, respectively). A total of 92 ThinPrep cervical samples, comprising 11 cases of HSIL, 61 cases of LSIL, and 20 negative cases were studied by immunocytochemical methods. The results obtained in LSIL cases were correlated with the available follow up data. Abnormal p53, PTEN, or Fas expression was found in a subset of HSIL cases, while positive expression for p16 was significantly associated with the diagnosis of HSIL (P < 0.0001, P = 0.001, P < 0.0001, and P < 0.0001, respectively). Among cases positive for p16 expression, the staining pattern was weak in 88.9% of LSIL cases and strong in 80% of HSIL cases (P < 0.0001). The p16 negative/L1 positive and p16 positive/L1 negative staining patterns were significantly associated with the presence of LSIL and HSIL, respectively (P < 0.0001). None of these markers had a significant prognostic value in LSIL cases (P > 0.05). Our results suggest that loss of PTEN or Fas expression and p53 overexpression may be involved in the process of neoplastic transformation of the cervical epithelium. Furthermore, negative or weak immunocytochemical staining for p16 in a Pap smear may strongly argue against the presence of a high grade lesion, while the combined p16/L1 staining pattern may be useful as a diagnostic adjunct for differentiating between LSIL and HSIL. Diagn. Cytopathol. 2014;42:465–475.

Bone marrow micrometastases in different solid tumors: Pathogenesis and importance

Early dissemination of cancer cells from the primary tumor via the circulatory system may result in the formation of microscopic metastatic deposits (micrometastases, MMs) in secondary compartments such as the bone marrow (BM), where there is a favorable environment for their subsequent growth and spread. MMs are considered the main reason for metastatic relapse in patients with early stage solid cancers after resection of the primary tumor. Although the molecular pathways leading to MMs remain only partly understood, there is increasing evidence that the detection of MMs in BM aspirates at the time of primary diagnosis is an independent prognostic factor, with a major influence in the stratification of these patients for adjuvant clinical treatment. Further potential applications of the detection of MMs include their use in monitoring therapeutic response or even in revealing targets for novel systemic therapies. All these intriguing possibilities are intensely investigated and carry great promise for radical improvements in the assessment and treatment of several epithelial cancers which are currently to blame for the majority of cancer-related deaths in the industrialized world.

Anaphylaxis during rapid oral desensitization to rifampicin

Rifampicin (also known as rifampin) is one of the most potent first-line antituberculosis drugs and an indispensable treatment option for isoniazid-resistant, rifampicin-sensitive tuberculosis (TB). Hypersensitivity reactions to rifampicin, mainly including fever, flu-like syndrome, rash, thrombocytopenia, acute renal failure, urticaria, and anaphylaxis, are considered rare but may occur among susceptible individuals and lead to premature discontinuation of the drug. Drug desensitization is a well-established procedure that may temporarily modify a patient’s immunologic response to the sensitizing agent, thus allowing for continuation of treatment. Desensitization to rifampicin has been previously described in rare case reports, almost invariably with successful results. We herein report a case of anaphylaxis during rapid oral desensitization to rifampicin in a male patient with active TB and a history of anaphylactic reactions to this agent. To the best of our knowledge, this is the first report in the English literature of a severe immediate-type reaction during desensitization to rifampicin. A 72-year-old man presented to the outpatient pulmonary clinic of “Sotiria” General Hospital, Athens, Greece, with fever, nonproductive cough, and weakness, lasting for 2 weeks. His medical history was significant for adult-onset diabetes mellitus and rheumatoid arthritis, treated with metformin and low-dose prednisone and intravenous infliximab, respectively. The patient was diagnosed with miliary TB and was started on anti-TB treatment with isoniazid (300 mg/day), rifampicin (600 mg/day), pyrazinamide (1500 mg/day), and ethambutol (1200 mg/day). Within 2 weeks after initiation of the above regimen, and 30 minutes after administration of the last dose of rifampicin, the patient developed fever and widespread urticaria; all drugs were subsequently discontinued and gradually reintroduced—after resolution of the cutaneous reaction—to identify the culprit drug. Urticaria, palmoplantar, and oropharyngeal pruritus were noted within 5 minutes after reintroduction of rifampicin and the drug was stopped; rifampicin was thereafter replaced with rifabutin. Ten days after initiation of rifabutin, the patient developed a maculopapular rash that affected the trunk and lower extremities. A skin biopsy was compatible with drug-induced eruption and rifabutin was discontinued. Approximately 3 years after his initial diagnosis of TB, the patient developed recurrent TB and was again started on a multidrug anti-TB regimen comprising isoniazid, rifabutin, pyrazinamide, and ethambutol. Twelve days after initiation of treatment a maculopapular rash appeared on the patient’s upper and lower extremities; rifabutin was again discontinued, followed by gradual resolution of the eruption, and the patient was referred to the Allergy Department of our hospital for further evaluation and management. At the time of the patient’s presentation to our department, skin prick test (SPT) and intradermal (ID) skin testing to rifampicin were performed, based on previous recommendations defining the highest nonirritant intradermal skin concentration of rifampicin (0.002 mg/mL). Histamine and saline were also used as positive and negative controls, respectively. SPT at a concentration of 2 mg/mL was negative, whereas a positive reaction (with a wheal of 15 17 mm and a flare of 42 44 mm) was shown on ID skin testing at a concentration of 0.002 mg/ mL. After obtaining the patient’s informed consent, oral desensitization to rifampicin was carried out in the intensive care unit. Premedication with antihistamines or steroids was not used (prednisone was discontinued for 3 days before the procedure) because these drugs may mask initial symptoms of anaphylaxis during desensitization, as previously emphasized, and the patient was not taking b-blockers or angiotensin-converting enzyme inhibitors. Increasing dosages of rifampicin were administered every 30 minutes, at a starting dose of 0.0002 mg followed by gradual dose escalation (Table I), as described in previously published desensitization protocols. Twenty minutes after administration of the 50 mg rifampicin dose, the patient started complaining of pruritus of the palms, soles, and groin followed by facial and trunk erythema, cough, generalized urticaria, hypotenstion, and sinus tachycardia followed by sinus bradycardia (without other ECG abnormalities). The desensitization procedure was discontinued, and the patient was treated with IV fluids, oxygen and nebulized salbutamol, intramuscular adrenaline, and intravenous methylprednisolone, dimetindene and ranitidine, with gradual recovery. Serum tryptase obtained at 1 hour after the onset of symptoms was 25 mg/L. Repeat serum tryptase, measured 1 week later, was found to be within normal limits (4 mg/L). Given the patient’s anaphylactic reaction during rapid desensitization, anti-IgE treatment and desensitization to rifampicin using slow dose increment over several days were recommended but the patient refused. Hypersensitivity reactions to anti-TB agents are relatively uncommon, encountered in approximately 4%-5% of the treated population, but may as well lead to withdrawal of the culprit drug and switching to an alternative agent. Rifampicin, in particular, is generally considered a well-tolerated drug with a low percentage of adverse events, especially when administered in usual therapeutic doses and outside the context of HIV infection. Delayed reactions, including a variety of cutaneous manifestations, are the commonest adverse reactions induced by rifampicin, whereas severe immediate reactions, such as anaphylaxis, are exceedingly rare.

