Malignant Tumors Identified in Adult Polycystic Kidney Disease Can Be Derived from Both Proximal Tubular and Distal Tubular Origins.

Adult polycystic kidney disease (APKD) is a genetic disorder leading to premature renal dysfunction and failure. The prevalence of malignant renal tumors occurring in the APKD setting has been rarely reported. OBJECTIVE: To better characterize malignant renal tumors in nephrectomy specimens of APKD and apply modern pathologic evaluation. METHODS: We reviewed our database of APKD specimens over the past 11 years (from 2012 to 2023) for primary malignant tumors within the kidneys of APKD. RESULTS: Of 48 nephrectomy specimens with APKD evaluated, 10 malignant renal tumors were identified, indicating a prevalence of 20.8 % (10/48). These included three clear cell (cc) renal cell carcinomas (RCC) (ranging from 1 mm to 6.7 cm), three papillary RCCs (2.5, 3.5, and 14 cm with lymph node metastasis), two cases of clear cell papillary (CCP) RCC, one acquired cystic disease (ACD) with associated RCC (4 mm), and one urothelial adenocarcinoma. The urothelial adenocarcinoma was found near a tubulovillous adenoma in a collecting duct and stained positively for GATA3 and Uroplakin-2 but was negative for PAX8 & CDX2. The tumor showed extensive invasion into perirenal fatty tissue and the rectum. Next generating sequencing (NGS) analysis of the tumor showed mutations in TERT, RB1, TP53, ERBB2, and TET1 genes, further supporting its urothelial origin. CONCLUSIONS: We found a prevalence of 20.8%, which was higher than in previous reports of malignant renal tumors in patients who underwent resections for APKD. Renal tumors were mostly from damaged proximal tubular origins (clear cell or papillary RCC), but less commonly were from distal tubular or urothelial cells as well (clear cell papillary RCC and urothelial adenocarcinoma).

Review: Mammalian Target of Rapamycin (mTOR) Pathway Is Critical in Developing Most Renal Cell Tumors.

OBJECTIVE: Various renal cell carcinomas (RCC) are derived from different segments of the renal tubular origin, which determines their morphological and immunohistochemical phenotype and their molecular signaling pathway as a therapeutic target. Most of these tumors utilize the mammalian target of rapamycin (mTOR) pathway to activate pathways involving metabolic and nutritional supplies. METHODS: Overexpressed mTOR signals are reported in more than 90% of the most common types of RCC. Many new renal tumor entities have been reported in recent years. RESULTS: Among them, somatic mutations in tuberous sclerosis complex (TSC) result in loss of its normal inhibitory control over mTOR, thus promoting mTOR-associated proliferative activities in several new renal neoplastic entities including RCC with fibromyomatous stroma (RCCFMS), eosinophilic vacuolated tumor, eosinophilic solid & cystic RCC, and low-grade oncocytic tumor. CONCLUSIONS: This short review provides a comprehensive correlation of tumor morphology and immunohistochemical phenotype with renal tubular differentiation and their shared mTOR. These essential pieces of knowledge are vital in the diagnosis and clinical management of renal cell neoplasms.

A Brief History, the Progress in the Variants of Therapies against Metastatic Neoplasms, and the Role of Pathologists.

Chemotherapy originated in the early 1960s. The initial chemotherapeutic agents focused on blocking metabolic pathways and found substantial success in certain types of tumors, but they are generally considered toxic to all normal and tumor cells, and they have significant side effects. As more scientific studies began to identify many new, specific targets and mutations, along with a multitude of growth pathways in tumor cells, new agents targeting cell growth pathways began to emerge in the late 1990s and early 2000s. In 2003, a method called morphoproteomics was developed to evaluate the immunohistochemical protein expressions of target markers in tumors, and it has been considered a pioneering method for guiding targeted therapy. Subsequently, many genomic techniques have been established for identifying specific mutations and tumor markers in order to guide the targeted therapy. More recently, immuno-oncology therapy targeting specific immune markers has been rapidly developed, and the immunohistochemical evaluation of specific immune markers such as PD-L1 demonstrates further expansion of oncologic morphoproteomics. This brief review will focus on the role of pathologists in developing various techniques and guiding targeted therapies during the era of personalized medicine.

