Israel Medical Association Journal

IgG4-related disease (IgG4-RD) is an immune-mediated fibroinflammatory condition. Accumulated research and data since 2003 have increasingly affirmed its classification as a systemic disease. Although IgG4-RD generally presents with involvement of one or several organ systems, it can affect almost any organ. The disease manifests gradually with the development of tumor-like lesions.

Constitutional symptoms, such as systemic fever and elevated inflammatory markers, are generally absent in association with this pathological condition. However, it is common for patients to exhibit allergy characteristics in addition to a slight increase in peripheral blood eosinophilia. The clinical manifestations of the disease exhibit variability on the specific organ system affected. Specific involvement of organs can ultimately result in organ failure. For example, retroperitoneal fibrosis commonly leads to post-renal failure [1]. The 2020 Revised Comprehensive Diagnostic (RCD) criteria for IgG4-RD include three components for diagnosis: clinical and radiological components (1), serological diagnosis (2), and unique pathological diagnosis (3). When all three are present it is a definitive diagnosis. The presence of components 1 + 3 constitutes a probable diagnosis, while the presence of components 1 + 2 indicates possible diagnosis [2].

Testicular involvement of IgG4-RD has been described in a few case reports. However, the uniqueness of our case is the manifestation of a testicular mass as a different target organ of relapse in a patient in remission from retroperitoneal fibrosis.

Neuroendocrine tumors (NETs) are a group of rare, heterogenous neoplasms that maintain unique morphologic and clinical features of neuroendocrine neoplasia and account for approximately 0.5% of all newly diagnosed malignancies. NETs are divided into two groups based on their histopathological morphology: well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). Well differentiated NETs are classified as G1, G2, or G3 based on their proliferation rate, whereas NECs are highly proliferative and poorly differentiated by definition [1]. Neuroendocrine neoplasms can occur almost anywhere in the body; however, they are most often seen in the gastrointestinal tract, pancreas, and lungs [2]. The extrahepatic bile duct is one of the rarest primary sites for NETs, accounting for 0.1% to 0.2% of NETs of the gastrointestinal tract [3]. Signet ring cell bile duct NETs are extremely uncommon and have no established incidence and prognosis due to their rarity. There is sparse information available regarding these tumors, and only a few cases have been reported in the literature to date. In this report, we presented the clinical course and surgical management of a 31-year-old female patient with a Klatskin signet ring cell NET.

Anti-tumor necrosis factor-alpha (anti-TNFα) medications are the most frequently used biologicals to treat inflammatory bowel disease (IBD). Little is known about the ocular side effects of this drug category. We present a case series of six young patients with Crohn disease (CD) and no previous ophthalmologic manifestations who developed blepharitis after commencing treatment with anti-TNFα therapy. Six otherwise healthy patients with CD, with no history of allergies or prior ocular complaints, developed blepharitis at a median of 7.5 months after the initiation of anti-TNFα therapy. All ophthalmic findings were treated topically. The ocular symptoms of two of the patients resolved shortly after discontinuation of the anti-TNFα treatment. The other four presented with relapsing-remitting symptoms. Blepharitis is a common ocular disease in the general population and an extra-intestinal manifestation in patients with IBD. It may be an adverse effect of anti-TNFα therapy in this patient population.

Nocardia species are gram-positive aerobic bacteria, usually acquired by inhalation or traumatic percutaneous inoculation [1,2]. It is a rare opportunistic infection that mainly occurs in immunocompromised hosts, patients with human immunodeficiency virus (HIV), organ transplant recipients, and long-term corticosteroid treated patients [1,2]. It is associated with high morbidity and mortality rates. The increased use of tumor necrosis factor (TNF) inhibitors has been accompanied by increased risk of different opportunistic infections including reactivation of tuberculosis, viral hepatitis B and C, listeria, fungal and bacterial infections [3,4]. To date, there are scarce case reports regarding nocardial infection with anti-TNF, particularly during the first 6 months of treatment.

We present a case of nocardial tenosynovitis of the hand in a patient with psoriatic arthropathy who was followed in our rheumatology clinic in Meir medical center in Israel after treatment with an anti TNF therapy.

Background: Depression has been shown to be associated with cervical tumors (CTs), an association mostly demonstrated in studies in which temporality could not have been ascertained.

Objectives: To study the association between depression and CTs and the influence of co-morbidities of this association in a large cohort study.