Additional slides from residual ThinPrep Pap tests: Of potential diagnostic benefit in equivocal cases?

The aim of this study was to further evaluate the diagnostic significance of additional slides prepared from residual ThinPrep (TP) Pap Tests. Up to 10 repeat slides were prepared from 105 residual TP cervical samples. All additional slides were evaluated for the presence of diagnostic elements which were not found on the primary TP slide. After the evaluation of the repeat slides, an upgraded diagnosis was noted in 15 cases (14.3%). The reclassified cases included: three negative cases reclassified as two ASC‐US and as one LSIL, seven cases of ASC‐US reclassified as six LSIL and as one HSIL, and five cases of LSIL reclassified as HSIL. The highest rate (7/15 cases, 46.7%) of cases with an upgraded diagnosis was noted in the ASC‐US diagnostic category. Our results suggest that repeat processing of residual TP cervical samples may represent an adjunctive diagnostic tool for a more accurate classification of ASC‐US cases. Nevertheless, the practical value of this approach seems to be limited by its significant cost and its uncertain effectiveness. Diagn. Cytopathol. 2012.

Repeat Processing of Residual ThinPrep Pap Tests: Sampling of the Vial May Not Be Invariably Homogeneous

Objective: To re-evaluate the reproducibility of additional slides prepared from residual cervical ThinPrep (TP) samples. Study Design: Sixty paired specimens (conventional smears and direct-to-vial TP) were studied. Up to 10 additional slides were prepared from each TP vial. All slides were reviewed for adequacy of material, presence of abnormal cells and presence of normal flora or other pathogens. The additional TP slides were further evaluated for the presence of diagnostic elements which were not found on the conventional smear and primary TP slide. Results: Abnormal cells found on the primary TP slide were also identified on all additional slides in 48/50 cases (96%) with squamous cell lesions. The distribution of material on TP slides was evaluated as homogenous in 51 cases (85%) and as non-homogenous in 9 (15%). Using the primary slides (conventional smear and TP) as a reference, additional diagnostic cells upgrading the cytologic diagnosis were found on the repeat slides in 7 cases (11.7%) and fungi consistent with Candida in 3 (5%). Conclusion: Repeat processing of residual cervical TP samples may not be an invariably reproducible procedure and the first slide may not be necessarily representative of the specimen as a whole. Nevertheless, both primary and repeat TP slides seem to be extremely effective in detecting a lesion (regardless of grade) in abnormal cases. The exact impact of non-homogeneous sampling of the vial on the diagnostic accuracy of the TP method should be further investigated.

Treatment response to omalizumab in patients with refractory chronic spontaneous urticaria

Previous clinical trials have demonstrated the efficacy and safety of the anti‐IgE monoclonal antibody omalizumab in chronic spontaneous urticaria (CSU) not responding to antihistamine treatment. The primary aim of our study was to describe the response patterns of patients with refractory CSU treated with omalizumab in a real‐world clinical setting.