A Novel Method Enables General Pathologists to Create Web Dynamic Forms for Synoptic Tumor Reporting.

CONTEXT.­: Tumor reporting constitutes a significant daily task of pathologists. An efficient tumor-reporting methodology is thus vitally important. The Web dynamic form (WbDF) method offers a multitude of advantages over the prevailing transcription-mediated reporting method based on static-text checklists. However, its adaptation has been severely hampered for 2 decades by its costly needs to maintain a complex back-end system and to change the system for frequent updates of reporting content. OBJECTIVE.­: To overcome these 2 obstacles with a serverless Web platform that enables users to create, customize, use, and download WbDFs as synoptic templates for structured tumor reporting. DESIGN.­: Deploy ReactJS as a Web platform. Create form components in JavaScript Object Notation files. Use JavaScript Object Notation files to make WbDFs on the Web platform. Use the WbDFs to generate final pathology reports. RESULTS.­: Ordinary users (pathologists) can create/customize reporting templates as WbDFs on the Web platform. The WbDF can be used to make a pathology report and stored/shared like ordinary document files. There is no back-end system to change, nor a requirement for computer programming skills. CONCLUSIONS.­: This strategy eliminates the need for a complex back-end system and the associated cost when updating tumor-reporting standards, making it possible to adopt the WbDF method without the technological drawbacks associated with content updates. It also opens a new field of how the tumor-reporting system should be organized, updated, and implemented.

Hepatocellular Carcinoma Arising in an HNF-1α-Mutated Adenoma in a 23-Year-Old Woman with Maturity-Onset Diabetes of the Young: A Case Report.

Hepatocyte nuclear factor-1α mutated hepatocellular adenomas (H-HCA) are thought to have no to minimal malignant potential. This report describes a 23-year-old woman with maturity-onset diabetes of the young who developed a 12.5-cm hepatic mass with a radiographically and pathologically distinct 3.0-cm region. Histologically and immunohistochemically, the bulk of the mass was an H-HCA with extensive pseudoglandular formation and only focal steatosis. The 3.0-cm nodule showed small cell change, thickened hepatocyte plates, pleomorphic and hyperchromatic nuclei, reticulin loss, and stromal and vascular invasion, diagnostic of hepatocellular carcinoma (HCC). Immunohistochemically, increased expression of glutamine synthetase in tumor cells and CD34 expression in sinusoidal endothelial cells were seen in the HCC component. Nuclear expression of ß-catenin, and exon 3 of CTNNB1 and TERT promoter mutations were absent in this case. Thus, we report a HCC arising in an H-HCA; although cases appear exceedingly rare, they reinforce the potential of H-HCA for malignant transformation.

Retrorectal teratoma: a rare cause of pain in the tailbone.

Retrorectal tumors are extremely rare and heterogeneous, requiring complete surgical excision for definitive diagnosis and optimal outcome. We describe a patient presenting with chronic "tailbone pain" who was found to have a benign cystic teratoma in the presacral space. She underwent en bloc resection and recovered well. Radiographic and pathologic images from this unique case are depicted and clinical features discussed.

IMP3, NESP55, TTF-1 and CDX2 serve as an immunohistochemical panel in the distinction among small-cell carcinoma, gastrointestinal carcinoid, and pancreatic endocrine tumor metastasized to the liver.