Methods: A retrospective computer-based cohort study was conducted. The cohort included 357,450 female members of Maccabi Healthcare Services. The cohort was classified as depressed or non-depressed using the International Classification of Diseases 9/10 codes. For each subgroup, demographic characteristics, behavioral characteristics, co-morbidities, and CTs diagnosis were obtained. The burden of co-morbidities was defined as the sum of major co-morbidities. We used zero-inflated negative binomial regression analysis due to over-dispersion to estimate the relative risk (RR) for CTs with 95% confidence interval (95%CI).

Results: Depression was diagnosed in 15,789 women. Among this group, CTs were diagnosed in 1585 (10.0%). Among the 341,661 non-depressed, CTs were diagnosed in 4185 (1.2%). After adjustment to age and socioeconomic status, the association between depression and CTs was RR=9.2 (95%CI 8.7–9.9, P-value < 0.0001). The association between depression and CTs increased as the burden of clinical conditions increased (P-value < 0.0001).

Conclusions: Women with depression are at a higher risk for CTs, especially among those who have several co-morbidities. Tighter gynecology surveillance is crucial among these women.

Background: National registries for acromegaly and population-based data make an important contribution to disease understanding and management. Data concerning the epidemiology of acromegaly in Israel is scanty.

Objectives: To evaluate the epidemiology of acromegaly in different industrial areas in northern Israel.

Methods: Data from adult patients diagnosed with acromegaly from 2000 to 2020, living in Haifa and the western Galilee District were collected using the electronic database and medical records from Clalit Health Services. The prevalence of acromegaly in three distinct areas and overall were reported. In addition, other epidemiological data including associated co-morbidities, pituitary tumor size, and treatment modalities were collected.

Results: We identified 77 patients with a confirmed diagnosis of acromegaly. The overall prevalence was 155 cases/10⁶ inhabitants without statistically significant differences between the three areas. The mean age at diagnosis was 50 ± 1.8 years and the male to female ratio was 1.1. Macroadenoma and microadenoma were identified in 44 (57%) and 25 (33%), respectively. The frequency rate of acromegaly-associated co-morbidities such as diabetes, hypertension, carpal tunnel syndrome, and osteoporosis was similar to previously reported studies. The mean body mass index (BMI) was 29 ± 5.6 kg/m² .Obesity, with a BMI ≥ of 30 kg/m², was found in 29 patients (38%). The majority of patients underwent transsphenoidal surgery 67 (87%). Normalized insulin-like growth factor 1 was reported in 64 (83%).

Conclusions: A high prevalence of acromegaly was found in northern Israel. The pituitary microadenoma frequency rate is the highest reported.

Cardiac tumors are rare and the majority are from a primary source outside of the heart. Most are found, incidentally, with echocardiography but often additional cardiac imaging is needed to refine the differential diagnosis. For this purpose, cardiac magnetic resonance imaging (MRI) and to a lesser extent cardiac computed tomography (CT) or ¹⁸F-fluorodeoxyglucose positron-emission tomography/computed tomography (¹⁸F-FDG PET/CT) are useful imaging modalities to better characterize a cardiac tumor and determine the likelihood of a neoplastic versus non-neoplastic origin. Cardiac CT may be useful to evaluate the effect of treatment while using ¹⁸F-FDG PET/CT to evaluate cardiac masses is under-studied but may be useful in patients who are already having a scan performed for oncologic reasons. It is through understanding the clinical context of a newly discovered cardiac mass, knowledge of the typical locations of various cardiac tumor types, combined with imaging techniques that avoid ionizing radiation that yield the greatest confidence in the noninvasive diagnosis of a cardiac mass

Background: Granulomatosis with polyangiitis (GPA) is a rare small vessel vasculitis. It usually involves the respiratory tract and kidney. Rarely, tumor-resembling inflammatory changes ensue.

Objectives: To report three unique cases of GPA presenting with tumor-like lesions in various organs.

Methods: We presented three cases of GPA. Case 1 presented with typical upper respiratory symptoms of GPA and a mediastinal mass. Case 2 presented with low back pain, a large retroperitoneal mass, and nodular skin lesions. Case 3 presented with epigastric pain and a paravertebral inflammatory mass.

Results: The patients were treated successfully with rituximab.

Conclusions: Clinicians should be aware of this presentation of granulomatosis with polyangiitis, which is known as Tumefaction Wegener’s granulomatosis

Background: Abdominal tumors invading the inferior vena cava (IVC) present significant challenges to surgeons and oncologists.