Histopathologic distinction among small-cell carcinoma (SCC), pancreatic endocrine tumor (PET), and gastrointestinal carcinoids metastasized to the liver in needle core biopsies can be extremely challenging because of limited material, crush artifact, and lack of detailed clinical history. In this study, a total of 61 surgically resected or biopsied specimens, including 27 SCCs (lung, 17; colon, 1; gallbladder, 2; stomach, 1; and unknown primary, 6), 18 gastrointestinal carcinoid tumors (GICTs) (stomach, 2; small intestine, 14; colon, 2), and 16 PETs were immunohistochemically examined for the expression of IMP3, TTF-1, CDX2, and NESP55 to evaluate their diagnostic value. The results showed that 24 (89%) of 27 SCCs exhibited strong cytoplasmic staining for IMP3 in 60% to 100% of the tumor cells. Eighteen (67%) SCCs were strongly and diffusely positive for TTF-1. In the remaining 9 TTF-1-negative SCCs (including 4 extrapulmonary cases), 7 showed strong and diffuse IMP3 expression. All SCCs were negative for CDX2 except for 1 case of colonic origin that showed strong CDX2 immunoreactivity. All 16 metastatic PETs were positively stained for IMP3 with 12 cases (75%) showing a diffuse and moderate-to-strong staining pattern while they were negative for TTF-1. Six PETs exhibited moderate-to-strong positivity for CDX2 with nuclear staining in 5% to 40% of tumor cells, and 5 showed a varying degree of positivity for NESP55. Three (17%) of 18 metastatic GICTs showed moderate IMP3 staining in 50% to 90% of the tumor cells, whereas CDX2 was expressed in 17 (94%) cases with moderate-to-strong staining in 50% to 100% of tumor cells. No NESP55 immunoreactivity was detected in metastatic SCCs and GICTs. In conclusion, a panel of these 4 markers is useful in segregating among SCC, PET, and GICT to help determine the primary site of hepatic metastasis.

Stereotactic hypofractionated radiation therapy as a bridge to transplantation for hepatocellular carcinoma: clinical outcome and pathologic correlation.

PURPOSE: We sought to determine efficacy, safety, and outcome of stereotactic hypofractionated radiation therapy (SHORT) as a suitable bridging therapy for patients awaiting liver transplantation (LT) for hepatocellular carcinoma (HCC). We also examined histological response to radiation in the resected or explanted livers. METHODS AND MATERIALS: Between August 2007 and January 2009, 18 patients with 21 lesions received SHORT. A median total dose of 50 Gy was delivered in 10 fractions. Three patients underwent either chemoembolization (n = 1) or radiofrequency ablation (n = 2) prior to SHORT. Radiographic response was based on computed tomography evaluation at 3 months after SHORT. Histological response as a percentage of tumor necrosis was assessed by a quantitative morphometric method. RESULTS: Six of 18 patients were delisted because of progression (n = 3) or other causes (n = 3). Twelve patients successfully underwent major hepatic resection (n = 1) or LT (n = 11) at a median follow-up of 6.3 months (range, 0.6-11.6 months) after completion of SHORT. No patient developed gastrointestinal toxicity Grade ≥3 or radiation-induced liver disease. Ten patients with 11 lesions were evaluable for pathological response. Two lesions had 100% necrosis, three lesions had ≥50% necrosis, four lesions had ≤50% necrosis, and two lesions had no necrosis. All patients were alive after LT and/or major hepatic resection at a median follow-up of 19.6 months. CONCLUSIONS: SHORT is an effective bridging therapy for patients awaiting LT for HCC. It provides excellent in-field control with minimal side effects, helps to downsize or stabilize tumors prior to LT, and achieves good pathological response.

Strongyloides colitis is a lethal mimic of ulcerative colitis: the key morphologic differential diagnosis.

Strongyloides stercoralis colitis is a severe, but easily curable, form of strongyloidiasis that carries a high mortality rate if untreated. Autoinfection characteristic of Strongyloides stercoralis frequently makes the infection a life-long disease unless it is effectively treated. Our experience with 4 cases of Strongyloides colitis prompted us to assess the clinical outcome of the disease by literature review. In this case series, the misdiagnosis and resultant mortality rates of Strongyloides colitis are 52% and 39.1%, respectively. A low index of suspicion and morphologic resemblance to ulcerative colitis were the main sources of diagnostic error. Ulcerative colitis alone accounted for 38.5% of the erroneous diagnoses. Features of Strongyloides colitis that contrast with those of ulcerative colitis include (1) skip pattern of the inflammation, (2) distal attenuation of the disease, (3) eosinophil-rich infiltrates, (4) relative intact crypt architecture, and (5) frequent involvement of submucosa. We also found that history of steroid therapy, chronic colitis refractory to conventional immune-modifying management, and endoscopic finding of distal attenuation of the colitis are helpful clues. It is also our experience that if Strongyloides colitis is included in the differential diagnosis, the correct diagnosis can usually be made. Current therapy with ivermectin or albendazole is very effective at a cure rate greater than 98%. We believe that the misdiagnosis and mortality rates of this curable, but often, unnecessarily deadly, infectious disease are alarming and warrant efforts to increase the awareness of the disease.

A teaching database for diagnosis of hematologic neoplasms using immunophenotyping by flow cytometry.

CONTEXT: In the diagnosis of lymphomas and leukemias, flow cytometry has been considered an essential addition to morphology and immunohistochemistry. The interpretation of immunophenotyping results by flow cytometry involves pattern recognition of different hematologic neoplasms that may have similar immunologic marker profiles. An important factor that creates difficulty in the interpretation process is the lack of consistency in marker expression for a particular neoplasm. For this reason, a definitive diagnostic pattern is usually not available for each specific neoplasm. Consequently, there is a need for decision support tools to assist pathology trainees in learning flow cytometric diagnosis of leukemia and lymphoma. OBJECTIVE: Development of a Web-enabled relational database integrated with decision-making tools for teaching flow cytometric diagnosis of hematologic neoplasms. DESIGN: This database has a knowledge base containing patterns of 44 markers for 37 hematologic neoplasms. We have obtained immunophenotyping data published in the scientific literature and incorporated them into a mathematical algorithm that is integrated to the database for differential diagnostic purposes. The algorithm takes into account the incidence of positive and negative expression of each marker for each disorder. RESULTS: Validation of this algorithm was performed using 92 clinical cases accumulated from 2 different medical centers. The database also incorporates the latest World Health Organization classification for hematologic neoplasms. CONCLUSIONS: The algorithm developed in this database shows significant improvement in diagnostic accuracy over our previous database prototype. This Web-based database is proposed to be a useful public resource for teaching pathology trainees flow cytometric diagnosis.

Synoptic reporting in tumor pathology: advantages of a web-based system.

The American College of Surgeons Commission on Cancer (ACS-CoC) mandates that pathology reports at ACS-CoC-approved cancer programs include all scientifically validated data elements for each site and tumor specimen. The College of American Pathologists (CAP) has produced cancer checklists in static text formats to assist reporting. To be inclusive, the CAP checklists are pages long, requiring extensive text editing and multiple intermediate steps. We created a set of dynamic tumor-reporting templates, using Microsoft Active Server Page (ASP.NET), with drop-down list and data-compile features, and added a reminder function to indicate missing information. Users can access this system on the Internet, prepare the tumor report by selecting relevant data from drop-down lists with an embedded tumor staging scheme, and directly transfer the final report into a laboratory information system by using the copy-and-paste function. By minimizing extensive text editing and eliminating intermediate steps, this system can reduce reporting errors, improve work efficiency, and increase compliance.

Advantages of combined touch screen technology and text hyperlink for the pathology grossing manual: a simple approach to access instructive information in biohazardous environments.