Objectives: To describe a surgical approach and patient outcomes.

Methods: The authors conducted a retrospective analysis of surgically resected tumors with IVC involvement by direct tumor encasement or intravascular tumor growth. Patients were classified according to level of IVC involvement, presence of intravascular tumor thrombus, and presence of hepatic parenchymal involvement.

Results: Study patients presented with leiomyosarcomas (n=5), renal cell carcinoma (n=7), hepatocellular carcinoma (n=1), cholangiocarcinoma (n=2), Wilms tumor (n=1), neuroblastoma (n=1), endometrial leiomyomatosis (n=1), adrenocortical carcinoma (n=1), and paraganglioma (n=1). The surgeries were conducted between 2010 and 2019. Extension of tumor thrombus above the hepatic veins required a venovenous bypass (n=3) or a full cardiac bypass (n=1). Hepatic parenchymal involvement required total hepatic vascular isolation with in situ hepatic perfusion and cooling (n=3). Circular resection of IVC was performed in five cases. Six patients had early postoperative complications, and the 90-day mortality rate was 10%. Twelve patients were alive, and six were disease-free after a mean follow-up of 1.6 years.

Conclusions: Surgical resection of abdominal tumors with IVC involvement can be performed in selected patients with acceptable morbidity and mortality. Careful patient selection, and multidisciplinary involvement in preoperative planning are key for optimal outcome.

Background: Evaluation of mismatch repair (MMR) deficiency is conducted via immunohistochemistry or by microsatellite instability (MSI) analysis. Heterogeneous immunohistochemistry staining for MMR proteins may show different patterns; however, according to current guidelines, all of those patterns should be interpreted as MMR proficient. This conclusion might lead to false negative results because although most cases of heterogeneity stem from technical factors and biological variability, other types of heterogeneity represent true MMR deficiency.

Objectives: To identify a unique heterogeneity pattern that is associated with true MMR loss.

Methods: We analyzed 145 cases of colorectal carcinoma. Immunohistochemistry staining for MLH1, PMS2, MSH2, and MSH6 were performed. We defined geographic heterogeneity as areas of tumor nuclear staining adjacent to areas of loss of tumor nuclear staining with intact staining in the surrounding stroma. All cases were evaluated for the presence of geographic heterogeneity. In addition, 24 cases were also evaluated by MSI testing.

Results: Of the 145 cases, 24 (16.5%) were MMR deficient. Of the 24 cases for which MSI analysis was also available, 10 cases (41.7%) demonstrated biological heterogeneity, 5 (20.8%) demonstrated technical heterogeneity, and 2 (8.3%) demonstrated geographic heterogeneity. Only the two cases with geographic heterogeneity were MSI-high via MSI analysis. In addition, a germline mutation in MSH-6 was identified in one of these cases.

Conclusions: Geographic heterogeneity may raise a suspicion for a MMR-deficient case, which should be further analyzed using additional methodologies such as MSI analysis.

Background: Primary retroperitoneal neoplasms (PRN) arise from diverse retroperitoneal tissues. Soft tissue sarcomas (STS) comprise the majority and are well studied. Other non-sarcomatous PRN are very rare and less familiar.

Objectives: To evaluate the clinicopathologic and radiologic features of non-sarcomatous PRN, as well as the outcome of complete tumor resection (TR).

Methods: Retrospective data were collected on consecutive patients (June 2006 to January 2015) who underwent resection of retroperitoneal lesions at our department. Final pathology of non-sarcomatous PRN was included.

Results: The study population included 36 patients (26% with PRN). PRN were neurogenic (17%), fat-containing (3%), and cystic (6%). The preoperative diagnosis was correct in only 28%. All patients underwent TR via laparotomy (72%) or laparoscopy (28%), for mean operative time of 120 ± 46 minutes. En bloc organ resection was performed in 11%. Complete TR was achieved in 97%. Intra-operative spillage occurred in 8%. Intra-operative, 90-day postoperative complications, and mortality rates were 11%, 36%, and 0%, respectively. The mean length of stay was 6.5 ± 5.5 days. The median overall survival was 53 ± 4.9 months.

Conclusions: Familiarity with radiologic characteristics of PRN is important for appropriate management. Counter to STS, other PRN are mostly benign and have an indolent course. Radical surgery is not required, as complete TR confers good prognosis. Expectant management is reserved for small, asymptomatic, benign neoplasms.