Gross examination, encompassing description, dissection, and sampling, is a complex task and an essential component of surgical pathology. Because of the complexity of the task, standardized protocols to guide the gross examination often become a bulky manual that is difficult to use. This problem is further compounded by the high specimen volume and biohazardous nature of the task. As a result, such a manual is often underused, leading to errors that are potentially harmful and time consuming to correct-a common chronic problem affecting many pathology laboratories. To combat this problem, we have developed a simple method that incorporates complex text and graphic information of a typical procedure manual and yet allows easy access to any intended instructive information in the manual. The method uses the Object-Linking-and-Embedding function of Microsoft Word (Microsoft, Redmond, WA) to establish hyperlinks among different contents, and then it uses the touch screen technology to facilitate navigation through the manual on a computer screen installed at the cutting bench with no need for a physical keyboard or a mouse. It takes less than 4 seconds to reach any intended information in the manual by 3 to 4 touches on the screen. A 3-year follow-up study shows that this method has increased use of the manual and has improved the quality of gross examination. The method is simple and can be easily tailored to different formats of instructive information, allowing flexible organization, easy access, and quick navigation. Increased compliance to instructive information reduces errors at the grossing bench and improves work efficiency.

Immunohistological detection of growth factors and cytokines in tissue mast cells.

The relative rarity of mast cells (MCs) and the rich content of heparin in the cytoplasmic granules of MCs pose technical challenges in reliably detecting growth factors (GFs) or cytokines in MCs by conventional immunohistological stain (IHS) methods. A variety of polypeptide growth factors are characterized by high-affinity to heparin. Binding of GFs to MC granules during detection can lead to highly specific yet falsely positive results that cannot be easily discovered by conventional procedure controls. Many reagents used in IHS detection or related experiments contain GFs and are potential nonphysiological sources of the detected GFs in MCs. In addition, heparin also exhibits high binding affinity to avidin and streptavidin, key components of the most widely used IHS detection and amplification system. Although biotin-avidin-free detection systems are readily available and are highly recommended for the future studies in this field, the vast majority of the studies of GFs in MCs in the literature have used biotin-avidin-based methods. In this chapter, the inherent technical pitfalls related to the aforementioned features of MCs, and suggested solutions are presented. They are intended to provide technical assistance to investigators in this field and to help interpret the results of the past studies in the literature.

Rituximab-induced acute liver failure after an allogeneic transplantation for chronic myeloid leukemia.

Autoimmune hemolytic anemia (AIHA) is a well-recognized complication of allogeneic bone marrow transplantation (BMT) and can affect up to 5% patients. Several recent case reports suggested the efficacy of anti-CD20 monoclonal antibody, rituximab, in treating this condition. We report our experience with a 21-year-old female with accelerated-phase chronic myeloid leukemia who underwent allogeneic hematopoietic stem cell transplantation from a matched, unrelated donor. The patient developed autoimmune hemolytic anemia that failed to respond to steroids, intravenous immunoglobulins, and plasma exchange. She was then treated with rituximab that resulted in fatal acute liver toxicity.

Adenomatoid tumor of the adrenal gland: a clinicopathologic study of 3 cases.

Adenomatoid tumors are relatively uncommon benign neoplasms of mesothelial origin, usually occurring in the male and female genital tracts. Rare extragenital adenomatoid tumors have been identified in the adrenal glands, heart, mesentery, pleura, and lymph nodes. In the adrenal gland, adenomatoid tumors may pose a diagnostic challenge. The differential diagnosis includes adrenocortical carcinoma and metastatic carcinoma, especially signet ring cell carcinoma. Because of its glandular pattern, an adenomatoid tumor may be confused with an adenocarcinoma. We present 3 cases of adrenal adenomatoid tumors, including one with a concurrent large hemorrhagic vascular adrenal cyst. The adenomatoid tumors were unilateral, appeared solid and white, and varied from 1.7 to 4.2 cm in diameter. They occurred in 3 male patients aged 33, 33, and 46 years. One patient presented with abdominal pain due to the presence of a concurrent large adrenal cyst. The tumor was an incidental radiological finding in another case and was discovered during the course of a workup for hypertension in the third case. The light microscopic appearances were consistent with those of typical adenomatoid tumors. Immunohistochemical stains for calretinin and cytokeratin 5/6 were positive, confirming the tumors' mesothelial origin. Ultrastructural studies performed in 2 cases revealed microvilli and desmosomes. Follow-up showed no evidence of recurrence or metastasis. In our experience, the key to the diagnosis of this rare benign tumor is to consider adenomatoid tumor in the differential diagnosis of any glandular tumor occurring in the adrenal gland.

Pseudoneoplastic proliferation of histiocytes with paclitaxel-induced ultrastructural changes in a mastectomy specimen.

A 49-year-old Hispanic woman with a T4N1M0 infiltrating duct carcinoma of the left breast underwent four courses of FAC (doxorubicin 86 mg, 5-fluorouracil 860 mg, cyclophosphamide 86 mg, and dexamethasone 10 mg) adjuvant chemotherapy plus four courses of paclitaxel (Taxol; Bristol-Myers Squibb Oncology, Princeton, NJ) and subsequent mastectomy. The tumor shrunk from 6.5 cm to 2.5 cm after the treatment. The residual tumor in the surgical specimen measured 1.5 cm with eight positive out of 24 axillary lymph nodes. The tumor showed typical chemotherapy changes and a massive proliferation of histiocytes that mimicked a neoplasm. A nodular proliferation of the same cells in one axillary node raised the impression of a second malignant tumor in the breast spreading to the node. The histiocytic cells contained lamellar and coarse periodic acid-Schiff-positive material distending their cytoplasm and they were strongly positive for CD68 and negative for CD1a, pan keratin, and S-100. These findings ruled out histiocytoid carcinoma, granular cell tumor, and Erdheim-Chester disease. The proliferating histiocytes had ultrastructural findings of paclitaxel-induced cytotoxicity with disorganized stacks of intermediate filaments positive for vimentin by immunostains and fewer masses of tubulin. The treated breast carcinoma cells were tubulin-positive but the proliferating histiocytes were tubulin-negative.

Ameloblastic fibroma of the maxillary sinus.

Ameloblastic fibroma is a rare true mixed tumor of odontogenic origin with both mesenchymal and ectodermal components. It usually arises from the mandibular dentition and presents in the second decade of life. It is a benign slow growing tumor that is less infiltrative than an ameloblastoma but tends to expand bone. It infrequently involves the maxilla and hence the management of these tumors in that region is controversial. The goal of therapy is to avoid cosmetic deformity without compromising on tumor eradication. We present the tenth reported case of this type of tumor in the maxilla, and the second one in an infant.

Hyperinfection syndrome in strongyloidiasis: report of two cases.

Hyperinfection in strongyloidiasis has been associated with corticosteroid treatment. Other immunodepressive conditions also seem to facilitate the state of hyperinfection. The etiologic diagnosis of this parasitosis can be difficult to reach and a positive urine microscopy is unusual. We report two patients under corticosteroid therapy with disseminated strongyloidiasis; both had eosinophilia. The first patient, followed for 8 years for autoimmune hemolytic anemia, recently developed abdominal symptoms. A colonoscopy was performed 1 month before admission and the biopsy was thought to show nonspecific changes. At admission, few larvae of Strongyloides stercoralis were disclosed by urine microscopy, and a review of the colonic biopsy uncovered a few larvae of Strongyloides. The patient received anti-helmintic therapy with a dramatic improvement. The second patient, under treatment for lupus erythematosus for 3 years, was admitted with pulmonary symptoms and during admission developed massive gastrointestinal bleeding. Disseminated strongyloidiasis was discovered only at autopsy. The low suspicion index for strongyloidiasis resulted in delaying the etiologic diagnosis in one patient and in failing to diagnose the disease in the other. The morphologic features of the parasite in the two cases are presented with emphasis on the difficulties of recognizing the larvae in the intestinal biopsy.